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Week Ending: December 26, 2009
Alan Franciscus
Editor-in-Chief
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This Issue:
December 21, 2009
Evolution of Hepatitis C Virus in Liver Allografts
www.newsrx.com
Research conducted at University of Pittsburgh has provided new information about the hepatitis C virus
According to recent research published in the journal Liver Transplantation, "Hepatitis C virus (HCV) RNA+ liver allograft recipients invariably reinfect the liver allograft within hours after transplantation, and the majority (>70%) develop chronic hepatitis."
The rate at which these patients experience progression to cirrhosis and the overall percentage are significantly increased in comparison with HCV infection in the nontransplant setting.
Core needle biopsy evaluation is used to establish the diagnosis of recurrent HCV, which can be difficult to distinguish from acute cellular rejection and other causes of allograft dysfunction. In the vast majority of cases, however, distinguishing recurrent HCV from other posttransplant syndromes is reliably achieved by a careful examination of hematoxylin and eosinstained sections and correlation with clinical and serological data.
Recurrent HCV often coexists with other causes of liver allograft dysfunction, and the determination of the most important cause of injury and whether other causes of injury are present is important. Included are residual changes of preservation/reperfusion injury, biliary sludging/structuring, acute cellular and chronic rejection, and autoimmune hepatitis.
The complex interplay between immunosuppression management, viral replication, and the recipient immune system results in distinct patterns of recurrent chronic HCV in the liver allograft: (1) conventional or usual acute and chronic HCV, which resembles that seen in the general population with HCV; (2) fibrosing cholestatic hepatitis; and (3) plasma cell-rich HCV, which might represent a variant of, or overlap with, autoimmune hepatitis and rejection.
The variable but usually hastened histopathological progression toward cirrhosis in HCV+ allografts is similar to that seen in the nontransplant setting, but in allografts, the overall severity of lymphocytic inflammation is less, and ductular reactions, stellate cell activation, and subsinusoidal fibrosis are accentuated. Hepatic stressors and causes of an impaired ability of hepatocytes to replicate include persistently high levels of viral replication, HCV-specific CD4+ T responses, advanced donor age, high levels or rapid withdrawal of immunosuppression, and coexistent liver damage from preservation/reperfusion injury, biliary structuring, or coexistent cytomegalovirus or herpes 6 viral infection.
Immunological effector mechanisms involved in the rejection and control of HCV replication/HCV elimination show significant overlap with very high levels of HCV RNA rarely show[ing] significant clinically significant acute or chronic rejection, whereas their occurrence is frequently associated with very low levels or clearance of HCV RNA
The researchers concluded: "Studying the evolution from recurrent HCV to acute rejection in patients treated with interferon and/or weaned from immunosuppression might provide valuable insights into the relationship between these 2 processes as well as liver allograft: acceptance."
Demetris and colleagues published their study in Liver Transplantation (Evolution of Hepatitis C Virus in Liver Allografts. Liver Transplantation, 2009;15(11 Suppl.):S35-S41).
For additional information, contact A.J. Demetris, University of Pittsburgh, Dept. of Pathology, Medical Center, Division Transplantation, Room E741, 3459 5th Avenue, Pittsburgh, PA 15213, USA.
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Scripps Researchers Identify Novel Hepatitis C Inhibitors
http://www.dddmag.com
Scientists from the Scripps Florida campus of The Scripps Research Institute and their colleagues at Boston University have described their discovery of several novel drug-like inhibitors of the hepatitis C virus (HCV). These new inhibitors have the potential to substantially widen the current options to treat HCV infection.
The research, from the laboratory of Professor Donny Strosberg, Ph.D., of Scripps Florida, supported by members of the Scripps Florida Lead Discovery Division directed by Peter Hodder, Ph.D., and colleagues from Boston University, was published in the December 2009 edition of the journal ASSAY and Drug Development Technologies and appears in the December 15, 2009 print edition of the journal Bioorganic & Medicinal Chemistry Letters.
With more than 130 million people infected worldwide by HCV, new therapeutic strategies are urgently needed for this blood-borne disease, which is the main cause, with hepatitis B, of liver cancer, according to the National Cancer Institute.
Using a new fluorescence-based assay, the scientists were able to identify four small-molecule inhibitors of dimerization of the viral core protein. In this process, which is essential to the survival of the virus, the core protein binds to itself and related proteins to form the viral capsid, the outer lipid-encapsulated protein shell that protects the virus’s genetic material like an eggshell protects its yolk sack.
“The fact that is so exciting is that no one has really considered the core protein as a viable target in HCV—in HIV, yes, but not HCV,” said Strosberg. “With this study, there is now no good reason why researchers shouldn’t go after the HCV core protein.”
One of the problems in developing drugs for HCV is that it mutates at such prodigious rates; mutations in viral enzymes tend to lead to increased drug resistance.
By targeting the interactions of the core protein with itself and with other proteins, Strosberg and his colleagues have sought to reduce the problem of rapid mutation—because the core protein mutates much less than the other HCV proteins, and because mutations that affect the interface between core and itself or other proteins would be more likely to deactivate the virus anyway. Core proteins orchestrate the assembly and release of the infectious virus, as well as the disassembly of viral particles upon entering host cells.
Significantly, the new compounds not only inhibited dimerization of the core but also inhibited propagation of HCV in isolated hepatoma cells.
The New Assay
In a study that appeared in the Journal of General Virology earlier this year, Strosberg and his colleague described how peptides (molecules of two or more amino acids that are the building blocks of proteins) derived from the HCV core protein also inhibited its dimerization. Peptides however, are difficult to administer orally, unstable in the blood circulation, and are therefore difficult to use therapeutically.
The new assay goes one step further, allowing Strosberg and his colleagues to identify the three times smaller molecules with potential to interfere with the core protein function in the virus.
“While there is no similarity structurally between these new small molecule inhibitors and the peptides, functionally they behave precisely the same way,” Strosberg said. “We developed an assay to screen small molecules that is robust and capable of revealing useful compounds that block protein-protein interactions and production of the virus.”
Protein-protein interactions, which involve such key physiological actions as signal transduction and protein assembly, are highly desirable drug discovery targets, not only for HCV, but also for other viral infections because inhibitors of these protein associations have been shown to lack many clinical complications, such as the adverse side effects of recombinant therapeutic proteins. However, designing small molecules that inhibit protein-protein interaction remains problematic for a number of reasons, primarily because proteins are so large—interactions are thought to often take place over a wide area and conformation/site-selectivity is difficult to engineer.
“We always look for the simplest solution,” Strosberg said. “We knew from our peptide study that we could split the core protein and use only one part that we knew still allowed the dimerization process. That simplified the process because the core protein is sometimes difficult to work with.”
Next, Strosberg and his team uncovered a domain on the core protein—what they call “a hot spot”—that was essential for the interaction that creates the capsid and allows the virus to function.
“Since we had already established a proof-of-concept that certain peptides could disrupt capsid formation, we left the peptide world and moved into the small-molecule world,” he said. “We developed the high-throughput version of the assay. That’s what the industry always wants to know first—can you move from a peptide to a small-molecule and can you find inhibitors among screen large collections?”
From there, the team screened small-molecule compounds that could potentially disrupt the protein-protein gears that create the viral capsid, using the protein library and high-throughput screening technology available at Scripps Florida. For initial screening, Strosberg and his colleagues used a relatively small library containing nearly 2,250 indoline alkaloid-type compounds, produced by their colleagues at Boston University.
These studies revealed the four promising compounds described in the study.
“These new compounds definitely put us closer to the ‘El Dorado’ of finding viable protein-protein inhibitors for HCV,” said Strosberg.
The small molecule inhibitor study made clear that three of the newly discovered inhibitors are relatively non-toxic compounds that could be the basis for the development of new anti-HCV drugs or could be used in combination with other compounds such as interferon on HCV targets other than the virus’s core protein.
“These small-molecule candidates are quite promising,” Strosberg said. “We continue to study the binding of these compounds with the HCV core protein and hope to design even more potent inhibitors based on their structures.”
The first author of the ASSAY and Drug Development Technologies study, “A Time-Resolved Fluorescence-Resonance Energy Transfer Assay for Identifying Inhibitors of Hepatitis C Virus Core Dimerization,” is Smitha Kota of The Scripps Research Institute. In addition to Strosberg, others authors include, Louis Scampavia, Timothy Spicer, Virginia Takahashi, and Peter Hodder of The Scripps Research Institute, and Aaron Beeler, John Snyder and John Porco of The Center for Chemical Methodology and Library Development, Boston University. See http://www.liebertonline.com/adt.
Source: The Scripps Research Institute
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Idera Pharmaceuticals Announces Positive Interim Data from Phase 1 Clinical Trial of IMO-2125 in Chronic Hepatitis C Patients
http://www.earthtimes.org
CAMBRIDGE, Mass. - (Business Wire) Idera Pharmaceuticals, Inc. (Nasdaq: IDRA) today announced positive interim results from a Phase 1 clinical trial of IMO-2125 in patients with chronic hepatitis C virus infection (HCV). IMO-2125 is an agonist of Toll-like Receptor 9 that Idera designed to treat HCV by inducing endogenous interferon-alpha and other Th1-type cytokines and chemokines.
