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PubMedDate not supplied

Insulin release in type 2 diabetes mellitus.

Impaired insulin response is a characteristic feature of Type 2 diabetes. Overt diabetes develops when beta-cells fail to release enough insulin to compensate for decreased insulin sensitivity. However, a subgroup of normal weight patients demonstrates a pronounced beta-cell secretory defect and a normal insulin sensitivity. The molecular basis behind the impaired insulin response in Type 2 diabetes is not clear. Our studies in two animal models of this disease (GK rat and ob/ob mouse) suggest that an impaired glucose metabolism may be a primary defect in the stimulus-secretion coupling in the beta-cells in Type 2 diabetes. In the GK rat, three major alterations in the islet metabolism of glucose have been demonstrated: 1) increased glucose utilization but unchanged glucose oxidation; 2) increased glucose cycling and 3) decreased activity of the glycerol phosphate shuttle. In ob/ob animals we have found an increased rate of glucose cycling. These derangements might result in an incomplete closure of ATP-sensitive K(+)-channels with a decreased insulin response as a consequence.

Animals↗
PubMed1994

[Factors of graft failure after chemical corneal injury].

83 cases (97 eyes) of keratoplasty after chemical corneal injury were followed up for a mean 14 months with the results that 21 (21.6%) grafts were transparent and 76 (78.4%) opaque or semitransparent. The success rate depended on the severity of the chemical injury; it was 87.5% for type A corneal scarring and 15.7% for type B. The causes of graft failure were postoperative epithelial erosion (70.7%) and corneal rejection (28.0%). Most patients with epithelial erosion had problems of insufficient tear secretion and tear-film defects. The prevention and management of graft failure were discussed.

Adolescent↗
PubMed1996

Histopathological findings of the endometrium in patients with dysfunctional uterine bleeding.

The histopathological examination of the endometrium in cases of abnormal functional uterine bleeding frequently reveals the type of functional disturbance and assists correct treatment. On this basis, 7,000 endometrial curettages from patients with abnormal uterine bleeding were studied. The 1,282 cases with no endometrium in phase, organic changes, or systemic disorders were defined as dysfunctional uterine bleeding; the endometrial lesions were then classified and the histological findings correlated with the patients' ages. The endometrial curettages revealed an anovulatory cycle in 984 (77%) of the patients, and an ovulatory cycle in 298 (23%). Of the cases with an anovulatory cycle, 446 patients (47.5%) showed endometrial hyperplasia, 412 (41.86%) showed abnormal endometrial proliferation due to prolonged persistence of a follicle, while 106 (10.77%) showed deficient endometrial proliferation. Three hundred and thirty four cases (71.67%) of endometrial hyperplasia were (simple) cystic hyperplasias, 124 (26.60%) were (complex) adenomatous hyperplasia, and 8 (1.71%) were atypical hyperplasia. Of the cases with an ovulatory cycle, 252 (84.56%) showed deficient endometrial secretion due to a prolonged proliferative phase, while the other 46 (15.43%) showed deficient secretion due to luteal phase defect. Seven hundred and thirty six patients with an anovulatory cycle and 212 with an ovulatory cycle-i.e. 948 (74%) of the 1282 patients studied-were at the climacteric. The conclusions may be summarised as follows. i) Dysfunctional abnormal uterine bleeding was found more often at the climacteric and chiefly in the form of an anovulatory endometrium; ii) 88.14% of cases (1130 patients) presented histological signs of oestrogen influence in the form of either an anovulatory endometrium or an ovulatory endometrium; iii) Cystic (simple) hyperplasia was the most common form of endometrial hyperplasia.

Animals↗
PubMedDate not supplied

Using genetically engineered mice to understand apolipoprotein-B deficiency syndromes in humans.

