Hypersecretory State Research Articles

Unravelling Peptic Ulcers: Comprehensive Insights into Etiology, Diagnosis, Screening Techniques, and Treatment.

The risk of illnesses is increasing in the modern era due to unhealthy and modern lifestyles. Research has shown that the most frequent acid-induced abrasion, which often occurs in the stomach and proximal duodenum, is gastric and Peptic Ulcer Disease (PUD), which is a primary worldwide health concern. The deformity is characterized by denuded mucosa and spreads into the submucosa. Non-steroidal antiinflammatory drugs (NSAIDs) and H. pylori infections are two common offenders. In the past, it has been thought that dietary variables, stress, and an acidic hypersecretory state encourage mucosal disruption in peptic acid disease patients. Peptic ulcers continue to be a significant health issue because of their potential for substantial consequences, including bleeding, blockage, and perforation, even with advancements in detection and treatment. This review discusses current screening methods for peptic ulcers and the challenges in diagnosis and treatment, emphasizing the need for precise diagnosis and more effective therapies.

The senescence-associated secretory phenotype and its physiological and pathological implications.

Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions.

EMT-activated secretory and endocytic vesicular trafficking programs underlie a vulnerability to PI4K2A antagonism in lung cancer.

Hypersecretory malignant cells underlie therapeutic resistance, metastasis, and poor clinical outcomes. However, the molecular basis for malignant hypersecretion remains obscure. Here, we showed that epithelial-mesenchymal transition (EMT) initiates exocytic and endocytic vesicular trafficking programs in lung cancer. The EMT-activating transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) executed a PI4KIIIβ-to-PI4KIIα (PI4K2A) dependency switch that drove PI4P synthesis in the Golgi and endosomes. EMT enhanced the vulnerability of lung cancer cells to PI4K2A small-molecule antagonists. PI4K2A formed a MYOIIA-containing protein complex that facilitated secretory vesicle biogenesis in the Golgi, thereby establishing a hypersecretory state involving osteopontin (SPP1) and other prometastatic ligands. In the endosomal compartment, PI4K2A accelerated recycling of SPP1 receptors to complete an SPP1-dependent autocrine loop and interacted with HSP90 to prevent lysosomal degradation of AXL receptor tyrosine kinase, a driver of cell migration. These results show that EMT coordinates exocytic and endocytic vesicular trafficking to establish a therapeutically actionable hypersecretory state that drives lung cancer progression.

McKittrick-Wheelock Syndrome Secondary to Rectal Adenocarcinoma

Abstract Introduction McKittrick-Wheelock syndrome is a rare condition that arises from a hypersecretory state secondary to large colorectal tumors, mainly villous adenomas, leading to an electrolytic disorder associated with chronic diarrhea that usually persists for years. It is a relatively unknown disease that can lead to severe complications such as acute kidney injury, severe hyponatremia, and hypokalemia. In fact, it causes death in most untreated cases. Surgical removal of the tumor is the most successful treatment, and symptoms tend to disappear after proper management. Case Report A 62-year-old man with a 2-year history of mucoid diarrhea preceded by abdominal pain presented with acute kidney injury, hyponatremia, and hypokalemia. A digital rectal examination and sigmoidoscopy were performed, and revealed a large laterally-spreading tumor in the rectum. Further investigation showed a rectal tubulovillous adenoma with secondary McKittrick-Wheelock syndrome. An anterior resection of the rectum with a colonic J-pouch and a diverting ileostomy were performed, and the patient improved with the resolution of the renal failure and electrolyte disturbances. The histopathological analysis revealed an invasive rectal adenocarcinoma. Discussion McKittrick-Wheelock syndrome is a condition with a low incidence that needs early intervention and proper diagnosis. It is of extreme importance that this disease is included in the differential diagnoses for chronic diarrhea associated with an electrolytic disorder.

