Features of patients and fracture risk in hypoparathyroidism; a single center study.

PURPOSE: Patients with hypoparathyroidism (hypoPT) have low bone turnover and high bone mineral density (BMD). However, data on fracture risk are conflicting. The objectives of this study were: 1. To describe clinical/biochemical characteristics of hypoPT patients followed at a single medical center. 2. To identify postsurgical hypoPT patients and investigate their fracture rate compared with gender/age-matched post-surgical normocalcemic patients. METHODS: Retrospective analysis of patient's medical records treated at the tertiary medical center in 2010-2021 identified by computerized medical database search. RESULTS: The cohort included 133 patients (91% women, mean age 64 ± 13 years) of whom 105 (79%) had post-thyroidectomy hypoparathyroidism and the remainder had an autoimmune/idiopathic/other etiology. Mean follow-up time was 21 ± 12 and 27 ± 12 years, respectively. The control group included 142 post-thyroidectomy patients without hypoparathyroidism. Patients in the postsurgical hypoparathyroidism group were older and had higher calcium and PTH levels at diagnosis than the non-surgical hypoPT patients. Comparing the postsurgical hypoPT and postsurgical normocalcemic control patients revealed a significantly higher BMD in the hypoPT group. Yet, fracture rates were 31% in the postsurgical hypoparathyroidism group and 21% in the control group (P = 0.1) over a similar median follow-up period (17 and 18.4 years, respectively). In both groups the most common fracture site was the spine (50% and 70%, respectively; p = 0.33), mainly nonclinical morphometric fractures. Higher phosphorus blood level was associated with increased fracture risk. CONCLUSIONS: The relatively high BMD in patients with postsurgical hypoparathyroidism is not associated with lower fracture risk. Silent morphometric fractures are quite common in this group of patients.

[Colorectal tumor evolution in inflammatory bowel disease : Dynamics of genomic alterations and potential molecular markers to predict malignant progression]. / Kolorektale Tumorevolution bei chronisch-entzündlichen Darmerkrankungen : Dynamik genomischer Alterationen und mögliche molekulare Marker zur Vorhersage einer malignen Progression.

Inflammatory bowel diseases (IBDs) increase the risk for colorectal cancer (CRC). In IBD, the evolution of potential tumor clones occurs long before neoplastic lesions become evident and these clones can be undetectable by endoscopy and histology at early stages. The spectrum of genomic alterations in IBD-associated colorectal carcinogenesis is distinct from the changes observed in the sporadic adenoma-carcinoma sequence. Predominant alterations include aneuploidies and mutations of TP53, which both occur early in IBD-related tumorigenesis. In some IBD patients, genomic alterations can already be detected in colonic mucosa without any histologic signs of dysplasia. Genomic analysis of multiregional samples from colectomy specimens of IBD patients revealed distinct tumor evolutionary patterns. This suggests an increased genomic instability in the chronically inflamed bowel that enables the emergence of multiple, phylogenetically unrelated neoplastic lesions within the colorectum of a single IBD patient. This article summarizes the genomic alterations underlying IBD-associated colorectal tumorigenesis and the evolutionary patterns from inflamed, not yet dysplastic epithelium to CRC. Furthermore, it is discussed how this knowledge can eventually be exploited for early detection of malignant progression of IBD and thus help to improve the clinical management and surveillance schedule of IBD patients.

[Crohn's disease-associated colorectal carcinogenesis : TP53 mutations and copy number gains of chromosome arm 5p as (early) markers of tumor progression]. / Morbus-Crohn-assoziierte kolorektale Karzinogenese : TP53-Mutationen und Kopienzahlzugewinne von Chromosomarm 5p als (frühe) Marker der Tumorprogression.

