Exhaled nitric oxide levels in infants with chronic lung disease

Chronic lung disease (CLD) is an inflammatory disorder; in patients with other inflammatory disorders exhaled nitric oxide (NO) levels are elevated. The aim of this study was to test the hypothesis that prematurely born infants with CLD would have elevated exhaled NO levels compared to those without CLD and healthy term-born infants. Ten infants with CLD (median gestational age 26 weeks; CLD group), ten infants without CLD (median gestational age 32 weeks; non-CLD group) and ten term-born infants (term group) were examined at post-conceptional ages between 36 and 45 weeks. NO levels were measured during spontaneous tidal breathing. A facemask was positioned over the infants nose and mouth and a sampling catheter was inserted through a small leak-free valve into the facemask. To measure nasal NO, the tip of the sampling catheter was placed in the nasal space and to measure facemask NO, the catheter tip was positioned inside the facemask at the infants lips. Nasal compared to facemask NO levels were higher in all three groups (CLD; non-CLD; term: P =0.017, P =0.012 and P =0.017, respectively). The CLD group had higher peak nasal and facemask NO levels than the non-CLD ( P =0.011 and P =0.034 respectively) and the term ( P =0.005 and P =0.01 respectively) infants. Regression analysis demonstrated that facemask NO levels were significantly related to CLD, independent of gestational, post-natal and post-conceptional age ( P =0.006). Conclusion:our results suggest that exhaled nitric oxide levels are elevated in chronic lung disease infants. Facemask measurement of nitric oxide levels might be a potentially useful method to monitor infants with chronic lung disease.Abbreviations CLD chronic lung disease - NO nitric oxide     

Human angiotensin II type-2 receptor inhibition of insulin-mediated ERK-2 activity via a G-protein coupled signaling pathway

While it has been shown that the angiotensin type-2 (AT(2)) receptor plays an important role in the development and differentiation of many tissues, the second messengers involved in its signaling pathways are just beginning to be understood. To further determine the signaling pathways for the AT(2) receptor, we have investigated whether human angiotensin type-2 receptor transfected into Chinese hamster ovary (CHO) cells can modulate insulin-induced extracellular signal-related protein kinase (ERK-2) phosphorylation via a G-protein coupled mechanism. Our results indicate that the human AT(2) receptor decreases insulin-induced ERK-2 phosphorylation through a G-protein mediated pathway since inhibition was attenuated by pertussis toxin (a G(i)/G(0) inhibitor). Our findings further indicate that the inhibitory response was insensitive to sodium orthovanadate (a PTPase inhibitor), but sensitive (attenuated) to okadaic acid, suggesting an important role for protein phosphatase 2A (PP2A). We have also shown that alanine substitution of the putative G-protein coupling DRY(141-143) motif of the second intracellular loop significantly decreases the human AT(2) receptor's ability to inhibit insulin-induced ERK-2 phosphorylation. Our results support the hypothesis that the AT(2) receptor inhibits insulin-induced ERK-2 activity via a G-protein coupled pathway involving the up-regulation of PP2A.     

Chemotherapy for gastro-enteropancreatic endocrine tumours

Despite similar histological and morphological aspects, gastro-enteropancreatic (GEP) endocrine tumours represent a heterogeneous group of tumours with varying clinical expression depending on tumour type (functional or not), origin and extension, but also on histological differentiation and proliferative capacity. The natural history of well-differentiated tumours is often favourable without treatment and GEP endocrine tumours may remain indolent for many years. Chemotherapy may however be indicated in the presence of symptomatic non-progressive disease (progression evaluated over 3-6 months). In contrast, poorly differentiated GEP endocrine tumours are frequently aggressive and early treatment is required. Accurate staging is mandatory and where surgery is possible (even in the event of limited metastatic disease), this option should be re-evaluated in a multidisciplinary approach. Approximately 2/3 of malignant GEP tumours are metastatic at discovery and surgery is possible in a minority of patients; therefore, chemotherapy, with/without other strategies (e.g. local ablation), is frequently indicated in patients with symptomatic, bulky or progressive disease. For well-differentiated pancreatic tumours, the reference association is Adriamycin with streptozotocin yielding objective responses (OR) in 40-60% of patients. Prolonged treatment is limited due to potential cardiotoxicity of Adriamycin and standard 2nd-line regimens are not of proven efficacy; thus, other treatment modalities are usually additionally required (e.g. chemo-embolisation). A significant OR may render a small number of patients secondarily amenable to surgery. Published series evaluating chemotherapy for midgut endocrine tumours are outdated and disappointing. Objective response rates with combined associations (including either 5-fluorouracil and/or streptozotocin) rarely exceed 20% and where possible, chemo-embolisation for hepatic metastases combined with somatostatin analogues (+/- interferon) should be preferred. Poorly differentiated GEP tumours are generally aggressive tumours with metastases at diagnosis and tend to progress rapidly. Surgery is rarely possible and ineffective even in locally advanced disease due to a high risk of recurrence. Chemotherapy, using cisplatin and etoposide, is the reference treatment and frequently yields OR rates >50%. However, despite being chemosensitive, disease control is limited (8-10 months). Overall, advances in therapeutic chemotherapeutic options are required in the management of all types of advanced GEP endocrine tumours and evaluation of new drugs (e.g. irinotecan) and combination strategies (chemotherapy with local ablative therapies) are required in the future.     