Several human diseases are characterized by defects in the synthesis and secretion of the apolipoprotein (apo) B-containing lipoproteins. Familial hypobetalipoproteinemia is caused by mutations in the apo-B gene and is characterized by abnormally low plasma concentrations of apo-B and low-density lipoprotein (LDL) cholesterol. Another apo-B deficiency syndrome, abetalipoproteinemia, is caused by mutations in the gene for microsomal triglyceride transfer protein (MTP). MTP is a microsomal protein that is thought to transfer lipids to the apo-B protein as it is translated, allowing it to attain the proper conformation for lipoprotein assembly. A third apo-B deficiency syndrome, Anderson's disease (or chylomicron retention disease), is characterized by the inability to secrete apo-B-containing chylomicrons from the intestine but an apparently normal capacity to secrete lipoproteins from the liver. To more fully understand these human apo-B deficiency syndromes, our laboratory has generated and characterized gene-targeted mouse models. This review summarizes what has been learned from these animal models.

Abetalipoproteinemia↗
PubMed1986

Cortisol insufficiency caused by electroconvulsive therapy? A case report.

A 30-year-old woman was treated with a series of electroconvulsive therapy (ECT) due to a personality disorder with depressive symptoms. Three days after the last ECT, anisocoria was noticed. It subsided after 2 days, and attacks of syncope, vertigo, anorexia and weight loss started. These symptoms ceased by administration of cortisone acetate and fluoro-cortisone. During an observation time of five years, repeated attempts to omit the cortico-steroids or reduce the cortisone dose to less than 20 mg/day have resulted in immediate symptoms of cortisol deficiency. Plasma adrenocorticotrophin (ACTH) and cortisol and urinary cortisol were low during cortisol withdrawal. Cortisol response to ACTH stimulation and cortisol and ACTH response to hypoglycemia were normal. The cortisol deficiency was considered to be due to a defect in the central nervous regulation of ACTH secretion. As it occurred in close connection to ECT, it seems likely that the treatment induced a defect, or aggravated a preexisting one, in neural pathways controlling corticotrophin-releasing factor and ACTH secretion.

Adrenocorticotropic Hormone↗
PubMed2003

Antagonists of myo-inositol 3,4,5,6-tetrakisphosphate allow repeated epithelial chloride secretion.

Cystic fibrosis (CF) patients suffer from a defect in hydration of mucosal membranes due to mutations in the cystic fibrosis transmembrane regulator (CFTR), an apical chloride channel in mucosal epithelia. Disease expression in CF knockout mice is organ specific, varying with the level of expression of calcium activated Cl(-) channels (CLCA). Therefore, restoring transepithelial Cl(-) secretion by augmenting alternate Cl(-) channels, such as CLCA, could be beneficial. However, CLCA-mediated Cl(-) secretion is transient, due in part to the inhibitory effects of myo-inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P(4)]. This suggests that antagonists of Ins(3,4,5,6)P(4) could be useful in treatment of CF. We have, therefore, synthesized a series of membrane-permeant Ins(3,4,5,6)P(4) derivatives, carrying alkyl substituents on the hydroxyl groups and screened them for effects on Cl(-) secretion in a human colonic epithelial cell line, T(84). While membrane-permeant Ins(3,4,5,6)P(4) derivatives had no direct effects on carbachol-stimulated Cl(-) secretion, Ins(3,4,5,6)P(4) derivatives, but not enantiomeric Ins(1,4,5,6)P(4) derivatives, reversed the inhibitory effect of Ins(3,4,5,6)P(4) on subsequent thapsigargin activation of Cl(-) secretion. The extent of the antagonistic effect of the Ins(3,4,5,6)P(4) derivatives varied with the position of the alkyl substituents. Derivatives with a cyclohexylidene ketal or a butyl-chain at the 1-position reversed the Ins(3,4,5,6)P(4)-mediated inhibition of Cl(-) secretion by up to 96 and 85%, respectively, whereas butylation of the 1- and 2-position generated a reversal effect of only 65%. Derivatives carrying the butyl chain only at the 2-position showed no antagonistic effect. These data: (1) Support the hypothesis that Ins(3,4,5,6)P(4) stereospecifically inhibits Ca(2+) activated Cl(-) secretion and that Ins(3,4,5,6)P(4) mediates most, if not all of the cholinergic-mediated inhibition of chloride secretion in T(84) cells; (2) Demonstrate Ins(3,4,5,6)P(4)-mediated inhibition can be completely reversed with rationally designed membrane-permeant Ins(3,4,5,6)P(4) antagonists; (3) Demonstrate that a SAR for membrane-permeant Ins(3,4,5,6) P(4) antagonists can be generated and screened in a physiologically relevant cell-based assay; (4) Indicate that Ins(3,4,5,6)P(4) derivatives could serve as a starting point for the development of therapeutics to treat cystic fibrosis.

