Biochemical correlates of airway hyperreactivity in guinea pigs: role of lysophosphatidyl choline

To elucidate the biochemical basis of airway hyperreactivity, we studied the relationships between in vivo airway sensitivity of guinea pigs to histamine and their tracheal beta-adrenergic binding sites, Ca++- and (Na+-K+)-ATPase activities, and composition of phospholipids. The relationships between tracheal and plasma phospholipids were also examined. beta-Adrenergic receptor binding with 3H-dihydroalprenolol in tracheal tissue showed an inverse relationship with in vivo airway sensitivity to histamine. Among the phospholipids, tracheal phosphatidyl ethanolamine content varied inversely with in vivo airway sensitivity, whereas tracheal and plasma lysophosphatidyl choline contents showed a direct correlation with airway sensitivity. A significant direct correlation was also observed between tracheal and plasma lysophosphatidyl choline levels. Both Ca++-ATPase and (Na+-K+)-ATPase activities increased with increasing airway sensitivity. These enzymes showed inverse correlations with phosphatidyl ethanolamine content and direct correlations with lysophosphatidyl choline content. Our data suggest that increased lysophosphatidyl choline may cause various biochemical changes associated with airway hyperreactivity.     

Atherosclerosis in diabetes mellitus: role of inflammation

Inflammation plays a central role in the pathophysiology of atherosclerosis, starting from initiation, through progression and ultimately the thrombotic complications of atherosclerosis. Diabetes mellitus is a major risk factor for atherosclerosis. Hyperglycemia-induced endothelial dysfunctions, along with hypercoagulable potential of diabetes mellitus, accelerate the process of atherothrombotic complications. Therefore, clinically feasible markers to monitor subtle systemic inflammatory burden and specific add-on therapy for the same constitute need of the present day. The understanding of the concept of inflammation in diabetes-accelerated atherosclerosis can be used practically to predict future cardiovascular risk by evaluating inflammatory biomarkers and to design clinical trials making inflammation as a therapeutic target.     

Quantitative study of radioiodinated metaiodobenzylguanidine uptake in children with neuroblastoma: correlation with tumor histopathology

Six children with neuroblastoma and one with ganglioneuroma received [125I] metaiodobenzylguanidine (MIBG) before major surgery. Uptake of [125I]MIBG in the excised tissues was measured by scintillation counting, and the material was submitted for histopathology. The ranges of uptake of [125I]MIBG, expressed as percent of the injected dose per gram of tissue, were as follows: for neuroblastoma 0.0013-0.071, for ganglioneuroma 0.0017-0.0028, and for non-neoplastic control tissues 0.0002-0.011. The quantitative uptake of [125I]MIBG by neuroblastoma varied between different patients and between different parts of individual tumors. The more undifferentiated tumors took up more [125I]MIBG and may be more likely to respond to targeted radiotherapy with MIBG.     

The collection of data on assisted reproduction treatments in the UK: Recommendations by BFS and ACE

Several pathophysiological mechanisms have been proposed for the development of ovarian hyperstimulation syndrome (OHSS), such as activation of the ovarian renin-prorenin-angiotensin system, release of ovarian cytokines and nitric oxide, but numerous reports now attest to the role of vascular endothelial growth factor (VEGF), an endothelial cell mitogen, as an important mediator of the syndrome. Luteinizing hormone (LH) or human chorionic gonadotrophin (hCG) regulates VEGF production by the ovary. Formation of multiple follicles, as seen in regimens of ovarian stimulation used for in vitro fertilization (IVF), and intensified sensitivity towards human menopausal gonadotrophin (hMG) and hCG, as seen in women with polycystic ovaries (PCO) or polycystic ovary syndrome (PCOS), result in increased serum VEGF concentrations, probably due to enhanced VEGF production by the ovaries. It is possible that the hypersecretion of VEGF in women with PCO is due to an increase in the number of VEGF secreting cells or that the cells individually hypersecrete VEGF. This hypothesis was tested by in vitro studies on granulosa lutein cells. After the cells were stimulated with gonadotrophins and hCG, VEGF production was higher in granulosa cells obtained from women with PCO compared with those obtained from women with normal ovaries under similar culture conditions. The studies performed in vivo and in vitro were consistent with increased VEGF expression as a constitutive feature of PCO. Increased VEGF may be responsible for the fluid shift from the vascular bed to the extravascular space, which characterizes OHSS. Prevention of OHSS focuses on predicting the possibility of developing OHSS. Markers such as serum oestradiol concentrations and number of follicles on the day of hCG administration, the presence of PCO and the number of oocytes retrieved may be subject to inter-observer and inter-operator variations. As individual markers of OHSS, each of these factors predicts less than a quarter of cases of the syndrome. It has been shown that a combination of pretreatment diagnosis of PCO along with number of follicles on the day of hCG administration and ‘VEGF rise’ gives the highest prediction rates for the risk of developing OHSS. Neither pathogenesis nor prevention and treatment of OHSS are specific. Therefore, at present, OHSS remains a condition that cannot be avoided altogether.     