Starvation and Its Effects on the Gut

There is growing awareness that intestinal dysfunction determines the clinical outcomes of situations as diverse as undernourished children in urban tropical slums and undernourished surgical patients in intensive care units. As experimental starvation in humans has only rarely been studied, and largely not using current biomedical research tools, we must draw inference from disparate clinical and experimental observations as to the derangements present in the starved gut. There is good evidence of intestinal atrophy and achlorhydria in starvation and severe undernutrition. Historical reports from concentration camps and conflict settings consistently reported a noncontagious phenomenon called "hunger diarrhea," but in settings where starved individuals are isolated from others (prisoners on hunger strike, anorexia nervosa) diarrhea is not a feature. Changes in intestinal permeability and absorption have been infrequently studied in experimental starvation; available data suggest that short-term starvation reduces sugar absorption but not permeability. Severe acute malnutrition in children is associated with severe changes in the intestinal mucosa. Experimental animal models may help explain some observations in humans. Starved rats develop a hypersecretory state and intestinal barrier defects. Starved pigs demonstrate prolongation of rotavirus diarrhea and reproduce some of the absorptive and barrier defects observed in malnourished children. However, there remains much to be learned about the effects of starvation on the gut. Given the high prevalence of undernutrition in hospitals and disadvantaged communities, the lack of attention to the interaction between undernutrition and gastrointestinal damage is surprising and needs to be corrected. Current sophisticated cellular and molecular techniques now provide the opportunity to create fresh understanding of gastrointestinal changes in pure undernutrition, using volunteer studies and samples from anorexia nervosa.

S2058 The Angry Gut: Immune-Mediated Widespread Gastrointestinal Inflammation Secondary to Pembrolizumab

INTRODUCTION: Pembrolizumab is an inhibitor of programmed death 1 (PD-1) receptor which has gained popularity in the treatment of squamous cell carcinoma of the head and neck, non-small cell lung carcinoma, and renal cell carcinoma and melanoma. Immune-mediated gastrointestinal symptoms after initiation of Pembrolizumab have been reported, however, remain uncommon. The current literature points to sporadic cases of isolated esophagitis, gastritis, and colitis however, we present a case of pembrolizumab induced Grade III mucositis with esophagitis, gastritis, and colitis in the same patient. To our knowledge, this is one of the first cases of widespread immune-mediated gastrointestinal inflammation from Pembrolizumab treatment. CASE DESCRIPTION/METHODS: A 65-year-old female with a medical history of Stage IV lung cancer with femur metastasis presented to the hospital with oral cavity ulcerations and bloody diarrhea that started one week after initiation of Pembrolizumab. She also had crampy lower abdominal pain with each bowel movement. She had difficulty tolerating solid food due to severe pain during swallowing, however, she was able to tolerate liquids. Physical examination showed pallor, lower abdominal tenderness, and hyperactive bowel sounds. Significant labs included hemoglobin 6.2 gm/dl, leukocyte count 1.0 × 103/uL, neutrophils 7300/uL, platelet count 8 × 103/uL, creatinine 3.36mg/dL and lactic acid 2.8 mmol/L. Infectious causes of diarrhea were ruled out with stool studies and blood cultures. In the hospital, her stool output was 3L per day. CT abdomen pelvis revealed wall thickening of left and sigmoid colon with increased air-fluid levels indicative of colitis and hyper-secretory state. EGD and colonoscopy revealed ulcerations of the oropharynx, severe esophagitis, non-bleeding gastric erosions, and inflamed recto-sigmoid and sigmoid colon mucosa. Biopsies revealed inflammatory changes. She was treated with diphenoxylate-atropine, octreotide, solumedrol, prednisone, and infliximab which partially controlled her symptoms. She opted for comfort measures and was discharged home on hospice care. DISCUSSION: With the growing utilization of immunotherapies in malignancies, it is imperative to report potential life-threatening complications such as widespread gastrointestinal inflammation mediated by pembrolizumab in our case. Physicians should be trained to promptly recognize and treat based on the severity of the gastrointestinal side effects.Figure 1.: CT Abdomen and Pelvis without contrast revealing left colon and sigmoid thickening with increased air-fluid levels.Figure 2.: EGD and Colonoscopy revealing severe esophagitis and sigmoid colon inflammation.Figure 3.: Biopsy revealing prominent crypt epithelial apoptosis and lymphocytic infiltration.

