Historical epidemiology of hepatitis C virus in select countries-volume 4.

Due to the introduction of newer, more efficacious treatment options, there is a pressing need for policy makers and public health officials to develop or adapt national hepatitis C virus (HCV) control strategies to the changing epidemiological landscape. To do so, detailed, country-specific data are needed to characterize the burden of chronic HCV infection. In this study of 17 countries, a literature review of published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates was conducted, and inputs were validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Hong Kong to 2.4% in Taiwan, while the largest viraemic populations were in Nigeria (2 597 000 cases) and Taiwan (569 000 cases). Diagnosis, treatment and liver transplant rates varied widely across the countries included in this analysis, as did the availability of reliable data. Addressing data gaps will be critical for the development of future strategies to manage and minimize the disease burden of hepatitis C.

Strategies to manage hepatitis C virus infection disease burden-Volume 4.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets-"WHO Targets" (65% reduction in HCV-related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.

The present and future disease burden of hepatitis C virus infections with today's treatment paradigm: Volume 4.

Factors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV-related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high-treatment rate will contribute to a reduction in total cases and HCV-related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV-related morbidity and mortality.

Emerging role for colorectal cancer screening in Asian countries.

BACKGROUND AND AIM: Colorectal cancer (CRC) is one of the leading causes of cancer related mortality globally. Though Asia has traditionally been considered a relatively low incidence area for colorectal cancer, the incidence is reportedly increasing. The Asia Pacific Working Group for Colorectal Cancer has recommended screening of individuals at average risk starting from 50 years of age. Based on these recommendations we conducted a pilot study to assess the need and feasibility of a colorectal cancer screening program in the state of Qatar. METHODS AND RESULTS: We screened 1385 individuals by fecal immunochemical testing for occult blood, at the primary health center level and positive cases were referred for colonoscopy. Among those who tested positive for fecal occult blood, we picked up five patients with cancers and seven with neoplastic polyps. CONCLUSION: Our results compare with the yield of screening programs in western countries thus suggesting an emerging role for colorectal cancer screening in Asian countries.

Hepatitis C virus genotype 4 with normal transaminases: histological changes, schistosomiasis and response to treatment.

Among individuals with chronic hepatitis C virus (HCV) infection, approximately 30% of patients show persistently normal alanine aminotransferase (PNALT). Individuals with PNALT have been historically excluded from antiviral treatment. However, some studies have reported sudden worsening of disease in patients with PNALT, suggesting the need to treat such individuals. To evaluate this further, we compared fibrosis severity and response to treatment in patients with PNALT to patients with abnormal ALT. In addition, we investigated whether liver histology and schistosomiasis affect response to treatment differently in those with PNALT and abnormal ALT. A retrospective cohort study of 176 HCV-Genotype 4 (HCV-G4) patients treated with pegylated interferon (PEG-IFN) and ribavirin. Of 176 cases studied, 53 (30.1%) had normal ALT. Prevalence of pretreatment severe fibrosis, sustained virological response (SVR) and relapse were not significantly different in patients with PNALT (26%, 66% and 5.7% respectively) compared to those with abnormal ALT (32.5%, 60.7%, and 6.6% respectively). Multivariable logistic regression revealed that pretreatment ALT, pretreatment viral load, inflammation and schistosomiasis were not significantly associated with SVR [OR (95% CI), 0.75 (0.34-1.65); 0.92 (0.61-1.37); 1.64 (0.64-4.18); 0.90 (0.44-1.84) respectively]. Severe fibrosis was the only significant predictor of SVR [OR (95% CI), 0.38 (0.14-0.99)]. PNALT does not reflect the degree of fibrotic changes or predict SVR. Furthermore, schistosomiasis is a predictor of neither fibrosis nor poor response in patients with PNALT. Severe fibrosis is a strong and independent predictor of response to treatment. Therefore, it is important to treat individuals with PNALT levels regardless of schistosomiasis.

Hoarseness due to Mycobacterium kansasii.

OBJECTIVE: To present a case of unilateral vocal fold paralysis due to Mycobacterium kansasii induced pressure on the left recurrent laryngeal nerve, a specific aetiology not previously reported in the world literature. CASE REPORT: A 57-year-old Caucasian man presented with a short history of productive cough, fever, hoarseness and 14-kg weight loss. He was a smoker, had an abnormal chest X-ray and was human immunodeficiency virus negative. A sputum sample was positive on direct microscopy for acid fast bacilli. Initially, the patient was treated with Rifater (rifampicin, isoniazid and pyrazinamide) and ethambutol. Mycobacterium kansasii was isolated and proved sensitive to this antimycobacterial treatment. Nasoendoscopy revealed diminished movement of the left vocal fold, and a computed tomography scan showed enlarged mediastinal lymph nodes anterior to the aortic arch. After three months of antimycobacterial treatment, the vocal folds were fully mobile at repeat nasoendoscopy, and this coincided with gradual resolution of the patient's hoarseness and weight loss. CONCLUSIONS: There are many causes of unilateral vocal fold paralysis. This case illustrates the importance of anatomical knowledge in reaching a diagnosis, and also presents the first reported case of Mycobacterium kansasii creating this clinical picture.