BACKGROUND: Patients with inflammatory bowel diseases, i. e., ulcerative colitis and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from ulcerative colitis, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. OBJECTIVES: In this study, we aimed to analyze the genetic events that define CD-CRCs, in particular the dynamics of their development from histologically undetectable precursor lesions to invasive disease. MATERIALS AND METHODS: We analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions by next generation sequencing (563 gene panel) and array-based comparative genomic hybridization. The results were compared with our own data and the Cancer Genome Atlas data on sporadic CRC. RESULTS: The gain of 5p was significantly more prevalent in CD-CRCs than in sporadic CRCs, despite an overall similar chromosomal aberration pattern. CD-CRCs had a distinct mutation signature with TP53 being the most frequently mutated gene in CD-CRCs. TP53 mutations and copy number alterations were early events in CD progression and could sometimes already be detected in non-dysplastic colonic mucosa, indicating occult tumor evolution. CONCLUSIONS: Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: gains of 5p and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predict disease progression and distinguishes CD-associated from sporadic colorectal neoplasia.

Synthesis and biological assessment of 3,7-dihydroxytropolones.

3,7-Dihydroxytropolones (3,7-dHTs) are highly oxygenated troponoids that have been identified as lead compounds for several human diseases. To date, structure-function studies on these molecules have been limited due to a scarcity of synthetic methods for their preparation. New synthetic strategies towards structurally novel 3,7-dHTs would be valuable in further studying their therapeutic potential. Here we describe the successful adaptation of a [5 + 2] oxidopyrilium cycloaddition/ring-opening for 3,7-dHT synthesis, which we apply in the synthesis of a plausible biosynthetic intermediate to the natural products puberulic and puberulonic acid. We have also tested these new compounds in several biological assays related to human immunodeficiency virus (HIV), hepatitis B virus (HBV) and herpes simplex virus (HSV) in order to gain insight into structure-functional analysis related to antiviral troponoid development.

Stem cells and bFGF in tendon healing: Effects of lentiviral gene transfer and long-term follow-up in a rat Achilles tendon defect model.

BACKGROUND: The influence of stem cells and lentiviral expression of basic fibroblastic growth factor (bFGF) on tendon healing and remodelling was investigated in an in-vivo long-term (12 weeks) rat Achilles tendon defect model. METHODS: In sixty male Lewis rats, complete tendon defects (2.4 mm) were created and either left untreated (PBS) or treated by injection of stem cells lentivirally expressing the enhanced green fluorescence marker gene eGFP (MSC-LV-eGFP) or basic fibroblast growth factor bFGF (MSC-LV-bFGF). Tendons were harvested after 12 weeks and underwent biomechanical and (immuno)-histological analysis. RESULTS: After 12 weeks the mean ultimate load to failure ratio (treated side to contralateral side) in biomechanical testing reached 97 % in the bFGF-group, 103 % in the eGFP-group and 112 % in the PBS-group. Also in the stiffness testing both MSC groups did not reach the results of the PBS group. Histologically, the MSC groups did not show better results than the control group. There were clusters of ossifications found in all groups. In immunohistology, only the staining collagen-type-I was strongly increased in both MSC groups in comparison to PBS control group. However, there were no significant differences in the (immuno)-histological results between both stem cell groups. CONCLUSION: The biomechanical and (immuno)-histological results did not show positive effects of the MSC groups on tendon remodelling in a long-term follow-up. Interestingly, in later stages stem cells had hardly any effects on biomechanical results. This study inspires a critical and reflected use of stem cells in tendon healing.

Androgen Receptor CAG Repeat Length in Relation to Phenotype Among Females with Nonclassical 21-Hydroxylase Deficiency.

