Complete Sella Turcica Bridges Prevalence and Dimensions

Interclinoid ligaments which connect the anterior and posterior clinoid processes comprise a group of intrinsic ligaments of sphenoid bone. The complete sella turcica bridge corresponds to the complete ossification of the interclinoid ligaments. 112 dry human adult skull bones were studied for presence of ossified interclinoid ligaments. Nine skulls (8.04%) showed sella turcica bridges, out of which six were unilateral and three bilateral. The average length of the bridge was 11.67mm. The average width and thickness at the anterior clinoid process was 6.33mm and 4.33mm ; atthe middle of the bridge 3.08mm and 2.66mm; and atthe posterior clinoid process, 4.91 mm and 3.66mm, respectively. Anomalies of sellar region are not very rare and may pose difficulties in interpretation of Magnetic Resonance Imaging or Computed Tomographyforthe radiologist. Thesefindings would also guide the neurosurgeons in planning neurosurgical procedures involving the sellar region.     

Identification of novel SRY mutations and SF1 (NR5A1) changes in patients with pure gonadal dysgenesis and 46,XY karyotype

Primary amenorrhea due to 46,XY disorders of sexual development (DSD) is complex with the involvement of several genes. Karyotyping of such patients is important as they may develop dysgerminoma and molecular analysis is important to identify the underlying mechanism and explore the cascade of events occurring during sexual development. The present study was undertaken for the genetic analysis in seven patients from five families presenting with primary amenorrhea and diagnosed with pure gonadal dysgenesis. Karyotyping was done and the patients were screened for underlying changes in SRY, desert hedgehog (DHH), DAX1 (NR0B1) and SF1 (NR5A1) genes, mutations in which are implicated in DSD. All the patients had 46,XY karyotype and two novel SRY mutations were found. In Family 1 (Patient S1.1) a missense mutation c.294G>A was seen, which results in a stop codon at the corresponding amino acid (Trp98X) and in Family 2 (Patients S2.1, S2.2 and S2.3), a missense mutation c.334G>A (Glu112Leu) was identified in all affected sisters. Both mutations were seen to occur in the conserved high mobility group box of SRY gene. One heterozygous change c.427G>A resulting in Glu143Lys in DHH gene in one patient and two heterozygous changes in the intronic region of SF1 (NR5A1) gene (c.244+80G>A+ c.1068-20C>T) in another patient were noted. One individual did not show changes in any of the genes analyzed. These results reiterate the importance of SRY and others, such as SF1 (NR5A1) and DHH, that are involved in the cascade of events leading to sex determination and also their role in sex reversal.     

Low-frequency H-reflex depression in trained human soleus after spinal cord injury

After spinal cord injury (SCI), widespread reorganization occurs within spinal reflex systems. Regular muscle activity may influence reorganization of spinal circuitry after SCI. The purpose of this study is to investigate the effects of long-term soleus training on H-reflex depression in humans after SCI. Seven subjects with acute (<7 weeks) SCI (AC group) underwent testing of H-reflex depression at several frequencies of repetitive stimulation. Eight subjects (including 3 from AC) stimulated one soleus muscle daily, leaving the other leg as an untrained within-subject control. Trained limb H-reflexes were assessed during year 1 (TR1) and year 2 (TR2) of training. Untrained limbs were tested during year 2 (UN). H-reflex amplitude was lower at 1, 2 and 5 Hz than at 0.1 or 0.2 Hz (p < 0.05). The pattern of depression differed between AC and UN (p < 0.05), but not between TR2 and UN (p > 0.05) despite significant adaptations in torque and fatigue resistance (p < 0.05). Three subjects who began training very early after SCI retained H-reflex post activation depression, suggesting that early intervention of daily muscular activity may be important.     

