Dual role of glutathione in modulating camptothecin activity: depletion potentiates activity,but conjugation enhances the stability of the topoisomerase I-DNA cleavage complex

Depletion of glutathione (GSH) in MCF-7 and MDA-MB-231 cell lines by pretreatment with the GSH synthesis inhibitor buthionine sulfoximine potentiated the activity of 10,11-methylenedioxy-20(S)-camptothecin, SN-38 [7-ethyl-10-hydroxy-20(S)-camptothecin], topotecan, and 7-chloromethyl-10,11-methylenedioxy-20(S)-camptothecin (CMMDC). The greatest potentiation was observed with the alkylating camptothecin CMMDC. Buthionine sulfoximine pretreatment also increased the number of camptothecin-induced DNA-protein crosslinks, indicating that GSH affects the mechanism of action of camptothecin. We also report that GSH interacts with CMMDC to form a stable conjugate, 7-(glutathionylmethyl)-10,11-methylenedioxy-20(S)-camptothecin (GSMMDC), which is formed spontaneously in buffered solutions and in MCF-7 cells treated with CMMDC. GSMMDC was synthesized and found to be nearly as active as 10,11-methylenedioxy-20(S)-camptothecin in a topoisomerase (topo) I-mediated DNA nicking assay. The resulting topo I cleavage complexes were remarkably stable. In cell culture, GSMMDC displayed potent growth-inhibitory activity against U937 and P388 leukemia cell lines. GSMMDC was not active against a topo I-deficient P388 cell line, indicating that topo I is its cellular target. Peptide-truncated analogues of GSMMDC were prepared and evaluated. All three derivatives [7-(gamma-glutamylcysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin, 7-(cysteinylglycylmethyl)-10,11-methylenedioxy-20(S)-camptothecin, and 7-(cysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin] displayed topo I and cell growth-inhibitory activity. These results suggest that 7-peptidyl derivatives represent a new class of camptothecin analogues.     

Yersinia-related Arthritis in the United Kingdom. A Report of 12 Cases and review of the Literature

Reactive arthritis following infection with Yersinia is endemicin Scandanavian countries; the prevalence is low in the UK,however. We have reviewed the literature pertaining to Yersinia-relatedreactive arthritis in the UK and describe 12 patients who presentedover a 3-year period with an asymmetrical seronegative polyarthropathyand serological evidence of recent Yersinia infection. Fivepatients recalled having a diarrhoeal illness prior to the onsetof the arthropathy. None had a prior history of psoriasis, inflammatorybowel disease or ankylosing spondylitis. A history of urethraldischarge was elicited from one patient. Extra-articular manifestationswere seen in three patients (iritis in two, erythema nodosumin another). Four patients developed chronic joint disease afterperiods of 4, 6, 8, and 18 months, respectively. The prevalenceof Yersinia-related arthritis in the UK may be higher than previouslythought.     

Change in neoadjuvant chemotherapy could alter the prognosis of patients with pancreatic adenocarcinoma: A case report

BACKGROUNDNeoadjuvant treatment has become a standard of care for borderline or locally advanced pancreatic cancer and is increasingly considered even for up-front resectable disease. The aim of this article is to present the case of a 62-year-old patient with locally advanced pancreatic adenocarcinoma who was successfully treated with gemcitabine plus nab-paclitaxel after the failure of the first line treatment.CASE SUMMARYComputerized tomography scan and magnetic resonance imaging demonstrated a nodular lesion of ill-defined limits in the body of the pancreas, measuring approximately 4.2 cm × 2.7 cm, with an infiltrative aspect. The tumor had contact with the superior mesenteric vein, splenomesenteric junction and the proximal segment of the splenic artery, causing focal reduction of its lumens. Due to vascular involvement, neoadjuvant chemotherapy treatment with eight cycles of “folinic acid, 5-fluorouracil, irinotecan and oxaliplatine” (FOLFIRINOX) were performed. At the end of the cycles, surgery was performed, but the procedure was interrupted due to finding of lesions suspected of metastasis. Gemcitabine plus nab-paclitaxel was then successfully used for neoadjuvant treatment with subsequent R0 surgical resection.CONCLUSIONGemcitabine plus nab-paclitaxel may be effective as an alternative regimen when FOLFIRINOX fails as the first line of treatment, suggesting the need for further studies to identify which patients would benefit from each type of therapeutic approach.     