Evaluation of serum beta HCG levels in pregnant females as a predictor of gestational hypertension

Human β-HCG is a glycoprotein that is expressed in trophoblastic cells and various malignant tumors. Placenta is the known primary trigger of gestational hypertension. Beta HCG is secreted in abundance from placenta.The aim of the present study is to estimate the serum Beta HCG levels in study group consisting of 50 patients (Pregnant Females) of gestational hypertension and in control consisting of same age matched pregnant females.The present hospital based observational and analytical study was conducted on 80 patients out of which 50 were diagnosed with gestational hypertension and 30 constituted the control group. The Beta HCG levels were analyzed by Sandwich ELISA Method. The results of the present study showed that there was increase in Beta HCG levels in the gestational hypertensive patients with a mean value of Beta HCG was 117.79 ± 57.7mIU/ml, mean value of Systolic blood pressure was 127.3 ±13.9 mm of Hg and mean value of Diastolic blood pressure was 78.6 ±16.1 mm of Hg which were statistically significant (p=<0.001). Serum Beta HCG levels were elevated in gestational hypertension, when compared with controls. Due to trophoblast response to hypoxia there exists an abnormal secretory function of the placenta in cases of gestational hypertension which leads to development of a hypersecretory state which is seen as a rise in Beta HCG levels. This study showed that estimating serum Beta HCG levels is a useful indicator to identify women who are likely to develop gestational hypertension in the same pregnancy.

Tissue Iron Promotes Wound Repair via M2 Macrophage Polarization and the Chemokine (C-C Motif) Ligands 17 and 22

Macrophages are important for effective iron recycling and erythropoiesis, but they also play a crucial role in wound healing, orchestrating tissue repair. Recently, we demonstrated a significant accumulation of iron in healing wounds and a requirement of iron for effective repair. Herein, we sought to determine the influence of iron on macrophage function in the context of wound healing. Interestingly, wound macrophages extensively sequestered iron throughout healing, associated with a prohealing M2 phenotype. In delayed healing diabetic mouse wounds, both macrophage polarization and iron sequestration were impaired. Invitro studies revealed that iron promotes differentiation, while skewing macrophages toward a hypersecretory M2-like polarization state. These macrophages produced high levels of chemokine (C-C motif) ligands 17 and 22, promoting wound reepithelialization and extracellular matrix deposition in a human exvivo wound healing model. Together, these findings reveal a novel, unappreciated role for iron in modulating macrophage behavior to promote subsequent wound repair. These findings support therapeutic evaluation of iron use to promote wound healing in the clinic.

Amitraz Poisoning: The not so (Un)common Poisoning

Amitraz is a widely used insecticide and antiparasitic drug. It can cause poisoning in humans via oral, inhalation, and dermal routes. Clinical features hence produced may mimic organophosphate (OP) poisoning because of several shared features (miosis, bradycardia, hypotension) along with a history of possible insecticide poisoning. But the presence of hyperglycemia, hypothermia, and reduced gastrointestinal motility along with normal serum cholinesterase levels and the absence of fasciculations and a hypersecretory state (salivation, lacrimation, perspiration, and diarrhea) point against OP poisoning. Analysis of the poison container also helps confirm the poison. Management is mostly supportive with a good prognosis.