Distinguishing roles for norepinephrine and serotonin in the behavioral effects of antidepressant drugs

Antidepressant drugs have typically been classified into sets of compounds with actions targeted at serotonin (selective serotonin reuptake inhibitors [SSRIs]), norepinephrine (norepinephrine reuptake inhibitors [NRIs]), or both neurotransmitters (serotonin-norepinephrine reuptake inhibitors). Their classification has been based predominantly on their acute pharmacologic effects, usually determined by in vitro radioligand binding assays. The pharmacologic selectivity of antidepressants can be altered after their systemic administration, however, by dose, drug metabolism, physiologic interactions between neurotransmitters, and adaptive effects that emerge after chronic administration. This review examines whether pharmacologic selectivity is maintained by different types of antidepressants in vivo and whether pharmacologic selectivity matters for the production of their behavioral effects. Antidepressants increase extracellular levels of neurotransmitters according to their ability to inhibit presynaptic transporters, although physiologic interactions among neurotransmitters can influence antidepressants' selectivity in certain brain regions. Chronic administration of many antidepressants also causes down-regulation of postsynaptic and presynaptic receptors. The pattern of responses of presynaptic markers suggests that pharmacologic selectivity is maintained after chronic administration of many antidepressants. Behavioral tests indicate that depletion of serotonin (5-HT) is capable of preventing the effects produced by SSRIs but not NRIs. The depletion of catecholamines also inhibits the effects of NRIs, although test results can be complicated by inhibition of motor activity. Depletion of norepinephrine may also inhibit the effects of some SSRIs, but not highly selective SSRIs like citalopram. Although the pattern of results from in vivo tests supports the concept that parallel neurotransmitter mechanisms lead to antidepressant activity, norepinephrine may participate in the effects of some SSRIs. It is also possible that compounds with dual actions at 5-HT and norepinephrine systems may be effective under circumstances in which selective antidepressants are ineffective.     

Purified complexes of HIV-1 envelope glycoproteins with CD4 and CCR5(CXCR4): production, characterization and immunogenicity

The ability to readily elicit broadly neutralizing antibodies to HIV-1 remains elusive. We and others have hypothesized that interaction of the viral envelope glycoprotein (Env, gp120-gp41) with its receptor molecules could enhance the exposure of conserved epitopes that may facilitate the elicitation of broadly neutralizing antibodies. The Env-CD4-coreceptor complexes mediate HIV-1 entry into cells and serve as a major target for inhibitors of this process. To begin to evaluate their potential also as vaccine immunogens we produced relatively large amounts of complexes of purified recombinant soluble truncated Env, gp140(89.6) or gp120(89.6), with CD4 and CCR5 or CXCR4. We found that gp140(gp120)-CD4-CCR5 complexes are stable and immunogenic in mice transgenic for human CD4 and CCR5. They elicited anti-gp120 and anti-gp140 antibodies that inhibited an heterologous primary HIV-1 isolate (JR-FL) with two- to threefold higher neutralizing activity than those elicited by gp120 and gp140. The antibodies elicited by the complexes competed better with the antibodies X5 and CG10 but not with b12 for binding to gp120 and gp120-CD4 complexes compared to those elicited with gp140(120) alone. These findings suggest that stable purified Env-CD4-CCR5(CXCR4) complexes can be produced in relatively large amount sufficient for their further characterization that may help in the development of novel vaccines candidates.