Prevention of Oxidative Damage and Phytoremediation of Cr(VI) by Chromium(VI) Reducing Bacillus subtilus PAW3 in Cowpea Plants

Bulletin of Environmental Contamination and Toxicology - Experiments were conducted to observe the role of plant growth promoting (PGP) strain PAW3 in reduction of Cr(VI) and cowpea growth. PAW3...     

Detection of antibodies to Trypanosoma cruzi among blood donors in the southwestern and western United States. II. Evaluation of a supplemental enzyme immunoassay and radioimmunoprecipitation assay for confirmation of seroreactivity

BACKGROUND: Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is endemic to Latin America and may be transmitted in the United States via blood donated by infected immigrants. Blood- borne pathogens such as T. cruzi require supplemental testing for confirmation of seroreactivity. STUDY DESIGN AND METHODS: A study was undertaken to determine an optimal scheme for confirmation of seroreactivity in repeatedly reactive samples identified by the Chagas antibody enzyme immunoassay (EIA). The procedure for initial confirmation involves three purified antigens coated onto three separate polystyrene beads and uses an EIA format. If the sample is reactive with two of three or three of three antigens, it is confirmed as seroreactive. If none or one of three beads is reactive, the sample is indeterminate and subjected to a radioimmunoprecipitation assay (RIPA). The RIPA must demonstrate characteristic bands at 32, 34, and 90 kDa. RESULTS: When tested with sera from persons with potentially cross-reactive diseases (n = 39) or against a presumed negative population from southeast Wisconsin (n = 289), the confirmatory EIA had a specificity of 100 percent. Sensitivity was 100 percent (28/28) with xenodiagnosis-positive sera and 97.6 percent (80/82) with chagasic sera from Latin America. The RIPA showed a specificity of 100 percent in EIA- nonreactive samples (n = 100) and a sensitivity of 100 percent with both xenodiagnosis-positive (28/28) and chagasic (82/82) sera. CONCLUSION: The confirmatory EIA and the RIPA together provide a highly specific and sensitive means of confirming seroreactivity for antibodies to T. cruzi.     

Prevalence of gestational diabetes mellitus in Kashmiri women from the Indian subcontinent

This prospective study was carried out to determine the prevalence of gestational diabetes mellitus (GDM) in Kashmiri women and to assess the effect of various demographic factors. Two thousand pregnant women (divided into groups A and B, being the first and last 1000 consecutive women) attending various antenatal clinics in six districts of Kashmir valley were screened for GDM by 1 h 50 g oral glucose challenge test. Four hundred and fourteen (20.8%) women (216 from group A and 198 from group B) had an abnormal screening test and proceeded to oral glucose tolerance testing. Women from group A had a 3 h 100 gram oral glucose tolerance test (OGTT) and GDM was as classified by Carpenter and Coustan. A 2 h 75 g OGTT was performed on group B subjects and WHO criteria applied for diagnosis of GDM. The overall prevalence of GDM was 3.8% (3.1% in group A versus 4.4% in group B-P-value 0.071). GDM prevalence steadily increased with age (from 1.7% in women below 25 years to 18% in women 35 years or older). GDM occurred more frequently in women who were residing in urban areas, had borne three or more children, had history of abortion(s) or GDM during previous pregnancies, had given birth to a macrosomic baby, or had a family history of diabetes mellitus. Women with obesity, hypertension, osmotic symptoms, proteinuria or hydramnios had a higher prevalence of GDM.     

Idiopathic Massive Spontaneous Hemothorax: Adhesion Disruption

Background  Hemothorax has been reported to occur along with spontaneous pneumothorax due to adhesion disruption. Rupture of pleural adhesions spontaneously or after unnoticeable trivial trauma causing massive hemothorax alone is rare. Methods  We present a series of seven cases of idiopathic massive spontaneous hemothorax due to adhesion disruption, of which all required emergency thoracotomy with ligation or cauterization of bleeding adhesions. Results  Six patients had bleeding pleural lung adhesions of which five involved the upper lobes. Another had bleeding from pleuropericardial adhesions. All patients are doing well on follow-up. Conclusions  Disruption of pleural adhesions may cause massive hemothorax, requiring early surgical intervention. After thoracotomy the outcome in these patients is excellent.     

Spectrum of abdominal organ injury in a primary blast type

Introduction  

Abdominal organ injury in a primary blast type is always challenging for diagnosis. Air containing abdominal viscera is most vulnerable to effects of primary blast injury. In any patient exposed to a primary blast wave who presents with an acute abdomen, an abdominal organ injury is to be kept in a clinical suspicion.