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PubMed2001

[Non-insulin dependent diabetes mellitus during development in the population ].

This type of diabetes mellitus is generally considered rare in children and adolescents. The incidence of type 2 diabetes has increased dramatically in the past decade in some ethnic groups. This increased incidence of youth-onset non-insulin dependent diabetes mellitus (NIDDM-Y) has corresponded temporally to an unprecedented increase in body weight and prevalence of obesity in youth in various ethnic populations. Maturity-onset diabetes of the young (MODY), another type of non-insulin-dependent diabetes mellitus, is characterized by an early onset and autosomal dominant inheritance. MODY blood glucose is primarily due to beta-cell defects resulting in inadequate insulin secretion for a given level. In contrast to NIDDM-Y there is no significant increase in insulin resistance.

Adolescent↗
PubMed2001

Fatal adenovirus type 7b infection in a child with Smith-Lemli-Opitz syndrome.

Adenovirus type 7 causes worldwide respiratory tract infections, mainly in children. Severe systemic infections can occur, especially in immunocompromised patients and in patients with underlying chronic diseases. This report describes the first case of a fatal disseminated adenovirus type 7 infection in a child with Smith-Lemli-Opitz syndrome, a rare autosomal recessive disorder due to a primary enzymatic defect in cholesterol metabolism. Nasopharyngeal secretions and autopsy specimens including liver, lung, pleural fluid, and rectum were collected for viral culture. Adenovirus serotype 7 strains were obtained from all anatomic sites, except the liver. All these clinical isolates were analyzed using restriction endonuclease digestion of the genome, identifying them as genome type 7b, a virulent type. In this case, the fatal evolution could have been accelerated by the presence of an immunodeficiency although immunodeficiency is not included in the definition of Smith-Lemli-Opitz syndrome. The frequent recurrent banal infections in Smith-Lemli-Opitz syndrome could be prevented by a cholesterol supplementation regimen. Finally, this report emphasizes the need for efficient therapy for disseminated adenovirus infections, especially for virulent genome types.

Adenovirus Infections, Human↗
PubMed2001

Characterization and structural impact of five novel PROS1 mutations in eleven protein S-deficient families.

Heterozygozity for four novel missense mutations (W108C, W342R. E349K and L485S) and one novel 4 bp deletion (ACdelAAAG affecting codons 632-633) was identified in PROS1 of unrelated thrombosis prone Danish families with protein S type I or III deficiency. The 4 bp deletion results in a frameshift leading to replacement of the coding sequence for the 3 C-terminal amino acids by an abnormal extended sequence that codes for 9 amino acids. The E349K substitution was found in 7 families. Haplotype analysis using 7 microsatellite markers flanking PROS1 was consistent with a common founder for this mutation. The mutations reported here are most likely the cause of the protein S deficiency. Firstly, the four missense mutations cosegregate with the abnormal plasma protein S phenotype and lead to the loss of highly conserved amino acids. Secondly, computer analysis of structural models of protein S predicts that the substitutions could affect proper protein folding and/or stability. Analysis of platelet mRNA from subjects with the W108C, E349K, L485S mutation or the 4 bp deletion showed that mutated mRNA was expressed in significant amounts suggesting that mutated molecules are synthesized. Our results are compatible with defective protein folding/unstable molecules, impaired secretion and intracellular degradation of mutated protein, which appear to be the major molecular disease mechanisms for missense mutations and certain other mutations found in genetic disorders.

Adolescent↗
PubMed2002

Growth and development of male "little" mice assessed with Parks' theory of feeding and growth.

