Daily profile of circulating C-type natriuretic peptide in pre-ascitic cirrhosis and in normal subjects: relationship with renal function

OBJECTIVE: To investigate whether the C-type natriuretic peptide (CNP) has a role in the regulation of fluid and sodium homeostasis in normal subjects and in pre-ascitic cirrhotic patients. MATERIAL AND METHODS: The daily profile of CNP plasma levels was assessed by serial measurements (0700 h, 0900 h, 1800 h, 2300 h) in 10 pre-ascitic cirrhotic outpatients (age 56+/-4 years) and in 10 age-matched healthy controls (54+/-2 years) on a normal sodium diet (150 mmol/day) while carrying on their usual activities (mobile from 0700 h to 2200 h), after an equilibration period of 5 days. Daily diuresis and natriuresis were also monitored. RESULTS: Mean daily CNP was comparable in cirrhotic and healthy subjects (3.64+/-0.32 versus 3.20+/-0.20 pg/ml; p=0.139); CNP concentration showed a tendency towards a circadian fluctuation in healthy subjects (p=0.053) but not in patients (p=0.171). Mean daily CNP concentration significantly correlated with 24-h natriuresis (r=0.709; p=0.022) and urine volume (r=0.745; p=0.013) in patients but not in healthy subjects. CONCLUSIONS: CNP plasma levels appear to play a role in the water-sodium balance regulation in patients with pre-ascitic cirrhosis.     

The hand: a reflection of arthritis

Hand joint involvement in rheumatic diseases is often precocious and predominant as compared to other skeleton-muscular regions. Clinical examination not always allows for easy detection of fluid outpouring and synovial involvement, and undoubtedly does not allow to diagnose pathognomonic bone alterations of several rheumatic conditions. Articular ultrasonography is an innocuous methodology, easily reproducible and directly applied by a rheumatologist. The aim of this vignette is to present ultrasonography elementary lesions of the hand for a prompt diagnosis.     

Extrinsic compression of left main coronary artery from aneurysmal dilation of pulmonary trunk in a adolescent: involution after surgery occlusion of sinus venosus atrial septal defect and pulmonary trunk plasty for reduction

We report the case of an adolescent referred with initial diagnosis of pulmonary hypertension. Non-invasive investigation disclosed a sinus venous atrial septal defect with pulmonary hypertension. The hemodynamic study confirmed diagnosis, and also showed extrinsic compression of left main coronary artery by pulmonary trunk. Surgical closure of the defect in addition to pulmonary trunk plasty were undertaken. Two years after the surgery the patient is well, with clinical signs of mild pulmonary hypertension, and showing no evidence--also on echocardiogram--of left coronary artery trunk obstruction.     

Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3',5'-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling

Among its pleiotropic actions, ghrelin modulates insulin secretion and glucose metabolism. Herein we investigated the role of ghrelin in pancreatic beta-cell proliferation and apoptosis induced by serum starvation or interferon (IFN)-gamma/TNF-alpha, whose synergism is a major cause for beta-cell destruction in type I diabetes. HIT-T15 beta-cells expressed ghrelin but not ghrelin receptor (GRLN-R), which binds acylated ghrelin (AG) only. However, both unacylated ghrelin (UAG) and AG recognized common high-affinity binding sites on these cells. Either AG or UAG stimulated cell proliferation through Galpha(s) protein and prevented serum starvation- and IFN-gamma/TNF-alpha-induced apoptosis. Antighrelin antibody enhanced apoptosis in either the presence or absence of serum but not cytokines. AG and UAG even up-regulated intracellular cAMP. Blockade of adenylyl cyclase/cAMP/protein kinase A signaling prevented the ghrelin cytoprotective effect. AG and UAG also activated phosphatidyl inositol 3-kinase (PI3K)/Akt and ERK1/2, whereas PI3K and MAPK inhibitors counteracted the ghrelin antiapoptotic effect. Furthermore, AG and UAG stimulated insulin secretion from HIT-T15 cells. In INS-1E beta-cells, which express GRLN-R, AG and UAG caused proliferation and protection against apoptosis through identical signaling pathways. Noteworthy, both peptides inhibited cytokine-induced NO increase in either HIT-T15 or INS-1E cells. Finally, they induced cell survival and protection against apoptosis in human islets of Langerhans. These expressed GRLN-R but showed also UAG and AG binding sites. Our data demonstrate that AG and UAG promote survival of both beta-cells and human islets. These effects are independent of GRLN-R, are likely mediated by AG/UAG binding sites, and involve cAMP/PKA, ERK1/2, and PI3K/Akt.     

Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor

INTRODUCTION: Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT). PATIENTS AND METHODS: Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing. RESULTS: Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95% confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest. CONCLUSION: Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.     

The anorexia of aging

Malnutrition in the elderly is one of the greatest threats to health, well-being and autonomy, it is therefore crucial to understand and to contrast the causal factors of inadequate energy intake. This review focuses on the mechanisms of the so-called 'anorexia of aging'. In recent years, it has been shown that elderly subjects have abnormal peripheral signal patterns and alterations in central hypothalamic control relays. Negative feedback from impaired gastric motility, exaggerated long-term adiposity signals (leptin, insulin) and postprandial anorexigenic signals (CCK, PYY) seem to prevail over the central feeding drive. If nutritional strategies of intervention are to be improved, these data need to be taken into account.     

Continuous evidence of fast HIV disease progression related to class-wide resistance to antiretroviral drugs: a 6 year follow-up analysis of a large observational database

Class-wide resistance (CWR) was increasingly associated with a higher risk of HIV progression after 72 months of follow-up among 1392 patients genotypic-tested after failure (AIDS risk 13% for no CWR to 34% for three CWR; AIDS/death risk 21-54%). At multivariate analysis, the detection of two and three CWR was significantly associated with a two and threefold increased risk, respectively, of death and AIDS/death, suggesting that extended resistance is a marker of disease progression in long-term observation.     

Treatment at scale in Brazil: a physician's perspective

In 1996, Brazil became the first developing country to provide universal access to antiretroviral therapy (ART), based on a strategy that utilizes an individualized approach to treatment and an open formulary. At the time, the number of patients in need of treatment was less than 15% of what it is today, there were six approved drugs for the treatment of HIV infection (compared with 25 today), and the life expectancy of patients was measured in months and years, not in decades. In recent years, preventable and treatable conditions such as cardiovascular diseases increased significantly faster as causes of death among HIV-infected individuals than in the general population. In the near future there will be a substantial increase in the number of patients in need of therapy and in the number of patients using more complex regimens who also have co-morbidities that impact prognosis. Brazil will thus need to expand its network of treatment facilities, increase its capacity to manage more complex clinical conditions, and decide on the proper balance of sophistication that will be required. As the Brazilian scientific output is not commensurate with its successes in the treatment and prevention of HIV infection, there is little empirical basis to inform decisions on how best to allocate finite resources. The Brazilian response to the HIV/AIDS epidemic, universal access to ART in particular, is an example to other developing countries. The Brazilian experience also shows that operational research should be an integral part of programmes of access to treatment, if their long-term sustainability is to be ensured.