Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia

Campomelic dysplasia (CD) is a rare, neonatal human chondrodysplasia characterized by bowing of the long bones and often associated with male-to-female sex-reversal. Patients present with either heterozygous mutations in the SOX9 gene or chromosome rearrangements mapping at least 50 kb upstream of SOX9. Whereas mutations in SOX9 ORF cause haploinsufficiency, the effects of translocations 5' to SOX9 are unclear. To test whether these rearrangements also cause haploinsufficiency by altering spatial and temporal expression of SOX9, we generated mice transgenic for human SOX9-lacZ yeast artificial chromosomes containing variable amounts of DNA sequences upstream of SOX9. We show that elements necessary for SOX9 expression during skeletal development are highly conserved between mouse and human and reveal that a rearrangement upstream of SOX9, similar to those observed in CD patients, leads to a substantial reduction of SOX9 expression, particularly in chondrogenic tissues. These data demonstrate that important regulatory elements are scattered over a large region upstream of SOX9 and explain how particular aspects of the CD phenotype are caused by chromosomal rearrangements 5' to SOX9.     

Effects of positive and negative social exchanges with various sources on depressive symptoms in younger and older adults

Addressing a previous gap in the gerontological literature, the present study examined the effects of both positive and negative social exchanges within key relationships (spouse, children, and other relatives/friends) on the depressive symptoms of younger (28 to 59 years old) and older (60 to 92 years old) men and women. Separate analyses were carried out on younger adults (N = 452) and older adults (N = 849) who were respondents in the Americans' Changing Lives study. In both age groups, positive and negative social exchanges with the same source were significantly (p < .001), inversely related (rs range from -.23 to -.43); and positive social exchanges exerted stronger net effects on depressive symptoms than negative social exchanges. For older adults, some buffering effects were found when negative and positive social exchanges were associated with different sources; for younger adults, buffering effects were found when negative and positive social exchanges were associated with the same source. These buffering effects were not conditioned by gender. The findings of the present study highlight the importance of taking into account the age of the recipient and the provider-recipient relationship when studying the joint influence of negative and positive social exchanges on adults' depressive symptoms.     

Experimental assessment of adaptive possibilities after chronic prenatal exposure to gamma irradiation at various absorbed doses

We measured the levels of serum IgG antibodies to CD outer membrane protein of Moraxella catarrhalis, P6 outer membrane protein of non-typeable Haemophilus influenzae and capsular polysaccharides of Streptococcus pneumoniae in 168 children with otitis media with effusion (OME) who were followed prospectively, using ELISA. Serum IgG antibodies to CD, P6 and pneumococcal capsular polysaccharides were detected in all samples. The anti-pneumococcal polysaccharides antibody level was highest, followed by the anti-P6 antibody level and anti-CD antibody was lowest (median:interquartile ranges were 45.9:19.1-100 microg/ml, 15.6:9.70-23.2 microg/ml and 1.06:0.73-1.87 microg/ml, respectively). In children aged 0-6 years, there were positive correlations among the antibody levels (anti-CD vs anti-P6, r=0.325, p <0.001; anti-CD vs anti-polysaccharide, r=0.397, p <0.0001; anti-P6 vs anti-polysaccharide, r=0.175, p=0.057). However, no relationship was seen in children aged 7-15 years. Children were classified according to severity of OME during the 1-year follow-up. In children aged 0-6 years, the severity of OME correlated inversely with the levels of anti-CD antibody (r=-.23, p=0.012), of anti-P6 antibody (r=-0.292, p=0.0015), and of anti-pneumococcal polysaccharides antibody (r=-0.25, p=0.0064). However, no correlation was found between antibody levels and severity of OME in children aged 7-15 years. These data suggest that persistence and/or recurrence of OME may be due to an insufficient serum antibody response to middle ear pathogens in young children.     

