Electron microscopic study of neurofibrillary tangles in Steele-Richardson-Olszewski syndrome

Summary The neurofibrillary tangles found in the neurons of a case of Steele-Richardson-Olszewski syndrome were studied by electron microscopy. Both the flame-shaped and globose type of tangles were present. The neurofibrillary tangles were composed of bundles of straight tubules measuring approximately 150 Å in diameter. This ultrastructural appearance of the tangles in Steele-Richardson-Olszewski syndrome is different from the appearance of tangles found in other neurological disorders and is probably indicative of intraneuronal accumulation of a new type of fibrous protein.This investigation received financial support from the World Health Organization.     

A study of urinary fistulae in Sokoto, Nigeria.

A retrospective study was conducted on 361 women to evaluate the factors influencing the development of urinary fistula. Primipara women (69.8%) in the age group of 15-19 years (51.52%) with a height less than 150 cm (68.14%) were most frequently affected. Prolonged labour (82.79%), spontaneous delivery (57.92%) and delivery by forceps and craniotomy (31.12%) were the most common obstetric causes. Operation by native doctors and lymphogranuloma venereum were responsible for 3.32% and 0.55% cases respectively. Juxtra-urethral fistulae (54.84%) were the commonest type and the size of fistulae ranged from 0.5-1 cm in 65.92% of cases. Of the associated conditions pelvic abnormality was most frequently (45.8%) observed followed by urinary tract infection (26.2%), ammoniacal dermatitis of vulva (22.19%), nerve palsy (20.26%), involvement of rectum and anus (10.5%), gynatresia (9.97%), cystolithiasis (7.4%), secondary amenorrhoea (4.15%) and pregnancy (3.1%). Absence of formal education and presence of poverty were observed in 95% and 75% of cases respectively.     

Hyaluronan oligosaccharides as a potential anticancer therapeutic

Hyaluronan (HA) polysaccharide has differential effects on cells depending on polymer size. One of the more exciting findings is that small chains or oligosaccharides of HA (6-18 sugar units), but not large polymers, will kill many types of cancer cells by triggering apoptosis while leaving normal cells unaffected. Even chemoresistant cells become drug-sensitive when co-treated with HA oligosaccharides. Overall, these observations form the basis for new anticancer therapeutics.     

Surgical Management of Cystic Duct Stump Stone or Gall Bladder Remnant Stone

Retained calculi in the cystic duct or gall bladder remnant can present as a post-cholecystectomy problem. Increased suspicion is necessary to diagnose this condition in a symptomatic post-cholecystectomy patient. Ultrasonography usually detects this condition, but magnetic resonance cholangiopancreatography is the test of choice for diagnosis as well as for surgical planning. Laparoscopic re-excision of the stump in most cases is feasible and safe. It is increasingly becoming the treatment of choice.     

Isothiocyanate analogs targeting CD44 receptor as an effective strategy against colon cancer

Inflammatory pathway plays an important role in tumor cell progression of colorectal cancers. Although colon cancer is considered as one of the leading causes of death worldwide, very few drugs are available for its effective treatment. Many studies have examined the effects of specific COX-2 and 5-LOX inhibitors on human colorectal cancer, but the role of isothiocyanates (ITSCs) as COX–LOX dual inhibitors engaged in hyaluronan–CD44 interaction has not been studied. In the present work, we report series of ITSC analogs incorporating bioisosteric thiosemicarbazone moiety. These inhibitors are effective against panel of human colon cancer cell lines including COX-2 positive HCA-7, HT-29 cells lines, and hyaluronan synthase-2 (Has2) enzyme over-expressing transformed intestinal epithelial Apc10.1Has2 cells. Specifically, our findings indicate that HA-CD44v6-mediated COX-2/5-LOX signaling mediate survivin production, which in turn, supports anti-apoptosis and chemo-resistance leading to colon cancer cell survival. The over-expression of CD44v6shRNA as well as ITSC treatment significantly decreases the survival of colon cancer cells. The present results thus offer an opportunity to evolve potent inhibitors of HA synthesis and CD44v6 pathway and thus underscoring the importance of the ITSC analogs as chemopreventive agents for targeting HA/CD44v6 pathway.     

Linagliptin: a novel xanthine-based dipeptidyl peptidase-4 inhibitor for treatment of type II diabetes mellitus

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor to complete pivotal phase III trials, which have demonstrated its superiority to its competitors based on its low therapeutic dose, long-lasting inhibition of DPP-4 activity and a good safety/tolerability profile. One of the unique characteristics of linagliptin is its primarily non-renal route of excretion. The drug has recently been approved by the US Food and Drug Administration and has been portrayed as a promising treatment option for patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.     

Investigation of the potential effects of metformin on atherothrombotic risk factors in hyperlipidemic rats

The increased mortality rate due to atherothrombotic events and related complications has necessitated the search for new pharmacological agents. Hyperlipidemia, thrombosis and oxidative stress are the primary underlying concerns in the pathogenesis of atherosclerosis. Metformin, although proved to be beneficial in micro and macrovascular complications of diabetes mellitus, its effects on pure cardiovascular subjects are still debatable. Hence, the aim of the present study was to investigate the effects of metformin on atherothrombotic risk factors in experimental hyperlipidemic rats. Hyperlipidemia was induced by an intra-peritoneal injection of criton X-100 (25 mg/kg). Assessment of the effects of metformin (300 mg/kg/day, 400 mg/kg/day and 500 mg/kg/day) on lipid profile, coagulation time (activated partial thromboplastin time and prothrombin time), fibrinogen level, thrombosis, lipid peroxidation, antioxidant enzymes level, plasma fluorescent oxidation products and aortic nitrite level revealed an overall improvement in the lipid profile at the dose of 400 mg/kg along with a significant reduction in oxidative stress as compared to criton X-100 treated control. Activated partial thromboplastin and prothrombin times were prolonged at all doses, while plasma fibrinogen level remained unaffected. Metformin pre-treatment also reduced endothelial cell damage in ferrous chloride induced thrombosis in carotid arteries. Thus, the results indicate a potential protective effect of metformin on atherothrombotic risk factors, as evident from an improvement in lipid profile, reduction in oxidative stress and thrombotic events.