Nonclassical 21-hydroxylase deficiency (NC21OHD) manifests with various degrees of post natal virilization. The length of CAG repeats of the androgen receptor gene (AR) is inversely correlated to activity of the human androgen receptor (AR) and affects phenotype of several androgen-dependent disorders. The aim of the study was to investigate the associations between CAG repeat length and the phenotype of females with NC21OHD. CAG repeat length and AR inactivation were assessed in females with NC21OHD, and related to their clinical presentation. CAG repeat length and AR inactivation were assessed in 119 females with NC21OHD. Biallelic mean (BAM) of the CAG repeat length and the weighted BAM (WBAM) were related to various clinical parameters. Age at diagnosis and age of menarche positively correlated with BAM (r=0.22, p=0.02, and r=0.23, p=0.01, respectively). A shorter (<25) BAM was associated with younger age at diagnosis (14.8 vs. 21.4 years, p<0.01), at adrenarche (8.1 vs. 10.2 years, p<0.01) and gonadarche (9.9 vs. 11.2 years, p<0.01), and higher corrected height standard deviation score at diagnosis (0.77 vs. 0.15, p=0.01). Precocious pubarche and precocious puberty were more frequent in these with the shorter BAM. Results of WBAM were similar. The CAG repeat length of the AR gene contributes to the clinical diversity of the phenotype in females with NC21OHD.

Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period.

BACKGROUND: The risk for acidic reflux is mainly determined by the position of the gastric acid pocket. It was hypothesised that compounds affecting proximal stomach tone might reduce gastro-oesophageal reflux by changing the acid pocket position. OBJECTIVE: To study the effect of azithromycin (Azi) on acid pocket position and acid exposure in patients with gastro-oesophageal reflux disease (GORD). METHODS: Nineteen patients with GORD were included, of whom seven had a large hiatal hernia (≥3 cm) (L-HH) and 12 had a small or no hiatal hernia (S-HH). Patients were randomised to Azi 250 mg/day or placebo during 3 days in a crossover manner. On each study day, reflux episodes were detected using concurrent high-resolution manometry and pH-impedance monitoring after a standardised meal. The acid pocket was visualised using scintigraphy, and its position was determined relative to the diaphragm. RESULTS: Azi reduced the number of acid reflux events (placebo 8.0±2.2 vs Azi 5.6±1.8, p<0.01) and postprandial acid exposure (placebo 10.5±3.8% vs Azi 5.9±2.5%, p<0.05) in all patients without affecting the total number of reflux episodes. Acid reflux occurred mainly when the acid pocket was located above, or at the level of, the diaphragm, rather than below the diaphragm. Treatment with Azi reduced hiatal hernia size and resulted in a more distal position of the acid pocket compared with placebo (below the diaphragm 39% vs 29%, p=0.03). Azi reduced the rate of acid reflux episodes in patients with S-HH (38% to 17%) to a greater extent than in patients with L-HH (69% to 62%, p=0.04). CONCLUSION: Azi reduces acid reflux episodes and oesophageal acid exposure. This effect was associated with a smaller hiatal hernia size and a more distal position of the acid pocket, further indicating the importance of the acid pocket in the pathogenesis of GORD. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1970 NTR1970.

Early metabolic markers that anticipate loss of insulin independence in type 1 diabetic islet allograft recipients.

The objective of this study was to identify predictors of insulin independence and to establish the best clinical tools to follow patients after pancreatic islet transplantation (PIT). Sequential metabolic responses to intravenous (I.V.) glucose (I.V. glucose tolerance test [IVGTT]), arginine and glucose-potentiated arginine (glucose-potentiated arginine-induced insulin secretion [GPAIS]) were obtained from 30 patients. We determined the correlation between transplanted islet mass and islet engraftment and tested the ability of each assay to predict return to exogenous insulin therapy. We found transplanted islet mass within an average of 16 709 islet equivalents per kg body weight (IEQ/kg BW; range between 6602 and 29 614 IEQ/kg BW) to be a poor predictor of insulin independence at 1 year, having a poor correlation between transplanted islet mass and islet engraftment. Acute insulin response to IVGTT (AIR(GLU) ) and GPAIS (AIR(max) ) were the most accurate methods to determine suboptimal islet mass engraftment. AIR(GLU) performed 3 months after transplant also proved to be a robust early metabolic marker to predict return to insulin therapy and its value was positively correlated with duration of insulin independence. In conclusion, AIR(GLU) is an early metabolic assay capable of anticipating loss of insulin independence at 1 year in T1D patients undergoing PIT and constitutes a valuable, simple and reliable method to follow patients after transplant.