Cell Line↗
PubMed1987

The insulin receptor concept and its relation to the treatment of diabetes.

The initial step in insulin action is binding to specific receptors. Two covalent receptor modifications possibly involved in producing pharmacodynamic effects as a result of insulin receptor binding are autophosphorylation and disulphide insulin binding. Insulin receptor numbers are 'down regulated' by insulin, but this effect may be minimised by pulsatile insulin secretion. Insulin receptor affinity is modulated rapidly by fasting, exercise and dietary composition. In non-insulin-dependent diabetes coupling of receptor binding to bioeffects is impaired. Binding is also reduced in those subjects with hyperinsulinaemia and non-insulin-dependent diabetes. Insulin-dependent diabetics have reduced insulin sensitivity, which is only partially reversed by conventional insulin therapy. 'Post-binding defects' in some diabetics could be related to defective covalent receptor modifications resulting from genetic receptor defects. High carbohydrate diets improve diabetes control through effects on the binding and coupling defects. In addition to stimulating insulin secretion, oral hypoglycaemics stimulate post-binding insulin action in vivo and in vitro. Insulin therapy in diabetes also tends to reverse post-binding defects. Pulsatile insulin delivery is more effective in lowering blood sugar than continuous administration, and produces less 'down regulation' of receptors. Combined insulin and sulphonylurea drugs reduce insulin requirements only in insulin-dependent diabetics with some endogenous insulin secretion, whereas metformin reduces insulin requirement in C-peptide negative insulin-dependent diabetes mellitus.

Diabetes Mellitus↗
PubMed2006

Hyposecretion, not hyperabsorption, is the basic defect of cystic fibrosis airway glands.

Human airways and glands express the anion channel cystic fibrosis transmembrane conductance regulator, CFTR, and the epithelial Na(+) channel, ENaC. Cystic fibrosis (CF) airway glands fail to secrete mucus in response to vasoactive intestinal peptide or forskolin; the failure was attributed to loss of CFTR-mediated anion and fluid secretion. Alternatively, CF glands might secrete acinar fluid via CFTR-independent pathways, but the exit of mucus from the glands could be blocked by hyperabsorption of fluid in the gland ducts. This could occur because CFTR loss can disinhibit ENaC, and ENaC activity can drive absorption. To test these two hypotheses, we measured single gland mucus secretion optically and applied ENaC inhibitors to determine whether they augmented secretion. Human CF glands were pretreated with benzamil and then stimulated with forskolin in the continued presence of benzamil. Benzamil did not rescue the lack of secretion to forskolin (50 glands, 6 CF subjects) nor did it increase the rate of cholinergically mediated mucus secretion from CF glands. Finally, neither benzamil nor amiloride increased forskolin-stimulated mucus secretion from porcine submucosal glands (75 glands, 7 pigs). One possible explanation for these results is that ENaC within the gland ducts was not active in our experiments. Consistent with that possibility, we discovered that human airway glands express Kunitz-type and non-Kunitz serine protease inhibitors, which might prevent proteolytic activation of ENaC. Our results suggest that CF glands do not display excessive, ENaC-mediated fluid absorption, leaving defective, anion-mediated fluid secretion as the most likely mechanism for defective mucus secretion from CF glands.

Amiloride↗
PubMed2000

Alteration of the lipopolysaccharide structure affects the functioning of the Xcp secretory system in Pseudomonas aeruginosa.

