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At least 253 records · Page 14Linked to original sources
PubMed1999

Free jejunal patch flaps in oral and oro-pharyngeal reconstruction.

Free jejunum has been commonly tubed to provide a reconstructive pharyngeal conduit following pharyngolaryngectomy. It is also common practice to repair small oral and oro-pharyngeal defects with skin-lined flaps i.e. radial free forearm or pectoralis major myocutaneous flap. Free jejunal patch flaps can provide cover for large defects, secrete mucus, tolerate radiotherapy well and do not contract. The operation is associated with a low morbidity and early return of swallowing is feasible. Here we describe the functional results of free jejunal patch flap reconstruction of extensive oral and oro-pharyngeal defects.

Adult↗
PubMed2001

Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance.

Although insulin regulates metabolism in both brown and white adipocytes, the role of these tissues in energy storage and utilization is quite different. Recombination technology using the Cre-loxP approach allows inactivation of the insulin receptor in a tissue-specific manner. Mice lacking insulin receptors in brown adipocytes show an age-dependent loss of interscapular brown fat but increased expression of uncoupling protein-1 and -2. In parallel, these mice develop an insulin-secretion defect resulting in a progressive glucose intolerance, without insulin resistance. This model provides direct evidence for not only a role for the insulin receptors in brown fat adipogenesis, the data also suggest a novel role of brown adipose tissue in the regulation of insulin secretion and glucose homeostasis.

Adipose Tissue, Brown↗
PubMed1975

Labile aggregation stimulating substance (LASS): the factor from storage pool deficient platelets correcting defective aggregation and release of aspirin treated normal platelets.

Mixtures of equal volumes of Hermansky-Pudlak (HP) syndrome (adenine nucleotide storage pool deficient) and aspirin treated (AT) platelets (inhibited release of adenine nucleotides) undergo irreversible aggregation when exposed to collagen or adrenaline, whereas neither alone will do so. The present investigation has explored the basis for the mutual correction. Correction in the mixed system was accompanied by release of significant amounts of [14C]5-hydroxy-tryptamine from the AT platelets, whereas very little isotope was released when AT platelets alone were exposed to collagen. The correction of aggregation and the release of isotope could both be suppressed by pre-treating HP platelets with aspirin. Labile aggregation stimulating substance (LASS) composed of two closely linked intermediates of prostaglandin (PG) E2 and PGF2alpha biosynthesis, produced using a microsomal fraction of HP platelets, could correct the aggregation and secretion defect of AT platelets exposed to collagen. These findings indicate that HP platelets when mixed with AT platelets and exposed to collagen secrete a substance which is responsible for the correction. LASS, identified as the factor involved, acted as an intercellular messenger which mediated the correction by overcoming the influence of aspirin on normal cells.

Adenine Nucleotides↗
PubMed2006

In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of the vonWillebrand factor (VWF) cleaving protease ADAMTS13. We investigated the spectrum of ADAMTS13 gene mutations in patients with TTP and congenital ADAMTS13 deficiency to establish the consequences on ADAMTS13 processing and activity. We describe five missense (V88M, G1239V, R1060W, R1123C and R1219W), 1 nonsense (W1016Stop) and 1 insertion (82_83insT) mutations. In two patients no mutation was identified despite undetectable protease activity. Expression in HEK293 mammalian cells (V88M, G1239V, R1123C and R1219W) documented that three missense mutants were not secreted, whereas theV88M was secreted at low levels and with reduced activity. We also provide evidence that impaired secretion of ADAMTS13 mutants observed in vitro translates into severely reduced ADAMTS13 antigen levels in patients in vivo. To evaluate whether the small amounts of mutant protease present in the circulation of patients had VWF cleaving activity, WT and mutant rADAMTS13 were stably expressed in Drosophila S2 cells under the influence of the Drosophila BiP protein signal sequence, which allows protein secretion. Drosophila expression system showed a 40-60% protease activity in the mutants. Several single nucleotide polymorphisms (SNPs) within exons and intron boundaries were found in patients, suggesting that the interplay of SNPs could at least in part account for ADAMTS13 functional abnormalities in patients without mutations. In conclusion, defective secretion and impaired activity of the mutants concur to determine an almost complete deficiency of ADAMTS13 activity in patients with a homozygous or two heterozygous ADAMTS13 mutations.

ADAM Proteins↗
PubMed2002

Role of transglutaminase 2 in glucose tolerance: knockout mice studies and a putative mutation in a MODY patient.