This work was designed to characterize the appetite kinetics and growth of male C57BL/6J (lit) mice. Those variables were assessed with Parks' function of ad libitum feeding and growth. Heterozygous mice (lit/+) attained their mature weight at 12-15 weeks of age, peak growth rate (3.5 g/week) at 5 weeks and displayed the normal decay of food conversion efficiency as a function of age. The homozygous genotype has a chronic defect in the synthesis and secretion of growth hormone (GH). Homozygous mice could not be assessed with Park's function. From the 4th to the 15th week of age, body weight increased linearly and exhibited constant food conversion efficiency. Food intake of both genotypes was commensurate with their body weights. Lit/lit mice became progressively obese. At 40 weeks of age, body fat of lit/lit mice was fivefold that of lit/+ and their body weight was similar to their heterozygous controls. The chronic deficiency of growth hormone produced a lower bone mass (compared to heterozygous controls). Bone mass of both genotypes attained maturity at 12-15 weeks with a maximum growth rate at 5 weeks. Body weight and bone mass grow harmoniously in lit/+ but not in lit/lit mice.

Adipose Tissue↗
PubMed2002

Mechanisms of impaired hypothalamic-pituitary-adrenal (HPA) function in diabetes: reduced counterregulatory responsiveness to hypoglycaemia.

In summary, our data suggest that in uncontrolled diabetes, increased HPA activity is caused by increased central drive at or above the level of the PVN. Insulin treatment only restores HPA activity at and below the pituitary level, presumably by GC-mediated suppression of ACTH secretion. We hypothesize that the defective HPA response to hypoglycaemia is at least in part due to a lack of a decrease in MR mRNA in response to hypoglycaemia, and diminished sensitivity of the pituitary and adrenal gland to stimulation. Interestingly, insulin treatment restores the HPA response, but not the defective epinephrine response. Therefore, defective epinephrine responses are not linked to defective HPA responses. Similarly, antecedent hypoglycaemia specifically impairs epinephrine responses, but not HPA responses to hypoglycaemia. These studies have revealed some of the mechanisms of impaired HPA function in diabetes and its impaired responsiveness to hypoglycaemia. Further investigations are essential for understanding poor counterregulation in insulin-treated diabetes and may lead to new strategies for preventing hypoglycaemia.

Adrenocorticotropic Hormone↗
PubMed2003

Inhibition of SRC family kinases and non-classical protein kinases C induce a reeler-like malformation of cortical plate development.

During development, most cortical neurons migrate to the cortical plate (CP) radially. CP development is abnormal in reeler and other mutant mice with defective Reelin signaling. Reelin is secreted by Cajal-Retzius cells and binds to the very low density lipoprotein receptor and apolipoprotein E receptor type 2 receptors on the surface of CP cells, inducing tyrosine phosphorylation of the intracellular Dab1 adapter. As with Reelin receptors, the identification of Reelin signaling partners is hampered by genetic redundancy. Using a new in vitro embryonic slice culture system, we demonstrate that chemical inhibitors of Src family kinases and Abl, but not inhibitors of Abl alone, generate a reeler-like malformation and that inhibitors of protein kinases C induce a malformation of cortical development that is also reminiscent of reeler. Our observations demonstrate a key role for these enzymes in radial migration to the cortical plate, possibly via interference with Reelin signaling.

Animals↗
PubMed2005

Type 2 diabetes mellitus: from genes to disease.

The development of type 2 diabetes (T2DM) is determined by two factors: genetics and environment. The genetic background of T2DM is undoubtedly heterogeneous. Most patients with T2DM exhibit two different defects: the impairment of insulin secretion and decreased insulin sensitivity. This means that there are at least two pathophysiological pathways and at least two groups of genes that may be involved in the pathogenesis of T2DM. As far as genetic background [corrected] of T2DM is concerned, the disease may be divided into two large groups: monogenic and polygenic forms. In this review, we present genes known to cause rare monogenic forms of diabetes with predominant insulin deficiency (MODY - maturity-onset diabetes of the young, MIDD - maternally inherited diabetes with deafness) and uncommon syndromes of severe insulin resistance. We also describe some of the main approaches used to identify genes involved in the more common forms of T2D and the reasons for the lack of spectacular success in this field. Although major genes for T2DM still await to be discovered, we have probably established a "road map" that we should follow.