Pseudomonas aeruginosa secretes a wide range of hydrolytic enzymes into the external medium by the Xcp secretion machinery. To better understand the role played by envelope constituents in the functioning of this type II secretory system, we have studied the influence of lipopolysaccharide (LPS) on the secretion of two extracellular enzymes, the elastase LasB and the lipase LipA. Strains with defective LPS decreased production of LasB and altered the secretion processes of both LasB and LipA without any apparent effect on the composition of the Xcp machinery. The PAO1algC strain, defective in the outer core of LPS, was leaky, as shown by the extracellular release of the periplasmic beta-lactamase. Generation of an xcpR mutation in this mutant led only to a partial accumulation of LasB within the cells, indicating that in strain PAO1algC with a functional xcpR gene, LasB was released in the extracellular medium partly by leakage and partly by secretion. The pool of LasB released into the medium by leakage was not recovered in an active form, while extracellular LasB was active when secreted via the secretory machinery. Further analysis revealed that the presence of a functional Xcp machinery is strictly required for the activation process of LasB. Our results provide evidence that the Xcp system is not fully functional when the LPS structure of P. aeruginosa is altered.

Aspartic Acid Endopeptidases↗
PubMed1996

The pathogenesis of type II diabetes mellitus. A polygenic disease.

Diabetes mellitus is the most common endocrine disease, consuming almost 15% of annual health care expenditures in the United States. The focus of this review is on type II (non-insulin-dependent) diabetes mellitus, which accounts for approximately 90% of diabetic patients. The current understanding of the pathogenesis of type II diabetes is multifaceted. Complex defects in both insulin action and insulin secretion produce the metabolic derangements responsible for the disease. The pathophysiology is the result of a combination of polygene defects and environmental factors. The search for the responsible gene or genes is described and several candidate genes are discussed. Diabetogenes are addressed in the context of type II diabetes representing a prototype for the identification of the genetic basis of common diseases.

Aged↗
PubMed1991

Banting lecture 1990. Beta-cells in type II diabetes mellitus.

In 1960, immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a beta-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet beta-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently, it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals, including other substrates, hormones, and neural factors. When both obesity and glucose are taken into account, it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose beta-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release. Before the development of fasting hyperglycemia, only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear, so that there is a 75% loss of beta-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose. The etiology of the islet beta-cell lesion is not known, but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin, which is the major constituent of islet amyloid deposits, is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing, secondary to or in conjunction with defects in hormone secretion, lead to progressive accumulation of intracellular IAPP and pro-IAPP, which in cats, monkeys, and humans form intracellular fibrils and amyloid deposits with a loss of beta-cell mass.(ABSTRACT TRUNCATED AT 400 WORDS)

Diabetes Mellitus, Type 2↗
PubMed1991

Chloride transport in the cystic fibrosis enterocyte.

Molecular mechanisms of intestinal chloride channel regulation and potential abnormalities in electrogenic chloride secretion in intestinal epithelium from cystic fibrosis (CF) patients were investigated by a combination of Ussing chamber, vesicle transport and off-cell patch-clamp analysis. Short circuit current (Isc) measurements in normal and CF rectal biopsies provided evidence for i) a defect in the cAMP-provoked activation of chloride secretion and a (hyper)expression of cAMP-dependent potassium secretion in all CF patients examined (n = 11); ii) a defect in the carbachol-provoked chloride secretion and a (hyper)expression of carbachol-induced potassium secretion in 6/11 patients; iii) a residual (but still impaired) carbachol-induced chloride secretion in 5/11 CF patients (including 2 sibs). The latter class of CF patients appeared to consist genetically of compound heterozygotes for the major delta-F508 deletion, suggesting a correlation between the nature of the mutation in the CF gene and the severity of the chloride secretory defect in CF intestine. In our search for a regulatory function of GTP-binding (G-) proteins detected previously in the luminal membrane of rat and human intestinal epithelial cells, evidence was found for the presence of a GTP[S]-activatable- and GDP[S]-inhibitable chloride conductance in the apical membrane of rat enterocytes and human colonocytes. In excised patches of human colonocyt membranes, this G-proteine-sensitive chloride conductance was identified further as a novel type of chloride channel (20pS; inwardly rectifying) that was different from the 33pS outwardly rectifying chloride channel activatable by cAMP-dependent proteinkinase (PK-A) and voltage depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Mechanisms of glucosamine-induced suppression of the hepatic assembly and secretion of apolipoprotein B-100-containing lipoproteins.