Stress Prophylaxis in Intensive Care Unit Patients and the Role of Enteral Nutrition

Use of acid-suppressive therapy (AST) to prevent stress gastropathy in the intensive care unit has grown rapidly over the past 20 years. The primary indications for such use of AST include need for mechanical ventilation, overt gastrointestinal bleeding, severe burn, and head trauma. Despite this limited list of indications, proton pump inhibitors (PPIs) often are overprescribed for purposes of stress prophylaxis. Decreased mucosal blood flow with subsequent tissue ischemia is thought to be the mechanism responsible for stress-induced gastropathy. Subsequent activation of inflammatory and vasoconstrictive mediators determines the severity of the gastropathy. Numerous basic science studies suggest that enteral nutrition (EN) can improve mucosal blood flow and reverse the generation of these inflammatory mediators. Clinical studies evaluating the effectiveness of EN vs acid-suppressive medications, however, have shown variable results (and there are no randomized controlled trials to date). In hypersecretory states (such as head trauma and burns), AST should be given, even in patients who are tolerating EN. In the absence of a hypersecretory state, pharmacologic AST may be avoided or discontinued in patients who are tolerating EN. Stress prophylaxis medications also should be discontinued in patients who do not have a clear indication for their use. Overt bleeding in a patient receiving EN for stress prophylaxis should prompt the initiation of a PPI. Randomized controlled studies investigating the efficacy of EN for stress ulcer prophylaxis are needed. Protocols should be developed to alert healthcare teams to consider discontinuation of AST, especially when tolerance of EN is achieved.

Persistent Reflux Symptoms in the Proton Pump Inhibitor Era: The Changing Face of Gastroesophageal Reflux Disease

Given the widespread use of potent acid suppressive therapies and primary caregivers’ increasing comfort with prescribing these medications at high doses, the patient population presenting to gastroenterologists for symptoms of gastroesophageal reflux disease (GERD) has changed. Whereas previous consultation often revolved around the control of erosive disease and other mucosal manifestations of GERD, and terminated with the prescription of proton pump inhibitor (PPI) therapy, gastroenterologists often now only enter the scene after failure of PPI therapy, for symptoms either resistant or only partially responsive to these medications. Because of the high proportion of subjects with esophagitis who are healed with PPI, 1,2 upper endoscopy of such individuals is low yield, 3 with only a small minority demonstrating erosive disease. The care of such patients is challenging. High-quality evidence supporting useful diagnostic testing or alternative effective therapies is largely lacking. However, the number of subjects with GERD symptoms incompletely or nonresponsive to PPI therapies is high, and their utilization of healthcare resources is substantial. The purpose of this mini-review is to examine the definition and epidemiology of esophageal GERD symptoms incompletely responsive to PPI therapy, the potential pathophysiologic mechanisms behind these symptoms, the differential diagnosis and evaluation of such patients, and current and developing therapeutic options.

Growth hormone/insulin-like growth factor I axis, glucose metabolism, and lypolisis but not leptin show some degree of refractoriness to snort-term fasting in acromegaly

Starvation exerts critical influence on somatotroph and leptin secretion. Fasting enhances GH levels in normal subjects, but not in GH hyposecretory states, while it always inhibits leptin secretion. We aimed to clarify the GH/IGF-I and metabolic response to short-term fasting in a GH hypersecretory state such as acromegaly. To this goal, in 8 active acromegalic (ACRO) and in 7 normal women (NS) we evaluated mean GH (mGHc), leptin (mLEPc), insulin (mINSc), glucose (mGLUc) concentrations as well as IGF-I, IGF binding protein (IGFBP)-3, IGFBP-1, and free fatty acid (FFA) levels before and after 36-h fasting. Before fasting, mGHc, IGF-I, mINSc, mGLUc, and FFA levels in ACRO were higher (p<0.01) than in NS. IGFBP-3, IGFBP-1, and mLEPc were similar in ACRO and in NS. Fasting clearly (p<0.02) increased mGHc in NS only. After 36-h fasting, significant IGF-I reduction was recorded in NS only (p<0.03). IGFBP-3 did not change both in ACRO and NS. IGFBP-1 significantly increased (p<0.05) after fasting in both groups but in ACRO were lower (p<0.03) than in NS. Fasting decreased (p<0.03) mLEPc, mGLUc, and mINSc in ACRO as well as in NS; mINSc and mGLUc after fasting in ACRO persisted higher (p<0.005) than in NS. FFA levels were increased by fasting in NS (p<0.02), but not in ACRO. This study shows that GH/IGF-I axis, glucose metabolism, and lypolisis but not leptin display some degree of refractoriness to short-term fasting in acromegaly. The lack of any GH response to fasting in acromegaly would likely reflect neuroendocrine alterations secondary to the GH hypersecretory state. On the other hand, the lack of somatotropic response and the peculiarly blunted metabolic reaction to short-term fasting would partially reflect the delayed adaptation of insulin resistance to starvation.