In this four-week trial, IMO-2125 was well tolerated and induced dose-dependent increases in endogenous interferon-alpha and other cytokines. IMO-2125 also demonstrated a treatment-related decrease in viral load at escalating dose levels. All patients enrolled in the trial are null responders, which is defined as patients who have failed to achieve a 2 log10 reduction in viral load during previous 12 to 24 weeks of treatment with pegylated recombinant interferon-alpha plus ribavirin, the current standard of care treatment.
“The interim data in the difficult-to-treat null responder HCV patient population through the first four dose levels of IMO-2125 in this four-week trial are very encouraging,” said Tim Sullivan, Ph.D., Vice President of Development Programs. “Based on these data, we are extending the trial to a fifth dose level and beginning to recruit patients in this cohort.”
“We believe that the mechanism of IMO-2125 which induces endogenous interferon-alpha may provide advantages over the use of recombinant interferon in the null responder HCV patient population,” said Sudhir Agrawal, D.Phil., Chief Executive Officer and Chief Scientific Officer. “We plan to use the results from this ongoing clinical trial to guide our strategy for further development of IMO-2125 for the null responder HCV patient population. In addition, we have ongoing a second clinical trial of IMO-2125 in combination with ribavirin in treatment-naïve HCV patients, the results of which will guide our development strategy for IMO-2125 in this patient population.”
Interim results through four dose levels of IMO-2125 are as follows:
- All dose levels of IMO-2125 were well tolerated for the four weeks of treatment
- IMO-2125-treated patients showed dose-dependent increases in endogenous interferon-alpha, interferon-inducible protein 10 (IP-10), and 2’,5’-oligoadenylate synthetase (2’,5’-OAS) concentrations
- At dose levels from 0.08 to 0.32 mg/kg, an increasing percentage of patients ranging from 40 to 75% achieved a maximum reduction in viral load of 1 log10 or more at least once during the treatment period
- None of the patients who received placebo treatment or IMO-2125 at the 0.04 mg/kg dose level showed a maximum reduction in viral load of 1 log10 or greater at any time during the treatment period
Detailed results of this trial will be presented at an upcoming scientific meeting.
About the Trial (2125-001)
In this trial, IMO-2125 was administered subcutaneously once per week for four weeks at four dose levels of 0.04, 0.08, 0.16, and 0.32 mg/kg and was evaluated for safety, immunological activity, and effect on HCV viral load. Cohorts of ten patients were enrolled at each dose level with two patients randomized to receive placebo treatment. All patients enrolled in the trial were null responders, which is defined as patients who failed to achieve a 2 log10 reduction in viral load during previous 12 to 24 weeks of treatment with pegylated recombinant interferon-alpha plus ribavirin.
To date, 41 patients have been enrolled in four dose cohorts. Forty of the 41 patients enrolled were genotype 1a or 1b. Weekly IMO-2125 treatment for four weeks was well tolerated at all dose levels, with no treatment-related discontinuations or serious adverse events. All adverse events were mild to moderate and most were flu-like symptoms or related to injection site reactions, which are consistent with the mechanism of action.
Based on the safety profile, immunological activity, and effect on HCV RNA viral titers through the first four IMO-2125 dose levels, the Company has amended the protocol to continue dose-escalation to 0.48 mg/kg/week.
The trial is being conducted at six U.S. sites with a central laboratory for safety, immunology, and HCV RNA assessments.
About IMO-2125
IMO-2125, a novel agonist of Toll-like Receptor 9 (TLR9), is designed to induce endogenous interferon-alpha along with other Th1-type cytokines and chemokines. IMO-2125 is Idera’s lead drug candidate for the treatment of chronic hepatitis C virus (HCV) infection.
In preclinical studies, IMO-2125 induced high levels of endogenous interferon-alpha and Th1-type cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (pDCs) (data presented at 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 2007, Abstract 2714). Subcutaneous administration of IMO-2125 in non-human primates led to dose-dependent induction of endogenous interferon-alpha, IP-10, and other cytokines. Cytokines induced in human PBMCs, pDCs, and in vivo in non-human primates demonstrate potent antiviral activity in the HCV replicon assay (data presented at ICAAC 2007, Abstract 1583 and at 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), 2009, Abstract 1593).
IMO-2125 has been shown to mediate immune responses through TLR9 and associated interferon-signaling pathways involving MyD88 and interferon-regulatory factor 7 (IRF-7) as evaluated in gene microarray studies. Additionally, many type 1 interferon-response genes, interferon-inducible proteins, antiviral proteins, TLR9 signaling molecules and transcription factors are up-regulated (data presented at AASLD 2009, Abstract 1597).
About the Trial in HCV-infected Treatment-naïve Patients (2125-201)
IMO-2125 also is being evaluated in a Phase 1 clinical trial in combination with ribavirin in treatment-naïve patients with chronic HCV infection. IMO-2125 is administered subcutaneously once per week for four weeks at escalating dose levels in combination with daily oral administration of standard doses of ribavirin. The primary objective of the trial is to assess the safety and tolerability of IMO-2125 in combination with standard doses of ribavirin. In addition, the effect of treatment on HCV viral load will be monitored. Patients enrolled in this trial have genotype 1 chronic HCV infection and are treatment-naïve. The clinical trial is currently being conducted at sites in France and Russia.
About Idera Pharmaceuticals, Inc.
Idera Pharmaceuticals develops drug candidates to treat infectious diseases, autoimmune and inflammatory diseases, cancer, and respiratory diseases, and for use as vaccine adjuvants. Our proprietary drug candidates are designed to modulate specific Toll-like Receptors (TLRs), which are a family of immune system receptors that direct immune system responses. Our pioneering DNA and RNA chemistry expertise enables us to create drug candidates for our internal development programs and our partnered programs, and generates opportunities for additional collaborative alliances. For more information, visit www.iderapharma.com.
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Unilife Completes Unitract 1ml Syringe Ageing Studies
http://drugdelivery.pharmaceutical-business-review.com
To commence commercial release and sale within Europe in Q1, 2010
Unilife Medical Solutions (Unilife) has commenced final preparations for the commercial release and sale of its Unitract 1ml syringes, following the completion of device ageing studies for product manufactured at its manufacturing facility in Pennsylvania.
The company expects to be in a position to shortly announce the appointment of a number of agreements for the sale and distribution of its Unitract 1ml syringes by pharmaceutical companies and other healthcare distributors, which are active across a number of international markets including North America and Asia.
Following the successful completion this week of a Medical Device Directive (MDD) audit for CE Mark registration of US-manufactured product, Unilife also expects to be in a position to commence Unitract 1ml syringe sales within Europe during the first quarter of 2010. Final negotiations regarding the placement of initial orders for the Unitract 1ml syringes with interested distributors in Europe are also now taking place.
Bernhard Opitz, senior vice president of operations at Unilife, said: “The operational resources of Unilife remain very much focused upon the on-time completion of the industrialisation program for the Unifill syringe. Also, I am pleased that we are now moving into a position where we can commence the commercial release of our Unitract 1ml Syringes. The company is building its product inventory at its Lewisberry facility in Pennsylvania to fulfil initial orders from a number of interested parties.”
Mark Iampietro, vice-president of quality and regulatory affairs at Unilife, said: “The completion of device ageing studies for the Unitract™ range of 1mL syringes manufactured at our Lewisberry facility in Pennsylvania is a positive sign. It reflects the significant work which has been undertaken this year to build a Quality Management System that is fully compliant to international medical device and pharmaceutical regulations. We are now in a strong position to commence the commercial release of our Unitract 1ml syringes within the US, Europe and other international markets.”
Mark Hassett, director of sales and marketing at Unilife, said: “The Unitract range of 1ml syringes is to our knowledge the world’s first product with an automatic retraction mechanism enabling operators to control the speed of needle withdrawal directly from the body into the barrel of the syringe. Our products are well positioned to protect those at risk of infection from HIV and hepatitis C via potential transmission routes such as needlestick injuries and splatter. We are excited by the level of interest we have received from healthcare workers, patients who selfadminister prescription medication, distributors and pharmaceutical companies. We look forward to strengthening our relationships with these, and other industry leaders, as we roll out our Unitract 1ml Syringes across key international markets throughout 2010.”
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AMA Endorses Senate Healthcare Reform Bill, but Warns It Will Withdraw Support Unless Sustainable Growth Rate Formula Is Amended
www.medscape.com
Mark Crane
December 21, 2009 — Although applauding the expansion of insurance coverage to millions and the elimination of denials based on preexisting conditions included in the Senate healthcare reform bill, the American Medical Association (AMA) warned that it will withdraw its support unless Congress works to reform Medicare's "fatally flawed physician reimbursement formula, the Sustainable Growth Rate."
The comments were made in a letter to Senate Majority Leader Harry Reid (D-Nevada).
The AMA, the nation's largest physician group, has been lobbying for an overhaul of the health system and worked closely with the Obama administration and Democratic congressional leaders. It endorsed the House of Representatives reform bill earlier this year but until now had withheld support of the Senate legislation. Last week, it opposed expanding Medicare coverage to those aged 55 to 64 years.
"All Americans deserve affordable, high-quality health coverage so they can get the medical care they need — and this bill advances many of our priority issues for achieving the vision of a health system that works for patients and physicians," said AMA President-Elect Cecil B. Wilson, MD, in a statement.
The Senate bill will improve choice and access to affordable health insurance coverage, the AMA said. "The bill will increase coverage for preventive and wellness care that can lead to better disease prevention and management, and further the development of comparative effectiveness research that can help patients and physicians make informed treatment decisions.
