Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation

Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi2 statistic). These studies suggest a possible treatment strategy for HGPS.     

Cadazolid: A new hope in the treatment of Clostridium difficile infection

Clostridium difficile infection (CDI) is a potential life-threatening consequence of antibiotic therapy. Although the risk increases with duration of treatment, it can also occur after a short treatment course. In addition to broad-spectrum antibiotics, anti-neoplastic agents, proton pump inhibitors, H² blockers, and several other drugs have been reported to induce intestinal dysbiosis, which is central to the pathogenesis of CDI. There is an increase in incidence and mortality attributed to CDI globally. Moreover, the epidemiology of C. difficile-associated diseases has changed significantly with an increasing occurrence of community-acquired CDI. Metronidazole and oral vancomycin are the first-line antibiotics used to treat CDI. However, metronidazole has limited effectiveness in severe cases and vancomycin use is associated with increasing risk of vancomycin resistance among Enterococcus spp. Cadazolid, a novel oxazolidinone antibiotic, has recently shown potent antimicrobial activity against C. difficile and has a lower propensity to induce resistance. The implications of its use in treating CDI have been reviewed based on current evidence.     

Enhancement of nootropic effect of duloxetine and bupropion by caffeine in mice

Objective:The existing evidence suggests an association between depression and memory impairment. The objective of present study was to assess the effect of low dose caffeine with duloxetine and bupropion on memory.Results:Caffeine with duloxetine treated group was better than other combination treated groups in terms of a significant decrease in TL and increase in the time spent in target quadrant recorded.Conclusion:Combining lower dose of caffeine with duloxetine may enhance cognitive benefits than respective monotherapies.KEY WORDS: And bupropion, caffeine, duloxetine, memory     

Natural course of the S-T segment and QRS complex in patients with acute anterior myocardial infarction

Sums of the S-T segment elevation from the 35 lead precordial electrocardiographic map (∑ST₃₅) and Standard 6 lead precordial electrocardiogram (∑ST₆) were obtained from 20 patients after acute anterior myocardial infarction and the calculations repeated 2, 4, 12, 24, 48, 72 and 240 hours later. Q and R wave areas were summed (∑Q₃₅, ∑Q₆, ∑R₃₅ and ∑R₆). ∑ST₃₅ and ∑ST₆ values decreased significantly in patients without pericarditis 7 to 12 hours after the onset of symptoms (P < 0.02), but increased significantly from these reduced values 25 to 48 hours after the onset of symptoms. An increase in ∑ST₃₅ and ∑ST₆ (P < 0.05) occurred 13 to 24 hours after the onset of symptoms in four patients with pericarditis before a pericardial rub was heard. No significant change in ∑Q₃₅ occurred from the initial to the final map study; a decrease in ∑R₃₅ (P < 0.02) occurred only in a group of patients studied at or before 5 hours after initial symptoms. No correlation was found between the initial level of S-T segment elevation and subsequent change in Q or R wave areas except in two patients whose initial electrocardiographic studies were performed at or within 5 hours of initial symptoms. Good correlation was found between ∑ST₃₅ and ∑ST₆ (r = +0.906, P < 0.001), ∑Q₃₅ and ∑Q₆ (r = +0.864, P < 0.001), and ∑R₃₅ and ∑R₆ (r = +0.903, P < 0.001). The course of the S-T segment and QRS complex after anterior myocardial infarction depends on the time of study after initial symptoms. The Standard 6 lead precordial electrocardiogram may offer a practical alternative to the 35 lead map for patients with anterior myocardial infarction.     

Hemorrhoidal ablation and fixation: an alternative procedure for prolapsing hemorrhoids

BACKGROUND: Many new techniques have been evolved to curb the problem of post-operative pain after hemorrhoidectomy. Stapler hemorrhoidopexy and Doppler-guided hemorrhoidal artery ligation are the two methods gaining popularity amongst proctologists. The author proposes another technique called radiofrequency ablation and fixation of hemorrhoids to add to this list. PATIENTS AND METHODS: The surgical technique and clinical follow-up of 410 patients operated by this technique are presented. An Ellman radiofrequency generator was used for hemorrhoidal ablation at the output power intensity of 80. Post-defecation pain and pain at rest were assessed using a visual analogue scale. Patient satisfaction score was calculated at the mean follow-up of 60 months (range 48-72). The results in terms of mean hospital stay, post-operative pain, post-operative complications, and period of incapacity for work were compared with the published data of results of stapled hemorrhoidopexy and Doppler-guided hemorrhoidal artery ligation. RESULTS: Pain score at first evacuation was 6. The post-defecation pain score in the first week was 4 (range 3-6) and it was 3 (range 2-5) in the second week. The mean pain score at rest in the first week was 2 (range 1-4) and 1 (range 0-2) in the second post-operative week. In the long-term follow-up at a mean of 60 months, this procedure was found in most of the cases to control prolapse, discharge, and bleeding, with no stenosis or incontinence. The recurrence rate was less than 2%. The patient satisfaction score was high. CONCLUSION: The results of this technique of radiofrequency ablation and fixation of hemorrhoids hold positive promises in terms of less post-operative pain, early discharge from the hospital and faster return to work. The results are comparable to stapled hemorrhoidopexy and are better than Doppler-guided hemorrhoidal artery ligation in terms of effectiveness and symptomatic relief on a long-term basis.     

Granulomatous disease in selective IgA deficiency

Although common variable immunodeficiency (CVID) is sometimes associated with sarcoidosis/granulomatous disease, there have only been isolated reports of selective immunoglobulin A (IgA) deficiency and granulomatous disease. We present a patient with IgA deficiency who developed Heerfordt syndrome, a variant of neurosarcoidosis. This specific entity has not been previously reported to occur in IgA deficiency. Our case expands the reported associations of IgA deficiency and provides another example to the paucity of reported cases of sarcoidosis occurring in patients with IgA deficiency. As CVID and IgA deficiency have common underlying genetic factors, such an association is biologically plausible.     

Double-inversion technique for coronary angiography viewing in dextrocardia.

This report describes a simple angiographic viewing rule for coronary angiography in patients of dextrocardia with obstructive coronary artery disease, which could correct the unfamiliar angulated pictures of the coronary tree in dextrocardia into the familiar conventional angiographic pictures of a normally located heart and its associated ease of interpretation.