Deafness↗
PubMed1991

Constitutional delay of growth: expected versus final adult height.

Constitutional delay of growth and puberty is believed to represent a variation of normal growth, and it is expected that children with this condition will grow for a longer duration than average and reach a height that is normal for their genetic potential. The records of children with constitutional delay of growth and puberty who were initially seen in the Pediatric Endocrine Clinic at the Oregon Health Sciences University between 1975 and 1983 were retrospectively reviewed. Criteria for study included a height more than 2 SD below the mean, a significantly delayed bone age, and a normal growth velocity on follow-up. Forty-two subjects were located and final adult height measurements were obtained. AT contact, the 29 male subjects (mean age = 23.9 years) were 169.5 +/- 4.5 cm tall (mean +/- SD), and the 13 female subjects (mean age = 20.5 years) were 156 +/- 3.8 cm tall. Adult height predictions during follow-up, using either the Bayley-Pinneau or Roche-Wainer-Thissen method, were close to final adult heights. The males were 1.2 SD and the females 1.3 SD below the 50th percentile as adults. This finding was not fully explained by genetic short stature; the males fell 5.1 cm and the females 5.3 cm below target heights based on midparental heights. It is concluded that this discrepancy is most likely explained by a selection bias of the shortest children referred to and observed in a subspecialty clinic, although a defect in human growth hormone secretion or function in children at the far end of the spectrum of constitutional delay of growth and puberty cannot be excluded.

Adult↗
PubMedDate not supplied

[Correlation of hydrocortisone and corticosterone content in assessing the functional state of the adrenal cortex in varying forms of hypercorticism].

Separate determination of hydrocortisone and corticosterone in the blood of patients with the hypercorticism symptom-complex showed that elevation of the corticosteroid concentration could occur on account of similar elevation of the concentration of both hormones, or one of the hormones alone. Analogous data were observed in patients after ACTH administration. Dexamethasone administration caused a reduction of the hydrocortisone and corticosterone concentration in patients with Itsenko-Cushing's disease, but to a lesser degree than in healthy individuals. Administration of the preparation to the patients with juvenile dyspituitrism decreased the cortizol level, but corticosterone chiefly; as to the patients with the hypothalamic syndrome--only the cortizol level was reduced, the level of corticosterone remaining unchanged. Thus, the evidence obtained before and after the administration of the ACTH preparations and dexamethasone permitted to assess the adrenal cortex function more fully and to defect disturbances of the corticosteroid secretion of interest of the understanding of the clinical symptoms of the disease.

11-Hydroxycorticosteroids↗
PubMed1991

Nutrition management for individuals with noninsulin-dependent diabetes mellitus in the 1990s: a review by the Diabetes Care and Education dietetic practice group.

Noninsulin-dependent diabetes mellitus (NIDDM), or Type II diabetes, is characterized by two primary defects: insulin resistance and insulin secretion. The two major goals of management of NIDDM are to achieve near normal metabolic control and to prevent/delay the microvascular and macrovascular complications of diabetes. Nutrition, exercise, and, if necessary, medication are the three primary treatment modalities used in NIDDM. Treatment regimens need to be individualized and developed with consideration for diabetes management goals and quality-of-life issues. Lean individuals with NIDDM should be encouraged to maintain their body weight and modify food composition and eating pattern to minimize glucose excursions. The primary treatment goal for an obese individual with NIDDM is weight loss. The process of teaching nutrition and meal planning involves developing a cooperative alliance, gathering information, setting realistic goals, intervention, and maintaining change. Nutrition intervention involves providing information in stages, beginning with "survival skill" information and progressing to in-depth information. The dietitian's responsibility is to promote continuity of learning by introducing new ideas and concepts and altering the learning environment. Dietitians can expand their role in the 1990s to that of a diabetes educator taking a leadership role to ensure that the individual with NIDDM receives comprehensive and individualized care.