"Lifetime limits on health coverage will be a thing of the past — as will higher premiums based on medical conditions or gender," said Dr. Wilson. "These are important benefits for those who have insurance now — and those who want it but have been unable to get it."
Wilson also said the bill increases payments to primary care physicians and general surgeons in underserved areas while no longer cutting payments to other physicians."It eliminates the tax on physician services for cosmetic surgery and drops the proposed physician enrollment fee for Medicare."
The Medicare payment formula, however, is a potential deal-breaker for the AMA. Physicians were facing a planned 21% cut in payment under the Sustainable Growth Rate until Congress recently acted.
The House voted to eliminate the Sustainable Growth Rate formula last month, but the Senate turned down a similar measure in October because the $245 billion cost was not paid for. Congress recently approved a 60-day stay to prevent Medicare payment cuts as part of a defense spending bill.
The AMA has argued that low Medicare pay threatens patient access to care.
"Physicians, and increasingly patients, are rapidly losing faith in the ability of Congress to address this critical issue," AMA Executive Vice President and Chief Executive Officer Michael D. Maves, MD, MBA, said in a letter to Reid.
"It is for that reason that the AMA will oppose efforts to apply temporary band-aids beyond the 60-day extension included in the FY 2010 Defense appropriations bill. Congress must replace the [Sustainable Growth Rate] early next year in order to achieve the access, payment and delivery reform goals.... We will not support a final Conference Report without a clear pathway for passage of a permanent repeal of the [Sustainable Growth Rate] formula early next year."
The American Hospital Association, which represents 5000 hospitals, also endorsed the Senate bill. In a letter to Reid, it said it hopes that lower Medicare payments to hospitals with high readmission rates can be changed before final passage.
America's Health Insurance Plans continues to oppose the bill, saying it will lead to higher premiums. The organization particularly objects to cuts to privately administered Medicare Advantage plans and caps on insurers' administrative costs.
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December 22, 2009
Snoring and Liver Disease Linked by Low Oxygen Levels
www.medicalnewstoday.com
Research published in the current issue of the journal, Clinical Science, appears to have found a link between obstructive sleep apnea and non-alcoholic steatohepatitis. Dr Anne-Christine Piguet and colleagues from the University of Bern, Switzerland, kept mice for a week in low-oxygen atmospheres and found that it led to increased levels of fat and inflammation in their livers.
Apnea means "without breath" and occurs when the muscles in the airways behind the tongue relax in sleep, causing the person to snore and briefly, to stop breathing.
Nonalcoholic steatohepatitis (NASH) is a common, often "silent" liver disease occurring in around 40% of the population. It resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. The major feature in NASH is fat in the liver, along with inflammation and damage. NASH can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to work properly.
Obesity predisposes patients to both fatty liver diseases and obstructive sleep apnea.
To mimic the effects of low oxygen levels caused by the repeated obstruction of the upper airways in sleep apnea, the researchers kept mice in a low oxygen environment for seven days. After this time they were found to have more fat and inflammation in their livers compared to mice that had been kept in atmospheres with normal levels of oxygen. When the mice were exposed to low oxygen levels, the genes that controlled fat synthesis in the liver seemed to be more active while those that controlled fat breakdown demonstrated reduced activity.
In addition, the mice exposed to low levels of oxygen became less sensitive to insulin. This is the mechanism by which the body regulates blood sugar and is a cause of diabetes. Metabolic disorders such as diabetes and obesity can cause complications in patients with NASH.
Commenting on the finding, Dr Piguet said, "Hypoxia (lack of oxygen) may be the link leading to accumulation of fat in the liver and to the progression of non-alcoholic steatohepatitis. Our findings show that it is important both to screen obese patients for obstructive sleep apnea to prevent it contributing to fatty liver disease and to treat those patients who already have NASH for hypoxia which may be making their condition worse".
Source: Biochemical Society
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Achillion Announces Positive Preliminary Results with Hepatitis C Treatment
http://www.tradingmarkets.com
December 21, 2009 (FinancialWire) -- Achillion Pharmaceuticals, Inc. (NASDAQ: ACHN | Quote | Chart | News | PowerRating) reported proof of concept data from the preliminary results of its phase 1b clinical trial of ACH-1625, demonstrating that treatment with ACH-1625 achieved a mean 3.94 log10 reduction in HCV RNA after five-day monotherapy, with continued good safety and tolerability in patients with hepatitis C . ACH-1625 is an inhibitor of HCV NS3 protease that was discovered and is being developed by Achillion.
In June 2009, Achillion initiated dosing in a randomized, double-blind, placebo-controlled phase 1a/1b clinical trial to investigate the safety, tolerability, pharmacokinetic profile and antiviral activity of ACH-1625 after single and multiple ascending oral doses in healthy volunteers and oral repeat doses for 5 days in subjects with hepatitis C infection. The trial is taking place in Europe and will enroll at least 54 subjects, including both healthy volunteers and HCV-infected patients.
In September 2009, Achillion announced positive results from the phase 1a segment of the study. Subjects in the phase 1a single ascending dose segment of the study received single doses of ACH-1625 ranging from 50 mg to 2000 mg. Subjects in the phase 1a multiple ascending dose segment of the study received 5 days of ACH-1625 up to a maximal dose of 2000 mg per day.
Preliminary data from the SAD and MAD trial segments demonstrated ACH-1625 was well tolerated at all doses and there were no serious adverse events, no clinically significant changes in vital signs, electrocardiograms, or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship.
Achillion announced proof of concept data from the preliminary results of the phase 1b segment of the study. Subjects in this first dosing cohort of HCV-infected patients received doses of 600 mg BID (n=9, randomized to 6 active drug, 3 placebo). Preliminary results showed that a mean reduction in viral load of 3.94 log10 was achieved in the treatment group, as compared to a mean reduction of 0.22 log10 in the placebo group. All subjects in the treatment group had viral load decline between 3.0 and 4.5 log10, and two subjects reached undetectable levels of HCV RNA. Safety results from this dosing group were similar to those observed in the phase 1a segment of the trial. There were no serious adverse events, no clinically significant changes in vital signs, ECGs, or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship.
Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 2.0 log10 from baseline through day 12, the last day of viral load measurement in the study.
Preliminary analysis of viral dynamics of ACH-1625 demonstrates a very rapid reduction in HCV RNA levels after the first dose. ACH-1625 displays high efficiency for inhibition of viral production, with mean efficiency of 0.9994 out of maximal efficiency of 1.0000.
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Suit: Doctors Misdiagnose Woman with HIV, Herpes and Hepatitis
http://www.foxnews.com
NEW YORK — A city hospital nearly destroyed a New Jersey woman's life and wrecked her marriage after misdiagnosing her with terminal HIV, hepatitis and herpes, according to a bombshell lawsuit.
Maria Osorio, 54, of Passaic, said she saw an ad on TV offering a $15 mammogram at Harlem Hospital over Valentine's Day last February and decided to take advantage of the screening.
When a nurse offered her a free instant cheek swab and blood test, too, she accepted. That's when she was told she had HIV.
"It was horrible. I wanted to throw myself on the subway tracks," she said.
The shocked Osorio immediately turned on her husband of 37 years, Gabriel Lezcano, 60, who works as a janitor in New Jersey.
"I started screaming violently at him. I pushed him. I pulled his hair. 'Who were you with?' I asked him. He kept denying that he was with anyone, but I kept raising my voice and pushing him. 'You must have been with someone. You must have had too many beers and maybe now you just don't remember,' " she recalled.
Lezcano fought back. "I've been a good man to you. I haven't been with anyone else. I am a very scrupulous man. I just do my work and I come home," he told his furious wife.
Lezcano told The Post that the accusations of his wife, a fellow Colombian immigrant, nearly killed him.
"She's my only woman," he said. "I felt that someone was trying to trick us."
His denials fell on deaf ears. The distraught Osorio was convinced her husband was lying. How else could she have contracted the sexually transmitted disease?
A few days later, the hospital called again to say the disease was very advanced, according to court papers.
"I wanted to kill him," she said. "I began to mistrust him and hate him. I couldn't believe that he had been with other women, that he had lied to me."
She also decided to commit suicide.
"I kept thinking how I could kill myself. All I did was plan how I was going to end my life," she said. "I resolved to do it at the beach in the summer, just to throw myself in the ocean and make it look like an accident."
She stopped sleeping. She threw up constantly. She couldn't work.
"I didn't want to get out of bed," she said.
Her husband stopped sleeping, too. They both became addicted to sleeping pills and took to sleeping in separate beds, alone in their misery and distrust.
Her two grown sons, who still live in Colombia, were hysterical. They would call, crying, insisting there was a mistake.
When Osorio, a home health aide, pointed out to the nurses that she had no medical problems whatsoever, they replied, "This is a silent disease."
"They told me that this machine does not lie," she said.
But almost three weeks later, the hospital called to say she was perfectly healthy.
Yet no one apologized or admitted to a mistake, she said. One secretary said she was sorry for her pain.
When she went to the hospital to talk to the nurses who had originally tested her, they hugged her and told her that "the hand of God had come down to bless me because the machine never lies," she said.
She was stunned by the reversal of fortune.
"I was in a dream. I kept saying, 'Thanks to God, thanks to God,' and I hugged my husband, and we prayed to the saints on the altar on our kitchen table."