Transglutaminase 2 (TGase 2) is a Ca+2-dependent enzyme that catalyzes both intracellular and extracellular cross-linking reactions by transamidation of specific glutamine residues. TGase 2 is known to be involved in the membrane-mediated events required for glucose-stimulated insulin release from the pancreatic beta cells. Here we show that targeted disruption of TGase 2 impairs glucose-stimulated insulin secretion. TGase 2-/- mice show glucose intolerance after intraperitoneal glucose loading. TGase 2-/- mice manifest a tendency to develop hypoglycemia after administration of exogenous insulin as a consequence of enhanced insulin receptor substrate 2 (IRS-2) phosphorylation. We suggest that the increased peripheral sensitivity to insulin partially compensates for the defective secretion in this animal model. TGase 2-/- mouse phenotype resembles that of the maturity-onset diabetes of young (MODY) patients. In the course of screening for human TGase 2 gene in Italian subjects with the clinical features of MODY, we detected a missense mutation (N333S) in the active site of the enzyme. Collectively, these results identify TGase 2 as a potential candidate gene in type 2 diabetes.

Adolescent↗
PubMed1998

HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency.

Previously, we found the first congenital deficiency of histidine-rich glycoprotein (HRG) in a Japanese woman with thrombosis. To elucidate the genetic basis of this deficiency, we first performed Southern blot analysis and found no gross deletion or insertion in the proband's HRG gene. We then examined the nucleotide sequences of all seven exons of the proband's HRG gene. A single nucleotide substitution, G to A at nucleotide position 429, which mutates Gly85 to Glu in the first cystatin-like domain, was found in exon 3 in 13 of 22 amplified clones. This mutation generates a unique Taq I site. Exon 3 was amplified from the proband, her family members, and 50 unrelated normal Japanese individuals, and Taq I fragmentation was examined. Fragmentation of exon 3 was observed in one allele of the genes from the proband and the family members who also have decreased plasma levels of HRG. Fifty unrelated normal Japanese individuals had a normal HRG gene, indicating that the G to A mutation is not a common polymorphism. To elucidate the identified mutation as a cause for the secretion defect of HRG in the proband's plasma, we constructed and transiently expressed the recombinant Tokushima-type HRG mutant (Gly85 to Glu) in baby hamster kidney (BHK) cells, and examined an intracellular event of the mutant protein. The results showed that only about 20% of the Tokushima-type HRG was secreted into the culture medium, and intracellular degradation of the mutant was observed. Thus, the present study strongly suggests that the HRG deficiency is caused by intracellular degradation of the Gly85 to Glu mutant of HRG in the proband.

Adult↗
PubMed2002

Impaired glucose effectiveness in chronic progressive external ophthalmoplegia.

Mitochondrial gene mutations have been recognized to be associated with diabetes mellitus. The incidence of diabetes mellitus in patients with other mitochondrial diseases, such as chronic progressive external ophthalmoplegia (CPEO), seems to be several times higher than in the normal population. The aim of the present investigation was to study insulin sensitivity index (SI), insulin secretion (AIR(Glucose)), and glucose effectiveness (Sg) in patients with CPEO. Six unrelated patients with CPEO and 6 matched-pair, unrelated, healthy control subjects underwent a modified intravenous glucose tolerance test (IVGTT) (Bergman's minimal model). Three patients demonstrated an impaired glucose tolerance (IGT), 1 patient already had diabetes mellitus. No significant difference between patients and controls could be demonstrated for SI, AIR(Glucose), or fasting insulin. However, there was a significant difference for glucose effectiveness Sg (P =.016) indicating an impaired glucose effectiveness in the CPEO patients. The diabetic patient showed insulin resistance, low AIR(Glucose), and low Sg. We conclude that there is a high incidence of IGT and diabetes mellitus in patients with CPEO. Impaired glucose effectiveness seems to play a major role in early pathogenesis. Overt diabetes in CPEO seems to be a combination of insulin resistance, an insulin secretion defect, and impaired glucose effectiveness.

Adult↗
PubMed2003

MxiK and MxiN interact with the Spa47 ATPase and are required for transit of the needle components MxiH and MxiI, but not of Ipa proteins, through the type III secretion apparatus of Shigella flexneri.