Factor Xa-like and fibrin(ogen)olytic activities of a serine protease from Hippasa agelenoides spider venom gland extract

In the recent past, a low molecular mass serine protease, the Hag-protease that caused pro-coagulant activity and as well as local toxicity was isolated and characterized from the Hippasa agelenoides spider venom gland extract (Devaraja et al., Toxicon 52:130–138, 2008). In the current study, the pro-coagulant property has been investigated further and the results are presented. The Hag-protease reduced the re-calcification time of citrated human plasma. It reduced the activated partial thromboplastin time (APTT), and prothrombin time (PT) suggesting its participation in common pathway of blood coagulation. Interestingly, it coagulated the citrated human plasma in the absence of CaCl₂ but, it was lacking thrombin-like activity as it did not clot the purified fibrinogen. Strikingly, the enzyme coagulated the factor X deficient congenital human plasma, suggesting the factor Xa-like activity. However, the cumulative augmented activity was observed in presence of CaCl₂ and phospholipids. Further, the Hag-protease preferentially hydrolyzed the Aα chain and then the Bβ-chain, but not the γ-chain. As a result, truncated fibrinogen generated was lacking in the polymerization property. It hydrolyzed all the subunits of partially cross-liked fibrin clot (α-polymer, α-chain, β-chain, and γ–γ dimers). Further, at low concentrations, the Hag-protease stimulated the aggregation of human platelets in platelet rich plasma, but at high concentrations caused spontaneous clumping. In contrast, it inhibited the collagen induced aggregation of washed human platelets. In summary, the present study for the first time reporting the factor Xa-like activity of a serine protease especially from the spider venom that exhibited opposing effects on hemostasis, the pro-coagulant activity and the anti-coagulant activity including fibrin(ogen)olytic and platelet aggregation inhibition activities.     

Direct structural insight into the substrate-shuttling mechanism of yeast fatty acid synthase by electron cryomicroscopy

Yeast fatty acid synthase (FAS) is a 2.6-MDa barrel-shaped multienzyme complex, which carries out cyclic synthesis of fatty acids. By electron cryomicroscopy of single particles we obtained a three-dimensional map of yeast FAS at 5.9-Å resolution. Compared to the crystal structures of fungal FAS, the EM map reveals major differences and new features that indicate a considerably different arrangement of the complex in solution compared to the crystal structures, as well as a high degree of variance inside the barrel. Distinct density regions in the reaction chambers next to each of the catalytic domains fitted the substrate-binding acyl carrier protein (ACP) domain. In each case, this resulted in the expected distance of ∼18 Å from the ACP substrate-binding site to the active site of the catalytic domains. The multiple, partially occupied positions of the ACP within the reaction chamber provide direct structural insight into the substrate-shuttling mechanism of fatty acid synthesis in this large cellular machine.     

The association of the Friesinger score and pulse pressure in an urban South Asian patient population: pulse pressure,an independent predictor of coronary artery disease

Increase in pulse pressure has been shown to be predisposing factor for Coronary Artery Disease (CAD) in diverse patient populations but its relationship with the severity of CAD, particularly in the South Asians immigrant population of United States has not been demonstrated. We performed a single-center, cross-sectional study. Pulse pressure was calculated by the difference between the systolic and diastolic brachial blood pressures, and the Friesinger score (FS) was used to quantify the severity of CAD with the score of 5 used as a cutoff for extensive disease. We also sought to assess the correlation between the Friesinger score and the 10-year cardiovascular event (CVD) risk as calculated by the Framingham score. Odds ratios and 95% confidence intervals for the associations between explanatory variables and a high Friesinger score were estimated using multivariate logistic regression models. P values below .05 were considered to be statistically significant. Statistical analysis was performed using STATA version 10 software package (College Station, TX). The mean pulse pressure was significantly higher in participants with an FS of ≥5 compared with participants with an FS of <5 (63 vs. 46 mm Hg; P = .004). In univariate analysis, a pulse pressure ≥40 mm Hg was associated with a five-fold increased odds of a higher FS compared with a pulse pressure <40 mm Hg (P = .039), which was unchanged in multivariate analysis. In multivariate analysis, even after adjustment for presence of hypertension, a 10 mm Hg increase in pulse pressure was associated with a 1.97-fold increased odds of a higher FS (95% CI 1.22–3.71, P = .009). The mean Framingham score was higher in participants with a higher FS, but this difference was not significant (32.7 vs. 20.3; P = .1139). Our study demonstrates that pulse pressure, a well-established marker of vascular health, is a significant independent predictor of the severity of CAD as assessed by coronary angiography in South Asians.     

Gestational diabetes mellitus (GDM) screening in morbidly obese pregnant women

Objective

To study the outcomes of two-stage GDM screening of morbidly obese women in our obstetric unit and to evaluate the diagnostic performance of 20-week oral glucose tolerance test (OGTT) values in predicting or excluding late onset GDM.