Total versus hemithyroidectomy for microscopic papillary thyroid cancer.

BACKGROUND: No increased mortality has been reported in patients with thyroid papillary microcarcinoma (PMC); however, neck recurrences and distant metastases have been described. In this study, we compare patients' outcomes after total thyroidectomy vs hemithyroidectomy for treatment of thyroid PMC. METHODS: Two hundred and ninety-three patients from two major medical centers in Israel were included. The mean follow-up period was 7.2±6.8 yr. RESULTS: Total thyroidectomy was performed in 214 patients and hemithyroidectomy in 79 patients. Mean tumor size was 6.3±3 mm. Lymph-node (LN) metastases and extraglandular extension were more frequent in the total thyroidectomy group than in the hemithyroidectomy group, 24.8% vs 1.3% (p<0.001) and 11.7% vs 3.8% (p=0.042), respectively. The cumulative incidence of recurrence at the end of follow-up was 13.2% in the total thyroidectomy group and 14.3% in the hemithyroidectomy group (p=ns). The incidence of recurrence was higher in patients with LN involvement in both groups. Considering low risk patients only (monofocal tumors, no LN involvement, no extraglandular extension; no.=63 in the total thyroidectomy group vs no.=60 in the hemithyroidectomy group) neck recurrence was found in 10% of patients in the hemithyroidectomy group but none in the total thyroidectomy group. In the hemithyroidectomy group, all locoregional recurrences were diagnosed using ultrasonography, compared to 47.6% in the total thyroidectomy group. CONCLUSION: For patients with monofocal disease within the thyroid gland and no LN involvement, hemithyroidectomy can be considered an option, bearing in mind a higher risk for recurrence. For all other patients with PMC, we propose total thyroidectomy as initial treatment.

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine.

The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.

Prognostic value of post-thyroidectomy thyroglobulin levels in patients with differentiated thyroid cancer.

BACKGROUND: Thyroglobulin is an excellent biological marker of persistent or recurrent thyroid cancer during long-term follow-up. Most studies investigated its diagnostic value but not its prognostic value over time. We aim to study the prognostic value of thyroglobulin levels early after total thyroidectomy, before iodine ablation. METHODS: The study was based on the Rabin Medical Center registry of patients with non-medullary thyroid carcinoma. Data were collected on the clinical, laboratory, and outcome characteristics of 420 consecutive patients followed at our institution for whom early post-operative pre-ablation thyroglobulin values (baseline thyroglobulin) were available. RESULTS: Patients were classified into 4 groups by baseline thyroglobulin level: 0-2, 2-10, 10-100, and >100 ng/ml. Higher levels were associated with a shift toward male gender (p=0.01), larger tumor size (p=0.02), and a more extensive disease (p<0.0001). They were also related to disease persistence and evidence of disease at last follow-up (p<0.0001). The 10 ng/ml cut-off level identified patients with persistent disease with a sensitivity and specificity of 73%, positive predictive value of 43%, and negative predictive value of 89%. On multivariate analysis, the following variables were predictive of persistent disease: baseline thyroglobulin level, male gender, lymph-node involvement, distant metastases, higher tumor invasiveness, and larger tumor size. However, the predictive power of baseline thyroglobulin level was relatively weak (odds ratio 1.002, 95% confidence interval 1.00-1.04). CONCLUSIONS: In patients with well-differentiated thyroid cancer, a post-thyroidectomy thyroglobulin level <10 ng/ml is associated with a low probability of having persistent disease and can be used combined with other disease characteristics for decisions regarding treatment and follow-up.