Protective role of the free glucocorticoid pool in development of autoimmune hemolytic anemia

OBJECTIVE: Patients with type II diabetes mellitus have an increased risk of coronary he disease. We investigated the efficacy and safety of pravastatin in the treatment of patients with diabetic nephropathy and hypercholesterolemia. METHOD: In this 6-months study, 12 patients (4 men, 8 women, mean age 60.5 +/- 10.8 years), with diabetic nephropathy and hypercholesterolemia (fasting plasma low-density lipoprotein cholesterol levels -LDL-C- > 130 mg/dl) received pravastatin 10 mg/day. The dose could be doubled after 4 weeks. Seven patients have chronic renal failure. RESULTS: Significant reductions in LDL-C (-19.1%, p < 0.05), total cholesterol (-16%, p < 0.01), very-low-density lipoprotein cholesterol (-29.2%, p < 0.05), apolipoprotein B (-21.5%, p < 0.05), and triglycerides (-26.0%, p < 0.01) were noted. No changes were found either in high-density-cholesterol or its fractions (HDL2 and HDL3) or in apolipoprotein A plasmatic levels. Pravastatin was well tolerated and no one side effect was detected. No clinically significant changes on the control of diabetes, renal function, as assessed by plasmatic creatinin and creatinin clearance, and proteinuria were seen during the follow-up time. CONCLUSIONS: The results of the study demonstrate that pravastatin is well tolerated and effective in lowering total cholesterol and LDL-C in patients with diabetic nephropathy and hypercholesterolemia.     

Role of calcineurin in Ca2+-induced release of catecholamines and neuropeptides

Neurotransmission requires rapid docking, fusion, and recycling of neurotransmitter vesicles. Several of the proteins involved in this complex Ca2+-regulated mechanism have been identified as substrates for protein kinases and phosphatases, e.g., the synapsins, synaptotagmin, rabphilin3A, synaptobrevin, munc18, MARCKS, dynamin I, and B-50/GAP-43. So far most attention has focused on the role of kinases in the release processes, but recent evidence indicates that phosphatases may be as important. Therefore, we investigated the role of the Ca2+/calmodulin-dependent protein phosphatase calcineurin in exocytosis and subsequent vesicle recycling. Calcineurin-neutralizing antibodies, which blocked dynamin I dephosphorylation by endogenous synaptosomal calcineurin activity, but had no effect on the activity of protein phosphatases 1 or 2A, were introduced into rat permeabilized nerve terminals and inhibited Ca2+-induced release of [3H]noradrenaline and neuropeptide cholecystokinin-8 in a specific and concentration-dependent manner. Our data show that the Ca2+/calmodulin-dependent phosphatase calcineurin plays an essential role in exocytosis and/or vesicle recycling of noradrenaline and cholecystokinin-8, transmitters stored in large dense-cored vesicles.     

Trends in the management of truncal valve insufficiency

Expression of c-fos-like immunoreactivity has been used as a marker for neuronal activation and is elevated in the periaqueductal gray following stressful and noxious stimuli, and opioid withdrawal. The present study examined the staining of c-fos-like immunoreactivity following opiate withdrawal or swim-stress (2.5-3 min at 21 degrees C) in periaqueductal gray neurons of the rat which had projections to and through the rostral ventromedial medulla identified by microinjection of the retrograde tracer, Fast Blue, into the nucleus raphe magnus prior to development of morphine dependence. Both naloxone-precipitated withdrawal and swim-stress increased numbers of neurons expressing c-fos-like immunoreactivity in periaqueductal gray. Naloxone-precipitated withdrawal did not increase the number of double-labelled neurons in periaqueductal gray suggesting that neurons excited during opioid withdrawal do not project to the ventromedial medulla. In contrast, swim-stress produced increases in double-labelled neurons in periaqueductal gray suggesting that many periaqueductal gray neurons activated by swim-stress project to the ventromedial medulla. These findings suggest that naloxone-precipitated withdrawal does not activate ventrolateral periaqueductal gray neurons which are involved in descending inhibitory pathways, consistent with behavioural observations that naloxone-precipitated withdrawal is qualitatively opposite to electrical and chemical stimulation of the ventrolateral periaqueductal gray. The results are also consistent with a role of descending projections from periaqueductal gray in stress-induced antinociception.     