Viral kinetic of HCV genotype-4 during pegylated interferon alpha 2a: ribavirin therapy.

Kinetics of hepatitis C virus (HCV) during pegylated interferon (PEG-IFN) and early monitoring of viral decline were recently described to predict treatment outcomes and in turn reduce the course of treatment, adverse effects and cost. However, there is limited (if any) information on the viral dynamics of HCV-4. Our aim is to follow the HCV-RNA kinetics during PEG-IFN alpha 2a and ribavirin therapy and the best time for predicting sustained viral response (SVR) in genotype-4 patients. Serum HCV-RNA levels before initial dosing (baseline level) and at 24 h, week 1, week 4, week 12, week 24, week 48 and week 72 were assessed in 84 HCV genotype-4 patients treated weekly by PEG-IFN alpha 2a and daily ribavirin. At the end of treatment, out of the 84 treated patients, 19 (22.6%) were non-responders while 65 (77%) showed end-of-treatment response (ETR). However, 8 patients relapsed (9.5%), thus the SVR was observed in 57 patients (67.9%). Younger patients were more likely to attain SVR, where the odds of SVR increased by a factor of 0.94 for each year increase in age (95% CI: 0.90-0.99, P = 0.019). Although a significant negative correlation between stage of fibrosis and rate of viral decline at weeks 1 and 4 (P < 0.005 and 0.001, respectively) was seen, neither fibrosis stage (χ(2) = 3.4882, P > 0.1) nor grade of inflammation (χ(2) = 0.0057, P > 0.1) significantly predicted response to treatment. Non-responders had no or only a limited decline at week 1 and week 4, whereas sustained virological responders had a significant decline at both week 1 and week 4. Area under the (receiver operating characteristic) curve (AUC) revealed that week 12 is better than any other time point in predicting the SVR (AUC = 0.97; 95% CI: 0.94-1.01), (sensitivity 98.3%; 95% CI: 90.7-99.9), (specificity 88.5%; 95% CI: 71.0-96.0), positive predictive value of 94.9% and negative predictive value of 95.8%. A drop of more than 1.17 log viral load at week 1 and viral clearance or decline >3 log were considered as the earliest predictors of SVR. In genotype-4 patients, while failure to achieve an EVR at week 12 predicts non-response, an RVR at week 1 and week 4 98% guaranteed SVR. These findings further re-enforce the value of week 12 in the course of IFN treatment. Genotype-4 patients who show significant viral clearance (>1.17 log viral load) by the first week of treatment and viral clearance >3 log by week 4 are expected to show SVR and should therefore be assigned to a shorter drug regimen lasting for 24 weeks. Those unfortunate cases who do not achieve viral clearance by week 1 or week 4 should not be deprived from the treatment but rather given more time till week 12 before being classified as non-responders.

Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage.

AIM: To evaluate pegylated interferon alpha2a (PegIFN-alpha2a) in Egyptian patients with HCV genotype 4, and the impact of pretreatment viral load, co-existent bilharziasis and histological liver changes on response rate. METHODS: A total of 73 naive patients (61 with history of bilharziasis) with compensated chronic HCV genotype 4 were enrolled into: group A (38 patients) who received 180 mg PegIFN-alpha2a subcutaneously once weekly for a year and group B (35 patients) received IFN alpha-2a 3 MU 3 times weekly. Ribavirin was added to each regimen at a dose of 1200 mg. Patients were followed for 72 wk and sustained response was assessed. RESULTS: Significant improvement in both end of treatment response (ETR) (P < 0.002) and sustained response (SR) (P < 0.05) was noted with pegylated interferon, where ETR was achieved in 29 (76.3%) and 14 patients (40%) in both groups respectively, and 25 patients in group A (65.8%) and 9 (25.7%) in group B could retain negative viraemia by the end of follow up period. Sustained virological response (SVR) showed a significant negative correlation with age and positive correlation with pretreatment inflammation in patients receiving PegIFN. Viral clearance after 3 mo of therapy was associated with high incidence of ETR and SR (P < 0.001), but without significant difference between both forms of interferon. Significant improvement in response was achieved in patients with high grade fibrosis (grade 3 and 4) with PegIFN-alpha2a, where SR was seen in 5 out of 13 patients in group A, but none in group B. There was no significant difference in response between bilharzial and non-bilharzial patients in both groups. In terms of safety and tolerability, neutropenia was the predominant side effect; both drugs were comparable. CONCLUSION: PegIFN-alpha2a combined with ribavirin results in improvement in sustained response in HCV genotype 4, irrespective of history of bilharzial infestation.