Skin electrical activity of the stomach and intestine during long-term antiorthostatic hypokinesia

The skin electrical activity of the gastrointestinal tract in the stomach and small intestine frequency ranges was studied for four months in 13 men under the conditions of antiorthostatic hypokinesia (AOH). On an empty stomach, both the gastric and small intestine electrical activities increased to a level comparable with that of the increase detectable after eating under the conditions of normal motor activity, whereas the response to food stimulation was inhibited. The ratios between the parameters of spectral analysis testified to a higher tonic component in the stomach and a higher peristaltic component in the intestine under the conditions of AOH. The observed changes in the gastric and intestinal electrical activities were observed against a background of a hypersecretory state of the stomach and an increase in the intestinal contents. During the readaptation period, both the gastric and intestinal electrical activities increased significantly, whereas the response to food stimulation was inhibited.

Validation of a New Endoscopic Technique to Assess Acid Output in Zollinger–Ellison Syndrome

To safely manage the hypersecretory state in patients with Zollinger-Ellison syndrome, both upper endoscopy and gastric analysis are required to titrate optimal medical therapy. Conventional gastric analysis requires more than 1 hour to perform and results in significant patient dissatisfaction. In this study, we have validated endoscopic gastric analysis as a novel technique that can effectively replace conventional gastric analysis. In a prospective, cross-over study, 12 patients with Zollinger-Ellison syndrome underwent gastric analysis, first by the conventional method and then by an endoscopic technique performed on the same day. Acid concentration was determined by titration, volume output was recorded, and acid output was calculated using standard methodologies and formulas. Agreement was assessed following the Bland-Altman method. To assess repeatability, both techniques were repeated on the same day in a subset of patients. Excellent agreement was reported between acid output (95% limits of agreement, -1.27 to 1.61 mEq/h) and acid concentration (95% limits of agreement, -0.01 to 0.01 mEq/mL), although poor agreement was observed between volume output measured. Endoscopic gastric analysis showed greater reproducibility regarding acid and volume output measured. We introduce a new, rapid, reproducible, and accurate endoscopic technique to measure acid output in patients with Zollinger-Ellison syndrome who require both annual endoscopy and gastric analysis. The data presented here suggest that endoscopic gastric analysis would be equally effective in determining acid output in other hypersecretory states. Additional analysis of cost effectiveness is needed to evaluate its use as a screening tool in select populations.

