Triterpenoid saponins, new metalloprotease snake venom inhibitors isolated from Pentaclethra macroloba.

We report here the antiproteolytic and antihemorrhagic properties of triterpenoid saponin inhibitors, named macrolobin-A and B, from Pentaclethra macroloba, against Bothrops snake venoms. The inhibitors were able to neutralize the hemorrhagic, fibrin(ogen)olytic, and proteolytic activities of class P-I and P-III metalloproteases isolated from B. neuwiedi and B. jararacussu venoms. Clotting and fibrinogenolytic activities induced by snake venoms and isolated thrombin-like enzymes were partially inhibited. Furthermore, the potential use of these inhibitors to complement antivenom therapy as an alternative treatment and/or used as molecular models for development of new therapeutical agents in the treatment of snake bite envenomations needs to be evaluated in future studies.     

Preoperative Chemotherapy Alone and Combined with Preoperative Radiotherapy in Small-Size Breast Cancer

Abstract: Breast conservation surgery is an effective and safe treatment for many breast carcinomas. It may be possible to further limit the extent of resection (or expand the indication for breast conservation) by the application of preoperative chemotherapy and radiotherapy. We explored the feasibility of this in a pilot study.
Seventy-three patients (mean age 48, 63% premenopausal) with confirmed breast cancer, less than 2.5 cm, received chemotherapy (Group A) or chemotherapy plus radiotherapy (Group B) prior to limited resection (tumorectomy). Axillary dissection was always performed. Results: In 6/31 (19%) Group A and 17/42 (40%) Group B patients the tumor was not palpable after preoperative treatment, with complete pathological remission in 1 and 3 cases respectively. Histologic grading, mitosis, cellular alteration, and cellularity evaluations indicated a consistently greater therapeutic effect with chemoradiotherapy than with chemotherapy alone.
In conclusion, radiotherapy appears useful in the preoperative treatment of breast cancer and its use in association with various drug combinations should be further explored.     

Phase II trial of piroxantrone in metastatic breast cancer

Summary Thirty-two eligible patients with advanced metastatic breast cancer who had received no more than 1 prior chemotherapy regimen for metastatic disease (16 had received prior doxorubicin) were treated with piroxantrone at a dose of 120 mg/m² intravenously every 21 days. In the twenty-seven patients evaluable for response, two partial responses were seen. Toxicities observed were primarily hematologic with grade 3 or greater granulocytopenia occurring in 34% of the patients. One patient developed symptomatic congestive heart failure at a total cumulative dose of 960 mg/m². We conclude that piroxantrone given at this dose and schedule has minimal activity in patients with metastatic breast cancer.     

Color Doppler imaging of the ocular ischemic syndrome.

PURPOSE: This study describes hemodynamic characteristics of the ophthalmic, central retinal, and posterior ciliary arteries in 16 eyes of 11 patients with the ocular ischemic syndrome. Understanding the hemodynamic characteristics of the retrobulbar circulation may elucidate the natural history and pathophysiology of the ocular ischemic syndrome and perhaps form the basis for rational treatment of this condition. METHODS: Color Doppler imaging, a procedure that permits rapid noninvasive imaging of the ophthalmic, central retinal, and posterior ciliary arteries, was used to quantitate peak systolic blood flow velocities and vascular resistance (pulsatility index) within these vessels in study group eyes and in an age-matched control population. RESULTS: We demonstrated markedly reduced ocular ischemic syndrome central retinal and posterior ciliary artery peak systolic velocities compared with control group eyes. Central retinal and posterior ciliary artery vascular resistance (pulsatility index) was greater in ocular ischemic eyes versus control group eyes. Reversal of ophthalmic artery blood flow was detected in 12 of 16 ocular ischemic syndrome eyes. Study group eyes with poor vision had no detectable posterior ciliary arterial blood flow. CONCLUSION: Color Doppler imaging quantitates hemodynamic characteristics of the retrobulbar circulation in the ocular ischemic syndrome. There is markedly reduced peak systolic velocity and increased vascular resistance in ocular end arteries such as the central retinal and posterior ciliary arteries. Ophthalmic artery reversal of flow seems to represent collateral blood flow to lower resistance vascular beds. Posterior ciliary artery hypoperfusion may correlate with poor vision in the ocular ischemic syndrome.     

Expression of a 1,25-dihydroxyvitamin D3 membrane-associated rapid-response steroid binding protein during human tooth and bone development and biomineralization.

