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PubMed2004

Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins.

Cyclic nucleotides acting through their associated protein kinases, the cGMP- and cAMP-dependent protein kinases, can relax smooth muscles without a change in free intracellular calcium concentration ([Ca2+]i), a phenomenon referred to as Ca2+ desensitization. The molecular mechanisms by which these kinases bring about Ca2+ desensitization are unknown and an understanding of this phenomenon may lead to better therapies for treating diseases involving defects in the contractile response of smooth muscles such as hypertension, bronchospasm, sexual dysfunction, gastrointestinal disorders and glaucoma. Utilizing a combination of real-time proteomics and smooth muscle physiology, we characterized a distinct subset of protein targets for cGMP-dependent protein kinase in smooth muscle. Among those phosphoproteins identified was calponin homology-associated smooth muscle (CHASM), a novel protein that contains a calponin homology domain and shares sequence similarity with the smoothelin family of smooth muscle specific proteins. Recombinant CHASM was found to evoke relaxation in a concentration dependent manner when added to permeabilized smooth muscle. A co-sedimentation assay with actin demonstrated that CHASM does not possess actin binding activity. Our findings indicate that CHASM is a novel member of the smoothelin protein family that elicits Ca2+ desensitization in smooth muscle.

Actins↗

PubMed2004

An active ingredient of Cat's Claw water extracts identification and efficacy of quinic acid.

Historic medicinal practice has defined Cat's Claw, also known as Una de Gato or Uncaria tomentosa, as an effective treatment for several health disorders including chronic inflammation, gastrointestinal dysfunction such as ulcers, tumors and infections. The efficacy of Cat's Claw was originally believed, as early as the 1960s, to be due to the presence of oxindole alkaloids. However, more recently water-soluble Cat's Claw extracts were shown not to contain significant amounts of alkaloids (<0.05%), and yet still were shown to be very efficacious. Here we characterize the active ingredients of a water-soluble Cat's Claw extract called C-Med-100 as inhibiting cell growth without cell death thus providing enhanced opportunities for DNA repair, and the consequences thereof, such as immune stimulation, anti-inflammation and cancer prevention. The active ingredients were chemically defined as quinic acid esters and could also be shown to be bioactive in vivo as quinic acid.

Animals↗

PubMed2006

Evidence-based perianesthesia care: accelerated postoperative recovery programs.

Prolonged stress response after surgery can cause numerous adverse effects, including gastrointestinal dysfunction, muscle wasting, impaired cognition, and cardiopulmonary, infectious, and thromboembolic complications. These events can delay hospital discharge, extend convalescence, and negatively impact long-term prognosis. Recent advances in perioperative management practices have allowed better control of the stress response and improved outcomes for patients undergoing surgery. At the center of the current focus on improved outcomes are evidence-based fast-track surgical techniques and what is commonly referred to as "accelerated postoperative recovery programs." These programs require a multidisciplinary, coordinated effort, and nurses are essential to their successful implementation.

Convalescence↗

PubMed2004

The significance of intrauterine growth restriction is different from prematurity for the outcome of infants with gastroschisis.

BACKGROUND/PURPOSE: Recent reviews of gastroschisis identify prematurity and low birth weight as predictors of morbidity and mortality. The authors compared the outcomes of intrauterine growth-restricted infants (IUGR) with gastroschisis to those without growth restriction because IUGR is different from prematurity. METHODS: A retrospective analysis was performed for infants born with gastroschisis between 1990 and 2000 at 2 pediatric hospitals. Patients were segregated into 3 groups based on birth weight corrected for gestational age: group 1 (IUGR, 25th percentile). Patient demographics, method of closure, number of surgeries, presence of atresia, and time to full enteral feedings (FPO days) were assessed. Mortality rate, length of stay (LOS), and readmission rates were also compared. Analysis of variance (ANOVA)/Student's t test and Fisher's. Exact tests were used for statistical analysis (P <.05 significant). Regression analysis was also performed. RESULTS: One hundred thirteen patients were included (group 1 = 17; group 2 = 43; group 3 = 53). Overall, infants with IUGR had similar outcomes to non-IUGR infants, including FPO and total parenteral nutrition (TPN) days, LOS, readmission, and mortality rates. The method of closure did not affect outcome. Infants with atresia had significantly increased times to full feeding (95 v 34 days; P =.034), more surgeries (2.7 v 1.4; P =.002), and longer LOS (106 v 48 days; P =.011). Infants born at less than 37 weeks' gestation had significantly increased fasting (NPO) days (28 v 18 days; P =.005) and longer LOS (65 v 37 days; P =.006) when compared with infants born at greater than 37 weeks. Logistic regression analysis identified the presence of atresia as an independent risk factor for gastrointestinal dysfunction and the need for prolonged TPN. Prematurity also adversely affected these same parameters, although it did not reach statistical significance. CONCLUSIONS: Although infants with gastroschisis are generally small for gestational age, the outcomes of growth-restricted infants are similar to those of other infants. The type of closure does not affect outcome, regardless of birth weight. The presence of atresia or prematurity does lead to longer times for full feeding and LOS. Therefore, routine premature delivery of infants with gastroschisis should not be advocated, even in the context of IUGR.