The type III secretion (TTS) pathway is used by numerous Gram-negative pathogens to inject virulence factors into eukaryotic cells. The Shigella flexneri TTS apparatus (TTSA) spans the bacterial envelope and its assembly requires the products of approximately 20 mxi and spa genes. We present a functional analysis of the mxiK, mxiN and mxiL genes. Inactivation of mxiK and mxiN, but not mxiL, resulted in the assembly of a non-functional TTSA that lacked the outer needle. The amounts of needle components MxiH and MxiI were drastically reduced in mxiK and mxiN mutants and in the secretion defective spa47 mutant, indicating that MxiH and MxiI are degraded if they do not transit through the TTSA. Remarkably, expression of MxiH-His in the mxiN mutant and MxiI-His in the mxiK mutant restored assembly of a functional TTSA, as shown by the ability of these strains to enter into epithelial cells and to secrete Ipa proteins in response to activation by Congo red. Using a two-hybrid screen in yeast and immunoprecipitation assays from S. flexneri extracts, we identified interactions between MxiK and Spa33 and Spa47 and between MxiN and Spa33 and Spa47. These results suggest that transit of the needle components MxiH and MxiI through the TTSA involves the concerted action of the cytoplasmic proteins Spa47, Spa33, MxiK and MxiN. They also show that neither MxiK nor MxiN are absolutely required for secretion of Ipa proteins, provided that the TTSA is correctly assembled.

Adenosine Triphosphatases↗
PubMed2002

Insulin secretion and sensitivity in non-obese and obese Japanese patients with coronary artery disease.

In a cross-sectional study of 240 patients with angiographically documented coronary artery disease (CAD), we investigated whether obese and non-obese subjects differed as to the influence of insulin deficiency and insulin resistance on glucose intolerance and cardiovascular risk. Patients were classified according to a 75-g oral glucose tolerance test as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or diabetes mellitus (DM). We defined obesity as a body mass index (BMI) exceeding 25 kg/m(2). Early phase insulin secretion (insulinogenic index) declined with worsening glucose intolerance in non-obese (tau = -.216, P <.001; Kendall's correlation coefficient) and obese subjects (tau = -.392, P <.001). Total insulin secretion was higher in obese subjects with NGT or IGT than in controls and decreased in association with worsening glucose intolerance in obese subjects (tau = -.239, P <.001). Insulin sensitivity was calculated by 3 proposed indices. The first of these decreased in association with worsening in glucose tolerance in non-obese subjects (tau = -.137, P <.01). The second showed such a pattern in both groups (non-obese, tau = -.407, P <.001; obese, tau = -.311, P <.001), as did the third (non-obese, tau = -.512, P <.001; obese, tau = -.488, P < 0.001). Because even prediabetic Japanese subjects with CAD showed a latent insulin secretion defect in response to a glucose load, as well as impaired insulin sensitivity, compensatory hyperinsulinemia is not a sensitive indicator of coronary risk.

Aged↗
PubMed1992

Deletions in the hepatitis B virus small envelope protein: effect on assembly and secretion of surface antigen particles.

The small envelope S protein of hepatitis B virus carrying the surface antigen has the unique property of mobilizing cellular lipids into empty envelope particles which are secreted from mammalian cells. We studied the biogenesis of such particles using site-directed mutagenesis. In this study, we describe the effect of deletions in the N-terminal hydrophobic and hydrophilic domains of the S protein. Whereas short overlapping deletions of hydrophilic sequences flanking the first hydrophobic domain were tolerated, larger deletions of the same sequences were not. Conversely, the hydrophilic region preceding the second hydrophobic domain was not permissive for even short deletions. Deletion of part or all of the first hydrophobic domain also completely blocked secretion, confirming that the entire apolar region serves an essential function. Most of the secretion-defective deletion mutants still entered the secretory pathway and translocated at least the second hydrophilic domain across the membrane of the endoplasmic reticulum. These mutants appeared to remain arrested in a membrane-associated configuration in the endoplasmic reticulum or the cis-Golgi compartment but preserved their capacity for oligomerization with the wild-type S protein. While secretion of wild-type S protein was specifically blocked by the formation of intracellularly retained mixed envelope aggregates, secretion of an unrelated protein (interleukin 9) was completely unaffected.

Base Sequence↗
PubMed1987

Substitution of tyrosine for either cysteine in beta-lactamase prevents release from the membrane during secretion.

Six independent secretion-defective mutations were found that result in failure to release protein from the membrane into the periplasmic space of Salmonella typhimurium after removal of the signal peptide. The mutant protein is found in a membrane-bound form accessible to trypsin added to intact spheroplasts. The phenotype of these mutations supports the existence in general of an intermediate in bacterial secretion. All six mutations changed one or the other of the two cysteine residues in the mature protein to tyrosine, suggesting that these residues are involved in the release of protein into the periplasmic space, most likely by affecting protein folding.

Cysteine↗
PubMed2006

Impaired insulin secretion after prenatal exposure to the Dutch famine.

