Diminished degradation of myelin basic protein by anti-sulfatide antibody and interferon-gamma in myelin from glia maturation factor-deficient mice

In this study we show the effect of anti-sulfatide (RmAb) antibodies and inflammatory cytokines, TNF-alpha and IFN-gamma in inducing myelin basic protein (MBP) degradation in myelin isolated from control wild type (WT) and glia maturation factor (GMF)-deficient (GMF-KO) mice. GMF was not detected in isolated myelin from WT and GMF-KO mice although it is present in brains of WT mice. Our results show that calcium-dependent neutral protease activity caused significantly elevated degradation of 18.5 and/or 17.5kDa isoforms of MBP in WT myelin treated with RmAb or IFN-gamma. In contrast, MBP degradation in isolated myelin from GMF-KO mice remained unaffected following treatment with RmAb, IFN-gamma, or GM-CSF. Neither the 14kDa isoform of MBP nor proteolipid protein (PLP) showed an elevated degradation compared to controls. A virtual absence of GM-CSF, TNF-alpha and IFN-gamma in GMF-KO brain compared to WT was also evident when the animals were challenged with MOG 35-55. Additionally, the myelin from GMF-KO mice showed difference in distribution of myelin oligodendrocyte glycoprotein (MOG) and beta-tubulin in a sucrose density gradient myelin-axolemmal fractions compared to WT. Taken together, our data suggests a role for GMF in the biochemical organization of myelin and thereby its effect on MBP degradation induced by RmAb and IFN-gamma.     

Trends in Demographics and Management of Obstructing Colorectal Cancer

Introduction

Obstructing colorectal cancer (CRC) has an aggressive clinical course and poorer prognosis. With the increasing incidence and differing clinical and pathologic spectrum of CRC among Black patients, as well as a paucity of African studies, regional analysis is required. Our aim was to describe the demographics and management of obstructing CRC among the different racial groups in South Africa and to compare these parameters with international standards.

Patients and methods

Patients referred to Inkosi Albert Luthuli Central Hospital, Durban, South Africa, with CRC between 2000 and 2012 were followed prospectively. Demographic information, site of obstruction, and management of patients who underwent emergency surgery for malignant large bowel obstruction were analyzed separately.

Results

CRC was diagnosed in 1,425 patients. A total of 203 three patients (14.3 %) required emergent treatment for acute large bowel obstruction. The mean age at presentation with obstructing CRC was 59 years. Black patients presented significantly younger (50 years) than White (64), Indian (60), or Colored (61) patients (p < 0.001). The most common sites of obstruction were the sigmoid colon and rectum. A total of 58 patients (29 %) had concomitant metastatic disease. No difference was found between race, sex, and sex per race in patients with concurrent metastatic disease (p = 0.227, p = 0.415, p = 0.798, respectively). Of the 203 patients, 128 (63 %) were managed by resection, 37 (18 %) by colonic stenting, 35 (17 %) by colostomy, and 3 (2 %) by colonic bypass. Stenting was unsuccessful in six patients.

Conclusion

Tumor location of patients presenting with obstruction is comparable to that cited in international literature; however, the age of presentation among Black patients is more than a decade earlier than in other ethnic groups. Surgical management should be individualized. Stenting remains a reliable alternative in select cases.     

Indications and outcomes of enucleation versus formal pancreatectomy for pancreatic neuroendocrine tumors

BackgroundPancreatoduodenectomy (PD) or distal pancreatectomy (DP) are common procedures for patients with a pancreatic neuroendocrine tumor (pNET). Nevertheless, certain patients may benefit from a pancreas-preserving resection such as enucleation (EN). The aim of this study was to define the indications and differences in long-term outcomes among patients undergoing EN and PD/DP.MethodsPatients undergoing resection of a pNET between 1992 and 2016 were identified. Indications and outcomes were evaluated, and propensity score matching (PSM) analysis was performed to compare long-term outcomes between patients who underwent EN versus PD/DP.ResultsAmong 1034 patients, 143 (13.8%) underwent EN, 304 (29.4%) PD, and 587 (56.8%) DP. Indications for EN were small size (1.5 cm, IQR:1.0–1.9), functional tumors (58.0%) that were mainly insulinomas (51.7%). After PSM (n = 109 per group), incidence of postoperative pancreatic fistula (POPF) grade B/C was higher after EN (24.5%) compared with PD/DP (14.0%) (p = 0.049). Median recurrence-free survival (RFS) was comparable among patients who underwent EN (47 months, 95% CI:23–71) versus PD/DP (37 months, 95% CI: 33–47, p = 0.480).ConclusionComparable long-term outcomes were noted among patients who underwent EN versus PD/DP for pNET. The incidence of clinically significant POPF was higher after EN.     