Correction of insulin sensitivity and glucose disposal after pancreatic islet transplantation: preliminary results.

AIMS: Pancreatic islet transplantation (PIT) represents a potential curative treatment for patients with type 1 diabetes, but only 10-15% of patients remain insulin independent 5 years post-transplant. It is not known whether intrinsic insulin resistance exacerbated by immunosuppression plays a pivotal role in low graft survival. The study objective was to understand the changes in insulin resistance, glucose effectiveness (S(g)) and free fatty acid dynamics (FFAd) before and after PIT. METHODS: Insulin sensitivity index (S(i)), S(g) and FFAd were measured before and after PIT in 10 lean patients, 8 of whom reached insulin independence. Modified Bergman minimal model of frequently sampled intravenous glucose tolerance tests were performed pretransplant and at 12 months post-transplant. Nine non-diabetic control (NDC) subjects matched by age, gender and BMI were used. RESULTS: Pretransplant S(i) and S(g) were 3.5 ± 0.8 × 10(-5)/min/(pmol/l) and 0.74 ± 0.24 × 10(-2)/min, respectively. S(i) was significantly lower than matched NDCs [10.8 ± 0.6 × 10(-5)/min/(pmol/l), p < 0.004]; S(g) did not reach statistical significance (1.27 ± 0.22 × 10(-2)/min, p = 0.25). Compared to pretransplant values, mean post-transplant S(i) and S(g) were 9.6 ± 1.3 × 10(-5)/min/(pmol/l)and 1.28 ± 0.22 ×10(-2)/min, respectively, indicating significant improvement for S(i) but not S(g) (p = 0.008 and p = 0.06). Twelve-month post-PIT compared to NDC values were not significantly different (p = 0.58 and 0.97, respectively). In addition, fractional disposal rate for FFA which directly depends on the endogenous insulin release (10-20 min) nearly normalized after PIT (p = 0.06). CONCLUSION: These preliminary findings demonstrate that PIT can restore glucose disposal and insulin sensitivity and partially correct glucose effectiveness and FFAd.

Clinically silent chromaffin-cell tumors: Tumor characteristics and long-term prognosis in patients with incidentally discovered pheochromocytomas.

BACKGROUND: Chromaffin-cell tumors (CCT), a rare group of catecholamine producing endocrine neoplasms, are traditionally suspected and diagnosed in patients presenting with episodic hypertension, together with the classic triad of headache, sweating, and tachycardia. Asymptomatic CCT are increasingly diagnosed, frequently as "incidentalomas". We have conducted a multicenter retrospective study, to assess the characteristics of a group of patients with clinically silent CCT, compared with a group of patients with typical CCT. METHODS: Forty-three consecutive patients with CCT (24 with silent and 19 with typical tumors) have been retrospectively studied for a period of up to 20 yr (between 1989 and 2009); clinical picture, biochemical tests, as well as topographic and functional assessment were analyzed at diagnosis and periodically following treatment. Surgical samples were reviewed for neuroendocrine markers and for signs of invasiveness. RESULTS: Patients with clinically silent CCT were significantly older than the typical ones (56.3±3.4 vs 48.0±4.8 yr; p<0.05); 15 of them (63%) were completely asymptomatic, and 9 patients (37%) complained of non-specific abdominal symptoms. Hypertension was present in only 6 silent CCT patients (25%), it was well controlled [mean blood pressure (BP) 134/84 mmHg], and persisted after surgery in only 2 patients. Fourteen out of twenty-four silent CCT patients (58%) were managed pre-operatively with prophylactic combination of α and ß blockade, despite normal BP values. Clinically silent CCT were larger than typical CCT (mean diameter of 5.2±2.3 cm vs 4.6±1.5 cm, p<0.05) and secreted higher a mounts of normeta neph rines. All clinically silent CCT patients were defined as "cured" after surgery. CONCLUSION: Clinically silent CCT are more prevalent than previously reported. With an adequate pre-surgical diagnosis and patient preparation, the prognosis of silent tumors is usually excellent.