Neurotoxicity produced by dibromoacetic acid in drinking water of rats.

An evaluation of potential adverse human health effects of disinfection byproducts requires study of both cancer and noncancer endpoints; however, no studies have evaluated the neurotoxic potential of a common haloacetic acid, dibromoacetic acid (DBA). This study characterized the neurotoxicity of DBA during 6-month exposure in the drinking water of rats. Adolescent male and female Fischer 344 rats were administered DBA at 0, 0.2, 0.6, and 1.5 g/l. On a mg/kg/day basis, the consumed dosages decreased greatly over the exposure period, with average intakes of 0, 20, 72, and 161 mg/kg/day. Weight gain was depressed in the high-concentration group, and concentration-related diarrhea and hair loss were observed early in exposure. Testing with a functional observational battery and motor activity took place before dosing and at 1, 2, 4, and 6 months. DBA produced concentration-related neuromuscular toxicity (mid and high concentrations) characterized by limb weakness, mild gait abnormalities, and hypotonia, as well as sensorimotor depression (all concentrations), with decreased responses to a tail-pinch and click. Other signs of toxicity at the highest concentration included decreased activity and chest clasping. Neurotoxicity was evident as early as one month, but did not progress with continued exposure. The major neuropathological finding was degeneration of spinal cord nerve fibers (mid and high concentrations). Cellular vacuolization in spinal cord gray matter (mostly) and in white matter (occasionally) tracts was also observed. No treatment-related changes were seen in brain, eyes, peripheral nerves, or peripheral ganglia. The lowest-observable effect level for neurobehavioral changes was 20 mg/kg/day (produced by 0.2 g/l, lowest concentration tested), whereas this dosage was a no-effect level for neuropathological changes. These studies suggest that neurotoxicity should be considered in the overall hazard evaluation of haloacetic acids.

13-week inhalation toxicity study (including 6- and 13-week recovery periods) with ammonium persulfate dust in albino rats.

The subchronic inhalation toxicity of ammonium persulfate was characterized using Sprague-Dawley rats (20/sex/group) at respirable dust concentrations of 0, 5.0, 10.3, and 25 mg/m(3). Whole-body exposures were conducted 6 h/day, 5 days/wk for 13 wk. Gravimetric airborne test material samples were taken daily and particle size samples were taken weekly from each exposure chamber for analysis. Ten animals/sex/group were necropsied after 13 wk of exposure, and 5 animals/sex/group were held for 6- and 13-wk recovery periods. Animals were observed for clinical signs. Effects on body weight, food consumption, clinical chemistry and hematology, ophthalmologic parameters, organ weights, gross lesions, and histopathology were evaluated. There were no exposure-related deaths during the study. Rales and increased respiration rate were noted in both males and females in the 25 mg/m(3) group, and in a few animals in the 10.3 mg/m(3) group. The incidence of these clinical signs decreased to zero during the first few weeks of the recovery period. Body weights for both males and females in the 25 mg/m(3) group were significantly depressed during most of the exposure period compared to the control group. By the end of the recovery period, body weights for the exposed animals were similar to the control group values. Lung weights were elevated in the 25 mg/m(3) group after 13 wk of exposure, but were similar to controls at 6 wk postexposure. Irritation of the trachea and bronchi/bronchiole was noted microscopically after 13 wk of exposure to 25 mg/m(3). These lesions had recovered by 6 wk postexposure. Based on the results of this study, the no-observed-adverse-effect level (NOAEL) was 10.3 mg/m(3), while the no-observed-effect level (NOEL) for exposure of rats to a dust aerosol of ammonium persulfate was 5.0 mg/m(3).

Qualitative investigation of uptake of fine particle size microcrystalline cellulose following oral administration in rats.