But the damage to the marriage had already been done.
"I met him when I was 17 years old. We were always very united as a couple," Osorio said. "We work and we come home, and that is our life."
Now they still sleep in separate beds, and still rely on pills to sleep.
"This has really hurt our marriage. We are afraid to have any sexual contact with each other. We are still very nervous," Osorio said.
Her husband agreed.
"My partner has been destroyed emotionally," he said.
Osorio filed a medical-malpractice notice of claim against the city in state Supreme Court in Manhattan last week.
"I can't believe there could be such errors," Lezcano said. "We don't want anyone else to go through what we've been through."
City officials said they would not comment on pending litigation.
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North West on Hepatitis C Health Alert
http://www.clitheroeadvertiser.co.uk
Latest figures from the Health Protection Agency show that out of the 8,000 people in England diagnosed with the disease last year, 1,679 came from the North-West.
Despite being a lower figure than in 2007, when 1,743 cases were reported, it still means the region has consistently recorded the highest figures across England since 1999.
Dr Erika Duffell, a hepatitis C expert, said: "Hepatitis C is a major public health issue in the North-West and despite the increase in testing over recent years, many infections remain undiagnosed.
"If the infection is diagnosed in the early stages, treatment can be offered that can clear the infection in more than half of those treated."
The HPA model indicates that in the North-West in six years time the estimated burden of associated illness will be high, with 1,086 individuals likely to have cirrhosis and 1,919 individuals dead as a result of the hepatitis C infection.
Dr Duffell added: "As it is likely this is an underestimate of the future disease burden, the need to continue strengthening specialist hepatitis C treatment services as well as general hepatology services is considerable. In the North-West, we have given the highest priority to testing individuals and bringing them into treatment for hepatitis C. However, more needs to be done to increase awareness and improve access to services."
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A Downside of Organ Donation
http://online.wsj.com/
By Laura Landro
Within three months of his kidney transplant last March at New York Presbyterian Hospital, Peter C. Platt was rehospitalized with serious infections that did not respond to treatment. The culprit: strongyloides, an intestinal parasite that had been found in the donated organ. He died on July 15, surrounded by his grieving family.
"The kidney transplant was supposed to be the gift of life, but it ended up taking it away," says his widow, Shirin Platt, who contacted state and federal health officials about the case and is lobbying for more-rigorous testing of donated organs. "At the very least, we need to make sure that possible recipients know more about the dangers from transplants." New York Presbyterian declined to comment, citing patient-privacy laws.
Mr. Platt's death, which is being investigated by the Centers for Disease Control and Prevention, is one of a small but growing number of transplant-related disease-transmission cases. Just last Friday, for example, the University of Mississippi Medical Center disclosed that two recipients had fallen seriously ill after receiving organs from the same deceased donor, whose organs went to four recipients in three states. The CDC found the donor was infected by a rare amoeba the hospital did not detect in routine testing.
The hospital said transplant surgeons deemed the organs suitable for transplant and it is "working closely with the CDC and the Mississippi State Department of Health to revisit our medical evaluation of the donor and what may have happened."
Most transplants do indeed save lives. But as demand grows for donated organs and tissues, so do concerns about the risk of disease transmission, including deadly bacterial infections and viruses, tuberculosis, rabies, parasites and even cancers. Some experts are calling for better testing and tracking of organ donors in order to limit the number of infections, though others warn that this could have the effect of delaying transplants, producing false-positive results that would eliminate safe organs and adding costs to the health-care system.
In late November, the United Network for Organ Sharing, the nonprofit that operates the nation's organ-transplant system, recommended that lungs and intestines from donors known to be infected with the H1N1 swine-flu virus not be used because of infectious risk, and said the lungs of donors with seasonal influenza should also be avoided. A Unos spokeswoman says the group is working on several fronts to "bring risks of transmissible disease to the lowest possible threshold."
Unos, which began collecting data about disease transmission through organs in late 2004, said in a study published earlier this year that it was reported in only about 1% of all deceased-donor donations. But the number of reported cases grew from seven in 2005 to 60 in 2006 and 97 in 2007, and the study acknowledged that the number of disease transmission is underreported.
In a new report commissioned by the U.S. Department of Health and Human Services, experts from the CDC and other government agencies warn that a patchwork of regulations and voluntary efforts by groups such as Unos aren't sufficient. The report, "Biovigilance in the United States: Efforts to Bridge a Critical Gap in Patient Safety and Donor Health," calls for the creation of a centralized system to monitor blood, organ and tissue safety, gather reports of illness or adverse reactions among recipients, and quickly trace organs and tissues from donors who are found to carry infectious diseases. (It is available at hhs.gov/bloodsafety.)
Balancing Need and Risk
The report highlights the growing dilemma of how to balance the need for organs and tissues against the risks of contracting a potentially fatal disease or infection from the donor. There are close to 30,000 organ transplants in the U.S. each year, and medical advances are making it possible to transplant hands, faces and intestines. Live donors may now give portions of a lung, liver or pancreas, in addition to providing kidneys.
Still, about 9,000 people in the U.S. die each year waiting for an organ. And with an ever-expanding waiting list of patients in need, transplant centers are more often accepting deceased donors with high-risk behavioral and social profiles, such as IV drug users, the report says. Moreover, in the scramble to match sick patients with organs, time is often short, increasing the potential for missing a potentially transmissible disease. While organ donors are screened for certain diseases, such as hepatitis C and HIV, screening tests are costly and imperfect and don't cover every infectious disease.
Organ donors are also often the source of donated tissues, ranging from bones and heart valves to skin and tendons. With about two million tissue grafts transplanted each year, new industry standards include more rigorous testing for disease, and tissues—unlike organs, which must be used right away—are typically sterilized before use. But that doesn't always eliminate infectious agents. One donor may be the source of 100 different grafts sent to multiple locations around the world, which can be difficult and sometimes impossible to track down.
"There has to be a balance between safety and availability, but right now all the emphasis is on availability," says Matthew Kuehnert, who oversees blood transfusion and transplant safety at the CDC and was one of the authors of the biovigilance report. Even with a dire need for organs, he says, patient safety should never be compromised, especially when some transplant patients can afford to wait for more-thorough screening.
"It is a horrible waste if a kidney recipient dies from a rabies infection from the donor, when they could have waited for a more suitable organ or remained on dialysis," Dr. Kuehnert says.
Jerry Holmberg, senior advisor for blood policy at the Department of Health and Human Services, says the agency is reviewing the biovigilance report and taking its recommendations "very seriously." He notes that doctors are expected to go over the pros and cons in the "informed consent" discussion prior to transplant and make a "risk-benefit" calculation. But he acknowledges that patients need tools and information to make the calculation. "A patient hanging on at the end of life may make a decision to take an organ from a high-risk donor," concluding that at the primary goal is to stay alive, and worry about treating an infectious disease later, Dr. Holmberg says.
Donor ID System
Unos recently completed a pilot program—dubbed the Transplantation Transmission Sentinel Network—to detect, report and track disease transmission from donors to organ-, tissue- and eye-transplant recipients, using a unique donor identification system. No disease transmissions were identified during the pilot. The CDC has asked industry groups and transplant organizations to help it determine how to operate and fund a national version of such a system, and is working with public health officials in Europe and Canada to coordinate programs for organ and tissue safety.
Michael G. Ison, medical director of Northwestern University's transplant service and head of the disease-transmission risk committee at Unos, says that many diseases transmitted through organs are treatable. And while it is relatively easy to discard donated tissues such as tendons or skin and get substitutes if there is concern about disease risk, it is much harder to make that call with organs, given the pressing need for donors. "The safer you make the organ pool, the fewer organs you are going to have," Dr. Ison says.
However, there is no guarantee that a disease contracted from a donor organ or tissue graft can be successfully treated. When Mr. Platt was readmitted to the hospital, he was vomiting blood.
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HEPATITIS C: Outbreak was preventable
http://www.lvrj.com
By Brian Haynes
And Paul Harasim
Las Vegas Review-Journal
Report says as many as 115 were infected through unsafe practices
The largest health-care-related hepatitis C outbreak in U.S. history, which could cost as much as $21 million in investigative and medical expenses, could have been prevented, according to the Southern Nevada Health District's final investigative report.
The two-year investigation determined that unsafe injection practices at the Endoscopy Center of Southern Nevada and its sister clinic, Desert Shadow Endoscopy Center, probably led to the infections of as many as 115 clinic patients, the 266-page report said.
Nine of the cases were linked to the clinics, while the other 106 were possibly linked, the report said.
The unsafe injection practices prompted health officials to notify some 63,000 clinic patients that they might have been exposed to hepatitis, HIV and other blood-borne diseases -- the largest patient notification of its kind in the country's history.
On average, more than 9 percent of the county's households had a member who could have been exposed, and more than 14 percent of the county's residents ages 65 to 69 were at risk, said Brian Labus, the health district's senior epidemiologist.
"When you have nearly 10 percent of the population potentially involved, people are always going to be interested in what happens," he said. "This wasn't just a few people getting sick eating at a restaurant. ... Everybody knows somebody who got a letter to get tested."
Through interviews and observations, investigators identified a combination of unsafe injection practices at the clinics, including reusing syringes on a single patient and reusing vials of anesthetic between patients.
Although investigators cannot say with certainty that the unsafe injection practices led to the infections, they ruled out every other possible source, including transmission from unclean scopes and reusing bite blocks, according to the report.