Utilization and Therapeutic Intent of PPI Prescription among Elderly NSAID Users

Purpose: To examine prescription of proton pump inhibitors (PPIs) among elderly NSAID users to determine therapeutic intent and to assess provider recognition of the necessity for gastroprotection. Methods: Administrative data identified patients ≥ 65 years with an NSAID and PPI prescription from 01/01/00–12/31/02 at a major VA medical center. Chart abstraction identified therapeutic intent of PPI prescription and assessed provider awareness of gastroprotection. The outcome of interest was an appropriate therapeutic intent, defined as GERD or endoscopic esophagitis, hypersecretory state, dyspepsia, ulcer with bleeding, perforation, or obstruction, H. Pylori eradication or NSAID gastroprotection. Logistic regression predicted appropriate therapeutic intent while adjusting for demographic characteristics, number of co-morbidities, type of NSAID prescribed, prescription of PPI following gastroscopy and prescribing provider. Results: Among 1491 patients (73 years [SD 5.6], 73% Caucasian, 99.8% male), 64% were prescribed a PPI for an appropriate indication. A geriatrician or primary care physician prescribed 68% of prescriptions; most (85%) for outpatients. Patients who used the VA only for pharmacy services were 60% less likely to be prescribed a PPI for an appropriate indication (OR 0.41; 95% CI: 0.31 – 0.54), as were inpatients (OR 0.47; 95% CI: 0.34 – 0.64) or prescriptions initiated by a cardiologist or otolaryngologist (OR 0.40; 95% CI: 0.25 – 0.64). Among non-selective NSAID users (80%), only 10% of providers identified the need for PPI. Gastroprotection was more likely if the provider was a rheumatologist (OR 46.7; 95% CI: 15.9 – 136.9), if the patient was African American (OR 2.5; 95% CI: 1.6 – 3.9) or had 3 to 5 co-morbidities (OR 1.8; 95% CI: 1.1–2.9). Among inpatients, the need for gastroprotection was less recognized (OR 0.40; 95% CI: 0.20–0.84), and 45% of PPI prescriptions were initiated for unknown reasons. Conclusions: The intent of PPI prescription is unclear among 36% of elderly NSAID users. Few providers recognize the need for gastroprotection and the medical specialty of the provider plays a key role in both appropriate use of PPIs and recognition of the need for gastroprotection. Inpatient prescription of a PPI is often associated with failure to recognize the importance of gastroprotection or an unknown therapeutic intent.

Peptic ulcer disease today

Over the past few decades, since the introduction of histamine H(2)-receptor antagonists, proton-pump inhibitors, cyclo-oxygenase-2-selective anti-inflammatory drugs (coxibs), and eradication of Helicobacter pylori infection, the incidence of peptic ulcer disease and ulcer complications has decreased. There has, however, been an increase in ulcer bleeding, especially in elderly patients. At present, there are several management issues that need to be solved: how to manage H. pylori infection when eradication failure rates are high; how best to prevent ulcers developing and recurring in nonsteroidal anti-inflammatory drug (NSAID) and aspirin users; and how to treat non-NSAID, non-H. pylori-associated peptic ulcers. Looking for H. pylori infection, the overt or surreptitious use of NSAIDs and/or aspirin, and the possibility of an acid hypersecretory state are important diagnostic considerations that determine the therapeutic approach. Combined treatment with antisecretory therapy and antibiotics for 1-2 weeks is the first-line choice for H. pylori eradication therapy. For patients at risk of developing an ulcer or ulcer complications, it is important to choose carefully which anti-inflammatory drugs, nonselective NSAIDs or coxibs to use, based on a risk assessment of the patient, especially if the high-risk patient also requires aspirin. Testing for and eradicating H. pylori infection in patients is recommended before starting NSAID therapy, and for those currently taking NSAIDs, when there is a history of ulcers or ulcer complications. Understanding the pathophysiology and best treatment strategies for non-NSAID, non-H. pylori-associated peptic ulcers presents a challenge.

The endocrine response to acute ghrelin administration is blunted in patients with anorexia nervosa, a ghrelin hypersecretory state.

