Analysis of CCR5 and SDF‐1 genetic variants and HIV infection in Indian population

HIV‐1 infection and progression exhibits interindividual variation. The polymorphism in the chemokine receptors CCR5 and CXCR4, the principal coreceptors for HIV‐1 and their ligands like SDF‐1 have a profound effect in altering the HIV‐1 disease progression rate. A single nucleotide polymorphism designated SDF1‐3′UTR‐801G‐A has been associated with resistance to HIV‐1 infection or delayed progression to AIDS. In this study, the SDF1‐3′A polymorphism, CCR5?32 polymorphism and CCR5 promoter polymorphism at positions 58934 G/T, 59029 G/A, 59353 T/C, 59356 C/T, 59402 A/G and 59653 C/T were analysed in Indian population. The polymorphisms in HIV‐1 patients and healthy individuals were evaluated by conventional PCR, RFLP‐PCR and direct sequencing techniques. The CCR5?32 mutant allele was found to be almost absent in Indian population. The analysis of the CCR5‐59356C/T polymorphism revealed a trend towards an association of the C allele with an increased risk of HIV‐1 infection. The frequency of allele CCR5‐59356C was higher in HIV‐1 patients (100%) as compared to healthy control subjects (89%, P = 0.003). The correlation of SDF1‐3′A and CCR5 promoter CCR5‐58934G/T, CCR5‐59029G/A, CCR5‐59353T/C, CCR5‐59402 A/G and CCR5‐59653C/T polymorphisms and protection to HIV‐1 infection and progression to AIDS was found to be nonsignificant. Nine haplotypes with more than 1% frequency were detected but were not significant in their protective role against HIV. Comparative analysis with global populations showed a noteworthy difference in CCR5 and SDF‐1 polymorphisms’ frequency distribution, indicating the ethnic variability of Indians. Although susceptibility to infections cannot be completely dependent on one or few genetic variants, it is important to remember that SDF‐1 and CCR5 variants have been correlated globally with HIV‐1 infection and disease progression. In the light of that, higher frequency of SDF‐1 variants in the Indian population is noteworthy.     

Design and synthesis of 5‐(5‐nitrothiophen‐2‐yl)‐3‐phenyl‐4,5‐dihydro‐1H‐pyrazole derivatives with improved solubility and potential antituberculosis activity

We report the design‐synthesis of several nitrothiophene containing molecules as antituberculosis agents. The molecules were designed on the basis of previously reported nitrofuran molecules in our laboratory, and the α,β‐unsaturated linker was modified to cyclized linker in order to overcome the challenge of low solubility and possible toxicity. The stereo‐electronic properties such as HOMO, LUMO, and HOMO‐LUMO gap along with other properties such as aqueous solvation energies and QPLogS values were studied. The designed molecules were synthesized and tested for in vitro antituberculosis activity, and some molecules were found to be highly active comparable to standard drugs. Further, the aqueous solubility was determined using visual inspection method and the designed molecules were found to be more soluble than their chalcone counterparts. Cytotoxicity studies were performed and the molecules were found to be non‐cytotoxic. Electroanalytical studies proved nitro reduction as the mechanism of action for these molecules. Thus, this study provides potential nitrothiophene containing hits with improved solubility and reduced chances of toxicity.     

A role for dynamin in triggering ethanol tolerance

Background: A prevailing hypothesis is that the set of genes that underlie the endophenotypes of alcoholism overlap with those responsible for the addicted state. Functional ethanol tolerance, an endophenotype of alcoholism, is defined as a reduced response to ethanol caused by prior ethanol exposure. The neuronal origins of functional rapid tolerance are thought to be a homeostatic response of the nervous system that counters the effects of the drug. Synaptic proteins that regulate neuronal activity are an important evolutionarily conserved target of ethanol. Methods: We used mutant analysis in Drosophila to identify synaptic proteins that are important for the acquisition of rapid tolerance to sedation with ethanol. Tolerance was assayed by sedating flies with ethanol vapor and comparing the recovery time of flies after their first sedation and their second sedation. Temperature‐sensitive paralytic mutants that alter key facets of synaptic neurotransmission, such as the propagation of action potentials, synaptic vesicle fusion, exocytosis, and endocytosis, were tested for the ability to acquire functional tolerance at both the permissive and restrictive temperatures. Results: The shibire gene encodes Drosophila Dynamin. We tested 2 temperature‐sensitive alleles of the gene. The shi^ts1 allele blocked tolerance at both the permissive and restrictive temperatures, while shi^ts2 blocked only at the restrictive temperature. Using the temperature‐sensitive property of shi^ts2, we showed that Dynamin function is required concomitant with exposure to ethanol. A temperature‐sensitive allele of the Syntaxin 1A gene, Syx1A^3–69, also blocked the acquisition of ethanol tolerance. Conclusions: We have shown that shibire and Syntaxin 1A are required for the acquisition of rapid functional tolerance to ethanol. Furthermore, the shibire gene product, Dynamin, appears to be required for an immediate early response to ethanol that triggers a cellular response leading to rapid functional tolerance.     