Combined Modality Therapy↗
PubMed1986

Endocrine and exocrine pancreatic functions following partial pancreatectomy + partial hepatectomy.

Comparative studies were performed on changes in endocrine and exocrine responses of the pancreas after partial hepatectomy, partial pancreatectomy or combination of these procedures in rats, in order to clarify the effect of the combined operation on the remnant pancreatic parenchyma. Three days after partial (60%) pancreatectomy with partial (70%) hepatectomy, endocrine function was better preserved than after partial pancreatectomy alone, suggesting that hypersecretion of insulin initiated by partial hepatectomy may ameliorate the defective glucose-induced insulin secretion following partial pancreatectomy. Further, exocrine function in terms of amylase output was relatively well maintained 3 days after partial pancreatectomy + partial hepatectomy as compared with partial pan after partial pancreatectomy + partial hepatectomy as compared with partial pancreatectomy alone.

Amylases↗
PubMedDate not supplied

Abnormal pro-opiomelanocortin processing in Alzheimer's disease. A case report.

Several authors have reported reduced levels of pro-opiomelanocortin (POMC)-related peptides in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), but the mechanisms regulating the CSF content of these substances are still debated. In this case report the processing of POMC peptides has been investigated post-mortem (HPLC and RIA methods) at the pituitary and hypothalamic level in an AD patient and in a control subject. From the results obtained it seems likely that defects of axonal transport and/or secretion rather than synthesis could account for the abnormalities of POMC peptides in the CSF.

Alzheimer Disease↗
PubMed1979

Uricosuric therapy and urate solubility in blood and urine.

In most patients with primary gout hyperuricaemia results from a renal defect in tubular uric acid secretion. An increased endogenous purine biosynthesis is observed in only 2% of all patients with gout. Secondary hyperuricaemai results either from an increased breakdown of endogenous nucleic acids as in polycythaemia or from a decreased renal excretion of uric acid due to drug treatment, renal insufficiency or metabolic disturbances. Hyperuricaemia may be defined either in statistical terms from epidemiological studies of normal and gouty populations or from physicochemical properties of urate. Monosodium urate and uric acid are soluble in water to the extent of 6.32 mmol/l and 0.39 mmol/l respectively. In human plasma saturation of monosodium urate occurs at a concentration of about 0.42 mmol/l. The solubility of uric acid and urate in urine is more complicated as it is affected by changes in pH and salt concentration. Uricosuric drugs decrease serum uric acid concentration by enhancing the renal excretion of uric acid. Effects and side effects of uricosuric therapy are discussed.

Gout↗
PubMedDate not supplied

Immune profile of infectious bursal disease (IBD). II. Effect of IBD virus on pokeweed-mitogen-stimulated peripheral blood lymphocytes of chickens.

Pokeweed-mitogen-stimulated peripheral blood lymphocytes from chickens infected with infectious bursal disease virus (IBDV) at 1 day and 3 weeks of age, together with those from uninfected age-matched control chickens, were examined at weekly intervals for their capacity to undergo in vitro terminal differentiation. This study included the determination of cytoplasmic-immunoglobulin (CIg)-containing peripheral blood lymphocytes and those bearing the surface membrane immunoglobulin (SmIg) cells to detect any defect in immunoglobulin synthesis and secretion, respectively. The results of our study indicated that there was a highly significant and pronounced progressive depletion of CIg-containing cells in chickens infected at 1 day of age. These findings suggest that IBDV affected the "immature" or precursor B cells to a far greater extent than mature B lymphocytes.

Animals↗
PubMed1983

Biosynthesis of C4 by mouse peritoneal macrophages. II. Comparison of C4 synthesis by resident and elicited cell populations.