Glucosamine-induced endoplasmic reticulum (ER) stress was recently shown to specifically reduce apolipoprotein B-100 (apoB-100) secretion by enhancing the proteasomal degradation of apoB-100. Here, we examined the mechanisms linking glucosamine-induced ER stress and apoB-lipoprotein biogenesis. Trypsin sensitivity studies suggested glucosamine-induced changes in apoB-100 conformation. Endoglycosidase H studies of newly synthesized apoB-100 revealed glucosamine induced N-linked glycosylation defects resulting in reduced apoB-100 secretion. We also examined glucosamine-induced changes in VLDL assembly and secretion. A dose-dependent (1-10 mM glucosamine) reduction was observed in VLDL-apoB-100 secretion in primary hepatocytes (24.2-67.3%) and rat McA-RH7777 cells (23.2-89.5%). Glucosamine also inhibited the assembly of larger VLDL-, LDL-, and intermediate density lipoprotein-apoB-100 but did not affect smaller HDL-sized apoB-100 particles. Glucosamine treatment during the chase period (posttranslational) led to a 24% reduction in apoB-100 secretion (P < 0.01; n = 4) and promoted post-ER apoB degradation. However, the contribution of post-ER apoB-100 degradation appeared to be quantitatively minor. Interestingly, the glucosamine-induced posttranslational reduction in apoB-100 secretion could be partially prevented by treatment with desferrioxamine or vitamin E. Together, these data suggest that cotranslational glucosamine treatment may cause defects in apoB-100 N-linked glycosylation and folding, resulting in enhanced proteasomal degradation. Posttranslationally, glucosamine may interfere with the assembly process of apoB lipoproteins, leading to post-ER degradation via nonproteasomal pathways.

Animals↗
PubMed2005

Functional and molecular defects of pancreatic islets in human type 2 diabetes.

To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

Shifting the LDL-receptor paradigm in familial hypercholesterolemia: novel insights from recent kinetic studies of apolipoprotein B-100 metabolism.

Familial hypercholesterolemia (FH) is a dominantly inherited disorder associated with elevated plasma cholesterol concentrations and premature cardiovascular disease. In addition to impaired low density lipoprotein (LDL) receptor-mediated clearance of low density lipoproteins in FH, evidence from in vitro and in vivo studies suggests that hepatic oversecretion of apoB may contribute to the hypercholesterolemia. The proposed association between apoB secretion and FH may, however, be a function of the class of LDL receptor defect. Hepatic cholesterol pools appear to regulate apoB secretion and LDL receptor activity. Therefore, therapeutic regulation of cholesterogenesis in FH may have the dual effect of reducing hepatic apoB secretion and upregulating the LDL receptor. These effects may also be genetically determined.

Animals↗
PubMed1997

Factors involved in rejection of concordant xenografts in complement-deficient rats.

BACKGROUND: Factors that contribute to xenograft (Xg) rejection were investigated in complement C6-deficient (C-) PVG rats. METHODS: First and second hamster hearts were transplanted in C6-deficient and C6-sufficient PVG rats. Xenoantibody (XAb) formation, hemolytic C (CH50) activity and immunohistochemistry were studied. RESULTS: PVG C6-deficient rats rejected Xgs 3 days later than PVG C6-sufficient rats. Surprisingly, C activation participated in the rejection in PVG C- rats, as shown by partially recovered serum CH50 levels and deposition of C factors in the Xgs. As we found that cultured endothelial cells produced C6 in vitro, we hypothesized that Xg endothelial cells corrected the C6 defect in PVG C- rats. This was probably induced by IgM XAbs as: (1) it did not occur in immunosuppressed PVG C- rats in which XAb formation was prevented, and (2) transfer of IgM XAbs to naive, xenotransplanted PVG C- rats accelerated the recovery of CH50 and concomitantly Xg rejection. Thirty days after rejection of a first Xg, when no IgM XAbs or CH50 activity but high levels of IgG XAbs were detected in PVG C- rats, second Xgs underwent a hyperacute rejection. This time, complement was not involved, as no serum CH50 nor C deposition was found in the Xg. Instead, IgG antibody-dependent cellular cytotoxicity was involved as: (1) IgG XAbs were deposited in the Xg and (2) hyperacute rejection was induced in naive PVG C- rats by transfer of IgG XAbs, and (3) this rejection was delayed to 5+/-3 days if the adoptive hosts were first irradiated. CONCLUSIONS: In the face of a defect of host C factors, IgM XAb may induce cells of the Xg to secrete C factors which may correct the C defect of the host. Even if activation of lytic C can be prevented, IgG XAb may still provoke an acute Xg rejection by antibody-dependent cellular cytotoxicity.