A discussion of airway and respiratory complications along with general considerations in obese patients.

Obesity is defined as the degree of excess weight associated with adverse health consequences. Within Great Britain, it is reported that a quarter of men and women are obese; these rates have trebled over the past 20 years. In 2001, it was estimated that obesity cost the National Health Service at least half a billion pounds, with a further two billion pounds lost on lower productivity and lost output. Obesity poses a significant risk factor for diseases, such as coronary heart disease, diabetes mellitus and certain forms of cancer, amongst others. Obese individuals pose significant problems to the clinician because of airway and respiratory complications. Sleep apnoea, obesity-hypoventilation syndrome, pulmonary atelectasis are associated with obesity and tracheostomy insertion is made all the more difficult in these patients. This article aims to discuss some of these issues relevant to the clinician and examine present strategies for dealing with them.

Integrating local and technical knowledge to support soil salinity monitoring in the Amudarya river basin.

The role of monitoring is changing due to the increasing awareness of complexity and uncertainty in environmental resources management. Monitoring systems are required to support critical reflection about the effectiveness of actions toward the achievement of management objectives. To this aim, monitoring should be based on a strong integrated and multi-scale approach. Monitoring costs could be prohibitive if the monitoring is only based on traditional scientific methods of measurements. To deal with these issues, the design of an innovative monitoring system should be based on the integration between different sources of knowledge and information. In this work the usability of local knowledge to support environmental monitoring is investigated. A multi-step participatory monitoring design process has been implemented aiming to design a program for soil salinity monitoring in the lower Amudarya river basin in Uzbekistan. Although there is an increasing awareness of the importance of stakeholders being involved in decision processes, the current socio-cultural and institutional context is not favourable to the participatory approach. The choice of method to be implemented in this work was influenced by such conditions. The analysis of the lessons learned from the experiences gained in this project revealed some important clues concerning the development of a locally-based monitoring program. These lessons can be subdivided according to three fundamental issues: the long term involvement of local community members in monitoring activities, the acceptance of locally-based monitoring systems by decision makers, and the reliability of monitoring information.

Cecal Resection with Bipolar Sealing Devices in a Rat Model.

Background: Bipolar sealing devices are routinely used to seal blood vessels. The aim of the study is to evaluate the feasibility and safety of colonic sealing with the use of the bipolar energy devices in rats as model for experimental appendectomy. Methods: Seventy-five male Wistar rats underwent a cecal resection with four different bipolar sealing devices or a linear stapler. The harvesting procedure was performed immediately or at postoperative day (POD) 7. The sealing front bursting pressure (BP) was measured in both groups. At POD7, the resection line was clinically examined and the hydroxyproline (HDP) levels were determined. Hematoxylin and Eosin (H&E) staining was used for histopathological evaluation of the sealing front as well. Results: There was no mortality and no insufficiency. The BPs between the bipolar sealing devices showed no statistical differences. The early phase of the seal (POD 0) provides a low BP with an 30.8% increase until POD 7. The BPs in the stapler group showed significant better values. The hydroxyproline levels did not differ statistically between the groups. Histopathologically, there were more signs of ischemic necrosis in the stapler group than in the sealing devices groups. Conclusion: The resection and sealing of the cecum as an experimental appendectomy model with the use of bipolar energy devices proved feasible and safe in rats. The different energy devices in this study produce comparable results. To justify clinical practice in humans, several studies on the underlying mechanisms of early stage wound healing are needed.

Carbon monoxide: a putative neural messenger.

