Compartment‐specific regulation of plasma membrane calcium ATPase type 2 in the chick auditory brainstem

Calcium signaling plays a role in synaptic regulation of dendritic structure, usually on the time scale of hours or days. Here we use immunocytochemistry to examine changes in expression of plasma membrane calcium ATPase type 2 (PMCA2), a high‐affinity calcium efflux protein, in the chick nucleus laminaris (NL) following manipulations of synaptic inputs. Dendrites of NL neurons segregate into dorsal and ventral domains, receiving excitatory input from the ipsilateral and contralateral ears, respectively, via nucleus magnocellularis (NM). Deprivation of the contralateral projection from NM to NL leads to rapid retraction of ventral, but not the dorsal, dendrites of NL neurons. Immunocytochemistry revealed symmetric distribution of PMCA2 in two neuropil regions of normally innervated NL. Electron microscopy confirmed that PMCA2 localizes in both NM terminals and NL dendrites. As early as 30 minutes after transection of the contralateral projection from NM to NL or unilateral cochlea removal, significant decreases in PMCA2 immunoreactivity were seen in the deprived neuropil of NL compared with the other neuropil that continued to receive normal input. The rapid decrease correlated with reductions in the immunoreactivity for microtubule‐associated protein 2, which affects cytoskeleton stabilization. These results suggest that PMCA2 is regulated independently in ventral and dorsal NL dendrites and/or their inputs from NM in a way that is correlated with presynaptic activity. This provides a potential mechanism by which deprivation can change calcium transport that, in turn, may be important for rapid, compartment‐specific dendritic remodeling. J. Comp. Neurol. 514:624–640, 2009. © 2009 Wiley‐Liss, Inc.     

Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness

Transforming growth factor beta (TGFbeta) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGFbeta pathway in tumor cells often leads to resistance to the antiproliferative effects of TGFbeta while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGFbeta receptor I kinase (TGFbetaRI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGFbeta-dependent Smad2 phosphorylation and expression of TGFbeta-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGFbeta-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGFbeta-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGFbeta signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGFbetaRI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.     

Peripheral generators of the vestibular evoked potentials (VsEPs) in the chick.

Electrophysiological activity in response to linear acceleration stimuli was recorded from young chickens by means of subcutaneous electrodes. This investigation had 2 purposes: (1) to establish the vestibular origin of the potentials; and (2) to investigate the contribution of each vestibular labyrinth to the response. The stimuli consisted of pulses of linear acceleration delivered by a mechanical vibrator (shaker). In the first set of experiments vestibular evoked potentials (VsEPs) were recorded prior to and 24 h after bilateral cochlea removal. In the second set of experiments responses were recorded before and after unilateral or bilateral intralabyrinthine injections of tetrodotoxin (TTX). Different groups of subjects were used for each experimental condition. The general morphology of the VsEPs was maintained after bilateral cochlea removal. Absolute latency of wave P2, the most prominent component of the response, was not significantly affected by the manipulation. Unilateral intralabyrinthine TTX injections consistently prolonged the latency and reduced the amplitude of wave P2. Following binaural TTX injections we were unable to elicit responses at the acceleration levels used in this study. The results from these experiments suggest that: (1) the activity recorded in response to linear acceleration stimuli is vestibular in origin; (2) when recorded from intact animals the evoked response is composed of activity from both vestibular systems; and (3) TTX consistently blocks the activity of the vestibular portion of the VIIIth cranial nerve.     

Social and cultural factors in the successful control of tuberculosis.

The burden of tuberculosis on the public health is staggering. Worldwide, annual incidence of new cases is estimated to be about 8 million. Almost 3 million deaths occur yearly. Early case identification and adherence to treatment regimens are the remaining barriers to successful control. In many nations, however, fewer than half those with active disease receive a diagnosis, and fewer than half those beginning treatment complete it. The twin problems of delay in seeking treatment and abandonment of a prescribed regimen derive from complex factors. People's confusion as to the implications of the tuberculosis symptoms, costs of transportation to clinic services, the social stigma that attaches to tuberculosis, the high cost of medication, organizational problems in providing adequate followup services, and patients' perception of clinic facilities as inhospitable all contribute to the complexity. Sociocultural factors are emphasized in this report because hitherto they have not been adequately explored. Salient among those sociocultural factors is the health culture of the patients. That is, the understanding and information people have from family, friends, and neighbors as to the nature of a health problem, its cause, and its implications. A knowledge of the health culture of their patients has become a critical tool if tuberculosis control programs are to be successful. Several anthropological procedures are recommended to help uncover the health culture of people served by tuberculosis clinics.     

