Therapeutic Efficacy of Albendazole and Mefloquine Alone or in Combination Against Early and Late Stages of Trichinella Spiralis Infection in Mice.

This study aimed to determine the effectiveness of mefl oquine alone or combined with albendazole in reduced doses against T. spiralis infection. One hundred and twenty albino mice were orally infected with 200 T. spiralis larvae/mouse. Drugs were administered during the enteral phase on days 1 to 3 and on the chronic phase on days 35 to 37 post-infection, and mice were sacrificed, respectively, at days 7 or 48 post-infection to count mature intestinal worms or encysted muscle larvae. The effect of the treatment on the histology of the target organs of each phase, intestine and diaphragm, was also evaluated. A signifi cant decrease in intestinal worms was found in all treated groups relative to the untreated control group at a peak of 93.7% in the combination albendazole-mefl oquine group. Results in all treated groups demonstrated a signifi cant decrease in muscle larvae relative to untreated control groups, achieving 86.2 % in the combined albendazole-mefl oquine group. There was a marked improvement in the intestinal and muscular architecture in all treated groups compared to the non-treated control group. Notably, the albendazole-mefl oquine group showed an almost complete recovery. The combined albendazole-mefl oquine low dose regimen had the highest effect on reducing parasite burden and restoring normal histological architecture.

The present and future disease burden of hepatitis C virus infections with today's treatment paradigm - volume 3.

The total number, morbidity and mortality attributed to viraemic hepatitis C virus (HCV) infections change over time making it difficult to compare reported estimates from different years. Models were developed for 15 countries to quantify and characterize the viraemic population and forecast the changes in the infected population and the corresponding disease burden from 2014 to 2030. With the exception of Iceland, Iran, Latvia and Pakistan, the total number of viraemic HCV infections is expected to decline from 2014 to 2030, but the associated morbidity and mortality are expected to increase in all countries except for Japan and South Korea. In the latter two countries, mortality due to an ageing population will drive down prevalence, morbidity and mortality. On the other hand, both countries have already experienced a rapid increase in HCV-related mortality and morbidity. HCV-related morbidity and mortality are projected to increase between 2014 and 2030 in all other countries as result of an ageing HCV-infected population. Thus, although the total number of HCV countries is expected to decline in most countries studied, the associated disease burden is expected to increase. The current treatment paradigm is inadequate if large reductions in HCV-related morbidity and mortality are to be achieved.

Strategies to manage hepatitis C virus infection disease burden - volume 3.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries in Europe, the Middle East and Asia, and the relative impact of two scenarios was considered: increased treatment efficacy while holding the annual number of treated patients constant and increased treatment efficacy and an increased annual number of treated patients. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. A 90% reduction in total HCV infections within 15 years is feasible in most countries studied, but it required a coordinated effort to introduce harm reduction programmes to reduce new infections, screening to identify those already infected and treatment with high cure rate therapies. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. Among European countries, the majority of patients were born between 1940 and 1985. A wider range of birth cohorts was seen in the Middle East and Asia (between 1925 and 1995).

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 3.

Detailed, country-specific epidemiological data are needed to characterize the burden of chronic hepatitis C virus (HCV) infection around the world. With new treatment options available, policy makers and public health officials must reconsider national strategies for infection control. In this study of 15 countries, published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates were gathered from the literature and validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Iran and Lebanon to 4.2% in Pakistan. The largest viraemic populations were in Pakistan (7 001 000 cases) and Indonesia (3 187 000 cases). Injection drug use (IDU) and a historically unsafe blood supply were major risk factors in most countries. Diagnosis, treatment and liver transplant rates varied widely between countries. However, comparison across countries was difficult as the number of cases changes over time. Access to reliable data on measures such as these is critical for the development of future strategies to manage the disease burden.

Evaluation of purified 27.5 kDa protoscolex antigen-based ELISA for the detection of circulating antigens and antibodies in sheep and human hydatidosis.

Hydatidosis is a zoonotic disease caused by the larval stage of Echinococcus granulosus, and the diagnosis of hydatidosis to date remains unresolved despite the development of many serological techniques. The present study aimed to develop an antigen-based enzyme-linked immunosorbent assay (ELISA) using IgG anti-27.5 kDa protoscolex antigen (27.5 PA) for measuring circulating protoscolex antigen (CPA), for comparison with an antibody detection assay, in sera of naturally infected sheep and humans in highly endemic areas in Egypt. In sheep, the sensitivity of ELISA in detecting anti-27.5 PA IgG and CPA was 75.0 and 60.0%, respectively, and the recorded specificity was 80.0 and 88.0%, respectively. In humans, the sensitivity of ELISA in detecting anti-27.5 PA IgG and CPA was 62.5 and 52.5%, respectively, while the specificity of the assay was 66.7 and 75.0%, respectively. In conclusion, an antibody detection assay is still superior and is more sensitive than an antigen detection assay, especially in diagnosing an active infection in which hydatid cysts are predominant. An antigen detection assay may be a useful approach to assessment of the efficacy of treatment, especially after removal of the cyst. Further studies are recommended to improve the diagnostic efficacy of an antigen-based ELISA method by using a highly purified recombinant antigen.