OBJECTIVE: We previously reported that people prenatally exposed to famine during the Dutch Hunger Winter of 1944-1945 have higher 2-h glucose concentrations after an oral glucose tolerance test in later life. We aimed to determine whether this association is mediated through alterations in insulin secretion, insulin sensitivity, or a combination of both. RESEARCH DESIGN AND METHODS: We performed a 15-sample intravenous glucose tolerance test in a subsample of 94 normoglycemic men and women from the Dutch Famine Birth Cohort. We used the disposition index, derived as the product of insulin sensitivity and the first-phase insulin response to glucose as a measure of the activity of the beta-cells adjusted for insulin resistance. In all analyses, we adjusted for sex and BMI. RESULTS: Glucose tolerance was impaired in people who had been prenatally exposed to famine compared with people unexposed to famine (difference in intravenous glucose tolerance test K(g) value -21% [95% CI -41 to -4]). People exposed to famine during midgestation had a significantly lower disposition index (-53% [-126 to -3]) compared with people unexposed to famine. Prenatal exposure to famine during early gestation was also associated with a lower disposition index, but this difference did not reach statistical significance. CONCLUSIONS: Impaired glucose tolerance after exposure to famine during mid-gestation and early gestation seems to be mediated through an insulin secretion defect.

Blood Glucose↗
PubMed2002

Complementation analysis of the flavivirus Kunjin NS3 and NS5 proteins defines the minimal regions essential for formation of a replication complex and shows a requirement of NS3 in cis for virus assembly.

We have previously reported successful trans-complementation of defective Kunjin virus genomic RNAs with a range of large lethal deletions in the nonstructural genes NS1, NS3, and NS5 (A. A. Khromykh et al., J. Virol. 74:3253-3263, 2000). In this study we have mapped further the minimal region in the NS5 gene essential for efficient trans-complementation of genome-length RNAs in repBHK cells to the first 316 of the 905 codons. To allow amplification and easy detection of complemented defective RNAs with deletions apparently affecting virus assembly, we have developed a dual replicon complementation system. In this system defective replicon RNAs with a deletion(s) in the nonstructural genes also encoded the puromycin resistance gene (PAC gene) and the reporter gene for beta-galactosidase (beta-Gal). Complementation of these defective replicon RNAs in repBHK cells resulted in expression of PAC and beta-Gal which allowed establishment of cell lines stably producing replicating defective RNAs by selection with puromycin and comparison of replication efficiencies of complemented defective RNAs by beta-Gal assay. Using this system we demonstrated that deletions in the C-terminal 434 codons of NS3 (codons 178 to 611) were complemented for RNA replication, while any deletions in the first 178 codons were not. None of the genome-length RNAs containing deletions in NS3 shown to be complementable for RNA replication produced secreted defective viruses during complementation in repBHK cells. In contrast, structural proteins produced from these complemented defective RNAs were able to package helper replicon RNA. The results define minimal regions in the NS3 and NS5 genes essential for the formation of complementable replication complex and show a requirement of NS3 in cis for virus assembly.

Amino Acids↗
PubMed1998

Overexpression of MID2 suppresses the profilin-deficient phenotype of yeast cells.

Profilin-deficient Saccharomyces cerevisiae cells show abnormal growth, actin localization, chitin deposition, bud formation and cytokinesis. Previous studies have also revealed a synthetic lethality between pfy1 and late secretory mutants, suggesting a role for profilin in intracellular transport. In this work, we document further the secretion defect associated with the pfy1delta mutant. Electron microscopic observations reveal an accumulation of glycoproteins in the bud and in the mother cell. The MATa, pfy1delta cells mate as well as wild-type cells, while the mating efficiency of MAT alpha, pfy1delta cells is reduced. Pulse-chase experiments demonstrate an accumulation of the 19 kDa alpha-factor precursor and delayed secretion of the mature alpha-factor. The TGN protein Kex2p is the principal enzyme responsible for the endoproteolytic cleavage of the alpha-factor precursor. An immunofluorescence detection of Kex2p shows an altered localization in pfy1delta cells. Instead of a discrete punctate distribution, the enzyme is dispersed throughout the cytoplasm. A high-copy-number plasmid containing MID2, which encodes a potential transmembrane protein involved in cell cycle control, suppresses the abnormal growth, actin distribution, alpha-factor maturation and the accumulation of intracellular membranous structures in pfy1delta cells.

Calcium-Binding Proteins↗
PubMed2000

Chaperone-like activities of the CsaA protein of Bacillus subtilis.