A subchronic toxicity study was conducted to evaluate the potential toxicological effects associated with intestinal translocation of a special fine particle size (median particle size 6 microns) microcrystalline cellulose (MCC). Four groups of Sprague-Dawley rats (20/sex/group) received either 0 (control), 500, 2500 or 5000 mg/kg/day MCC (25% w/v in tap water) daily by oral gavage for 90 d. At study termination, organs and tissues from high-dose and control animals, including multiple sections of intestine with gut-associated lymphoid tissue, were processed for light microscopy with subsequent examination under polarised light for the presence of birefringent MCC particles. None were observed in any tissue examined. No toxicologically significant effects or lesions were found in any other parameter or organ evaluated. The 'no observed adverse effect level' (NOAEL) for toxicological effects was greater than 5000 mg/kg/day MCC, which was the highest dosage tested. These results further verify the safety of commercial MCC products for use in food and pharmaceutical applications.

A cytotoxicity assay for Clostridium spiroforme enterotoxin in cecal fluid of rabbits.

Clostridium spiroforme enterotoxin-mediated diarrhea can be a common cause of mortality among weanling age rabbits. Definitive diagnosis of this disorder requires detection of the causative enterotoxin. Using filtered cecal supernatant from necropsy specimens, antibodies to C. spiroforme and its products and Vero cells, a cytotoxicity assay was performed on 22 rabbits with clinical signs and lesions consistent with C. spiroforme enterotoxin-mediated diarrhea. A cytotoxic effect was detected, generally within 4 h, in 18 of 22 rabbits. The cytotoxic effect was blocked by preincubation of the cecal material with antibodies to C. spiroforme and its products. Culture of cecal contents and smears of cecal contents identified C. spiroforme in 10/22 and 12/22 cases, respectively. This cytotoxicity assay provided a rapid and sensitive method for diagnosing C. spiroforme enterotoxin-mediated diarrhea.

Spinal lymphosarcoma and disseminated mastocytoma associated with feline immunodeficiency virus infection in a cat.

The course of naturally acquired infection with feline immunodeficiency virus was monitored in a cat over an 18-month period after diagnosis. The cat was admitted with diarrhea, poor body condition, a bite wound abscess, gingivitis, chronic fever, and splenomegaly. The cat's condition improved after splenectomy and remained stable for approximately 15 months, then began to deteriorate, as gingivitis, polyuria, polydipsia, pyrexia, multiple cutaneous masses, and hind limb paresis developed. The in vitro response of the cat's lymphocytes to mitogens was suppressed, and absolute lymphocyte counts were low. Spinal lymphosarcoma, disseminated mastocytoma, and presumptive diabetes mellitus were diagnosed after euthanasia. Decreased immune surveillance associated with feline immunodeficiency virus-related immunosuppression possibly played a role in the development of neoplastic disease in this cat.

Determination of the number of mast cells in lymph node, bone marrow, and buffy coat cytologic specimens from dogs.

Cytologic samples of popliteal lymph node, proximal femoral bone marrow, and the buffy coat fraction of blood were obtained from 56 dogs. The number of mast cells on 1 slide of each sample was determined by microscopic examination. Eleven of 46 slides of lymph node aspirate contained mast cells (range, 1 to 16; mean, 6.4; median, 5 mast cells/slide). Fifty-one bone marrow aspirate slides were evaluated. Two of these contained a single mast cell. None of the 53 buffy coat smear slides examined contained any mast cells. These results indicated that in clinically normal dogs, a few to several mast cells may be encountered in smears of lymph node aspirate, mast cells are rare in smears of bone marrow aspirate, and mast cells are absent from smears of buffy coat.

Encephalitic listeriosis in two adult llamas (Lama glama): clinical presentations, lesions and immunofluorescence of Listeria monocytogenes in brainstem lesions.

Encephalitic listeriosis was diagnosed in 2 adult llamas. Both had a multifocal suppurative encephalitis with mixed lymphocytic and neutrophilic perivascular infiltrates. Listeria monocytogenes was cultured from the brain stem of 1 llama using cold enrichment techniques; the other llama was culture negative. Formalin-fixed and paraffin embedded sections of brainstem lesions from both affected animals were labeled with a fluorescein-conjugated, anti-L. monocytogenes antibody. Using this technique, intralesional L. monocytogenes were identified in both llamas.

Iatrogenic transmission of Cytauxzoon felis from a Florida panther (Felix concolor coryi) to a domestic cat.

A laboratory cat died 12 days after intraperitoneal inoculation of a 1 ml suspension containing 1.5 x 10(6) blood mononuclear cells from a Florida panther (Felis concolor coryi). Gross, histologic and ultrastructural investigations revealed the cause of death to be infection by Cytauxzoon felis, a protozoal parasite known to cause a rapidly fatal disease (cytauxzoonosis) in domestic cats. The bobcat (Felis rufus) has been identified as a natural host for C. felis. This report implicates the Florida panther as another possible host for C. felis.