Adult↗

PubMed2006

The inflammation in the gut after experimental subarachnoid hemorrhage.

BACKGROUND: Gastrointestinal dysfunction could be frequently observed in the patients suffering from SAH. This study test the hypothesis that experimental SAH could induce histopathological changes and inflammatory response associating with NF-kappaB activation pathway in the gut. MATERIALS AND METHODS: A total of 17 rabbits were randomly divided into two groups: control group (n = 8) and SAH group (n = 9). In the SAH group, the animals were subjected to experimental SAH according to the "two-hemorrhage" method. The histopathological study was performed to detect the intestinal mucosal morphological changes and immunohistochemical study was used to detect the TNF-alpha and ICAM-1 expressions. NF-kappaB binding activity was measured using the electrophoretic mobility shift assay. RESULTS: It was demonstrated that some damage changes and leukocytes infiltration occurred in the intestinal mucosa after SAH. More positive cells for TNF-alpha and ICAM-1 were observed in the SAH group. The NF-kappaB binding activity in the intestines was significantly increased in the SAH group (P < 0.01). CONCLUSIONS: The results of the present study suggest that SAH in the rabbits could induce NF-kappaB and proinflammatory cytokines activation in the intestine, which is associated with morphological changes.

Animals↗

PubMed2004

Acute and chronic cough.

Individuals are generally content to self-medicate for acute cough. It is only when the cough becomes persistent that they seek medical assistance. It is not known why patients cough in association with an acute upper respiratory tract infection (URTI), although interest has focused on how viruses may influence airway sensory nerve function and contribute to heightened cough reflex sensitivity. Why some patients develop a persistent cough following a viral URTI is also unclear. Much more is known about the causes and aggravants of chronic cough although there is no broad agreement as to the best way to manage such patients. Asthma, upper gastrointestinal dysfunction and rhinitis are frequently associated with chronic cough, although the impact of cough in suppurative lung disease and interstitial lung fibrosis is rarely considered. The development of effective treatments for cough remains a challenge and will require co-operation between clinicians, scientists and the pharmaceutical industry.

Acute Disease↗

PubMed2003

Effects of prenatal dexamethasone on the intestine of rats with gastroschisis.

BACKGROUND/PURPOSE: Intestinal lesions observed in gastroschisis (Gx) are accompanied by neonatal gastrointestinal dysfunction. This study examines the effects of transplacental dexamethasone on the eviscerated intestine of fetal rats with Gx. METHODS: Gx was created surgically in rat fetuses on gestational day 18, and the dams were treated either with 0.4 mg/kg intraperitoneal dexamethasone or with vehicle only on days 19 and 20. The intestine recovered on day 21 were processed for total DNA and protein. Immuno-histochemical staining for ki-67, TUNEL, and synaptophysin were used for assessing the proportions of proliferating and apoptotic cells and the density of intramural ganglia. Analysis of variance (ANOVA) was used for comparison among groups. Significance level was set at P less than.05. RESULTS: Body weight was reduced in Gx fetuses in comparison with controls. Intestinal weight per centimeter and mucosal and seromuscular layer thicknesses were increased in Gx and Gx + dexa groups. Total intestinal DNA was diminished in Gx animals but it was near normal in Gx + dexa ones. Total intestinal protein was similar in all groups. DNA and protein per centimeter of bowel were very increased in Gx animals but only slightly in Gx + dexa ones. Proliferating cells were decreased in Gx animals and increased in Gx+dexa ones, whereas the opposite was observed for apoptosis. Density of intramural ganglia was decreased significantly in both Gx groups. CONCLUSIONS: Late intrauterine exposure to dexamethasone of rat fetuses with Gx decreased wall thickening, normalized total DNA, and induced proliferation in the exposed bowel while limiting apoptosis. This medication could have some yet incompletely defined beneficial effects on the wall of the eviscerated bowel in Gx.

Animals↗

PubMed1989

Continent urinary diversion.

