Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model.

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg(-1)·day(-1) by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

Mitochondrial DNA haplogroups and susceptibility to prostate cancer in a colombian population.

Prostate cancer (PC) is one of the most common cancers and the second leading cause of mortality from cancer in Colombian men. Mitochondrial DNA (mtDNA) haplogroups have been associated with the risk of PC. Several studies have demonstrated dramatic differences regarding the risk of PC among men from different ethnic backgrounds. The present study was aimed at assessing the relationship between mtDNA haplogroups and PC. The mitochondrial DNA hypervariable segment I (HSV-1) was sequenced in a population-based study covering 168 cases (CA) and 140 unrelated healthy individuals as a control group (CG). A total of 92 different mtDNA sequences were found in CA and 59 were found in the CG. According to the geographical origin attributed to each mtDNA haplogroup, 82% of the mtDNA sequences found in both groups were Native Americans (A, B, C, and D). The most frequent was A (41.1%CA-42.1%CG), followed by B (22.0%CA-21.4%CG), C (12.0%CA-11.4%CG), and D (6%CA-10.0%CG). A lower percentage of European haplogroups (U, H, K, J, M, T, and HV) were also found (13.1%CA-12.9%CG), likewise African haplogroups (L0, L1, L2, and L3) (6.5%CA-2.1%CG). There were no statistically significant differences between the distribution of mtDNA haplogroups in CA and the CG in this study.

Tratamiento con antipsicóticos atípicos del síndrome de Gilles de la Tourette / Treatment with atypical antipsychotics of Gilles de la Tourette syndrome

El tratamiento óptimo del síndrome de Gilles de la Tourette (SGT) incluye intervenciones educativas, de apoyo, psicológicas y tratamiento farmacológico. El tratamiento farmacológico, en especial con fármacos antipsicóticos, es la modalidad de tratamiento más efectiva para suprimir tics graves, El tratamiento actual con antipsicóticos atípicos (risperidona, olanzapina) de niños y adolescentes con SGT parece ser tan efectivo como con los antipsicóticos clásicos, aunque con menos efectos secundarios. Trastornos comórbidos como trastorno por déficit de atención con hiperactividad, trastorno obsesivo-compulsivo (TOC) y trastornos del aprendizaje, pueden ser fuente de mayor malestar y deterioro que los propios tics. El tratamiento farmacológico del TOC incluye inhibidores selectivos de la recaptación de serotonina (ISRS) como sertralina. Objetivo: La finalidad de este estudio fue evaluar la eficacia y seguridad de los antipsicóticos atípicos en el tratamiento del SGT en niños y adolescentes, Método: Este estudio de casos incluía cuatro sujetos (todos varones) con una edad media de 11.00+-0.50 años. Todos los sujetos cumplían criterios de la Clasificación Internacional de las Enfermedades (CIE-lO) para SGT. Tres niños presentaban también un TOC comórbido. Resultados: La respuesta clínica cuantificada según la escala Impresión Clínica Global (ICG) indicaba mejoría y disminución en la gravedad de los tics motores y fónicos. El efecto secundario más frecuente fue el aumento de peso. Conclusiones: Estos hallazgos sugieren que los antipsicóticos atípicos parecen ser efectivos y seguros para reducir la frecuencia e intensidad de los tics motores y fónicos en niños y adolescentes con SGT

The optimal treatment of Gilles de la Tourette syndrome (GTS) involves educational and supportive interventions, psychological approaches and pharmacological treatment. Pharmacotherapy, especially with antipsychotic drugs, has been the most effective treatment modality in suppressing severe tics. Current treatment with atypical antipsychotics (risperidone, olanzapine) of children and adolescents with GTS appears to be as effective as traditional antipsychotics, while having fewer side effects. Comorbid conditions as attention-deficit/hyperactivity disorder, obsessive-compulsive disorder (OCD), and learning disorders, can be a source of more distress and impairment than the tics themselves. Drug treatment of OCD includes selective serotonin reuptake inhibitors (SSRIs) as sertraline. Objective: The purpose of this study was to assess the efficacy and safety of atypical antipsychotics in the treatment of GTS in children and adolescents. Method: This case study inc1uded four subjects (all boys) with a mean age of 11.00 +- 0.50 years. All subjects met Intemational Classification of Diseases (ICD-l0) criteria for GTS. Three children also had a comorbid OCD. Results: Clinical response, as measured by the Clinical Global Impression (CGI) scale showed improvement and reduction in the severity of motor and phonic tics. The most common side effect was weight gain. Conc1usions: These findings suggest that atypical antipsychotics appear to be effective and safe in diminishing motor and phonic tics frequency and intensity in children and adolescents with GTS