Five elicited macrophage populations synthesized one-third to one-tenth as much hemolytically active C4 when compared with resident peritoneal macrophages. This decrease in functional C4 activity was not caused by inhibitors or protease activity in the elicited macrophage supernatants. Analysis of C4 antigen indicated a similar reduction in the elicited cells compared with the resident macrophages. A defect in precursor processing or secretion was deemed unlikely because the intracellular C4 precursor was appropriately reduced in the elicited cells. We postulate that mouse resident peritoneal macrophages are a pluripotent cell population with broad capabilities in regard to the initiation of the inflammatory response. In contrast, elicited or activated macrophages may be more specialized cells, with one manifestation of this being the "down" regulation of C4 synthesis.

Animals↗
PubMed1984

Oral phosphate-loading test for the assessment of distal urinary acidification in children.

Neutral phosphate infusion results in an elevated urinary minus blood PCO2 gradient (U-B PCO2), providing that the urinary pH is close to the pK (6.8) of the phosphate buffer system. The present investigation was designed to evaluate whether an oral phosphate load could achieve similar results in children. 18 normal children, aged 3-13 years, were studied. Following the oral phosphate load, the urinary phosphate concentration increased to 44.8 +/- 4.7 mmol/l (mean +/- SEM), and U-B PCO2 reached 68.8 +/- 7.0 mm Hg, with a urinary pH of 6.87 +/- 0.07. With a urinary phosphate concentration above 20 mmol/l, all children reached a U-B PCO2 above 40 mm Hg. 4 children with primary distal renal tubular acidosis were also studied. All exhibited a U-B PCO2 below 20 mm Hg despite values of urinary phosphate concentration at or above 20 mmol/l, indicating the presence of a true secretory defect in distal hydrogen ion secretion. The present study demonstrates that an oral phosphate load is as effective as a phosphate infusion in elevating the urinary PCO2 and, therefore, could have a wide application in the pathophysiologic evaluation of renal tubular acidosis.

Acidosis, Renal Tubular↗
PubMed1982

Temperature-sensitive yeast mutants deficient in asparagine-linked glycosylation.

A [3H]mannose suicide selection has been used to isolate mutants in yeast which contain temperature-sensitive defects in asparagine-linked glycosylation. The surviving cells were screened at the nonpermissive temperature for a decreased ability to incorporate [3H]mannose and for defects in glycosylation of the secreted protein invertase. One of these mutants (alg1-1) has been characterized and found to be blocked in the assembly of the lipid-linked oligosaccharide precursor. The alg1-1 cells synthesize mannosyl compounds at 60% of the wild type level at the nonpermissive temperature and 105% of the wild type level at the permissive temperature. In vivo labeling experiments have demonstrated that alg1-1 cells are able to synthesize GlcNAc2-lipid but are unable to synthesize any mannose-containing oligosaccharide-lipids. This result was confirmed by in vitro labeling of yeast membranes. When incubated with UDP-[3H]GlcNAc, alg1-1 membranes synthesized GlcNAc2-lipid but failed to elongate it when GDP-Man was added. The alg1-1 membranes also failed to elongate exogenous GlcNAc2-lipid but were able to convert Man1GlcNAc2-lipid to Man5-Glc-NAc2-lipid in the presence of GDP-Man. These results indicate that the alg1-1 mutant is blocked specifically in the addition of the first mannose residue to the lipid-linked oligosaccharide precursor.

Asparagine↗
PubMed1981

The mouse pale ear pigment mutant as a possible animal model for human platelet storage pool deficiency.

The mouse pigment mutant pale ear, ep/ep, which has a defect in kidney lysosomal enzyme secretion, had prolonged bleeding on experimental injury. Platelet counts and platelet protein did not differ from normal. There was, however, a deficiency in the platelet dense granule contents, serotonin, ATP, and ADP. Furthermore, a marked reduction of platelet dense granules was observed by electron microscopy. The results suggest that pale ear is a useful animal model in the study of platelet storage pool disease. Studies on this mutant and other pigment mutants have established that one gene can regulate at least three subcellular organelles, including the melanosome, the lysosome, and the platelet dense granule.

Adenosine Diphosphate↗