"We can never prove that it was done that way, but we looked at every possible alternative," Labus said.
The health investigation prompted scores of civil lawsuits and pending criminal investigations centered on Dr. Dipak Desai, the clinics' principal owner.
Desai's criminal lawyer, Richard Wright, had no comment on the final report.
Some nurse anesthetists told investigators they were instructed to use the unsafe practices, according to the report.
Trial lawyers who are representing hundreds of former clinic patients with lawsuits, said they were pleased with the final report's findings.
"It's pretty clear from the report that there is only one way that this could have happened," lawyer Will Kemp said.
Attorney Gerald Gillock said some patients and their lawyers worried the health district would back off its initial findings about the unsafe injection practices.
"It was a general concern on behalf of the litigants," he said. "But I think the health department stood by its responsibilities. There was nothing that would exonerate the clinics."
The health district's investigation began Dec. 4, 2007, with the first report of a hepatitis C case from a former patient at the Endoscopy Center of Southern Nevada.
Investigators soon identified a cluster of hepatitis C cases linked to the clinic and contacted the U.S. Centers for Disease Control for help.
Federal, state and local health officials worked together on the investigation, which included interviews with clinic workers and observations of their practices.
The investigation genetically linked seven hepatitis C infections to the Endoscopy Center, including six on Sept. 21, 2007. Patients who went to the clinic that day were 31 million times more likely to develop an acute hepatitis C infection, the report said.
Another case was directly linked to the Endoscopy Center, and an additional case was linked to the Desert Shadow clinic. Health officials identified another 106 cases from both clinics that were possibly linked to the clinics. Other possible infection sources could not conclusively be ruled out.
After announcing the outbreak and patient notification in February 2008, health officials set up a hot line that took 35,391 calls through the end of October 2008. At one point the line took 510 calls in one hour, Labus said.
Costs for the health district investigation were $828,369. Add in the $13.8 million spent to test thousands of clinic patients and future medical costs for hepatitis treatment, and the final cost for the outbreak will range from $16 million to $21 million, the report estimated.
Labus said the report focused on details about what happened and how it happened, but not why.
"I imagine there will be people who wish we had the motive for what happened," he said. "But that's not what the health district does. We laid the groundwork to find out the why."
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December 23, 2009
Low Platelets, Anti-HCV Antibodies Predict HCV Viremia
http://www.thedoctorschannel.com
NEW YORK (Reuters Health) – A low platelet count in the presence of hepatitis C viremia indicates the need to begin interferon-based treatment, regardless of the degree of liver fibrosis, a Taiwanese research team advises based on a new study.
Between 2002 and 2005, Drs. Wan-Long Chuang and Dr. Ming-Lung Yu and colleagues at Kaohsiung Medical University Hospital surveyed various clinical indicators in residents of the Kaohsiung area in southern Taiwan (n = 11,239; ages 40-65 years). Their findings appeared online in the Journal of Hepatology on December 3.
The researchers defined low platelet count as less than 150,000 platelets/microliter, and determined fibrosis noninvasively using the FT score (FibroTest, Biopredictive, Paris, France), which is based on five serum biochemical markers.
The prevalence of anti-HCV antibodies was 6.3%. Prevalence rates for abnormal alanine aminotransferase (ALT) and low platelet count were 20.3% and 4.2%, respectively. Among a subset of 642 individuals positive for anti-HCV antibodies, 74.5% tested positive for HCV RNA.
On multivariate analysis, low platelet counts in patients with anti-HCV antibodies were linked with abnormal ALT levels (OR 3.70) and positive HCV RNA (OR 2.00). The authors also report that in anti-HCV antibody-positive patients, a low platelet count predicted HCV viremia with 88% sensitivity.
“The presence of HCV RNA plays an essential role in disease progression,” the authors note, adding that the association of low platelet count with viremia “should help clinicians identify patients with active HCV infection for further intervention.”
The add, “No matter if the ALT levels are normal or elevated, the platelet counts are a good predictor for positive HCV RNA in clinical applications.”
Further studies to explain the underlying biologic mechanisms of their findings “are mandatory,” the researchers conclude.
Reference: J Hepatol 2009.
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Therapeutic HCV Vaccines May Lower Viral Load and Improve Response to Interferon-Based Therapy
www.hivandhepatitis.com
By Liz Highleyman
SUMMARY: Two investigational therapeutic hepatitis C virus (HCV) vaccines may help control the virus in infected individuals, according to data presented last month at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) in Boston. GI-5005 increased the likelihood of response to pegylated interferon plus ribavirin. Another vaccine candidate, IC41, was associated with a steady decrease in HCV viral load.
Unlike prophylactic vaccines, which are intended to prevent initial infection, therapeutic vaccines are designed to stimulate an immune response in people who are already infected.
GI-5005
In the first study (abstract LB15), John McHutchison from Duke Clinical Research Institute and colleagues evaluated GI-5005 in both treatment-naive chronic hepatitis C patients and those who were non-responders to previous interferon-based therapy.
GI-5005 is a Tarmogen, a vaccine containing whole, heat-killed Saccharomyces cerevisiae, a type of yeast, genetically engineered to express HCV NS3 and core antigens. Prior studies have shown that GI-5005 elicits antigen-specific T-cell responses. The goal of the vaccine is to promote elimination of liver cells carrying HCV.
In this open label Phase 2b trial, 140 HCV genotype 1 patients received standard-of-care therapy with pegylated interferon plus ribavirin. Half were randomly assigned to also receive injections of GI-5005, first as monotherapy for 12 weeks before starting standard therapy, then as triple therapy with pegylated interferon/ribavirin. Treatment-naive participants were treated for 48 weeks and prior non-responders for 72 weeks.
The researchers found that among treatment-naive patients, in a modified intent-to-treat analysis at the end of 48 weeks of treatment, 74% receiving triple therapy achieved HCV RNA < 25 IU/mL, compared with 59% receiving standard therapy. Furthermore, nearly twice as many triple therapy recipients experienced ALT normalization. Among non-responders, the end-of-treatment response rate was 32% in both the triple therapy and standard therapy arms.
Triple therapy including GI-5005 was well tolerated, with no significant new toxicities other than those normally associated with pegylated interferon/ribavirin. Similar proportions (7%-10%) discontinued treatment in the standard therapy and triple therapy groups. The most common adverse events associated with GI-5005 were injection site reactions, which were usually mild and transient.
"The efficacy and safety data generated thus far in this trial are encouraging and suggest a potentially important role for this compound in the treatment of HCV," said Dr. McHutchison in a press release issued by GI-5005 developer GlobeImmune.
Clinical Development and Regulatory Affairs, GlobeImmune, Louisville, CO; Duke Clinical Research Institute, Durham, NC; Weill Cornell Medical College, New York, NY; University of Arizona, Tucson, AZ; Center for Liver Diseases, University of Miami, Miami, FL; University of Colorado Denver, Aurora, CO; University of Texas Southwestern Medical Center, Dallas, TX; Scripps Clinical Research Center, La Jolla, CA; Maryland Digestive Disease Research, Laurel, MD; Baylor College of Medicine, Houston, TX; Alamo Medical Research, San Antonio, TX; South Denver Gastroenterology, PC, Englewood, CO; Center for Disease of the Liver and Pancreas, Swedish Medical Center, Englewood, CO; University of Hawaii, Honolulu, HI; QST Consultations, Allendale, MI.
IC41
In the second study (abstract 1558), C.S. Klade from Intercell in Vienna, Austria, evaluated IC41, a peptide vaccine containing HCV antigens as CD4 and CD8 T-cell epitopes, using poly-L-arginine as an adjuvant (an agent that promotes immune response).
This Phase 2 study included HCV genotype 1 patients naive to standard therapy. In the first group, 50 participants received an optimized IC41 dose schedule consisting of 8 intradermal injections at biweekly intervals with topical application of the TLR 7/8 agonist immune-modulator imiquimod (Aldara). In the second group, 21 patients received an intensified dose schedule consisting of 16 subcutaneous injections of IC41 at weekly intervals without imiquimod.
At week 16, in an intent to-treat analysis, patients who received the optimized schedule experienced a highly significant HCV viral load decline of 0.21 log. At week 38 (24 weeks after the last dose), HCV RNA decreased by 0.47 log. Patients with a high baseline viral load (> 2 million U/mL) had a more pronounced decline, of 0.61 log. Eight patients (24%) achieved virological response, defined as a decline of > 0.8 log. However, there was no apparent effect on HCV viral load in the group that received the intensified dosing schedule.
Overall, 40% to 60% of patients exhibited T-cell responses during therapy and up to 6 month after vaccination in both treatment groups, but there was no significant correlation between viral load decrease and T-cell response.
"This is the first report showing a significant antiviral effect of a peptide vaccine in HCV infected patients," the investigators concluded. "The time course with increased RNA decline 24 weeks after the last vaccination is encouraging and justifies further clinical studies potentially in combination with standard therapy or novel antiviral medications."
Intercell AG, Vienna, Austria; Hannover Medical School, Center for Internal Medicine, Hannover, Germany.
References
JG McHutchison, IM Jacobson, TD Boyer, and others. GI-5005 therapeutic vaccine plus PEG-IFN/ribavirin improves end of treatment response at 48 weeks versus PEG-IFN/ribavirin in naive genotype 1 chronic HCV patients. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract LB15.