From August 1982 through March 1988, 531 patients have undergone continent urinary diversion using an ileal reservoir constructed according to the method of Kock. For the last 18 months we have used the principle of Kock reservoir construction for primary lower urinary tract reconstruction after cystectomy in 39 highly selected male patients by means of a ureteroileal urethrostomy. Early complications occurred in 86 of 531 patients (16.2 per cent), resulting in an operative mortality rate of 1.9 per cent (10 of 531). The early complication rate was 16.5 per cent among patients undergoing 1-stage cystectomy and Kock pouch construction, and 15.2 per cent among patients undergoing Kock pouch conversion. Late complications have been analyzed in 489 patients who have undergone Kock cutaneous diversion. The complications unique to continent urinary diversion, their incidence and the effect of technical modifications in reducing the number of late complications are shown. Note that since the last modification in July 1985 the over-all incidence of late complication has decreased to 22 per cent. Based on this ongoing experience we conclude that the continent ileal reservoir, as conceived by Kock, remains the ideal internal reservoir for bladder replacement in terms of volume accommodation with the lowest internal pressures, and the intussuscepted ileal nipple valve mechanism is a reproducible, highly effective mechanism that prevents reflux and pyelonephritis in greater than 95 per cent of the patients and produces excellent continence. Our enthusiasm remains tempered by the need for reoperation in approximately 10 to 15 per cent of the patients, usually due to a pinhole fistula or false passage at the base of the efferent nipple valve mechanism. Electrolyte abnormalities rarely occur and in the absence of radiation gastrointestinal dysfunction is unusual. Continent urinary diversion is a viable concept that provides a real alternative in terms of quality of life and self-image for the patient who requires urinary diversion for any reason.

Adolescent↗

PubMed1986

Acute adrenal insufficiency as a complication of urological surgery.

Acute adrenal insufficiency postoperatively is an uncommon problem and, if unrecognized, it may cause serious morbidity and can be fatal. It can occur as the result of acute bilateral adrenal hemorrhage associated with anticoagulation, inadvertent injury to or removal of a solitary adrenal gland, or postoperative stress in an individual with incipient adrenal insufficiency. Its manifestations, such as fever, tachycardia, hypotension, lethargy, abdominal pain and gastrointestinal dysfunction, mimic the other more common postoperative complications and compound the difficulty in establishing the correct diagnosis. Once the diagnosis is made the condition is readily managed successfully. We report 3 cases of acute adrenal insufficiency occurring after salvage cystectomy, ileal replacement of the ureter and retropubic prostatectomy, which illustrate the salient clinical features, problems in diagnosis and predisposing risk factors. All 3 patients survived once the diagnosis of adrenal insufficiency was made. These cases emphasize the need to be aware of the possibility of this complication to make the correct diagnosis and to institute proper treatment.

Adenocarcinoma↗

PubMed2000

Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention.

Free radicals have been implicated in over a hundred disease conditions in humans, including arthritis, hemorrhagic shock, atherosclerosis, advancing age, ischemia and reperfusion injury of many organs, Alzheimer and Parkinson's disease, gastrointestinal dysfunctions, tumor promotion and carcinogenesis, and AIDS. Antioxidants are potent scavengers of free radicals and serve as inhibitors of neoplastic processes. A large number of synthetic and natural antioxidants have been demonstrated to induce beneficial effects on human health and disease prevention. However, the structure-activity relationship, bioavailability and therapeutic efficacy of the antioxidants differ extensively. Oligomeric proanthocyanidins, naturally occurring antioxidants widely available in fruits, vegetables, nuts, seeds, flowers and bark, have been reported to possess a broad spectrum of biological, pharmacological and therapeutic activities against free radicals and oxidative stress. We have assessed the concentration- or dose-dependent free radical scavenging ability of a novel IH636 grape seed proanthocyanidin extract (GSPE) both in vitro and in vivo models, and compared the free radical scavenging ability of GSPE with vitamins C, E and beta-carotene. These experiments demonstrated that GSPE is highly bioavailable and provides significantly greater protection against free radicals and free radical-induced lipid peroxidation and DNA damage than vitamins C, E and beta-carotene. GSPE was also shown to demonstrate cytotoxicity towards human breast, lung and gastric adenocarcinoma cells, while enhancing the growth and viability of normal human gastric mucosal cells. The comparative protective effects of GSPE, vitamins C and E were examined on tobacco-induced oxidative stress and apoptotic cell death in human oral keratinocytes. Oxidative tissue damage was determined by lipid peroxidation and DNA fragmentation, while apoptotic cell death was assessed by flow cytometry. GSPE provided significantly better protection as compared to vitamins C and E, singly and in combination. GSPE also demonstrated excellent protection against acetaminophen overdose-induced liver and kidney damage by regulating bcl-X(L) gene, DNA damage and presumably by reducing oxidative stress. GSPE demonstrated excellent protection against myocardial ischemia-reperfusion injury and myocardial infarction in rats. GSPE was also shown to upregulate bcl(2) gene and downregulate the oncogene c-myc. Topical application of GSPE enhances sun protection factor in human volunteers, as well as supplementation of GSPE ameliorates chronic pancreatitis in humans. These results demonstrate that GSPE provides excellent protection against oxidative stress and free radical-mediated tissue injury.