Pancreatitis in the setting of the metabolic syndrome

There is paucity of literature on the relation of obesity with recurrent and chronic pancreatitis. We recorded the clinical details and the outcome of five patients with recurrent pancreatitis who had components of the metabolic syndrome. Their age ranged from 8 to 20 years. All five patients had acanthosis nigricans. Body mass index (BMI) could not be evaluated as these patients lost weight following episodes of pancreatitis. Three patients had two or more first-degree relatives who had diabetes mellitus. Only one patient had severe necrotizing pancreatitis. Coexisting liver disease was seen in two patients. Elevated serum cholesterol levels and moderately elevated serum triglycerides along with elevated serum amylase levels observed in these patients suggest possibility of a different mechanism from that of hypertriglyceridemia-related pancreatitis. Evaluation of pancreatic steatosis should be considered in patients with pancreatitis in the setting of metabolic syndrome.     

Foreign Bodies in Facial Trauma-Report of 3 Cases

Background

Foreign bodies embedded deep in facial tissues presents a challenge to maxillofacial surgeons. Approximately one third of all foreign bodies are missed during initial examination. After facial trauma foreign bodies like grit particles, wooden pieces, thorns, pebbles, glass particles may get embedded into deeper facial tissues which are detected only accidently either with the help of radiographs or at a later stage when patient presents with some signs & symptoms like pain, pus discharge, sinus formation etc. Trauma to maxillofacial region especially after road traffic accidents is one of major cause of embedment of foreign body, but many of these cases go unnoticed. This article contains 3 cases of foreign bodies embedded in facial tissues.

Conclusion

Proper initial examination of facial lacerations with thorough debridement is very essential for finding embedded foreign bodies. Foreign bodies embedded in deeper tissues are missed by surgeon eyes, so whenever in doubt radiographs must be advised to rule out presence of foreign bodies.     

Does Femoral Rotation Influence Anteroposterior Alpha Angle,Lateral Center-edge Angle,and Medial Proximal Femoral Angle? A Pilot Study

Background

Femoral rotation on AP radiographs affects several parameters used to assess morphologic features of the proximal femur but its effect on femoroacetabular impingement parameters remains unknown.

Question/purposes

We therefore evaluated and characterized the potential effect of femoral rotation on (1) AP alpha angle, (2) lateral-center edge angle (LCEA), and (3) medial proximal femoral angle (MPFA) on AP hip radiographs.

Methods

We took seven AP hip radiographs at intervals of successive femoral rotation on a single dry, cadaveric specimen: 60°, 40°, and 20° internal rotation; 0° neutral/anatomic rotation; and 20°, 40°, and 50° external rotation. The AP alpha angle, LCEA, and MPFA were measured on all radiographs by two independent evaluators.

Results

Within the range of femoral rotation studied, the AP alpha angle ranged from 39° to 62°, the LCEA from 25° to 35°, and the MPFA from 70° to 115°. MPFA and AP alpha angle showed a linear relationship with femoral rotation. Each additional degree of internal rotation produced a reciprocal reduction of the MPFA by 0.36° and the AP alpha angle by 0.18° and vice versa in external rotation. The LCEA, especially within the internal rotation range, showed minimal variation.

Conclusions

These changes in radiographic parameters emphasize the importance of femoral rotation and patient positioning. We recommend radiographs be evaluated for excessive femoral rotation or nonstandardized positioning before interpretation for diagnostic and treatment implications. It may be prudent to repeat radiographs in these circumstances or, when standardized positioning is not feasible, proceed toward advance imaging.     

Telmisartan in the management of diabetic nephropathy: a contemporary view

Diabetic nephropathy, a complex disorder with heterogeneous etiologies, remains one of the most threatening diseases worldwide. There were around 177 million people with diabetes mellitus worldwide, and it has been estimated to be increased to 360 million by 2030. Given that about 20-30% of these people develop diabetic nephropathy, the present treatment protocols primarily aim for an efficient glucose and blood pressure control to arrest the initiation and progression of diabetic nephropathy. The treatment of diabetic nephropathy near the beginning at microalbuminuria stage with angiotensin-II-AT1 receptor blockers (ARBs) improves blood pressure control and halts disease progression of diabetic nephropathy. In fact, ARBs exert renoprotective effects independently of their blood pressure lowering effect, as they have direct defensive action on the diabetic kidney. Indubitably, it would be better if an ARB has both glucose-lowering and blood pressure controlling potentials efficiently. Intriguingly, telmisartan has such possessions considering its dual role of AT1 receptor blocking action and peroxisome proliferator-activated receptor gamma (PPARγ) partial agonistic property. The additional PPARγ agonistic potential of telmisartan could make it a distinctive intervention in the ARB class to prevent the progression of diabetic nephropathy through activation of PPARγ-mediated insulin sensitization, and renal anti-inflammatory and anti-oxidant actions. Indeed, telmisartan reduced insulin resistance and glucose intolerance, and halted the progressive renal dysfunction associated with diabetic nephropathy by inhibiting the incidence of albuminuria, and preventing the progression of glomerulosclerosis, renal interstitial inflammation and fibrosis. This review will discuss the current status of therapeutic potentials of telmisartan in treating diabetic nephropathy.