Highly diffusion-sensitized MRI of brain: dissociation of gray and white matter.

The brains of six healthy volunteers were scanned with a full tensor diffusion MRI technique to study the effect of a high b value on diffusion-weighted images (DWIs). The b values ranged from 500 to 5000 s/mm(2). Isotropic DWIs, trace apparent diffusion coefficient (ADC) maps, and fractional anisotropy (FA) maps were created for each b value. As the b value increased, ADC decreased in both the gray and white matter. Furthermore, ADC of the white matter became lower than that of the gray matter, and, as a result, the white matter became brighter than the gray matter in the isotropic DWIs. Quantitative analysis showed that these changes were due to nonmonoexponential diffusion signal decay of the brain tissue, which was more prominent in white matter than in gray matter. There was no significant change in relation to the b value in the FA maps. High b value appears to have a dissociating effect on gray and white matter in DWIs.     

Postinfarction Left Ventricular Remodeling: A Pathophysiological and Therapeutic Review

Over the last 50 years, studies investigating the pathogenesis of left ventricular dysfunction have resulted in many potential therapeutic targets being identified and novel classes of drugs designed to treat this condition. Despite this, the long-term prognosis of patients with clinical heart failure remains poor with mortality rates equivalent to many terminal malignancies. This article reviews our present understanding of the pathophysiology of post-infarction left ventricular dysfunction and provides a rationale for current drug usage, drugs undergoing clinical trials and compounds still under pre-clinical development. In addition, the complexities involved in deciphering intra-cellular signalling pathways mediating ventricular hypertrophy which may form the basis of future treatments are also discussed.     

Lower doses of vanadate in combination with trigonella restore altered carbohydrate metabolism and antioxidant status in alloxan-diabetic rats

BACKGROUND: Vanadate treatment to diabetic rats has been reported to correct the altered carbohydrate metabolism and antioxidant status. However, vanadate exerts these effects at relatively high doses and several toxic effects are produced. We used low doses of vanadate in combination with Trigonella foenum graecum seed powder (TSP) and evaluated their effect on the enzyme changes in diabetic rats. METHODS: Alloxan-diabetic rats were treated separately with insulin, vanadate (0.6 mg/ml), TSP and a combined dose of Vanadate (0.2 mg/ml) and TSP for 21 days. At the end of the experimental period, blood glucose levels and activities of pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (PEPCK), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) were measured in cytosolic fraction in the liver and kidney. RESULTS: Blood glucose levels increased markedly in diabetic rats. Treatment with antidiabetic compounds resulted in the reduction of glucose levels. Rats treated with combined dose of vanadate and trigonella had glucose levels comparable to control ones. Similar results were obtained with the activities of PK, PEPCK, SOD, GPx, GR, and CAT in liver and kidney of diabetic rats. Combined dose of vanadate and Trigonella was found to be most effective in correcting these alterations. CONCLUSIONS: Lower doses of vanadate could be used in combination with TSP to effectively counter diabetic alterations without any toxic side effects.     

Drug development in NZ: can a country be a cluster?

The aims of this research were to assess New Zealand's (NZ) growing drug development industry, and compare it with drug development and biotechnology clusters overseas. This article presents the results of questionnaires administered dutring interviews with 60 senior people representing the industry. It narrates their expertise, knowledge management, and innovative behaviors. NZ's industry comprises highly qualified, very experienced, and motivated people. Their organizations have particular expertise in drug discovery, which has arisen from long‐term government support for biomedical research. There is also significant expertise in early‐stage clinical development and contract clinical research. Knowledge sharing was rated as better within organizations than externally. The participants gave the highest ratings of their organizations' innovative performance to solving problems that had caused others difficulty, teamwork and having new ideas; they prefer informal methods of knowledge acquisition. These factors may reflect the NZ approach of applying ingenuity to solve problems and preference for casual and internal knowledge sharing. NZ has a hub of drug development activity; however, its size, limited resources, and remoteness from major markets may limit the development of a complete pharmaceutical industry. NZ could be promoted as a unique “country cluster” offering niche areas of expertise especially in drug discovery and clinical research. Drug Dev Res 73: 51–58, 2012. © 2011 Wiley Periodicals, Inc.