Animals↗

PubMed2000

The neuroleptic malignant and serotonin syndromes.

The neuroleptic malignant syndrome and the serotonin syndrome share many clinical features and may exist on a spectrum of the same disorder. The neuroleptic malignant syndrome, however, is an idiosyncratic drug reaction, whereas the serotonin syndrome is an effect of drug toxicity. Both syndromes present with varying degrees of mental status changes and autonomic instability. In general, patients with the neuroleptic malignant syndrome have higher fevers and pronounced extrapyramidal signs with muscle rigidity, whereas patients with the serotonin syndrome have lower fevers, more gastrointestinal dysfunction, and myoclonus. Treatment for both syndromes consists of removing the offending agent and providing intensive supportive care. Syndrome-specific therapies are controversial.

Diagnosis, Differential↗

PubMed1997

Home parenteral lipids in AIDS: a three-month study.

Parenteral nutrition is a part of the nutritional support regimen of patients with AIDS-associated wasting syndrome and gastrointestinal dysfunction. The cholesterol (CHOL) level in human immunodeficiency virus (HIV) membrane is very high, and recent lipid formulations with high phospholipid (PL) content have demonstrated the ability to trap CHOL from endogenous sources, modifying the composition of cell membranes. We administered lipid-based home parenteral nutrition for 3 mo to malnourished AIDS patients. The patients were randomly divided into two groups: 23 received the regular 20% fat emulsion formulation, and 27 received a 2% formulation enriched 10-fold with PLs but containing the same amount of triglycerides. All patients gained weight and improved their activity level. Those receiving the high-PL composition showed increased serum CHOL concentrations (from 147 to 241 mg/dL; P < 0.01), but no increase was seen in the number of CD4 cells or improvement in immune function. HIV infectivity was not modified. Patients receiving regular PLs had significantly decreased (P < 0.02) IgA concentrations (from 776 to 300 mg/dL) and improved mitogen response to phytohemagglutinin and to concanavalin A. This formula, too, had no effect on HIV infectivity. We conclude that standard parenteral nutritional influences the nutritional and immune status of malnourished AIDS patients. A PL-enriched parenteral formulation can trap CHOL, but it does not affect the immune profile or HIV infectivity in patients with advanced disease.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Abnormalities of small intestinal endocrine cells in non-obese diabetic mice.

The endocrine cells in the duodenum of pre-diabetic and diabetic female non-obese diabetic (NOD) mice aged 22-24 weeks were studied by means of immunohistochemistry and computed image analysis as well as by radioimmunoassays of tissue extracts. As controls, 12 female BALB/cJ mice of the same age as NOD mice were used. The number of secretin-immunoreactive cells increased in diabetic but not in pre-diabetic NOD mice. The level of extractable secretin was higher in both pre-diabetic and diabetic NOD mice. The number of GIP-, CCK/gastrin-, and serotonin-immunoreactive cells was significantly reduced in both pre-diabetic and diabetic NOD mice. There was no statistical difference in the number of somatostatin-immunoreactive cells between the NOD mice and controls. The level of GIP was higher and gastrin was lower in NOD mice compared to controls. There was no statistical difference in the somatostatin level between the NOD mice and controls. The cell secretory index was elevated in all the endocrine cell types except CCK/gastrin cells. It has been suggested that some of the changes in the duodenal endocrine cells could be attributed to the diabetes state, but most of the changes seem to take place before the onset of diabetes. The abnormalities in the duodenal endocrine cells observed here in an animal model for diabetes type I might have relevance for the gastrointestinal dysfunction displayed in human diabetes.

Animals↗

PubMedDate not supplied

Neuroendocrine peptides in stomach and colon of an animal model for human diabetes type I.