Requirements for authorisation of internal dosimetry services.

In order to ensure that a facility is in compliance with the occupational exposure requirements established by regulatory authorities, the measurements and dose assessments specified in the individual monitoring programme need to be reliable. There are two important questions that shall be addressed here: one is how the licensed facilities can demonstrate to their workers and regulatory bodies compliance with the regulatory limits and the reliability of the results of the individual monitoring programmes; the other concerns the mechanisms used to demonstrate to a facility in another country the reliability of the measurement results of an individual monitoring bioassay programme. The accreditation of the bioassay laboratory, according to ISO/IEC 17025, shall be the basic requirement for obtaining the authorisation granted by the national regulatory authority. For the second question, such confidence can be achieved through International Laboratory Accreditation Cooperation (ILAC).

GST-pi expression in BCR-ABL+ and BCR-ABL- cells from CML patients.

Our laboratory has been involved in the study of glutathione-sulfhydryl-transferase-pi (GST-pi) for several years. We have recently observed that during haematopoiesis in BMSC liquid cultures from CML patients who were candidates for transplant GST-pi was expressed in presumably malignant cells during different stages of cellular maturation. To confirm this finding, in the present work we are detecting GST-pi expression by immunofluorescence in BCR-ABL+ and BCR-ABL- cells done by FISH of PB from 30 CML patients during different clinical status: treatment (T), hematological relapse (R), blastic crisis (BC) or post-allotrasplant (PT). As well as in PB from 30 Blood-Bank donors. The results were %BCR-ABL+ GST-pi+ cells: T = 1-67, R = 33-69, BC = 90-100 and PT = 1-2; %BCR-ABL- GST-pi+ cells: T = 2-31, R = 5-18, BC = 0-10 and PT = 2-5; %BCR-ABL- GST-pi- cells: T = 2-97, R = 13-62, BC = 0 and PT = 93-96; %BCR-ABL+ GST-pi- cells: T = 0, R = 0, BC = 0 and PT = 0. GST-pi was not expressed in donor cells. The results obtained confirm our previous observations and suggest that GST-pi expression might be used for the evaluation of the minimal residual disease in CML patients.

DNA damage and repair in cells of lead exposed people.

BACKGROUND: One of the main sources of occupational exposure to lead in Colombia is in workers of battery industries and lead smelters. Genotoxic studies in human populations exposed to this metal have had conflicting results; this type of study has not been reported in Colombia. METHODS: Genotoxic effects of lead were studied in blood cell samples from workers of electric battery factories exposed to lead compounds. Single strand breaks and interference with DNA repair processes after an in vitro exposure of x-rays (300 cGy) were analyzed using the Comet Assay. The battery workers (n = 43) and 13 people not occupationally exposed to lead compounds who were selected as a control group, were classified into four categories according to their blood lead level. RESULTS: A significant difference was observed in DNA damage before the x-rays exposure (basal) between the lowest and highest categories of lead (mean DNA migration 55.6 micro and 85.9 micro, respectively). Additionally, a significant difference in DNA migration was also found immediately after irradiation between the lowest and highest lead categories (mean DNA migration: 199.8 micro and 317.8 micro respectively). The DNA migrations at different times after irradiation did not show a significant difference among the different lead levels. CONCLUSIONS: We concluded that although the single strand breaks following irradiation were not affected by blood lead concentration, the metal seems to sensitize the cells to damage induced by other genotoxicants.

The adult with cerebral palsy.