The growth and protein export defects of Escherichia coli secA51(Ts) strains can be suppressed by the CsaA protein of Bacillus subtilis. The present studies indicate that this effect can be attributed to chaperone-like activities of CsaA. First, CsaA stimulated protein export in secB, groES and dnaJ mutant strains of E. coli. Second, CsaA suppressed the growth defects of dnaK, dnaJ and grpE mutants of E. coli. Third, and most importantly, CsaA exhibited chaperone-like properties by stimulating the reactivation of heat-denatured firefly luciferase in groEL, groES, dnaK and grpE mutant strains of E. coli, and by preventing the aggregation of heat-denatured luciferase in vitro. Thus, it seems that CsaA suppresses the growth and secretion defects of E. coli secA(Ts) strains either by improving the translocation competence of exported pre-proteins, thereby making them better substrates for mutant SecA proteins, or by stimulating the translocation activity of mutant SecA proteins.

Adenosine Triphosphatases↗
PubMed1990

Congenital disorders of platelet function.

Platelets play a major role in normal hemostasis and congenital defects in platelet function are associated with bleeding manifestations that are largely mucocutaneous in origin and markedly variable in severity. They arise by different mechanisms and may be classified as disorders of: (1) platelet-agonist interaction, (2) platelet-vessel wall interaction (vWD and Bernard-Soulier syndrome), (3) platelet-platelet interaction (congenital afibrinogenemia and Glanzmann's thrombasthenia), (4) platelet secretion, and (5) platelet-coagulant protein interaction. Excluding vWD, most congenital platelet dysfunctions currently fall in the category of platelet secretion defects. Some of these patients have storage pool deficiency or defects in thromboxane synthesis, but the majority have normal granule stores. The underlying mechanisms in this large, heterogeneous group of dysfunctions remain to be elucidated. Bleeding episodes of vWD are managed by the administration of DDAVP or cryoprecipitate. The major treatment modality in the management of bleeding episodes and surgical procedures in patients with congenital platelet defects is platelet transfusions. Evidence is becoming available that many of these patients may respond to intravenous infusion of DDAVP with a shortening of the bleeding time. The specific groups of patients who will respond, and the efficacy of DDAVP in clinical situations remains to be established.

Arachidonic Acids↗
PubMed1993

Isolation and analysis of novel mutants of Escherichia coli prlA (secY).

Plasmid libraries of prlA mutants containing single-base-pair changes throughout the gene were generated by in vitro random mutagenesis. The prlA mutations capable of suppressing the secretion defect of LamB caused by mutations in the LamB signal peptide were selected and analyzed. Together with additional mutations generated by site-directed mutagenesis, a number of novel prlA mutations and/or suppressors were identified. These mutations provide the starting points for studying the relationship of structure and function of PrlA in its interaction with LamB and/or other component(s) in the Escherichia coli protein secretion-translocation complex.

Amino Acid Sequence↗
PubMed2003

[Cyproterone acetate improves beta-cell function in postmenopausal women with diabetes mellitus type 2].

Menopause is associated with two main risk factors for the development of type 2 diabetes mellitus--impaired beta-cell insulin secretion and insulin resistance. Physiologically estrogens improve carbohydrate metabolism, but this is not the case with different progestogens. The aim of the present study was to evaluate the effect of Cyproterone acetate (a progestogen with antiandrogenic activity) on insulin secretion, peripheral insulin sensitivity, lipid parameters and parameters of oxidative stress. Seven type 2 diabetic females, of mean age 55.4 +/- 4.7 years and mean BMI 30.8 +/- 9.39 kg/m2, in menopause for average 5 years, in good borderline glycaemic control (mean HbAic 7.8%), with dyslipidaemia, normal parameters of calcium and phosphate metabolism and with osteopenia (T-score < 88%) were enrolled in the study. They were treated with Estradiol valerate + Cyproterone acetate (Climen, Schering) for three months. Phases of insulin secretion--first phase (FPIS), second phase (SPIS) and AUC for FPIS and SPIS were assessed during IVGTT. Insulin sensitivity was determined with the manual method of euglycaemic hyperinsulinaemic clamp technique. The postmenopausal diabetic women in the present study were with overweight and obesity; they did not increase their body weight during HRT and even decreased it by mean 0.7%. Insulin secretion improved after Climen--FPIS increased by 16% and SPIS by 44%. Insulin sensitivity increased by 15%; triglycerides decreased by 16% and HDL-cholesterol increased by 27%. Total antioxidant capacity of the serum (TAOK) increased by 7%. The favourable effect on the pathophysiological mechanisms improved metabolic control--HbAic was reduced by mean 3% after 3 months. In conclusion, our results suggest that HRT with the progestogen Cyproterone acetate (Climen) should be preferred in postmenopausal type 2 diabetic females with predominant beta-cell insulin secretion defect.

Blood Glucose↗