The calciotropic hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has been established to control skeletal tissue formation and biomineralization via the regulation of gene expression. This action involves the well-characterized nuclear 1,25(OH)2D3 receptor. However, it has been recognized that several cellular responses to 1,25(OH)2D3 may not to be related to the exclusive nuclear receptor. Indeed, this secosteroid is able to generate rapid responses that have been proposed to be mediated by interactions of the ligand, which is a putative cell membrane-associated rapid-response steroid (MARRS) binding protein for 1,25(OH)2D3 [1,25D3-MARRS]. The nongenomic pathway of 1,25(OH)2D3 was studied here in detail by immunolocalization of the 1,25D3-MARRS during the specific context of human prenatal development. Western blotting with proteins extracted from 4 week- to 27-week-old embryos was performed, evidencing a 65-kDa molecular species recognized by antibody Ab 099 generated against synthetic peptides corresponding to the N terminus of the 1,25D3-MARRS from chick intestinal basolateral membranes. Based on this biochemical conservation of protein in the human species, the temporospatial expression patterns were established in the craniofacial skeleton at the same ages. Comparative analysis was performed in teeth and bones from early morphogenesis to terminal cell differentiation and extracellular biomineralization. The data show the potential implication of 1,25D3-MARRS in the heterogeneous cell population including ameloblasts, odontoblasts, osteoblasts, and osteoclasts. The epithelial-mesenchymal cascade related to odontogenesis was coincident with a sequence of up- and down-regulation of immunoreactive 1,25D3-MARRS. Biomineralization was associated with a striking up-regulation in the adjoining secretory cells in all tissues. Finally, osteoclasts appeared also to express the 1,25D3-MARRS during these early phases of bone modeling. Previously obtained data of the nuclear vitamin D receptor (VDR) expression and this study on 1,25D3-MARRS suggest the existence of cross-talk between the genomic and nongenomic pathways during human development.     

Automated assessment of cervical dystonia.

We developed an automated and objective method to measure posture and voluntary movements in patients with cervical dystonia using Fastrack, an electromagnetic system consisting of a stationary transmitter station and four sensors. The junction lines between the sensors attached to the head produced geometrical figures on which the corresponding aspects of the head were superimposed. The head position in the space was reconstructed and observed from axial, sagittal, and coronal planes. Four patients with cervical dystonia and 6 healthy subjects were studied. Each patient was representative of one of the typical patterns of cervical dystonia. The study allowed the authors to collect quantitative data on posture and range of motion of the head. This pilot study demonstrates the efficacy of the Fastrack system to objectively measure the head position in cervical dystonia patients.     

Immune cell imbalance in major depressive and panic disorders.

We investigated subsets of peripheral immunologic cells in 12 drug-free patients affected by major depression according to DSM-III-R criteria, and who had recent evidence of somatic diseases. They were compared with 10 drug-free depressives, with 10 patients with panic disorder, and with 12 healthy volunteers, all without somatic disease. The immune subsets were measured by flow cytometry. The results showed that both groups of depressives had the same abnormalities in immune cells compared with the healthy volunteers or the panic disorder patients; in particular they presented a lower number of CD3+, CD8+ and HLA-DR+. The patients with panic attacks did not differ from healthy controls, except for CD4+ cells which were significantly lowered, even in comparison with the depressive groups. These data, although preliminary and in a small sample, suggest that some immune parameters may be influenced by the presence of a major psychiatric disorder.     

Sub-acute intoxication by Senna occidentalis seeds in rats.

Senna occidentalis (So) is a weed that grows in pastures along fences and in fields cultivated with cereals such as corn and soybean, and many reports have been showing intoxication with this plant in different animal species. It is also used in many medicinal purposes. The objective of the present study was to better evaluate the toxic effects of prolonged administration of So seeds to rats. Forty male Wistar rats were divided into four groups of 10 animals each, three of them respectively fed rations containing 1%, 2% and 4% So seeds, and the last one (control) fed commercial ration for a period of 2 weeks. Fourteen rats were also used in a pair-feeding (PF) experiment. The rats of the experimental groups showed lethargy, weakness, recumbency, depression and emaciation. Two rats of the 4% group and two of the PF group died during the experiment. Histopathological study showed fiber degenerations in the skeletal (Tibial, pectoral and diaphragm) and cardiac muscles. In the liver parenchyma, was observed vacuolar degeneration and, in the kidney, mild nefrosis in the proximal convoluted tubules. All of these alterations occurred in a dose-dependent fashion. Moderate to severe degeneration and spongiosis in the central nervous system, especially in cerebellum. Electron microscopy revealed mitochondrial lesions in all analyzed tissues.     

CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population.

The human small-conductance Ca(2+)-activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family-based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case-control analysis that has demonstrated a significant over-representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co-morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive-compulsive disorder (OCD) co-morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN.