Antiproliferative potential of sarcophine and its semisynthetic sulfur-containing derivatives against human mammary carcinoma cell lines

The marine-derived cembranoid sarcophine (1) and its sulfur-containing semisynthetic derivatives (2–6) were evaluated for anticancer potential using cell cycle progression markers. No effect on MCF-7 cell viability or apoptosis was seen with these derivatives at concentrations of up to 100 μM after 72 h of incubation. At 100 μM, sarcophine and its derivatives 2–5 arrested the MCF-7 cells in G0/G1 phase, with concomitant decrease in the cell populations at S and G2+M phases. MDA-MB-231 cells were not responsive to any of the derivatives. Our preliminary results suggest that the sulfur-containing derivatives of sarcophine, especially 2 and 3, show potent and cell-specific antiproliferative activity.     

Vinblastine and erythromycin: an unrecognized serious drug interaction

Vinblastine and erythromycin are among the most commonly used chemotherapeutic and antimicrobial agents, respectively. No interaction between the two has ever been reported. Towards the end of a phase I study of vinblastine plus oral cyclosporin (to reverse multidrug resistance), three patients also received erythromycin to raise their cyclosporin levels. All developed severe toxicity consistent with a much higher vinblastine dose than was actually given. This apparent potentiation of vinblastine toxicity has not been previously described.     

Anterior versus posterior approach in reconstruction of infected nonunion of the tibia using the vascularized fibular graft: potentialities and limitations

The potentialities, limitations, and technical pitfalls of the vascularized fibular grafting in infected nonunions of the tibia are outlined on the basis of 14 patients approached anteriorly or posteriorly. An infected nonunion of the tibia together with a large exposed area over the shin of the tibia is better approached anteriorly. The anastomosis is placed in an end-to-end or end-to-side fashion onto the anterior tibial vessels. To locate the site of the nonunion, the tibialis anterior muscle should be retracted laterally and the proximal and distal ends of the site of the nonunion debrided up to healthy bleeding bone. All the scarred skin over the anterior tibia should be excised, because it becomes devitalized as a result of the exposure. To cover the exposed area, the fibula has to be harvested with a large skin paddle, incorporating the first septocutaneous branch originating from the peroneal vessels before they gain the upper end of the flexor hallucis longus muscle. A disadvantage of harvesting the free fibula together with a skin paddle is that its pedicle is short. The skin paddle lies at the antimesenteric border of the graft, the site of incising and stripping the periosteum. In addition, it has to be sutured to the skin at the recipient site, so the soft tissues (together with the peroneal vessels), cannot be stripped off the graft to prolong its pedicle. Vein grafts should be resorted to, if the pedicle does not reach a healthy segment of the anterior tibial vessels. Defects with limited exposed areas of skin, especially in questionable patency of the vessels of the leg, require primarily a fibula with a long pedicle that could easily reach the popliteal vessels and are thus better approached posteriorly. In this approach, the site of the nonunion is exposed medial to the flexor digitorum muscle and the proximal and distal ends of the site of the nonunion debrided up to healthy bleeding bone. No attempt should be made to strip the scarred skin off the anterior aspect of the bone lest it should become devitalized. Any exposed bone on the anterior aspect should be left to granulate alone. This occurs readily when stability has been regained at the fracture site after transfer of the free fibula. The popliteal and posterior tibial vessels are exposed, and the microvascular anastomosis placed in an end-to-side fashion onto either of them, depending on the length of the pedicle and the condition of the vessels themselves. To obtain the maximal length of the pedicle of the graft, the proximal osteotomy is placed at the neck of the fibula after decompressing the peroneal nerve. The distal osteotomy is placed as distally as possible. After detaching the fibula from the donor site, the proximal part of the graft is stripped subperiosteally, osteotomized, and discarded. Thus, a relatively long pedicle could be obtained. To facilitate subperiosteal stripping, the free fibula is harvested without a skin paddle. In this way, the use of a vein graft could be avoided. Patients presenting with infected nonunions of the tibia with extensive scarring of the lower extremity, excessively large areas of skin loss, and with questionable patency of the anterior and posterior tibial vessels are not suitable candidates for the free vascularized fibular graft. Although a vein graft could be used between the recipient popliteal and the donor peroneal vessels, its use decreases flow to the graft considerably. These patients are better candidates for the Ilizarov bone transport method with or without free latissimus dorsi transfer.     