Ghrelin, a gastric-derived natural ligand of the GH secretagogue (GHS)-receptor (GHS-R), strongly stimulates GH secretion but also possesses other neuroendocrine actions, stimulates food intake and modulates the endocrine pancreas and energy homeostasis. Ghrelin secretion is negatively modulated by food intake. Similarly, glucose and also insulin probably exert an inhibitory effect on ghrelin secretion. Fasting ghrelin levels are reduced in obesity, elevated in anorexia nervosa and restored by weight recovery. The chronic elevation of circulating ghrelin levels in anorexia suggested the hypothesis of an alteration of the sensitivity to the orexigenic action of ghrelin in this condition. The aim of this study was to define the endocrine actions of ghrelin in patients with anorexia nervosa. We enrolled nine women with anorexia nervosa of restricter type [AN; age (mean +/- SEM) 24.2 +/- 1.8 years; body mass index (BMI) 14.7 +/- 0.4 kg/m2] and seven normal young women in their early follicular phase as control group (NW; age 30.6 +/- 3.1 years; BMI 20.3 +/- 0.5 kg/m2). In all the subjects we studied the GH, PRL, ACTH, cortisol, insulin and glucose responses to acute ghrelin administration (1.0 microg/kg as i.v. bolus). The GH response to GHRH (1.0 microg/kg as i.v. bolus) and basal ghrelin and IGF-I levels were also evaluated in all the subjects. Basal morning ghrelin and GH levels in AN (643.6 +/- 21.3 ng/l and 10.4 +/- 0.5 microg/l, respectively) were higher (P < 0.05) than in NW (233.5 +/- 14.2 ng/l and 0.7 +/- 0.7 microg/l, respectively). However, IGF-I levels in AN (145.3 +/- 10.9 microg/l) were lower (P < 0.05) than in NW (325.4 +/- 12.6 microg/l). The GH response to GHRH in AN was higher (P < 0.05) than that in NW, but in AN the GH response to ghrelin was lower (P < 0.05) than that in NW. In AN and NW ghrelin also induced similar increases (P < 0.05) in PRL, ACTH and cortisol levels. Ghrelin administration was followed by significant increase in glucose levels in NW (P < 0.05) but not in AN. This study demonstrates that anorexia nervosa, a clinical condition of ghrelin hypersecretion, shows a specific reduction in the GH response to ghrelin, despite the hyper-responsiveness to GHRH administration. The impaired GH response to ghrelin in anorexia nervosa agrees with previous evidence of blunted GH response to synthetic GH secretagogues and could reflect desensitization of the GHS receptor induced by the chronic elevation of ghrelin levels in this pathological state.

Mucosal changes in rhinitis medicamentosa.

To evaluate the nasal mucosal changes in rhinitis medicamentosa (RM), especially those related to goblet cells and subepithelial glands, we studied specimens of the inferior turbinate mucosa from 8 patients with RM, 8 patients with chronic hypertrophic rhinitis (CHR), and 5 patients with normal nasal mucosa. All specimens were assessed by electron microscopy and immunohistochemical study. Under a scanning electron microscope, hyperplasia of goblet cells was most prominent in the RM group, and an increased number of gland openings was evident in the RM and CHR groups. In addition, the immunoreactivity of epidermal growth factor receptor staining was strongest in the hyperplastic epithelium of the RM group. According to our results, it is feasible that the mucosa of patients with RM is in a chronic inflammatory, hypersecretory state. Degenerative changes in the secretory elements may cause impairment of mucociliary transport and may be responsible for the nasal obstruction and posterior nasal drip in RM.

Somatostatin infusion withdrawal: studies in the acute and recovery phase of anorexia nervosa, and in obesity.