Study design

A retrospective study in which 190 pregnant women with BMI ≥40 had two-stage screening: a 75 g OGTT is performed at 20 weeks and repeated at 28 weeks if the 20-week OGTT was normal. Receiver operating characteristic (ROC) curves for 20-week OGTT values were constructed in order to obtain an optimal cut-off value of fasting and/or 2-h glucose at 20 weeks from which GDM could be predicted or excluded at 28 weeks. Sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were determined for each of the fasting and 2-h post-load glucose values at 20 weeks.

Results

Forty six (24%) women were diagnosed with GDM. Thirty-two (70%) were diagnosed at 20 weeks and 14 (30%) at 28 weeks. The 2-h cut-off value of ≥6 mmol/l at the 20-week OGTT had a negative likelihood ratio of 0.12 to predict GDM at 28 weeks. The low negative likelihood ratio reduces the probability of detecting GDM at 28 weeks from 9% (pre-test probability) to 1% (post-test probability).

Conclusion

Nearly 70% of the women were diagnosed with GDM at 20 weeks, which gives an early opportunity to treat maternal hyperglycaemia with consequent health benefits. A 2-h cut-off glucose value of 6 mmol/l at 20 weeks OGTT has a low negative likelihood ratio which virtually excludes GDM at 28 weeks. Hence women with a 2 h value of <6 mmol/l at 20 weeks can avoid a repeat 28 week OGTT test.     

Toll-like receptors: Significance,ligands, signaling pathways,and functions in mammals

This review attempts to cover the implication of the toll-like receptors (TLRs) in controlling immune functions with emphasis on their significance, function, regulation and expression patterns. The tripartite TLRs are type I integral transmembrane receptors that are involved in recognition and conveying of pathogens to the immune system. These paralogs are located on cell surfaces or within endosomes. The TLRs are found to be functionally involved in the recognition of self and non-self-antigens, maturation of DCs and initiation of antigen-specific adaptive immune responses as they bridge the innate and adaptive immunity. Interestingly, they also have a significant role in immunotherapy and vaccination. Signals generated by TLRs are transduced through NFκB signaling and MAP kinases pathway to recruit pro-inflammatory cytokines and co-stimulatory molecules, which promote inflammatory responses. The excess production of these cytokines leads to grave systemic disorders like tumor growth and autoimmune disorders. Hence, regulation of the TLR signaling pathway is necessary to keep the host system safe. Many molecules like LPS, SOCS1, IRAK1, NFκB, and TRAF3 are involved in modulating the TLR pathways to induce appropriate response. Though quantification of these TLRs helps in correlating the magnitude of immune response exhibited by the animal, there are several internal, external, genetic and animal factors that affect their expression patterns. So it can be concluded that any identification based on those expression profiles may lead to improper diagnosis during certain conditions.     

The IL‐23/Th17 axis is involved in the adaptive immune response to Bacillus anthracis in humans

The neutralization of toxins is considered essential for protection against lethal infection with Bacillus anthracis (BA), a select agent and bioterrorism threat. However, toxin‐neutralizing activity alone would not be expected to provide sterile immunity. Therefore, we hypothesized that the development of an adaptive immune response against BA is required for bacterial clearance. We found that human monocyte‐derived dendritic cells (hDCs) kill germinated BA bacilli, but not nongerminated BA spores. hDCs produce IL‐1β, IL‐6, IL‐12, and IL‐23, and these cytokines are differentially regulated by germination‐proficient versus germination‐deficient BA spores. Moreover, the IL‐23 response to BA spores is regulated by IL‐1R‐mediated signaling. hDCs infected with germinating BA spores stimulated autologous CD4⁺ T cells to secrete IL‐17A and IFN‐γ in a contact‐dependent and antigen‐specific manner. The T‐cell response to BA spores was not recapitulated by hDCs infected with germination‐deficient BA spores, implying that the germination of spores into replicating bacilli triggers the proinflammatory cytokine response in hDCs. Our results provide primary evidence that hDCs can generate a BA‐specific Th17 response, and help elucidate the mechanisms involved. These novel findings suggest that the IL‐23/Th17 axis is involved in the immune response to anthrax in humans.