Attempted eyelid closure affects intraocular pressure measurement in open-angle glaucoma patients

PURPOSE: To evaluate the effect of attempted eyelid closure on intraocular pressure (IOP) measurements in normal-tension (NTG) and high-tension (HTG) open-angle glaucoma patients. DESIGN: Prospective clinical trial. METHODS: Forty randomly selected eyes of 40 patients underwent corneal pachymetry and IOP measurements using both Goldmann applanation tonometry and Tono-pen XL (Mentor, Inc., Norwell, Massachusetts, USA). Intraocular pressure was measured by the same examiner holding the eyelids open, both with and without the subject simultaneously attempting forced eyelid closure. Subjects were seated during all measurements and waited 5 minutes between measurements with each instrument; the order of measurement was randomized. RESULTS: Twenty NTG and 20 HTG eyes were enrolled. The mean age was 63.0 +/- 13.0 years (range, 31-80 years). The average corneal thickness was 540 +/- 32 microm (range, 480-608 microm) in NTG patients and 552 +/- 40 microm (range, 449-610 microm) in HTG patients (P =.07, analysis of variance [ANOVA]). Using Goldmann applanation tonometry, IOP measurement in eyes with NTG increased by 3.9 +/- 2.0 mm Hg with attempted eyelid closure (P <.0001, paired t test; range, 2-11 mm Hg). With the Tono-pen XL, IOP measurements increased 4.2 +/- 2.7 mm Hg (P <.0001, paired t test; range, 1-14 mm Hg). With attempted forced eyelid closure, the Goldmann applanation measurement in eyes with HTG increased 4.1 +/- 2.1 mm Hg (P <.0001, paired t test; range, 1-9 mm Hg). Using the Tono-pen XL, measurements increased 4.5 +/- 2.0 mm Hg (P <.0001, paired t test; range, 2-11 mm Hg). CONCLUSION: Attempted eyelid closure during tonometry is a significant and common source of error in eyes with glaucoma and may influence the clinical management and decision-making in the treatment of NTG and HTG.     

Clinical validation of methods of diagnosis of neuropathy in a field study of United Kingdom sheep dippers

Objectives: To investigate the reproducibility of measured indices of chronic peripheral neuropathy from a field study of sheep dippers when compared with similar measurements carried out in a clinical setting. Methods: A stratified random sample of field study subjects was invited to attend a clinic. Neuropathy was measured both in the field and at the clinic with a modified version of a standard symptoms questionnaire and quantitative sensory thresholds for hot, cold, and vibration. These were combined into a classification of the likelihood of neuropathy with a neuropathy scoring system. Indicators of sensory abnormality were based on comparison of sensory thresholds to age dependent reference values derived from an external reference group. Results: Only 51% of subjects were assigned similar classifications in the field and clinic based on the neuropathy scoring system. Of the component indices, grouped symptom scores, with 65% of subjects showing exact agreement, proved to be more reproducible than quantitative sensory test indicators. There were biases in the comparison of field and clinic measurements of hot and vibration sensations, but no evidence of greater variation between individual people in sensory thresholds in the field relative to at the clinic. Conclusions: The neuropathy scoring system proved to be of limited reproducibility, due in a large part to the lack of reproducibility of the indicators of sensory test abnormality caused by inadequate temperature control. However, the symptoms score and measured sensory thresholds could be used separately as indices of neuropathy in exposure-response analyses.     