CS Klade, A von Gabain, and MP Manns. Significant continuous viral load decline in treatment-naive HCV genotype 1 patients after therapeutic peptide vaccination with IC41. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1558.
Other source
GlobeImmune's Hepatitis C Therapeutic Vaccine Combined with Standard of Care Increases End of Treatment Response Rate by 15%. Press release. November 2, 2009.
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Jury Says Former Morris County Sheriff's Officer Was Not Harassed by Colleagues
http://www.nj.com
By Joe Moszczynski/The Star-Ledger
A former Morris County sheriff’s officer was not subjected to vicious and repeated harassment by his colleagues after they found out the former officer was afflicted with hepatitis C, a jury unanimously determined today.
After just two hours of deliberations, the nine-member jury found the Morris County Sheriff’s Office was not liable to pay former officer John Cicchetti compensatory damages for the emotional distress he allegedly suffered from the harassment. The verdict came following a trial that began earlier this month in Superior Court in Newton.
Cicchetti declined to comment.
The verdict was a vindication for the personnel regulations practiced by the sheriff’s office and Undersheriff John "Jack" Dempsey.
Dempsey had testified last week that a probe into Cicchetti’s harassment claims was hampered by the plaintiff’s unwillingness to subject the two officers to a formal investigation.
In his hour-long closing argument today, attorney John Bowens, representing the sheriff’s office, portrayed Cicchetti as a habitual liar who didn’t like his job and had long planned to sue the county, looking for a "payday."
"He did not want a formal investigation, it was all part of his intent to file a lawsuit," said Bowens, noting that Cicchetti had at least five attorneys represent him over the years.
In his disability discrimination lawsuit, Cicchetti, now 52, claimed the sheriff’s office had ignored a hostile work environment by allowing two officers to unmercifully harass him for 1 1/2 years.
Cicchetti quit his $59,000-per-year job in February 2002, two months before he filed the lawsuit.
Cicchetti and his attorney, Vincent Paragano, had claimed the two officers, John McWilliams and Gerard Marinelli, began harassing Cicchetti in November 1998 for having hepatitis C. They claimed they wore surgical gloves and masks around him, blocked his radio transmissions, called him "hepatitis boy" and "hepa-chetti," a derogatory mix of the word, "hepatitis" and Cicchetti’s last name.
Cicchetti also claimed he was "ostracized" daily in the sheriff’s office two-table lunchroom by officers who shunned him went he walked in.
Bowens disputed the lunchroom harassment.
"The way he described it, it was like Moses parting the Red Sea, it’s absolutely false," said Bowens. "You can’t make somebody want to have lunch with you."
In his own hour-long closing argument, Paragano claimed Bowers employed a "blame-the-victim" defense and Cicchetti did not want a formal investigation because it would have caused further friction among his fellow officers.
"He just want it (the harassment) to stop" and had not planned to file a lawsuit against the sheriff’s office until his harassment claims went ignored, Paragano told the jury.
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December 24, 2009
Senate Passes Historic Healthcare Reform Bill, Merger with House Bill Is Next
www.medscape.com
Robert Lowes
December 24, 2009 — Early this morning, the Senate passed the historic healthcare reform legislation along party lines that would extend insurance coverage to 31 million more Americans during 10 years.
Although it caps weeks of hyperbolic debate and political horse-trading to win over holdout senators, the Christmas Eve vote does not mean peace in the Senate, much less peace on earth. The $871 billion Senate bill, called the Patient Protection and Affordable Care Act, must now be harmonized with reform legislation passed by the House in November, with a single bill needing to come before both the House and the Senate for a final vote.
This harmonization process, to be tackled by a so-called conference committee consisting of House and Senate members, promises to be daunting. Although the House and Senate bills are virtual twins in many respects, the House version calls for the notorious public option — a government-operated health plan — whereas the Senate version does not.
Supporters of the public option say the nation needs a nonprofit alternative to for-profit insurers, but critics call it the first step toward a federal takeover of healthcare.
If a conference-committee bill is passed by both chambers, it would go to President Barack Obama for his signature.
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Scientists Visualize How a Vital Hepatitis C Virus Protein Moves Along Its Nucleic Acid Substrate
http://newswire.rockefeller.edu
By taking three conformational snapshots of a hepatitis C virus motor protein in association with its substrate, researchers at Rockefeller University have provided the first structural explanation of how a representative superfamily 2 helicase moves unidirectionally along nucleic acid, suggesting new ways that drug designers could block virus replication.
It has long been known that triphosphate nucleotides, such as ATP, are required to power the movement of the HCV NS3 helicase, and crystal structures of NS3 were solved long ago. Now reporting in the Proceedings of the National Academy of Sciences, Charles M. Rice, head of the Laboratory of Virology and Infectious Disease, and Meigang Gu, a postdoc in the lab, show how ATP successively remodels the contacts between the substrate and NS3 and pinpoint key elements that play a role in the helicase translocation.
“There are key transitions that occur to NS3 and DNA when ATP binds the protein and when ATP proceeds into the transition state of hydrolysis,” says Gu. “Targeting the elements involved in these transitions could inhibit the helicase and stop the virus from replicating.”
In a series of three molecular snapshots, Rice and Gu capture details of how NS3 moves along its nucleic acid substrate. They show that when bound to DNA, the protein resembles the Greek letter lambda. When the protein-DNA complex binds ATP, lambda’s back leg sweeps forward to meet its front, closing the space between them — a move that is associated with the back leg’s weak grip on DNA. Then, as ATP hydrolysis proceeds, lambda’s back leg springs toward DNA and regrips it. It’s like a stealthy cartoon character tiptoeing with exaggerated steps.
A key component of this process is unidirectional movement of a phosphate group in the middle of the DNA strand. As the back leg sweeps forward, the front leg detaches itself from this phosphate, allowing it to form water-mediated interactions with the back leg, which stretches to recapture this phosphate group in the transition state. By reconstituting the actions of the helicase, Rice and Gu found that one ATP molecule propels NS3 forward by one genetic letter.
“Like the actions of a ratchet, the successive transitions within NS3 prevent phosphate 3 from walking in the opposite direction,” explains Gu. “This mechanism is likely adopted by other superfamily 2 DExH helicases with similar motifs, especially a newly defined motif Y.”
The atomic details of ATP and DNA binding in different conformational states provide additional insights into drug development. “The advantage of targeting these sites is that the virus should have difficulty generating resistance through simple point mutations,” says Rice.
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Life with Hepatitis C for London's Teenage 'It Girl'
http://www.cnn.com
By Anouk Lorie for CNN
London, England (CNN) -- Recently named London's "It Girl" by society magazine Vanity Fair, 18-year-old Jazzy de Lisser is said to have it all. She is beautiful and affluent, her best friends include Sting's daughter, Coco Sumner, and she is often compared to another famous British trend-setter, Kate Moss.
Yet underneath the glitz and glamour of a privileged lifestyle, de Lisser has fought a lifelong battle with what is termed the "silent killer" -- Hepatitis C -- an infectious blood-borne virus that attacks and scars the liver.
The virus is usually passed on through sexual contact or drug use, but in de Lisser's case, she got it from her mother, at birth.
At the age of three, blood tests revealed that de Lisser's mother -- fashion designer Serena Bute -- had unknowingly passed on the deadly disease to her daughter.
Bute revealed that at the same time, she also discovered her own infection with Hepatitis C and that her dabbling in drugs and needle-sharing in the 70s had most likely been the cause.
Bute was unaware of her own disease for so long because Hepatitis C is generally asymptomatic, or "silent," until liver scarring has reached such an extreme level that it can lead to liver failure and even liver cancer.
"When I was 13 years old, doctors told me my liver was already in worse shape than that of a middle-aged alcoholic," de Lisser told CNN.
If her liver ever stops functioning, de Lisser's only option may be to undergo a liver transplant. But even then, the virus is likely to attack the new liver.
De Lisser is hoping never to get to that stage. Since the age of six, the teenager has undergone a series of very painful and as-yet unsuccessful treatments in the hope of getting rid of the disease.
Yet for de Lisser, the biggest battle has not been with the illness that affects every aspect of her life, but with the stereotypes that come with any sexually-transmitted or drug-related disease.
"It's a disease that's very hard to relate to and it's embarrassing," de Lisser told CNN. "If someone told me about having Hepatitis C and I didn't know much about it, I would be freaked out as well," she continued.
"I'm always scared of how people, boys, will react. How do I tell someone?" she said.
After keeping her secret under wraps for over a decade, de Lisser recently decided not only to tell her story, but also to become a strong advocate for the cause against liver disease by releasing an award-winning video diary and raising impressive funds for her own charity, Liver Good Life.
The documentary diary follows de Lisser through the ages of 15 and 16, as she attempts a new treatment which has a 40 percent success rate of eliminating the disease, according to leading liver specialist Professor Mieli-Vergani.
The diary shows de Lisser begging for the pain to stop as she receives her weekly injections and her mother fighting back the tears as she addresses her feelings of guilt.
De Lisser invites the cameras into her home, where the side-effects of the powerful drugs -- Ribavirin to prevent the virus multiplying, and Interferon to boost her immune system -- become apparent. The teenager loses almost three quarters of her hair, switches from raging moods to lethargic states and her mouth is full of ulcers.
In the last few scenes of the film, the viewer shares de Lisser's intense relief as she is told the virus has gone, and then, her pain as she learns it has returned.