Carbon monoxide, an activator of guanylyl cyclase, is formed by the action of the enzyme heme oxygenase. By in situ hybridization in brain slices, discrete neuronal localization of messenger RNA for the constitutive form of heme oxygenase throughout the brain has been demonstrated. This localization is essentially the same as that for soluble guanylyl cyclase messenger RNA. In primary cultures of olfactory neurons, zinc protoporphyrin-9, a potent selective inhibitor of heme oxygenase, depletes endogenous guanosine 3',5'-monophosphate (cGMP). Thus, carbon monoxide, like nitric oxide, may be a physiologic regulator of cGMP. These findings, together with the neuronal localizations of heme oxygenase, suggest that carbon monoxide may function as a neurotransmitter.

Pathophysiology and management of gastroesophageal reflux disease.

Gastroesophageal reflux is a physiological phenomenon but becomes pathological if troublesome symptoms and/or complications occur. Gastroesophageal reflux disease (GERD) has different phenotypes ranging from non-erosive reflux disease (NERD), through reflux esophagitis and Barrett's esophagus, and can present with either typical symptoms such as regurgitation and heartburn, or extra-esophageal symptoms such as cough and laryngitis. In the diagnosis of GERD endoscopy, empirical PPI test, and pH impedance testing all have their own position. Although proton pump inhibitors (PPIs) are very effective in the treatment of esophagitis, a significant proportion of patients have persistent symptoms even during high dosing of PPIs. Therefore, insight into the multifactorial pathophysiology of GERD is needed to develop new anti-reflux therapies. The predominant mechanism underlying reflux is the transient lower esophageal sphincter relaxation (TLESR). Hiatal hernia, impaired esophageal clearance and reduced lower esophageal sphincter pressure play a significant role in patients with moderate to severe reflux disease. Refluxate containing acid, pepsin and bile can cause epithelial injury when epithelial barrier of the esophagus fails to defend. In the majority of patients there is histopathological evidence of epithelial injury, even with NERD where there are more dilated intercellular spaces. The perception of heartburn can be enhanced due to visceral hypersensitivity, leading to more and more severe symptoms. Anti-reflux surgery is as effective as PPI therapy, but has higher morbidity and results decline in the long term. Therefore, new pharmacological, endoscopic and surgical interventions are being developed for these patients.

Neurotransmitter release regulated by nitric oxide in PC-12 cells and brain synaptosomes.

BACKGROUND: Nitric oxide is a messenger molecule of the nervous system, which is produced by the enzyme nitric oxide synthase, which may regulate cyclic guanosine monophosphate levels and which has been implicated in the control of neurotransmitter release. PC-12 pheochromocytoma cells differentiate to form neuronal cells in culture when they are exposed to nerve growth factor. The levels of cyclic guanosine monophosphate in the cells and their ability to release acetylcholine in response to K(+)-depolarization are both maximal after eight days of treatment with nerve growth factor. We set out to assess a possible role for nitric oxide in the processes that occur in differentiating PC-12 cells. RESULTS: Nitric oxide synthase is first evident in differentiating PC-12 cells eight days after beginning treatment with nerve growth factor, coinciding with the marked increase in K(+)-depolarization-induced release of acetylcholine. The release of both acetylcholine and dopamine in response to K(+)-depolarization is blocked by inhibitors of nitric oxide synthase and by hemoglobin, which binds nitric oxide. Providing l-arginine, a precursor required for nitric oxide synthesis, reverses the effects of the inhibitors. In synaptosomal preparations from the corpus striatum, inhibitors of nitric oxide synthase prevent the release of glutamate in response to the glutamate derivative N-methyl-d-aspartate but not in response to K(+)-depolarization. CONCLUSION: Nitric oxide may mediate the release of acetylcholine and dopamine in response to K(+)-depolarization in PC-12 cells and the release of glutamate in response to N-methyl-d-aspartate in striatal synaptosomes. Nitric oxide synthase expression is induced after eight days of treating PC-12 cells with nerve growth factor, coinciding with a marked enhancement of the release of neurotransmitters in response to K(+)-depolarization.