A pyridazine series of alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety

The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.     

The L-type calcium channel blocker nimodipine mitigates cytoskeletal proteins phosphorylation in dichlorvos-induced delayed neurotoxicity in rats

The present investigation was carried out to assess the protective efficacy of nimodipine against dichlorvos-induced organophosphate induced delayed neurotoxicity (OPIDN). Single subcutaneous dose of dichlorvos (200 mg/kg body weight) led to a consistent increase in the activity of both microtubule associated protein kinases viz. Ca2+/Calmodulin-dependent and cAMP dependent protein kinases, at all post exposure intervals (day 7, 15 and 21) as compared to that of controls. Autoradiography followed by microdensitometric studies demonstrated enhanced phosphorylation of 55 kDa and 280 kDa proteins in dichlorvos-exposed animals. These two proteins were confirmed to be tubulin and microtubule associated protein-2 (MAP-2) by western blotting. The hyperphosphorylation of these two proteins was shown to interfere with the assembly of neuronal microtubules as shown by electron microscopic studies that may eventually lead to possible disruption of neuronal cytoarchtecture resulting in axonal degeneration. Administration of nimodipine along with dichlorvos brought about a significant reduction in the activities of both the kinases as well as the extent of microtubule associated protein phosphorylation. This indicates that nimodipine, a centrally acting calcium channel blocker, may contribute to the amelioration of dichlorvos induced neurotoxicity by attenuation of calcium mediated disruption of cytoskeletal proteins and hence, calcium channel blockers like nimodipine have great future as new therapeutic agents for OPIDN.     

Diffuse Colonic Lipomatosis,Presenting as Perforation Peritonitis and Mimicking Carcinoma Colon

Lipomas and lipomatosis of colon are rare in clinical practice. We herein report a case of diffuse colonic lipomatosis, fifth such case in literature which presented as perforation peritonitis, a presentation, never been reported earlier. On laparotomy, the findings suggested malignancy and appropriate surgery was done. Diffuse Colonic Lipomatosis, a rare and benign condition mimicks malignancy and should be kept as a differential diagnosis is unusual cases of colonic perforations.     

Interaction of passive smoking with GST (GSTM1, GSTT1, and GSTP1) genotypes in the risk of cervical cancer in India

Human papilloma virus (HPV) infection is a major cause of cervix cancer, but a number of infected women do not develop invasive lesions, suggesting that HPV infection in itself is not a sufficient factor and that other cofactors, such as smoking, play an important role in development of cervix cancer. Alongside active cigarette smoking, passive smoking is an independent risk factor for cervix cancer. Smoking maintains cervical HPV infection longer and decreases potential of clearing an oncogenic infection. Thus, it is quite possible that polymorphism at detoxifying enzyme coding loci such as GSTM1, GSTT1, and GSTP1 may determine susceptibility to cervix cancer. This study evaluates the combined effects of genetic polymorphisms of GSTM1, GSTT1, and GSTP1 on susceptibility to cervical cancer and interaction of these genes with smoking. On individual analysis of GSTM1, GSTT1, and GSTP1, it was observed that passive smokers having genotypes GSTM1 (null) (OR = 7.0, 95% CI = 2.19-22.36, P = 0.0005), GSTT1 (null) (OR = 10.2, 95% CI = 1.23-84.18, P = 0.02), and GSTP1 (ile/val) (OR = 6.4, 95% CI = 2.25-18.38, P = 0.0005) have an increased risk of developing cervix cancer. It is thus concluded that cervical cancer risk is increased in passive smokers with GSTM1 (null), GSTT1 (null), and GSTP1 (ile/val) genotypes.     