Important aspects of eliciting a proper history, obtaining a review of systems, and performing a physical examination in adults with cerebral palsy are presented. Information regarding diagnosis, etiology, and epidemiology of cerebral palsy as well as suggestions for performing examinations and procedures on uncooperative and extremely dysmorphic patients are included. A MEDLINE search of all English-language publications related to cerebral palsy from 1985 to 1999 was conducted. Other older references also were obtained from articles published during this period. Our personal experiences in caring for a group of approximately 300 adults with cerebral palsy and other developmental disabilities in specialized centers for nearly a decade are used frequently throughout this review. Emphasis is given to studies of adults. Studies of children are included because there is a lack of data on adults. These studies are identified as such in the text, with extrapolation to adults only where there is a sound clinical or scientific basis. The number of adults with cerebral palsy is increasing. This growth is due to increased survival of low-birth-weight infants and increased longevity of the adult population. Depending on clinical status and the age at which survival is calculated, 65% to 90% of children survive until adulthood. Despite these observations, there is a lack of information in the literature and a lack of relevant post-graduate training programs for physicians in the adult health care system.

[And the sex workers, what about?]. / Y las trabajadoras del sexo, qué?

AIDS: Puerto Rico has more than 16,000 reported cases of AIDS, of which 20 percent are women. Women who provide sexual favors are at a great risk of becoming HIV-infected. The government fails to understand and provide for women who work the streets. These women may be rejected by family, mistreated by customers, and subjected to unwanted pregnancies. A newly established drop-in program provides syringe exchange, medical treatment, support groups, and outreach programs. Resources for women are listed.^ieng

Bilateral lower limb amputee rehabilitation. A retrospective review.

We retrospectively reviewed 61 cases of bilateral lower limb amputations in patients admitted to a regional amputee rehabilitation program. Of the 61 cases, 41 were analyzed as to functional outcome on discharge, at 1 month, and at 3 months; 20 were not included owing to transfers to acute care or loss to follow-up. There were 41 men and 20 women, the average age was 61.5 years, and 47 patients (77%) were discharged to home. There were 25 bilateral below-knee, 14 above-knee and below-knee, 12 bilateral above-knee, 5 below-knee and partial-foot, 3 above-knee and partial-foot, and 2 bilateral partial-foot amputations. The average length of stay for all levels was 24.2 days. Most of the patients at the time of discharge achieved a level of limited household walking with the exception of those with bilateral above-knee amputations. A significant improvement in function was noted for all patients at 3-month follow-up, with most patients achieving household ambulation level, but 10 remained independent at wheelchair level for mobility.

Thrombin decreases von Willebrand factor binding to platelet glycoprotein Ib.

Thrombin is a physiological agonist that promotes platelet aggregation and secretion. In this study we observed that thrombin can also inhibit a function of platelets related to primary hemostasis. Platelet stimulation by thrombin decreased the binding of von Willebrand factor (vWF) to glycoprotein (GP) Ib and decreased ristocetin-induced agglutination, in vitro reactions that correlate with initial platelet adhesion to the vessel wall. Binding of the monoclonal antibody API to GP Ib was also decreased. Cytoskeletal participation in the change of GP Ib was suggested because pretreatment of platelets with cytochalasin to prevent actin filament formation prevented the thrombin-induced decreases in vWF binding. API binding, and ristocetin-induced agglutination. Measurement of GP Ib in detergent extracts by electroimmunoassay demonstrated no loss after thrombin stimulation. Electroimmunoassay also demonstrated that the API epitope of GP Ib on intact thrombin-treated platelets was accessible for complete digestion by chymotrypsin. Therefore GP Ib was neither released from the platelet surface nor internalized by thrombin treatment. A previously recognized effect of thrombin is its induction of receptor sites on platelet surface GP IIb-IIIa for contact-promoting proteins, including vWF that are involved in the platelet spreading and aggregation that follow adhesion. Therefore the action on GP Ib may combine with the effect on GP IIb-IIIa to shift platelet reactivity from GP Ib-vWF-mediated initial contact with the vessel wall to GP IIb-IIIa-mediated spreading and aggregation.