Changes in GH/IGF-I axis activity occur in both anorexia nervosa (AN) and obesity (OB). A GH hypersecretory state with very low plasma IGF-I levels is present in AN, whereas in morbid OB, GH secretion is dull and plasma IGF-I levels are generally preserved. Endogenous GHRH activity in AN and OB has never been directly studied, although indirect evidence would indicate that GHRH function is altered in either condition, possibly enhanced and reduced respectively. Somatostatin (SS) infusion withdrawal (SSIW) is followed by a rebound rise of plasma GH in animals and humans, an event which, allegedly, is mediated by endogenous GHRH release. In the present study, 28 young women, eight with active AN (A-AN), six with AN in the recovery phase (R-AN), eight with morbid OB, and six healthy age-matched normal weight subjects (NW), were studied. All subjects underwent, on different occasions, the following two tests: (i) acute GHRH injection (1 microg/kg, i.v.); (ii) infusion of SS (9 microg/kg per h i.v. over 60 min), with blood samples drawn prior to and at different intervals after drug injections. Plasma GH levels were measured at each time interval in all sessions, and, in addition, baseline plasma estradiol, free triiodothyronine, TSH, IGF-I and insulin were measured at -30 min. Baseline plasma GH concentrations were significantly higher in A-AN than in NW (4.7+/-0.7 vs 2.1+/-0.6 microg/l, P<0.01). Baseline GH levels in R-AN were also higher than in NW, but the difference did not reach statistical significance (5.6+/-1.7 microg/l, not significant (NS)). Baseline plasma GH concentrations were significantly lower in OB than in NW (0.3+/-0.1 microg/l, P<0.01). GHRH-stimulated GH release was significantly higher in A-AN than in NW (mean change in area under the curve (DeltaAUC) 1904.9+/-626.1 vs 613.9+/-75.9 microg/l per min, P<0.01), whereas no statistically significant difference was present between R-AN and NW (mean DeltaAUC 638.2+/-293.0 microg/l per min, NS); in OB, GHRH failed to evoke a plasma GH rise (mean DeltaAUC 239.8+/-89.9 microg/l per min vs A-AN, R-AN, and NW, P<0.01). SS infusion markedly reduced plasma GH concentrations in both A-AN and R-AN and, to a lesser extent, in NW, but failed to do so in OB. In A-AN, SSIW was followed by a plasma GH rise markedly higher than that present in NW (mean DeltaAUC 193.0+/-42.3 vs 60.1+/-11.4 microg/l per min, P<0.01), whereas in R-AN the GH response after SSIW was nearly superimposable on that registered in NW (mean DeltaAUC 72.9+/-22.8 microg/l per min, NS). There were no changes in plasma GH levels after SSIW in OB (mean DeltaAUC 22.8+/-9.7 microg/l per min). In all groups, DeltaAUCs of the GH response to GHRH and after SSIW were highly positively correlated (r=0.7, P<0.01). These data support the view that a high endogenous GHRH tone, which subsides in the recovery phase of the disease, is present in AN, whereas GHRH hypofunction, possibly associated with pituitary impairment, might indicate OB.

Induction of mucin and adhesion molecules in middle ear mucosa.

We hypothesized that inflammation molecules induce the secretory hyperplasia characteristic of otitis media with effusion (OME). The purpose of the present study was to compare the location of inflammation molecules and mucin in the middle ear mucosa of both normal and OME ears. OME was created by bisection of the tensor veli palatini muscle in germ-free rabbits, and the development of middle ear effusion was confirmed by otomicroscopy and tympanometry. Ventilation tubes (VTs) were inserted in half of the ears. The animals were decapitated after 8 weeks, and serial sections of the middle ear mucosae were either periodic acid-Schiff (PAS)-stained or stained immunohistochemically for inflammation molecules or mucins. The length of stained epithelium was measured and related to the total epithelial length. There was a striking resemblance between mucin-type MUC5B- and PAS-positive epithelium and areas positive for the chemoattractant inflammation molecules intercellular adhesion molecule-1 (ICAM-1) and RANTES (reacted upon activation, normal T expressed and secreted). The percentages of ICAM-1- and PAS-stained epithelium were significantly higher in OME ears than in normal ears. OME ears treated with VTs also contained significantly more PAS-positive epithelium than normal ears, but less than OME ears. Based on the spatial and temporal coincidence between ICAM-1 and mucin, it is suggested that: (i) inflammation may initiate and maintain the hypersecretory state of the middle ear mucosa which is presumably responsible for the chronicity of OME; and (ii) that MUC5B is a major mucin component of OME effusions.