Granulomatous inflammation in Acanthamoeba sclerokeratitis

This report describes the histopathological findings in a patient with Acanthamoeba sclerokeratitis (ASK). A 58-year-old patient with ASK underwent enucleation and sections of the cornea and sclera were subjected to histopathology and immunohistochemistry with monoclonal mouse antihuman antibodies against T cell CD3 and B cell CD20 antigens. Hematoxylin and Eosin stained sections of the cornea revealed epithelial ulceration, Bowman''s membrane destruction, stromal vascularization, infiltration with lymphocytes, plasma cells, and granulomatous inflammation with multinucleated giant cells (MNGC). The areas of scleritis showed complete disruption of sclera collagen, necrosis and infiltration with neutrophils, macrophages, lymphocytes, and granulomatous inflammation with MNGC. No cyst or trophozoites of Acanthamoeba were seen in the cornea or sclera. Immunophenotyping revealed that the population of lymphocytes was predominantly of T cells. Granulomatous inflammation in ASK is probably responsible for the continuance and progression of the scleritis and management protocols should include immunosuppressive agents alongside amoebicidal drugs.     

Comparative bioavailability of rifampicin, isoniazid and pyrazinamide from a four drug fixed dose combination with separate formulations at the same dose levels

Fixed dose combination (FDC) formulations became popular in the treatment of tuberculosis (TB) because of the better patient compliance, reduced risk of monotherapy and emergence of drug resistance in contrast to treatment with separate formulations of two to four first-line drugs. However, its successful implementation in national programs is limited by probable bioinequivalency of rifampicin if present in FDC form. In this regard, World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. Hence, bioequivalence study of four drug FDC tablet was conducted using 22 healthy male volunteers according to WHO recommended protocol to determine bioavailability of rifampicin, isoniazid and pyrazinamide compared to standard separate combination at the same dose level. The study was designed as two period, two treatment crossover experiment with a washout period of 1 week. Bioequivalence of rifampicin was estimated by plasma and urinary method for both rifampicin and its active metabolite, des-acetyl rifampicin whereas isoniazid and pyrazinamide were estimated from plasma. Mean concentration time profiles and all the pharmacokinetic parameters of rifampicin, isoniazid and pyrazinamide from FDC tablet were comparable to individual formulations and passed the bioequivalence test with power of the test above 95%. Further, bioequivalence of both rifampicin and isoniazid shows that in vitro interaction of rifampicin and isoniazid is clinically insignificant. Thus, it was concluded that FDC formulation is bioequivalent for rifampicin, isoniazid and pyrazinamide and ensures the successful treatment of TB without compromising therapeutic efficacy of any of these components of anti-TB therapy.     

Pre-operative variables affecting final vision outcome with a critical review of ocular trauma classification for posterior open globe (zone III) injury

Purpose:

To identify pre-operative variables affecting the outcome of posterior open globe (zone III) injuries. Secondary objective was to re-look at the definition or landmarks for zone III injury and its clinical significance for predicting visual prognosis following open globe injury.

Materials and Methods:

Retrospective review of medical records of all hospitalized patients with surgical repair of open globe injury over last 10 years at a tertiary referral eye care center in Singapore. Out of 172 eyes with open globe injury, 28 eyes (16.3%) with zone III injury was identified and reviewed further. Pre-operative visual acuity (VA) and other variables, extent of scleral wound in reference to rectus insertion, relative afferent pupillary defect (RAPD) and final vision outcome were recorded.

Results:

Median age was 37 years with male predilection (92.9%). Mean follow-up was 12.9 months. Pre-operative VA was no light perception (NLP) in 16 (57.1%) eyes. Final VA remained NLP in 14 eyes (50.0%). The factors contributing to poor post-operative vision based on univariate regression analysis were the presence of RAPD, poor pre-operative VA, blunt trauma, extent of trauma, associated traumatic cataract, hyphema, vitreous loss and associated vitreo-retinal trauma. Further on, zone III injuries with scleral wound limited anterior to rectus insertion (6 eyes) had better vision outcome than those with injuries extending beyond rectus insertion (22 eyes).

Conclusion:

Initial VA, blunt ocular trauma, visual axis involvement, loss of light perception, presence of RAPD, traumatic cataract, hyphema, vitreous loss were the important determinants for final visual outcome in patients with zone III injury. Wound extending posterior to rectus insertion has poorer outcome as those limited anterior to rectus insertion. We suggest that there may be a need to relook at zone III injuries with reference to rectus insertion for prognostic significance, and further studies are warranted.