Twelve prediabetic and 12 diabetic non-obese diabetic (NOD) mice, all females aged 22-24 weeks, were investigated. As controls, 12 BLAB/cJ Bom mice of the same age and gender as the NOD mice were used. The concentration of several neuroendocrine peptides was determined by radioimmunoassay of tissue extracts of transmural specimens of antrum and distal colon. The neuroendocrine peptides investigated were peptide YY (PYY), somatostatin, vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), neurotensin, and galanin. In the antrum, VIP, NPY, and galanin concentrations were all significantly lower in prediabetic and diabetic NOD mice than in controls. There was no statistical difference between NOD mice and controls regarding neurotensin content. In the colon, the concentrations of PYY, somatostatin, VIP, NPY, and galanin were lower in prediabetic and diabetic NOD mice than in controls. The concentration of neurotensin in prediabetic, but not in diabetic NOD mice was lower than that of controls. The present observations support the previously reported studies on animal models for human type I diabetes that the neuroendocrine system of the gut is disturbed. It also shows that the neuroendocrine system of the stomach and large intestine is affected. The present findings may have some implications for the gastrointestinal dysfunction observed in patients with human type I diabetes.

Animals↗

PubMedDate not supplied

A randomized comparison of the effects of continuous thoracic epidural analgesia and intravenous patient-controlled analgesia after posterior spinal fusion in adolescents.

BACKGROUND AND OBJECTIVES: Pain and gastrointestinal dysfunction are primary factors that delay recovery after posterior spinal fusion. Previous reports suggest that the choice of analgesic management may effect the course of recovery. This prospective, randomized study compared continuous thoracic epidural analgesia and patient-controlled analgesia in the postoperative care of adolescents undergoing posterior spinal fusion for idiopathic scoliosis. METHODS: Patients between 11 and 18 years of age were randomized to receive continuous thoracic epidural analgesia with bupivacaine-fentanyl (CEA, n = 17) or intravenous patient-controlled analgesia with morphine sulfate (n = 16). After surgery under general anesthesia, pain intensity was evaluated using a self-report visual analog scale (VAS). Postoperative time to resumption of bowel sounds, liquid intake, and side effects were also recorded. RESULTS: There were no significant differences between groups in VAS pain scores, side effects, or time to resumption of liquid intake. There was a significant difference (P = .0089) between groups in return of bowel sounds, which occurred earlier in patients receiving CEA. CONCLUSIONS: Continuous epidural analgesia and patient-controlled analgesia are comparably effective and safe after posterior spinal fusion. Return of bowel sounds occurred significantly more rapidly in patients receiving CEA postoperatively.

Adolescent↗

PubMed1998

Antral endocrine cells in nonobese diabetic mice.

The antral endocrine cells were investigated in nonobese diabetic (NOD) mice by means of immunohistochemistry, image analysis, and radioimmunoassays (RIA). As controls BALB/CJ mice of the same age and sex as the NOD mice were used. The number of gastrin- and somatostatin-immunoreactive cells was significantly decreased in both prediabetic and diabetic mice. There was no statistical difference between the NOD mice and controls regarding the serotonin-immunoreactive cells. Somatostatin levels as revealed by RIA in the antrum of both prediabetic and diabetic NOD mice were lower than those of the controls. There was no statistical difference in the level of antral gastrin between NOD mice and the controls. It was concluded that the changes in antral cells are primary to the onset of diabetes, and that the abnormalities observed in the antral cells in an animal model for diabetes type I might have relevance for the upper gastrointestinal dysfunction displayed in human diabetes.

Animals↗

PubMed1999

Gastrointestinal endocrine cells in an animal model for human type 2 diabetes.

Endocrine cells were investigated in various parts of the gastrointestinal tract in an animal model for human type 2 diabetes, namely the homozygous obese mouse. As controls, age- and sex-matched homozygous lean mice were used. The different endocrine cell types were stained by using immunocytochemistry and quantified by computerized image analysis. The numbers of PYY- and enteroglucagon-immunoreactive (IR) cells were decreased in the colon of obese diabetic mice vis-à-vis controls. Serotonin-IR cells were significantly decreased in numbers in the duodenum and colon. Furthermore, colonic serotonin cells had a high cell secretory index (CSI), but an unchanged nuclear area, indicating an impaired cellular release of this amine. There was no statistical difference between obese diabetic mice and lean controls regarding the numbers and CSI of antral gastrin/CCK-, somatostatin- and serotonin-; and duodenal secretin-, gastric inhibitory peptide (GIP)-, CCK/gastrin-, and somatostatin-IR cells; nor was there any difference regarding nuclear area, with the exception of the antral somatostatin- and duodenal GIP-IR cells. It is concluded that the abnormalities in gut endocrine cells observed in the present study might explain the gut dysmotility reported in animal models for human diabetes. They may also be of importance in gastrointestinal dysfunction occurring in diabetes patients.

Animals↗

PubMed2026

Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy.

SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1-2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient's phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490 .

Adolescent↗