Animals↗
PubMed1987

Progestin-dependent human endometrial protein: a marker for monitoring human endometrial function.

Progesterone (P), which is the major secretory product of the corpus luteum (CL) is the key hormone of pregnancy. CL defects that cause P to be secreted for too brief a period or at too low a rate are associated with an underdeveloped or inadequate endometrium which is incapable of supporting pregnancy. Some investigators, therefore, have recommended the use of exogenous P support in chronic CL defect patients who wish to conceive. However, the mechanisms by which P regulates endometrial function are poorly understood and there is no suitable, non-invasive method to monitor in individual patients the endometrial response to either endogenous or exogenous progesterone. We therefore initiated a search for progesterone-dependent endometrial protein(s) which might serve as a marker to assess effects of progestin therapy on endometrial function, and which might also afford insight into the mechanism of P action. We have detected a hormone-dependent endometrial protein designated "progestagen-associated (or -dependent) endometrial protein" or PEP. PEP is a glycoprotein (molecular weight approximately 47,000) which is synthesized in the endometrial glands and secreted into the blood. Its synthesis increases dramatically during pregnancy, as indicated by a more than 1000-fold greater PEP concentration in the decidua. PEP is not synthesized by the immature placenta, but binds to placental cell membranes. In normally cycling women, the serum PEP concentration increases in an exponential manner during the late luteal phase. In cycling infertile women, a direct relationship was found to exist between serum PEP levels they attained in the late luteal phase and their endometrial development, the serum levels being subnormal in women with inadequate endometrium. Menstrual cycles that are anovulatory or with a CL-defect are associated with low luteal phase serum PEP levels. In both pre- and post-menopausal women, serum PEP levels increase following a progestin challenge, demonstrating that PEP is indeed a progestin-dependent protein. Very low luteal phase serum PEP levels are encountered in some women who do not conceive following in vitro fertilization and embryo transfer (IVF/EF), suggesting that endometrial inadequacy is a major cause of failure in this procedure. In patients who undergo ovarian stimulation by exogenous hormones but do not conceive following IVF/ET, luteal phase serum PEP levels are markedly higher in those who receive luteal phase P support than those with no support.(ABSTRACT TRUNCATED AT 400 WORDS)

Decidua↗
PubMed1999

Bone defect healing enhanced by ultrasound stimulation: an in vitro tissue culture model.

Ultrasound has many medical applications. Previous animal and clinical studies have clearly shown a positive effect of ultrasound on the rate of osseous repair. The present in vitro study was designed to elucidate the specific response of bony tissue to ultrasound treatment. Bilateral femora were obtained from 36 mature male Wistar rats. A bone defect was created at the center of each distal metaphysis. The femora were maintained for either 7 or 14 days in in vitro tissue culture and received 15 min of ultrasound stimulation or a sham exposure. The ultrasound intensity used was either 320 or 770 mW/cm2. Healing of the bone defect was evaluated by histomorphological examination and by analysis for the synthesis and secretion of prostaglandin E2. The results showed that ultrasound stimulation can accelerate both defect healing and trabecular bone regeneration. All experimental femoral defects treated with ultrasound healed faster than the untreated cortical defects, but only the defects receiving 770 mW/cm2 reached a level that was significantly different. The healing rate for the 320-mW/cm2 stimulated defects was intermediate between that of the 770-mW/cm2 and sham-exposed defects. With ultrasound stimulation, prostaglandin E2 secretion by the experimental femora decreased significantly. Changes in the prostaglandin synthesis and concentration were found to correspond to changes in the amount of trabecular regeneration and to acceleration of bone healing. This highly controlled and well-studied model of ultrasound stimulation of bone healing in vitro can be used to further examine the biological mechanisms involved.

Animals↗

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