Sensitization of adenylate cyclase by Galpha i/o-coupled receptors

Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. This heterologous sensitization of cyclic AMP signaling, also called superactivation or supersensitization, likely represents a cellular adaptive response, a mechanism by which the cell compensates for chronic inhibitory input. Recent advances in our knowledge of G protein-mediated signaling, regulation of adenylate cyclase, and other cellular signaling mechanisms have extensively increased our insight into the mechanisms and significance of this phenomenon. In particular, recent evidence points to the Galpha(s)-adenylate cyclase interface as a locus for the expression of the sensitized adenylate cyclase response, and to isoform-specific phosphorylation of adenylate cyclase as one mechanism that can produce sensitization. Galpha i/o-coupled receptor-induced heterologous sensitization may contribute to enhanced Galpha(s)-coupled receptor signaling following neurotransmitter elevations induced by the administration of drugs of abuse and during other types of neuronal function or dysfunction. This review will focus on recent advances in our understanding of signaling pathways that are involved in sensitization and describe the potential role of sensitization in neuronal function.     

Transcatheter closure of atrial septal defects

Transcatheter closure of atrial septal defects has evolved significantly over the last 20 years. Transcatheter closure has replaced surgical closure for the treatment of most secundum atrial septal defectsat the current time. A major reason for this is the lower morbidity of transcatheter closure procedures. Several closure devices have come into clinical use. The Amplatzer septal occluder (AGA Medical Co.) currently has the largest reported experience and subsequently the best-established safety and efficacy features. Clinically challenging situations, such as larger atrial septal defects, atrial septal defects with deficient rims and multiple atrial septal defects, are increasingly being addressed using the transcatheter approach, with improved results. The incidence of most complications has significantly reduced over time, and serious side effects are relatively uncommon. In this review, the literature is summarized regarding the current role of transcatheter closure, the evolution of the different available devices for clinical use and the complications that occur with their use. A comparison is also made with surgical closure techniques.     

Selective regulation of beta-1 and beta-2 adrenergic receptors by atypical agonists

The interactions of the atypical agonists pindolol and celiprolol with beta adrenergic receptors were compared with those of the full agonist, isoproterenol. Studies were carried out using intact cells as well as membranes prepared from C6 glioma cells. Computer-assisted analysis of dose-response curves resulting from the inhibition of the binding of [125I]iodopindolol by the beta-1 and beta-2 selective compounds ICI 89,406 and ICI 118,551 revealed that approximately one-third of the beta adrenergic receptors on these cells were beta-1 receptors. Addition of GTP to the binding assay simplified the dose-response curve for inhibition of the binding of [125I]iodopindolol by isoproterenol and diminished the potency of the agonist. GTP had no effect on the binding of pindolol or celiprolol, suggesting that these drugs do not induce the formation of a ternary complex with the receptor and the guanine nucleotide-binding protein for stimulation of adenylate cyclase activity. When added to the growth medium of intact C6 cells, isoproterenol induced a 40-fold increase in cyclic AMP accumulation. Pindolol and celiprolol, however, caused no elevation of enzyme activity. Addition of isoproterenol to the growth medium of intact cells resulted in an 80% decrease in the density of both beta-1 and beta-2 adrenergic receptors within 8 hr. Growing cells in the presence of pindolol or celiprolol induced a 50% decrease in the density of beta-2 receptors, which was inhibited by beta adrenergic antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

De novo membranoproliferative glomerulonephritis III in a renal transplant patient: case report and review of the literature

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a rare cause of renal failure with a cumulative incidence of 0.3% of all ESRD and 4% of all primary glomerulonephritis for types I and II. Membranoproliferative glomerulonephritis type III is more uncommon and idiopathic de novo MPGN III in a renal transplant patient has not been reported. We present the case of a 57-year old white female patient with a diagnosis of lithium toxicity as cause of end stage renal disease (ESRD) who developed MPGN III in her allograft 6 years after a renal transplant. Despite treatment, she progressed to ESRD within four and a half years from the time of diagnosis.     

Radiation-induced oesophagitis in lung cancer patients

Background

Radiation-induced oesophagitis is a major side effect of concurrent chemotherapy and radiotherapy. A strong association between neutropenia and oesophagitis was previously shown, but external validation and further elucidation of the possible mechanisms are lacking.

Methods and patients

A total of 119 patients were included at two institutions. The concurrent group comprised 34?SCLC patients treated with concurrent carboplatin and etoposide, and concurrent chest irradiation, and 36?NSCLC patients with concurrent cisplatin and etoposide, and concurrent radiotherapy, while the sequential group comprised 49?NSCLC patients received sequential cisplatin and gemcitabine, and radiotherapy.

Results

Severe neutropenia was very frequent during concurrent chemoradiation (grade: 4 41.4%) and during induction chemotherapy in sequentially treated patients (grade?4: 30.6%), but not during radiotherapy (only 4% grade?1). In the concurrent group, the odds ratios of grade?3 oesophagitis vs. neutropenia were the following: grade?2 vs. grade?0/1: 5.60 (95% CI 1.55–20.26), p?=?0.009; grade?3 vs. grade?0/1: 10.40 (95% CI 3.19–33.95); p?=?0.0001; grade?4 vs. grade?0/1: 12.60 (95% CI 4.36–36.43); p?Conclusion We confirm that neutropenia is independently correlated with oesophagitis in concurrent chemoradiation, but that the susceptibility for chemotherapy-induced neutropenia is not associated with radiation-induced oesophagitis. Further studies focusing on the underlying mechanisms are thus warranted.     

Socioeconomic disparities in the uptake of breast and cervical cancer screening in Italy: a cross sectional study

Background

Malaria during pregnancy is a major public health problem in Nigeria leading to increase in the risk of maternal mortality, low birth weight and infant mortality. This paper is aimed at highlighting key predictors of the ownership of insecticide treated nets (ITNs) and its use among pregnant women in Nigeria.

Methods

A total of 2348 pregnant women were selected by a multi-stage probability sampling technique. Structured interview schedule was used to elicit information on socio-demographic characteristics, ITN ownership, use, knowledge, behaviour and practices. Logistic regression was used to detect predictors of two indicators: ITN ownership, and ITN use in pregnancy among those who owned ITNs.

Results

ITN ownership was low; only 28.8% owned ITNs. Key predictors of ITN ownership included women who knew that ITNs prevent malaria (OR = 3.85; p < 0001); and registration at antenatal clinics (OR = 1.34; p = 0.003). The use of ITNs was equally low with only 7.5% of all pregnant women, and 25.7% of all pregnant women who owned ITNs sleeping under a net. The predictors of ITN use in pregnancy among women who owned ITNs (N = 677) identified by logistic regression were: urban residence (OR = 1.87; p = 0.001); knowledge that ITNs prevent malaria (OR = 2.93; p < 0001) and not holding misconceptions about malaria prevention (OR = 1.56; p = 0.036). Educational level was not significantly related to any of the two outcome variables. Although registration at ANC is significantly associated with ownership of a bednet (perhaps through free ITN distribution) this does not translate to significant use of ITNs.

Conclusions

ITN use lagged well behind ITN ownership. This seems to suggest that the current mass distribution of ITNs at antenatal facilities and community levels may not necessarily lead to use unless it is accompanied by behaviour change interventions that address the community level perceptions, misconceptions and positively position ITN as an effective prevention device to prevent malaria