Induction of long-term protective effects against heterologous challenge in SIVhu-infected macaques

A group of three rhesus macaques were inoculated with SIV isolated from a human (SIVhu) accidentally exposed and infected with SIVsm. Extensive sequence analyses of SIVhu obtained from the human and macaques following infection indicated the presence of truncated nef. Not only did nef fail to repair itself in vivo postinfection (p.i.), but instead, further mutations added additional stop codons with increasing time p.i. Infection of these animals was associated with minimal acute viral replication, followed by undetectable plasma viral loads and only intermittent PCR detection up to 5 years p.i. The three SIVhu infected and three control monkeys were then challenged with the heterologous highly pathogenic SHIV89.6p. All three controls became infected and showed rapid declines in peripheral CD4(+) lymphocytes, disease, and death at 10 and 32 weeks p.i., respectively. In contrast, all three animals previously infected with SIVhu are healthy and exhibit stable CD4(+) lymphocyte levels and undetectable plasma viral loads at >20 months post-SHIV89. 6p challenge. Only transient, low levels of SHIV replication were noted in these animals. Whereas responses to SIVgag/pol were noted, no evidence for SIV/SHIV envelope cross-reactivity was detected by antibody or CTL analyses, suggesting that the protective immune mechanisms to the heterologous challenge isolate were most likely not directed to envelope but rather to other viral determinants.     

Four novel C20orf54 mutations identified in Brown-Vialetto-Van Laere syndrome patients

Brown-Vialetto-Van Laere syndrome (BVVLS) is a very rare neurodegenerative disorder characterized by pontobulbar palsy and sensorineural hearing loss. Its mode of inheritance in affected families has usually been autosomal recessive, although autosomal dominant inheritance and incomplete penetrance have also been reported. Recently, C20orf54 was identified as a causative gene for BVVLS. Twelve different mutations have so far been identified in 10 patients affected with BVVLS or the related disorder Fazio Londe syndrome. Here, results of screening of C20orf54 in three unrelated BVVLS patients are reported. Four novel mutations that affect amino acid changes, p.Asn21Ser, p.Pro220His, p.Ala312Val and p.Gly375Asp, were identified in the patients. The causative nucleotide variations were not observed in 200 control individuals. One of the patients harbored compound heterozygous mutations, but only one mutated allele was observed in each of the two remaining patients.     

Clock genes alterations and endocrine disorders

Background

Various endocrine signals oscillate over the 24‐hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.

Design

We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases.

Results

Various human single nucleotide polymorphisms of brain and muscle ARNT‐like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue‐specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio‐melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue‐specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers.

Conclusions

Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue‐specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.     

Olfactory mucosa, aluminosilicates and Alzheimer's disease

Age-related degenerative changes in mucosal epithelium may result in decreased barrier function. This change may predispose the adjacent brain areas to invasion by organisms and toxins leading to regional tissue damage as seen in Alzheimer's disease (AD). Age-related decrease in nasal mucosal barrier function, however, would explain some but not all the pathologic changes associated with AD.     

Accuracy of ultrasonography in the diagnosis of acute appendicitis.

Aims and Objectives: To assess the accuracy of ultrasonography in the diagnosis of acute appendicitis. Methodology: A prospective randomized study was carried in the Dept. of Radiology and Imaging, Tribhuvan University, Teaching Hospital, Maharajgunj, Kathmandu, Nepal. A total of 120 patients, who were clinically diagnosed as acute appendicitis were subjected to ultrasonography of the abdomen. A detailed ultrasonography was performed and the findings were recorded. Twenty one cases had alternate diagnosis. Ninety nine cases ultimately underwent laparotomy and the retrieved appendices were sent for histopathological examination. Intra-operative, histopathological and ultrasonographic diagnoses were then statistically analyzed. Results: Ultrasonographic, intra-operative and histopathological findings were statistically insignificant (P0.05). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy percentage of ultrasonography in the diagnosis of acute appendicitis was 85.7%, 100%, 100%, 6.7% and 85.9% respectively. Conclusion: Ultrasonography has a high degree of accuracy in the diagnosis of acute appendicitis. However, the diagnosis should be considered with the diameter of appendix over 6 mm. Therefore acute appendicitis with diameter of appendix having less than 6 mm should be evaluated with other diagnostic parameters. Key words: Acute Appendicitis, Ultrasonography.     

Comparative analysis of portal cell infiltrates in antimitochondrial autoantibody-positive versus antimitochondrial autoantibody-negative primary biliary cirrhosis

Substantial evidence supports dysregulated B-cell immune responses in patients with primary biliary cirrhosis (PBC), including the presence of serum antimitochondrial antibodies (AMAs). However, recent reports from murine models of PBC suggest that B cells may also provide regulatory function, and indeed the absence of B cells in such models leads to exacerbation of disease. The vast majority of patients with PBC have readily detectable AMAs, but a minority (<5%) are AMA negative (AMA(-)), even with recombinant diagnostic technology. This issue prompted us to examine the nature of B-cell infiltrates surrounding the portal areas in AMA-positive (AMA(+)) and AMA(-) patients, because they display indistinguishable clinical features. Of importance was the finding that the degree of bile duct damage around the portal areas was significantly milder in AMA(+) PBC than those observed in AMA(-) PBC patients. The portal areas from AMA(-) patients had a significant increase of cluster of differentiation (CD)5(+) cells infiltrating the ductal regions, and the levels of B-cell infiltrates were worse in the early phase of bile duct damage. The frequency of positive portal areas and the magnitude of CD5(+) and CD20(+) cellular infiltrates within areas of ductal invasion is associated with the first evidence of damage of biliary duct epithelia, but becomes reduced in the ductopenia stage, with the exception of CD5(+) cells, which remain sustained and predominate over CD20(+) cells. CONCLUSION: Our data suggest a putative role of B-cell autoimmunity in regulating the portal destruction characteristic of PBC.     

Port site metastasis after laparoscopic radical nephrectomy: A single-center experience

Objective: To assess the incidence and review the probable etiologies of port site recurrence in patients undergoing laparoscopic radical nephrectomy. Materials and Methods: One hundred thirty-six patients undergoing laparoscopic surgeries for renal malignancy, including 133 radical nephrectomies and 3 partial nephrectomies, from December 1999 to December 2008 at our institution were followed up for a median period of 59 months (12-120 months). Of the procedures, 121 were performed by transperitoneal, 5 by retroperitoneal and 10 by combined approach (retroperitoneal renal artery clipping followed by transperitoneal nephrectomy). Formal lymphadenectomy was not performed. Postoperative surveillance after radical nephrectomy included history and physical examination with blood tests 3-6 monthly, chest X-ray yearly and abdominal contrast-enhanced computed tomography (CECT) 1-2 yearly. The development of port site recurrence was diagnosed by physical examination, CECT and pathological findings. Results: Conversion to open surgery was done in 33 patients. Two (1.47% overall) port site recurrences were observed, both after radical nephrectomies done for renal masses with clinical stages T2N0M0 and TIN0M0. The pathological staging in the two were T2N1M0 Fuhrman's Grade III and T3aN1M0 Grade III, respectively. Conclusion: Our results report that laparoscopic approach does not necessarily increase the risk of port site recurrence, provided the cases are carefully chosen, principles of oncologic surgery are followed, and conditions that increase the risk of port site metastasis are avoided.