Diagnostic potential of Fasciola gigantica-derived 14.5 kDa fatty acid binding protein in the immunodiagnosis of bubaline fascioliasis.

The 14.5 kDa fatty acid binding protein (FABP) was isolated from the crude extract of adult Fasciola gigantica worms. Polyclonal anti-FABP IgG was generated in rabbits immunized with prepared FABP antigen. Sandwich enzyme-linked immunosorbent assay (ELISA) was applied to detect coproantigen in stools and circulating Fasciola antigen (CA) in sera of 126 water buffaloes by using purified and horseradish peroxidase (HRP)-conjugated anti-FABP IgG. Sandwich ELISA sensitivity was 96.97% and 94.95%; while specificity was 94.12% and 82.35% for coproantigen and CA detection, respectively. However, sensitivity and specificity of the Kato-Katz technique was 73.74% and 100%, respectively. The diagnostic efficacy of sandwich ELISA was 96.55% and 93.1% for coproantigen and CA detection, respectively. In contrast, the diagnostic efficacy of the Kato-Katz technique was 77.59%. In conclusion, these results demonstrate that the purified 14.5 kDa FABP provides a more suitable antigen for immunodiagnosis of early and current bubaline fascioliasis by using sandwich ELISA.

Three years of alendronate treatment does not continue to decrease microstructural stresses and strains associated with trabecular microdamage initiation beyond those at 1 year.

UNLABELLED: The effects of a 3-year alendronate treatment on trabecular stresses/strains associated with microdamage initiation were investigated using finite element modeling (FEM). Severely damaged trabeculae in the low-dose treatment group were associated with increased stresses compared with the high-dose treatment group (p = 0.006) and approached significance in the control group (p = 0.02). INTRODUCTION: Alendronate, a commonly prescribed anti-remodeling agent, decreases fracture risk in the vertebrae, hip, and wrist of osteoporotic individuals. However, evaluation of microdamage accumulation in animal and human studies shows increased microdamage density relative to controls. Microstructural von Mises stresses associated with severe and linear damage have been found to decrease after 1 year of alendronate treatment. In the present study, stresses/strains associated with damage were assessed after 3 years of treatment to determine whether they continued to decrease with increased treatment duration. METHODS: Microdamaged trabeculae visualized with fluorescent microscopy were associated with stresses and strains obtained using image-based FEM. Stresses/strains associated with severe, diffuse, and linearly damaged and undamaged trabeculae were compared among groups treated for 3 years with an osteoporotic treatment dose of alendronate, a Paget's disease treatment dose of alendronate, or saline control. Architectural characteristics and mineralization were also analyzed from three-dimensional microcomputed tomography reconstructed images. RESULTS: Severely damaged trabeculae in the osteoporotic treatment dose group were associated with increased stress compared with the Paget's disease treatment dose group (p = 0.006) and approached significance compared to the control group (p = 0.02). Trabecular mineralization in severely damaged trabeculae of the low-dose treatment group was significantly greater compared to severely damaged trabeculae in the high-dose treatment and control group, suggesting that changes at the tissue level may play a role in these findings. CONCLUSIONS: Trabecular level stresses associated with microdamage do not continue to decrease with prolonged alendronate treatment. Changes in mineralization may account for these findings.

Alendronate treatment results in similar levels of trabecular bone remodeling in the femoral neck and vertebra.

SUMMARY: We aimed to determine whether trabecular bone in sites that have different surface-based remodeling rates, the femoral neck and vertebra, are differently affected by alendronate treatment. Alendronate treatment resulted in similar levels of turnover in both sites, suggesting that a lower limit of bone turnover suppression with alendronate may exist. INTRODUCTION: Bone turnover suppression in sites that already have a low surface-based remodeling rate may lead to oversuppression that could have negative effects on the biomechanical properties of bone. The goal was to determine how alendronate suppresses bone turnover at sites with different surface-based remodeling rates. METHODS: Dynamic histomorphometric parameters were assessed in trabecular bone of the femoral neck and lumbar vertebrae obtained from skeletally mature beagles treated with saline (1 ml/kg/day) or alendronate (ALN 0.2 or 1.0 mg/kg/day). The ALN0.2 and ALN1.0 doses approximate, on a milligram per kilogram basis, the clinical doses used for the treatment of postmenopausal osteoporosis and Paget's disease, respectively. RESULTS: Alendronate treatment resulted in similar absolute levels of bone turnover in the femoral neck and vertebrae, although the femoral neck had 33% lower pre-treatment surface-based remodeling rate than the vertebra (p < 0.05). Additionally, the high dose of alendronate (ALN 1.0) suppressed bone turnover to similar absolute levels as the low dose of alendronate (ALN 0.2) in both sites. CONCLUSIONS: Alendronate treatment may result in a lower limit of trabecular bone turnover suppression, suggesting that sites of low pre-treatment remodeling rate are not more susceptible to oversuppression than those of high pre-treatment remodeling rate.

