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.     

An overview of new pharmacological treatments for cerebrovascular dysfunction after experimental subarachnoid hemorrhage

Cerebral vasospasm and the resulting cerebral ischemia occurring after subarachnoid hemorrhage (SAH) are still responsible for the considerable morbidity and mortality in patients affected by cerebral aneurysms. Mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia after SAH have been intensively investigated in recent years. It has been suggested that the pathogenesis of vasospasm is related to a number of pathological processes, including endothelial damage, smooth muscle cell contraction resulting from spasmogenic substances generated during lyses of subarachnoid blood clots, changes in vascular responsiveness and inflammatory or immunological reactions of the vascular wall.A great deal of experimental and clinical research has been conducted in an effort to find ways to prevent these complications. However, to date, the main therapeutic interventions remain elusive and are limited to the manipulation of systemic blood pressure, alteration of blood volume or viscosity, and control of arterial dioxide tension.Even though no single pharmacological agent or treatment protocol has been identified which could prevent or reverse these deadly complications, a number of promising drugs have been investigated. Among these is the hormone erythropoietin (EPO), the main regulator of erythropoiesis. It has recently been found that EPO produces a neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is systemically administered.This topic review collects the relevant literature on the main investigative therapies for cerebrovascular dysfunction after aneurysmal SAH. In addition, it points out rHuEPO, which may hold promise in future clinical trials to prevent the occurrence of vasospasm and cerebral ischemia after SAH.     

Use of colistin and sorbitol for better isolation of Serratia marcescens in clinical samples

A comparison was made of different culture media and procedures for detection of Serratia marcescens from faecal, pharyngeal and ocular swabs collected from 213 neonates. MacConkey agar and MacConkey agar with sorbitol (1%) and/or colistin (200 i.u./ml) were used both for primary isolation and after enrichment using Mossel Enterobacteriaceae broth with colistin (200 i.u./ml). The use of MacConkey agar supplemented with colistin for primary isolation improved considerably the isolation rate of S. marcescens from faecal swabs but not from pharyngeal swabs; the number of ocular isolations were insufficient to demonstrate differences between procedures. Moreover the enrichment procedures consistently increased the number of S. marcescens isolates especially from pharyngeal and ocular swabs. Use of sorbitol made detection of S. marcescens from clinical specimens easier and time- and cost-efficient.     

Butylated hydroxyanisole (BHA) does not cause forestomach hyperplasia by inhibiting the release of gastric mucus

High doses of BHA cause hyperplasia and subsequent neoplasia in the rodent forestomach and can inhibit gastric prostaglandin (PG) synthesis in vitro. This paper examines the hypothesis that BHA induced forestomach hyperplasia occurs in response to a reduction of gastric mucus, with consequent irritation of the forestomach. This could result from inhibition of the formation of the PG's which mediate the synthesis and release of protective mucus. Groups of 10 rats received 0 or 2% BHA in the diet for 1 or 3 weeks and a positive control group was fed a diet containing indomethacin (3.5 mg/kg), a potent inhibitor of PG synthesis. After 1 week BHA caused focal erosion and ulceration of the forestomach consistent with an irritant effect, but 2 weeks later the epithelium was healed, thickened and markedly hyperplastic. Histochemical staining for mucus showed that the development of forestomach hyperplasia was associated with increased amounts of gastric and duodenal mucus and increased numbers of serotonergic-cells in the gastric and duodenal epithelium. In contrast, indomethacin caused a marked reduction in both gastric and Brunner's gland mucus. Neither BHA nor indomethacin exerted an effect on one specific type of mucus (viz: neutral, acidic or mixed) in the stomach. These results do not support the hypothesis that forestomach hyperplasia arises from an inhibition of either the synthesis or release of gastric mucus. It is possible that the increased numbers of serotonergic-cells are related to the initial ulcerative, or subsequent hyperplastic response.     

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.     

Revisiting the prognostic role of gallium scintigraphy in low-grade Non-Hodgkin’s lymphoma

The purpose of this study was threefold: to evaluate the role of gallium-67 scintigraphy in the staging of low-grade non-Hodgkin’s lymphomas (LGNHL), to assess the relationship between the expression of CD71 on the surface of the neoplastic cells and the ⁶⁷Ga uptake by the tumour, and to establish the contribution of ⁶⁷Ga scan in defining the prognosis of LGNHL. Forty-eight patients with untreated LGNHL diagnosed in a single institution over a decade were reviewed. The end point of the study was survival of the patients according to the scintigraphic ⁶⁷Ga score at diagnosis. In addition to ⁶⁷Ga scan, other prognostic variables were studied, relating to the neoplastic burden, the biology of the tumour and the host. Univariate and multivariate analyses were used. ⁶⁷Ga scan identified only 116/286 (41%) nodes involved by lymphoma that were detected by clinical examination or computed tomography scan. A scintigraphic scoring system with an arbitrary cut-off value of 3 (high scan score) was able to predict patients with a dismal prognosis: with a mean follow-up of 47 months (range: 1–146 months) the median survival time was 28 months in patients with a high scan score and 74 months in patients with a low scan score (P=0.002). CD71 values were 27.4%±14.9% (mean ±SD) in the former and 8.9%±7.2% in the latter (P=0.0001). Only performance status and extranodal sites were significant variables for prognosis in multivariate analysis. It is concluded that ⁶⁷Ga scan is inaccurate in staging but might be very important in defining the prognosis in LGNHL, in association with other prognostic variables. Received 1 May and in revised form 6 August 1997