"When it was cleared for a while, Jazzy was so incredibly happy," Bute told CNN. "We knew it was a possibility, but we really never thought it would come back."
The treatment left de Lisser's body "severely battered by the side-effects," and she was ordered to recover for a year and a half.
"I wouldn't try this treatment again," de Lisser told CNN. "I want a new treatment to be invented, much more powerful."
To fund the research into a new treatment, Jazzy last year launched Liver Good Life, her charity that has already raised £300,000 ($496,300) of the £1.9 million ($3.1 million) it would cost to build a research lab at London's prestigious King's College Hospital.
The charity also creates short animation clips explaining liver disease that de Lisser hopes will be featured in sex education classes in schools across the UK.
Aside from her charitable endeavors, de Lisser is taking a gap year to travel and enjoy life like many other young adults. "I don't want this to define me," she said. "But it's hard; I can't ever drink alcohol, I ingest dozens of homeopathic pills daily and often feel tired and sick."
The only time de Lisser appears less comfortable talking about her disease is when the subject of sex and children is brought up. "It's not an easy topic. I'm still unsure how to deal with this. When do I tell a boy? It's so personal," she explains.
But de Lisser remains optimistic: "When it comes to having children, I don't even think of the possibility of passing it on to them. I know I will get rid of it. It has always been my goal to be free of Hepatitis C before I reach 21. I just have to believe it."
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Terre Haute Regional Hospital earns Silver Award
http://www.tribstar.com
TERRE HAUTE — Terre Haute Regional Hospital earns Silver Award from Indiana State Department of Health
The Indiana State Department of Health has awarded Terre Haute Regional Hospital with the Silver Award for their Perinatal Hepatitis B Prevention program.
Brenda Mason, Public Health Investigator for the Perinatal Hepatitis B Prevention Program, presented the award at the hospital to Chris Hill, CEO; Carolyn Hamilton, CNO; Michelle Farris, director of Women’s and Children’s Services and Kathy Whitecotton, manager of Women’s and Children’s Services.
“We are thrilled with this award from the Indiana Department of Health and it is a tribute to the great care that our staff provides to every patient, every time. It is also gratifying that this award is awarded during a year with a record number of mothers-to-be choosing Terre Haute Regional Hospital,” Hamilton said.
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For Helping Hungry, Food Runners Takes the Cake
http://www.sfgate.com
Amanda Gold, Chronicle Staff Writer
One weekend afternoon several years ago, a bridegroom returned an untouched, multitiered wedding cake to the baker - right after his wedding was called off.
Across town at a family shelter, a 5-year-old girl was celebrating her birthday, although there really wasn't much to celebrate. With limited funds, her mother was unable to give her gifts or a cake.
Enter Food Runners.
In a few short hours, someone from the volunteer organization picked up the cake and delivered it to the shelter, presenting the 5-year-old with perhaps the most magnificent "birthday cake" she'd ever seen.
The wedding cake swap is just one tiny example of the impact Food Runners has had since it started in San Francisco in 1987. It feeds the hungry by providing extra food - from restaurants, caterers, hotels, culinary schools, food services and private individuals - that would otherwise be discarded.
And at this time of year, with holiday parties in full swing, there's a lot of extra food.
Food Runners picks up and delivers approximately 10 tons of perishable and prepared food per week. Over the course of the year, that food, from about 500 donors, is distributed to more than 450 San Francisco organizations.
"I really believe that in San Francisco there is a culture of people who want to do good for others," says Mary Risley, the founder and acting executive director of Food Runners.
For Risley, Food Runners was a solution to her own problem. A few years after starting Tante Marie's Cooking School in San Francisco, the chef and instructor found herself making a nightly decision about what do with the leftover food from class.
"Do I drive it to Glide?" Risley remembers thinking. "Give it to staff? Neighbors? Throw it away?"
Looking for answers, Risley called then-Mayor Dianne Feinstein's office, which referred her to the San Francisco Food Bank. She then got a list of shelters from the food bank, gathered a group of interested people and started Food Runners. It was completely grassroots then and still is today.
Volunteers like Julia Bromley, a board member and Marina resident, do "runs" throughout the week, conveniently located near her neighborhood.
Monday, Bromley starts at the Cliff House, where she'll pick up leftovers from Sunday brunch.
"I have seven pans of food that I'll take to the Edgewood Family Center," Bromley says. Wednesdays she hits a few places on Polk Street - Starbucks, Bagelry, Escape from New York Pizza - while Fridays, she adds, are the most fun. "I get to go to Kara's Cupcakes, Chestnut Bakery and the Polk Street group again," which she then shuttles to the Curry Senior Center on Turk Street.
Seeing the results
Bromley says the best part is that she often sees firsthand how it helps, while getting to know the recipients in the process.
"I learn what these organizations do," she says. "Some of them become a part of my life."
The runs are coordinated by Nancy Hahn, a paid dispatcher who figures out what goes where. Much of the extra food comes from large hotels and individual restaurants such as Delfina, Kokkari and Piperade.
"Most restaurants have to pay for composting," she says. "We're just a service that picks it up for free."
Some potential donors might worry about the liability when feeding the homeless, but Risley says that's a nonissue. Federal and state laws in effect since the 1990s relieve donors of liability.
"When we started out, the health department had an inspector come and investigate us," Risley recalls. The inspector was so taken with Food Runners, Risley says, that she signed up to volunteer, and is still with the organization today.
The food doesn't just have to come from high-volume outlets, Risley points out. Any one can donate the leftover food by calling the organization. Hahn or one of her associates will direct individuals to a group in need, or will send a volunteer or refrigerated truck to help.
Less surplus
Risley says finding food has been especially hard in the current economy, as restaurants don't order as excessively as they used to - a sentiment echoed by local chefs.
"The thing that we have learned in these interesting times is how to run a pretty trim ship," says Annie Sommerville, executive chef of Greens in San Francisco. "We really try not to have too much left over."
Still, Sommerville - who has been donating to Food Runners since its inception - makes a point to package several gallons of short-grain organic brown rice each week for the organization to pick up.
And for Kokkari chef Eric Cosselmon, it's not so much about what's going to be tossed, but more about how the restaurant can help.
"We plan what we're making for staff meal, and then make extra meals for Food Runners," Cosselmon says. The staff packages about 20 to 30 meals that include a starch, vegetable and protein. Volunteers take the food to St. James Infirmary on Mission Street.
Ultimately, Risley says, Food Runners always finds a place for the food, and will accept donations from almost any source or event.
"Hey, if your wedding gets canceled," she says, a smile creeping into her voice, "donate your cake."
Food Runners
To donate food, package it and leave a message at (415) 929-1866, detailing the type and amount of food and the name and address of the business. If you're calling about food prepared at home, a representative will tell you where to take the food in your neighborhood.
To volunteer, go to www.foodrunners.org/volunteer-in-san-francisco.asp, and fill out the appropriate form.
For more information, call (415) 929-1866 or go to www.foodrunners.org.
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Across the Country, Conversations on Health Care
http://www.theepochtimes.com
By Nicholas Zifcak
Throughout the nation, countless people are watching as health care legislation is being worked through Congress. The final legislation that emerges will impact the majority of U.S. citizens through its effects on the health insurance industry. While recently traveling across the country by train, I met people from a wide variety of backgrounds who shared their stories, and I asked them about their experiences and opinions regarding health care.
A Real Survivor
While waiting in line to board the train in Washington, D.C., I was observing two women in front of me when one of them turned and said, "Could you help her? She's a transplant survivor. We're really lucky to have her." That was how Kathryn McConnell and I met.
Speaking to me was an off-duty Amtrak employee who was carrying Ms. McConnell's backpack. She was asking if I could take over. I helped with the backpack, talked with Ms. McConnell, and we got to know each other while on the train ride to Chicago. She had been visiting her daughter and newest grandchild outside Washington, D.C., and was now on her way to San Antonio by way of Chicago.
Ms. McConnell is a caring and chatty lady who makes friends easily. She is 57 and said her biggest accomplishment was "raising four happy, healthy, responsible, working citizens of this world. They are my gifts from God and my gifts to the world." She is now a grandmother of five.
In 2004, while working as a part-time teacher and as a bartender, she began to feel tired all the time. A doctor found that a past bout with Hepatitis C had returned, and her liver was severely damaged. She needed a transplant.
At that time she was engaged to be married, and her fiance helped her through the transplant process. Hoping for a future with him helped her endure the drugs and their side effects. In November 2007 a liver became available, and she successfully underwent an organ transplant.
Sadly, her fiance died of a heart attack four days after bringing her home from the hospital. It was a difficult time in her life, and her eyes began to water as she recalled her fiance and how he had supported her through her ordeal.
"It's ironic, because I had nothing, I was able to afford a transplant. If I had owned a home or anything, it would have been taken," she said.
Ms. McConnell believes health care should be free and universal, and that no one should die for lack of basic care. "I am not a socialist—but I believe there are basic needs everyone should have provided for—water, food, shelter from the elements."
She blames the high price of drugs on companies that "require such huge profits." People "sicken and die or become a disabled drain on society" because they cannot afford the "simplest medicines," said McConnell.
"I sometimes feel I don't deserve this miracle. I am no one special."
Connecting in Chicago
During a layover in Chicago, I had the opportunity to reconnect with a middle school classmate, Annie. She works as a pediatric nurse in a Chicago hospital, so I asked her what she thinks about health care.
"There are way more problems than people just not being covered," she said based on her experience.
"The reality is that people are going to get care even if they don't have insurance," because publicly financed and nonprofit hospitals in Chicago will take care of them.
She believes there should be some type of public option, but people should also pay a certain amount, because of the "tendency to take it for granted."
To her, the problem of how to pay for health care for Americans runs deeper because of factors based in the health care industry itself.
One example she mentioned is the cost of medical procedures done "to cover the bases," to avoid liability, rather than to heal the patient.
According to Annie, failure to emphasize healing the patient starts higher up. She said she sees hospitals being built around the need for profits, rather than focusing on patient care. So, the administration invested in amenities, to attract patients. Patients may initially be attracted to such hospitals she said, but if the care is poor, they will transfer to hospitals that make patient care the top priority.
On to the West
I was watching the Eastern Montana plains go by when I met Gerald Odegard. He is a retired home and boat builder who lives in South Dakota. Now he takes care of his wife and mother-in-law. Mr. Odegard lived much of his life in Northwest Washington State where he worked building model boats and prototypes for a manufacturer of runabouts, cruisers, deck boats, and motor yachts.
Years ago, his wife was in a car accident, afterward she developed problems in her joints. She went through twenty operations. While in the hospital, she contracted an infection that damaged her inner ear and ability to maintain balance. She now needs a walker. She rode in a special car on the train, one more accessible for her. The Odegards were on their way to visit their son and grandchildren in Seattle.
Because of his wife's condition, insurance was essential for them. He said he doesn't know what they would have done without the uninsured motorist insurance they had when his wife was hit. That covered initial fees because the other driver lacked car insurance.
Later, because of job loss, they lost health insurance. However, she became eligible for Medicare because of her disability. Medicare covered 80 percent of their insurance needs, but they also needed a 20 percent supplemental policy to cover the rest. Because of his wife's condition, they were denied coverage. When she turned 65, they were finally able get full coverage through through provisions of the Medicare program.
Mr. Odegard said he is glad that it is likely Congress will prohibit the practice of denying coverage to those with pre-existing conditions.
"You have to control profits and control costs," he said, referring to the health care industry. "What the government is for is to control excess. If they don't, then somebody ends up with the short end of the stick."
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December 25, 2009
Beating the Odds
http://www.boston.com
Steven Syre
Here’s the problem with every promising new drug that pops out of a lab: There are a million ways to fail before any treatment completes the testing and clinical trials required for commercial approval. Hope springs eternal, but the odds stink.
As in every other year, in 2009 there were encouraging small developments at Massachusetts life sciences companies looking for new ways to treat serious illnesses. Curis Inc. and Infinity Pharmaceuticals Inc., to highlight just a couple, both seemed to make real progress with difficult problems treating cancer. The two Cambridge companies have big pharmaceutical industry partners, but they are a long way from having anything like an approved cancer-fighting drug.
For my money, the year’s most encouraging story about the development of medical products that can really help people isn’t new at all. In fact, it feels like it’s been around forever.
Vertex Pharmaceuticals Inc., of Cambridge, is working on lots of things, but everyone is paying keen attention to the company’s Telaprevir treatment for hepatitis C. Telaprevir appears to offer a dramatically better way to treat patients with a serious disease. The promise, in a nutshell: less pain and suffering, much higher success rates, and faster results.
A lot of people could benefit - more than 3 million in the United States suffer from hepatitis C, a liver disease spread mainly through contact with the blood of infected patients. Globally, that number balloons to 170 million.
Nothing dramatic happened in the development of Telaprevir in 2009, but Vertex pushed forward on clinical and financial fronts to prepare for a new drug application in the year ahead. There were no unexpected setbacks as Telaprevir entered the development home stretch.
A series of final clinical trials involving 2,200 patients were launched in 2009. Meanwhile, Vertex produced good new data about the convenience of the drug and its ability to attack the toughest cases.
The current treatment for hepatitis C, an antiviral pill combined with alpha interferon, drags on for nearly a year, with side effects that can be debilitating. Success is a 50-50 proposition, at best, and there is little in the way of incremental improvement. You’re cured or you’re not.
Telaprevir is a protease inhibitor, given to patients as a pill along with the conventional treatment. Results from clinical trials so far suggest a treatment timeline of 24 weeks, half the standard duration, cures about 80 percent of patients. That would boost the current success rate by at least half.
The progress of Telaprevir has been slow, even by drug development standards. News about its potential has been widely reported for nearly five years. Though Vertex plans to seek approval for Telaprevir next year, it probably won’t be on the market until 2011.
The pokey pace has been caused by the length of the current hepatitis C treatment. Each clinical trial of Telaprevir is compared with standard treatment given to some patients. That means waiting 48 weeks, plus another six months to see what happens to patients after treatment.
But the news, while slow to develop, has been consistently good. Among the new data this year, Vertex showed that two daily Telaprevir pills instead of the standard three did not hurt the results. The drug also did well among the toughest group of patients - those who did not respond at all to a previous round of standard treatment.
Vertex has been gearing up to bring Telaprevir to the medical market for a few years now, and that takes money. Clinical progress helped the company raise more than $750 million in two separate stock sales this year.
Vertex shares are up 42 percent in 2009, but the idea shareholders will ride Telaprevir to continued riches is questionable. Other competitors are far along in the development of their own hepatitis C treatments. The big money may have been made by investors whose shares quadrupled to $45 in a year by spring 2006 on the earliest hopeful news about Telaprevir. Nearly four years later, Vertex shares are worth $43 each.
I don’t know what is in store for shareholders, but there’s no doubt prospects are improving for so many patients who could benefit from the drug. In 2009, Telaprevir was the most hopeful story to come out of a local industry built on medical hope.
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For Transplant Recipient, Holidays Are 'Bittersweet': Officials Help Clear Road to Health
http://www.trib.com
By Sally Ann Shurmur
Star-Tribune staff writer
There's no mistaking the sweet in this holiday season for Meeteetse's Chuck Forbes.
He turned 60 in mid-December, a birthday he never thought he'd see in a year when Christmas seemed a long way away.
"He knows he'd be dead by now," said his wife, Ruth. "Especially this time of year, it's bittersweet. It's an emotional time, because he knows someone died for him to get the liver. The doctor says it's a normal way to feel."
The fact that Forbes is improbably healthy for the first time in 30 years and spending Christmas at his retirement home of six years with his wife made national news in April.
"As Christmas approaches, he is overwhelmed with the biggest gift that anyone could possibly get in the world," Ruth said.
"Clinically, he's doing just great," she said. "We haven't been back to Denver for a checkup since September. He sees Dr. Mark Dowell in Casper once a month."
Forbes, a retired veterans hospital administrator, suffered from cirrhosis and hepatitis C, both chronic diseases of the liver. When cancer was found in the liver two years ago, "it was just the final step," Ruth said.
Enduring chemotherapy, watching the tumors grow became life for the couple. Knowing that a transplant was the only hope, Forbes was "on the list" for a year and a half at the University of Colorado Medical Center in Aurora.
The trouble was, Aurora was a long stretch down Interstate 25 from Meeteetse, and it became more difficult when it began snowing on April 4.
The Forbeses were called at 7:30 in the morning on that day and told that a liver was available. With Ruth behind the wheel, they set out for Thermopolis, then through Wind River Canyon to Casper.
"We get to Wheatland about 3ish [in the afternoon], and the barrier is down," she recounted in April. "Everybody else had turned around or gotten off, so we were the first one behind the barrier."
Frustrated and a tad panicked, she called 911.
"The operator said, 'The road is closed; we've been forecasting this storm all week,'" Ruth remembered. "Then she said, 'Hang on, I'll get a patrolman to come talk to you.'"
Trooper Chuck Bloom responded, talked to the couple, and then returned to his patrol car.
"He came back to our car and said, 'If you wait right here, the area boss for WYDOT [John Benton] will be right here.'"
"In a matter of 10 minutes, we had a convoy of plow trucks," Ruth said.
Snowplow drivers Rick Schultz, Howard Bise, Dennis Ebel, Bryan Hays, Monte Hubbard, Paul Lovett, Dave Round and Dan Stafford escorted the Forbeses from Wheatland to the Colorado border.
At first, she was nearly on the bumper of the plow in completely whiteout conditions and estimates she was driving between 20 and 25 mph.
In Chugwater, a convoy of plows widened the path, and in Cheyenne, another set led them to the state line.
"At the state line, I realized I hadn't gone to the bathroom since Meeteetse, and my gas gauge is on 'E,' and the electronic thing says I have 32 miles to go before I run out of gas," she recounted.
Because luck was with them, they reached a restroom/gas station and arrived at the hospital at 9:30 on Saturday night.
He underwent his transplant at 7:30 on April 5, and by April 20 was strong enough to honor Trooper Bloom and the snowplow drivers in a ceremony at the State Capitol in Cheyenne.
The Forbeses took two nice trips this summer, traveling to Virginia and New England, and then to Minnesota, something they could not have done before the transplant. They were at her family's Fourth of July reunion in New Hampshire, an event they had no hope of attending just a few short months before.
"I hope those WYDOT guys know they performed a miracle," Ruth Forbes said in April.
Recently, she said, "They are amazing people. To think that what they did made all the difference is something we are always aware of."
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