Effect of lindane on eggshell characteristics and calcium level in the domestic duck

Adult laying domestic ducks (Anas platyrhynchos domesticus) were forced fed lindane (gamma-hexachlorocyclohexane) 20 mg/kg body weight daily, thrice/week and twice/week for 8 weeks. Significant shell thinning (18-21%) was observed in ducks with daily and thrice/week lindane feeding. SEM studies of thinned eggshells revealed reduced and tightly clustered mammillae with apparent decrease in intermammillary spaces and signs of inhibition of calcite formation. Such structural changes of thinned shells were associated with a significant reduction in the level of calcium both of the plasma and of shell gland of the ducks. Simultaneously, density of the pore in the shell and pore area/cm2 of the shell in these birds were drastically reduced, presumably because of total absence of 'large' pores in such shells. Such porosity change is suggestive of reduced conductivity of eggshell implying impaired hatching success. Diethyl stilboestrol post-treatment neutralized all the adverse effects of lindane on duck eggshell, indicating induced estrogen deficiency in such birds by lindane.     

Bleeding complications in patients on celecoxib and warfarin

PURPOSE: Non-selective non-steroidal anti-inflammatory drugs (nNSAIDs) used in combination with warfarin are associated with an approximately 3-fold increased risk of upper gastrointestinal bleeding (UGIB) compared with warfarin alone. Celecoxib, a selective inhibitor of cyclo-oxygenase 2 (COX-2), is associated with less gastric mucosal injury and platelet dysregulation than nNSAIDs. We compared rates of bleeding complications in patients taking celecoxib and warfarin with those taking warfarin alone. SUBJECTS AND METHODS: We performed a retrospective analysis using data from our Protime Clinic and pharmacy databases from January 2001 to April 2004. We identified 123 patients who took celecoxib and warfarin concurrently (overlap group). We compared rates of bleeding complications in this group with 1022 control patients who were taking warfarin alone. Bleeding complications were defined as major if they resulted in hospitalization, blood transfusion or death. RESULTS: During approximately 1063 months of exposure to both celecoxib and warfarin, 10 bleeding complications were identified, only one of which was considered major. No patients had UGIB. In the control group, 116 bleeding complications were identified over approximately 16 520 months of exposure to warfarin alone, with 101 minor and 15 major events, including six episodes of UGIB. The relative risk of all bleeding complications was 1.34 (95% CI: 0.70-2.57) in the overlap vs. control groups, and for major bleeds was 1.04 (95% CI: 0.14-7.85). CONCLUSIONS: There is a mild but non-significant increase in bleeding complications in patients taking celecoxib and warfarin compared with those taking warfarin alone.     

G1862T mutation among hepatitis B virus-infected individuals: association with viral genotypes and disease outcome in Kolkata, Eastern India

OBJECTIVE: To study the prevalence of G1862T mutation in hepatitis B virus (HBV) isolates among Eastern Indian patients and its relationship with genotypes, HBeAg status and disease manifestation. METHODS: HBV DNA was isolated from patients, amplified by nested PCR and sequenced directly. RESULTS: Of the 102 patients, 32 were HBeAg positive and 70 HBeAg negative; 55, 24 and 23 isolates were infected with genotypes D, A and C, respectively. G1862T was detected in 18 samples, 15 (83%) of them belonged to genotype A (subgenotype HBV/A1), 3 (17%) to genotype D. This mutation was more frequent in HBeAg-negative than in HBeAg-positive patients (21 vs. 9%), whereas in HBV/A1 it was as common in HBeAg-positive as in HBeAg-negative patients and significantly associated with T1762/A1764 mutation. The mean viral load was lower in patients with G1862T mutation. Furthermore, this mutation was common in various clinical outcomes. CONCLUSION: In our community, G1862T mutation was predominantly found in HBV/A1 isolates irrespective of HBeAg status. Moreover this mutation could not be correlated to the clinical outcome. These findings indicate that the G1862T mutation is probably a part of the natural variability of HBV/A1.