CD4+ T-helper cells stimulated in response to placental ischemia mediate hypertension during pregnancy

We have shown that hypertension in response to chronic placental ischemia is associated with elevated inflammatory cytokines and CD4(+) T cells. However, it is unknown whether these cells play an important role in mediating hypertension in response to placental ischemia. Therefore, we hypothesize that reduced uterine perfusion pressure (RUPP)-induced CD4(+) T cells increase blood pressure during pregnancy. To answer this question, CD4(+) T cells were isolated from spleens at day 19 of gestation from control normal pregnant (NP) and pregnant RUPP rats, cultured, and adjusted to 10(6) cells per 100 μL of saline for intraperitoneal injection into NP rats at day 13 of gestation. On day 18, in the experimental groups of rats, arterial catheters were inserted, and on day 19 mean arterial pressure was analyzed. Inflammatory cytokines and antiangiogenic factor soluble fms-like tyrosine kinase 1 were determined via ELISA. Mean arterial pressure increased from 104±2 mm Hg in NP rats to 124±2 mm Hg in RUPP rats (P<0.001) and to 118±1 mm Hg in rats receiving RUPP CD4(+) T cells (P<0.001). Circulating tumor necrosis factor-α and soluble fms-like tyrosine kinase 1 were elevated in recipients of RUPP CD4(+) T cells to levels similar to control RUPP rats. In contrast, virgin rats injected with NP or RUPP CD4(+) T cells exhibited no blood pressure changes compared with control virgin rats. Importantly, mean arterial pressure did not change in recipients of NP CD4(+) T cells (109±3 mm Hg). These data support the hypothesis that RUPP-induced CD4(+) T cells play an important role in the pathophysiology of hypertension in response to placental ischemia.     

Can Chiari malformation negatively affect higher mental functioning in developmental age?

Numerous studies on adults have confirmed that the cerebellum has a role in processing higher brain functions, and evidence of this role has emerged more recently in developmental age as well. Various types of congenital lesion are associated with neuropsychological impairments and behavioral changes that can sometimes even give rise to a picture of autism. Acquired cerebellar lesions (especially tumors and stroke) in children of normal intelligence have enabled different neuropsychological profiles to be identified, depending on the cerebellar site involved. In Chiari malformation, the cerebellar structures are squeezed and crowded inside the posterior fossa and along the time this could generate various kinds of cognitive and behavioral disorders. Currently available data remain inconclusive, however, and prospective longitudinal studies on sizable series will be needed to ascertain whether and to what degree Chiari malformations may negatively affect mental functioning in developmental age.     

Prospective validation of the provisional criteria for the evaluation of response to therapy in childhood‐onset systemic lupus erythematosus

Objective

To prospectively validate the provisional criteria for the evaluation of response to therapy in children with systemic lupus erythematosus (SLE).

Methods

In this multicenter study, childhood‐onset SLE patients (n = 98; 81 girls, 17 boys, 50% white, 88% non‐Hispanic) were followed every 3 months for up to 7 visits (total number of visits 623). The 5 childhood‐onset SLE core response variables were obtained at the time of each visit: 1) physician assessment of overall disease activity, 2) parent assessment of patient well‐being, 3) Child Health Questionnaire, 4) proteinuria, and 5) global disease activity measure score, as measured by the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), or the Systemic Lupus Activity Measure (SLAM). Physician‐rated relevant changes in the disease course (clinically relevant improvement, no change in disease, or worsening) between visits served as the criterion standard. Mixed models were used to assess the diagnostic accuracy of the 4 highest‐ranked provisional definitions of response to therapy.

Results

There were 89 episodes of clinically relevant improvement between 2 consecutive visits, and 448 episodes without improvement. Irrespective of the choice of the global disease activity measure (ECLAM, SLAM, SLEDAI), sensitivities of all 4 highest‐ranked definitions were low (all ≤31%), whereas their specificities were excellent (all >88%). Using logistic models, alternative definitions can be developed with both 80% sensitivity and specificity.

Conclusion

The provisional criteria of response to therapy in childhood‐onset SLE may have considerably lower sensitivity than previously reported. Additional validation in clinical trials is necessary to further evaluate the measurement properties of the provisional Paediatric Rheumatology International Trials Organisation/American College of Rheumatology criteria for response to therapy in children with SLE.