Role of endothelial adenosine receptor-mediated vasorelaxation in ethanol-induced hypotension in hypertensive rats

Our previous findings showed that chronic ethanol feeding lowers blood pressure in spontaneously hypertensive rats. The present study investigated the role of the adenosine receptor-endothelial nitric oxide (NO) pathway in the hypotensive response to ethanol. Changes in blood pressure were evaluated in radiotelemetered pair-fed rats receiving liquid diet with or without ethanol (2.5% or 5%, w/v) for 12 weeks. The vasorelaxant activity of the adenosine analogue 5'-N-ethylcarboxamidoadenosine (NECA) in isolated aortic rings obtained from ethanol and control rats were evaluated. Ethanol (2.5% and 5%) lowered blood pressure in a dose-dependent manner. The hypotension started at week 1, reached its maximum at week 4 and remained so thereafter. In aortas with intact endothelium, NECA (10(-10) to 10(-4) M) produced a concentration-dependent relaxation of the phenylephrine-precontracted aortas. Compared with control rats, ethanol (2.5% and 5%) caused significant and concentration-related increases in NECA responses. This effect of ethanol was attenuated by the adenosine receptor antagonist 8-sulfophenyltheophylline and the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). Further, endothelium denudation abolished the ethanol-evoked enhancement of NECA responses. The vasorelaxant responses to acetylcholine or sodium nitroprusside in aortic rings were not influenced by ethanol. In conclusion, the present findings suggest that chronic ethanol enhances the NO-dependent vasorelaxant responses to adenosine receptor activation and this may explain, at least partly, the mechanism of the hypotensive effect of ethanol in spontaneously hypertensive rats.     

In vitro activity of 15 antimicrobial agents against clinical isolates of Clostridium difficile in Kuwait

A total of 73 clinical isolates of Clostridium difficile isolated from stool/rectal swabs of patients admitted to the intensive care units at Mubarak Hospital, Ibn Sina Hospital Burn unit and Haematology wards at the Kuwait Cancer Control Centre, were investigated for their susceptibility to 15 antibiotics using the Etest. Amoxycillin-clavulanic acid, ampicillin, meropenem, metronidazole, penicillin, piperacillin, piperacillin/tazobactam, teicoplanin and vancomycin had excellent activities with MIC(90)s of 0.38, 0.5, 1, 0.19, 1.5, 2, 3, 0.25 and 0.75 mg/l, respectively. Of the 73 C. difficile isolates, 86% were resistant to imipenem (MIC(90) >32 mg/l) and almost 97% were resistant to trovafloxacin (MIC(90)>256 mg/l). Forty eight percent of the isolates were resistant to clindamycin. A total of 18 isolates were highly clindamycin-resistant with an MIC of >256 mg/l; 10 of these were toxin producers. Multiple antibiotic resistance (two or more antibiotics) was noted in 63 isolates. These were more common among the toxigenic strains than the non-toxigenic strains by a ratio of 2.5:1.     

Biological activities of the crude skin toxin of the Suez Gulf oriental catfish (Plotosus lineatus) and its antitumor effect in vivo (mice)

Quantitative determination of newly reported enzymes activity in the crude skin toxin (CST) of catfish revealed highest activities of hyaluronidase and lipase, lesser activities of phospholipase A2, lactate dehydrogenase (LDH), cholinesterase (CE), alkaline phosphatase (ALP), and aspartate transaminase (AST), and least activities of proteinase and 5-nucleotidase (5'-NT). The CST has a hemolytic activity of 54% and no ichthyotoxicity up to 500 ug/ml. The chosen dose of CST (LD12.5) showed a potential cytotoxic activity against solid Ehrlich carcinoma-bearing mice demonstrated by an increase in the mean survival time (238.8%) and tumor growth inhibition ratio (T/C) of 73%. The CST ameliorated the relative weights of heart and liver after three weeks, while modulating the elevation in the relative spleen weight throughout the treatment periods (three, six, and nine weeks). The levels of serum triglyceride, total cholesterol, and liver total lipids were normalized after three weeks, whereas the serum albumin and hepatic glycogen concentrations, as well as ALT, AST, 5'-NT, and G-6-Pase activities were ameliorated after 6 weeks. Serum levels of glucose, LDH, and creatine kinase (CK) activities were significantly modulated throughout the treatment periods. Histological examinations of the tumor and liver tissues of treated tumor-bearing animals were carried out. Tumor tissues showed many cytolytic and cytopathic changes after treatment, while liver tissues showed moderate dysplastic changes after six weeks of treatment, which became more marked after nine weeks.