Age-dependent fatigue behaviour of human cortical bone.

Despite a general understanding that bone quality contributes to skeletal fragility, very little information exits on the age-dependent fatigue behavior of human bone. In this study four-point bending fatigue tests were conducted on aging bone in conjunction with the analysis of stiffness loss and preliminary investigation of nanoindentation based measurements of local tissue stiffness and histological evaluation of resultant tensile and compressive damage to identify the damage mechanism responsible for the increase in age-related bone fragility. The results obtained show that there is an exponential decrease in fatigue life with age, and old bone exhibits different modulus degradation profiles than young bone. In addition, this study provides preliminary evidence indicating that during fatigue loading, younger bone formed diffuse damage, lost local tissue stiffness on the tensile side. Older bone, in contrast, formed linear microcracks lost local tissue stiffness on the compressive side. Thus, the propensity of aging human bone to form more linear microcracks than diffuse damage may be a significant contributor to bone quality, and age related fragility in bone.

Effects of damage morphology on cortical bone fragility.

Despite a general understanding that bone microdamage has distinct strain dependent morphologies, very little information exists on how different damage morphologies develop and participate in bone fracture. In this study, cortical bone beams were subjected to the primary or tertiary phases of bending fatigue followed by either post-hoc fracture toughness tests or microdamage analysis to determine the sequence in which linear microcracks and diffuse damage form during bending fatigue and how they affect the propensity of bone to fracture. The results demonstrate that, following the primary phase, linear microcracks and diffuse damage are formed on the compressive and tensile sides, respectively (p<0.05). Furthermore, this mode of damage formation results in a greater toughness loss if a fracture crack initiates from the tensile side rather than the compressive side (p<0.05). Continued loading of bone specimens to the tertiary phase, however, leads to further accumulation of damage only on the compressive side (p<0.05), and this mode of damage formation results in a further toughness loss if a fracture crack initiates from the compressive side rather than the tensile side (p<0.05). Thus, cortical bone compartmentalizes the damage morphologies in different regions and the sequence of damage production in different phases of cyclic loading to dissipate energy and resist a catastrophic fracture.

The effects of propofol in the area postrema of rats.

UNLABELLED: Propofol has an antiemetic effect that may be mediated by gamma-aminobutyric acid (GABA) influences on the serotonin system, the mechanism of which is not known. We used three techniques, immunohistochemistry, High Performance Liquid Chromatography, and electrophysiology, to define propofol's effects on the rat's brainstem. Paired male Wistar rats received propofol, 20 mg/kg/hr, or Intralipid for 6 h. The brains were then subjected to immunohistochemical analysis of serotonin. In a separate experiment after a propofol or Intralipid infusion, cerebrospinal fluid (CSF) was extracted from the fourth ventricle and analyzed for the amount of serotonin and 5-hydroxyindoleacetic acid. Electrophysiological neuronal recordings were made in the area postrema (AP) in response to propofol with and without a GABA or serotonin antagonist. Results showed that immunohistochemical staining for serotonin in the propofol rats was significantly increased (28 +/- 12%) in the dorsal raphe and decreased in the AP (17 +/- 6%) compared with control. There were no significant changes in the isoflurane-anesthetized animals. Both serotonin and 5-hydroxyindoleacetic acid in the CSF of the fourth ventricle at the level of the AP were significantly reduced by 63% and 36%, respectively. Both propofol and pentobarbital injections reduce AP neuronal activity, but only the propofol response was blocked by bicuculline, a GABA antagonist. We conclude that the reduced levels of serotonin in the AP and the CSF may explain the antiemetic property of propofol. Propofol may also directly act on AP neurons via a GABA(A) receptor to reduce their activity. IMPLICATIONS: Propofol may produce its antiemetic effect by depleting the area postrema of serotonin as well as by a direct gamma-aminobutyric acid-mediated inhibition.

Efficacy of an antipathology vaccine in murine schistosomiasis administered with and without chemotherapy.