Lower gastrointestinal bleeding as the initial presenting symptom of renal cell carcinoma

Renal cell carcinoma is known as one of the "great mimics encountered in clinical medicine," along with syphilis and tuberculosis. It can present clinically as a wide range of symptoms, with a classic triad described as hematuria, pain, and a palpable abdominal mass. However, this triad is present only in <20% of patients with renal cell carcinoma. Gastrointestinal bleeding has been described in renal cell carcinoma, although mainly secondary to metastasis in the upper gastrointestinal tract, with few cases due to local invasion. Lower gastrointestinal bleeding as a presenting symptom of an invasive primary renal cell carcinoma has been described in only one patient in the literature. Our patient is the first in whom a colonoscopic biopsy was used as a successful diagnostic modality.     

The effects of different envelope patterns and uncertainty for the detection of a tone added to SAM complex tonal maskers

Thresholds for the detection of a tone added in-phase to the carrier of a fully modulated SAM tone were measured. In some conditions the signal was added to a single SAM tone, and in other conditions the signal was added to the sum of three or more SAM tones. Level equalization ensured that the addition of the tonal signal did not lead to increases in energy. When multiple SAM tone maskers were used, a small number of reproducible maskers were tested, each masker being composed of SAM tones with a variety of relative modulator phases. The maskers were either fixed across intervals and trials, roved across trials but fixed across intervals, or randomly chosen across both intervals and trials. The frequency separation between the signal-centered and off-frequency SAM tones was also varied. For small signal-centered/off-frequency SAM tone frequency separations, a separation ratio of 1.3, thresholds in the fixed condition depend on the relative modulator phases, and a simple mixture model reasonably predicted thresholds in the roving condition based on thresholds in the fixed condition for two of the three observers. For signal-centered/off-frequency SAM tone frequency separation factor of 1.68, effects of relative modulator phases were not obtained. Thresholds in the target-alone condition were generally superior to thresholds measured with the comodulated masker. Comodulated thresholds were better than target-alone thresholds only when level equalization was not used, and so the addition of the signal led to increases in level.     

Formation of 1,N6-etheno-2''-deoxyadenosine adducts by trans,trans-2, 4-Decadienal

This study was designed to investigate the effect of glucogon-like peptide-1 (GLP-1) on pancreatic beta-cell function in normal, Zucker diabetic fatty (ZDF) rats, a model for non-insulin-dependent diabetes mellitus (NIDDM or type II diabetes) and their heterozygous siblings. Pancreas perfusion and enzyme-linked immunosorbent assay (ELISA) were used to detect the changes in insulin release under fasting and hyperglycemic conditions and following stimulation with GLP-1. Animals from the ZDF/Gmi-fa rats (ZDF) were grouped according to age, sex, and phenotype (obese or lean), and compared with LA lean rats. Glucose stimulation (10 mmol/L) in obese rats showed repressed response in insulin release. Glucose plus GLP-1 stimulation caused increased insulin release in all groups. The degree of this response differed between groups: lean > obese; young > adult; female > male. The LA lean control group was most sensitive, while the ZDF overtly diabetic group had the lowest response. In addition, the pulsatile pattern of insulin secretion was suppressed in ZDF rats, especially in obese groups. These results support the hypothesis that GLP-1 can effectively stimulate insulin secretion. Insulin release was defective in ZDF obese rats and could be partially restored with GLP-1. ZDF lean rats also showed suppression of beta-cell function and there was a difference in beta-cell function related to sex in ZDF strain. This study documents the efficacy of GLP-1 to stimulate insulin release and contributes to our understanding of the pathophysiological mechanisms underlying NIDDM.     

Prognosis of bleeding from duodenal ulcers

Clinical and pathogenetic findings on 147 patients with duodenal ulcer (DU) and 29 patients with DU complicated by ulcerogenic bleeding were compared. This allowed to single out significant criteria for prediction of development of bleeding in such patients: male sex freguent seasonal exacerbations, hereditary load, location of the ulcer at the back wall of the duodenal bulb, negative atropine test, HLA-phenotype B35, A2 A3, A2 AX. High acidity and large sixe of DU were hot prognostically independent. The importance of complex approach in solution of prognostic problems is emphasized.