This study was undertaken to study the efficacy of praziquantel (PZQ) in potentially tolerized Schistosoma mansoni infected, egg-injected C57BL/6 mice, receiving multiple administrations of soluble egg antigen (SEA) intravenously (i.v.). Four animal groups were studied. Experimental group I received four injections of SEA (10 micrograms) intravenously on days -7, -5, -3 and -2 before infection and PZQ orally (500 mg/kg over two consecutive days 7 weeks post-infection. Three control groups received the following treatment: group II received the same tolerizing dose of SEA without PZQ, group III received PZQ in the same dose and at the same timing. Group IV received S. mansoni infection and egg injection 8 weeks post-infection and served as an infected, egg-injected control. Egg injection was conducted 8 weeks post-infection using viable S. mansoni eggs via the tail vein. Animals were killed 16 days post-egg injection, i.e. 10 weeks post-infection. After sacrifice, lungs and livers were removed for histopathological study and measurement of granuloma diameters. Spleens and serum were collected for the assay of lymphoproliferative response to SEA and antischistosomal immunoglobulins. The worm and egg burdens were also studied. Compared to infected, egg-injected untreated controls, repeated i.v. administrations of SEA down-regulated egg-injected (pulmonary) and egg-deposited (hepatic) granulomas and the lymphoproliferative response to SEA. Antischistosomal IgG level was increased. Susceptibility to S. mansoni infection was not found to be different from that in the infected, egg-injected controls. PZQ in the dose used caused complete eradication of worms, disappearance of immature egg stages, decrease in the number of mature eggs and an increase in the number of dead eggs. Hepatic granuloma diameter, lymphoproliferative response to SEA and IgG level were reduced. In mice receiving a combined regimen of multiple SEA administrations and PZQ with down-regulated granuloma and reduced lymphoproliferative response to SEA, the efficacy of PZQ was the same as in mice receiving PZQ alone. This was shown by comparable grades of worm and egg reduction. The histopathological examination of liver and lung sections in the different treated groups revealed moderate to small-sized hypocellular granulomas. Although no statistically significant difference was recorded between the mean granuloma diameters of the experimental group receiving both the tolerizing dose of SEA and PZQ compared to the group receiving the tolerizing dose of SEA without chemotherapy, this experimental group showed the least associated histopathological parenchymal changes. It appears from this work that combined SEA and PZQ provided many complementary goals; a reduction of egg-induced pathology, minimal parenchymal changes and the eradication of worms.

Time-course of neuropeptide changes in peri-ischemic zone and amygdala following focal ischemia in rats.

Previously, using a middle cerebral artery occlusion model in Wistar rat, we showed autonomic disturbances similar to those seen clinically and observed striking neurochemical changes in cortical and subcortical sites at 5 days following stroke. The neurochemical changes may account for functional recovery and/or autonomic disturbances after focal ischemia. To understand the possible mechanisms and to facilitate future studies, it is necessary to define the time-courses of these changes. Using immunohistochemical staining with the peroxidase-antiperoxidase reaction, the changes in several neuropeptides over the peri-ischemic region and the ipsilateral central and basolateral nucleus of the amygdala were investigated at different times after middle cerebral artery occlusion. In the experimental group, neuropeptide Y immunoreactivity appeared to increase by 6 hours in the peri-ischemic region. Using image analysis to quantify the staining intensity, the change became statistically significant at 1 day, peaked around 3 days, and subsided at 10 days. There was a delayed increase in neuropeptide Y in the ipsilateral basolateral nucleus of the amygdala with a peak around 3 days. Immunoreactive staining for leucine-enkephalin, dynorphin, and neurotensin demonstrated an increase that was localized to the ipsilateral central nucleus of the amygdala with a peak around 3 days and a return to baseline levels by 10 days. The results support a specific time-course for each of the neuropeptides studied and indicate that a survival time of 3 days after focal ischemia is the critical period for examining the relationship between neuropeptide responses and neuronal or functional recovery.

Neoadjuvant and salvage chemotherapy with cisplatin (CDDP) and 5-fluorouracil (5-FU) in cervical carcinoma.

A regime of cis-platin (CDDP) (80 mg/m2) and 5-fluorouracil (5-FU) (1000 mg/m2/day, day 1 to 5) repeated after 21 days, was prospectively analyzed in 12 advanced epidermoid cervical cancers as first treatment, prior to radiotherapy (neoadjuvant chemotherapy), and in 30 cases of progressive, recurrent or metastatic disease after radiotherapy (salvage chemotherapy), in order to evaluate efficacy and toxicity. Among the 10 evaluable neoadjuvant cases we observed 2 complete, 7 partial responders and 1 stabilized. They all achieved a complete response after radiotherapy and 6 remain alive after 18 to 72 months. None of the salvaged patients achieved a complete response and only 26.9% responded partially. Only one case, though fatal, of myelodepression was found in the neoadjuvant group. Conversely, 70% of salvages showed some grade of myelodepression, being severe or extremely severe in 23.3%, with another case of death. Neoadjuvant chemotherapy with CDDP and 5-FU seems promising in advanced cervical carcinoma and is acceptably well tolerated. In contrast, salvage therapy with the same regime yields worse results and is much more toxic.