Esophagitis in Sprague-Dawley rats is mediated by free radicals

Free radical-mediated esophagitis was studied during duodenogastroesophageal reflux (mixed reflux) or acid reflux in rats. The influence of reflux on esophageal glutathione levels was also examined. Mixed reflux caused more gross mucosal injury than acid reflux. Gross mucosal injury occurred in the mid-esophagus. Total glutathione (GSH) in the esophageal mucosa of control rats was highest in the distal esophagus. The time course of esophageal GSH in rats treated by mixed reflux showed a significant decrease 4 hr after initiation of reflux, followed by a significant increase from the 12th hour on. Mucosal GSH was increased in both reflux groups after 24 hr but significantly more so in the mixed than in the acid reflux group. The free radical scavenger superoxide dismutase (SOD) prevented esophagitis and was associated with decreased GSH levels. GSH depletion by buthionine sulfoximine (BSO) prevented esophagitis and stimulated SOD production in the esophageal mucosa. It is concluded that gastroesophageal reflux is associated with oxidative stress in the esophageal mucosa. The lower GSH levels in the mid-esophagus may predispose to damage in this area. Duodenogastroesophageal reflux causes more damage than pure acid reflux. Oxidative stress leads to GSH depletion of the esophageal mucosa in the first few hours following damage but then stimulates GSH production. GSH depletion by BSO does not worsen esophagitis since it increases the esophageal SOD concentration.     

The STOP-NIDDM Trial: an international study on the efficacy of an alpha-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Study to Prevent Non-Insulin-Dependent Diabetes Mellitus

OBJECTIVE: To describe the rationale and design, and to discuss the preliminary screening data, of the Study to Prevent NIDDM (STOP-NIDDM Trial), an international study on the efficacy of the alpha-glucosidase inhibitor acarbose in preventing or delaying the development of type 2 diabetes in a population with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: A total of 1,418 subjects diagnosed with IGT according to the World Health Organization's criteria and having a fasting plasma glucose concentration > or =5.6 mmol/L were randomized in a double-blind fashion to receive either acarbose (100 mg t.i.d.) or placebo for a predictive median follow-up period of 3.9 years. The primary outcome is the development of type 2 diabetes diagnosed using a 75-g oral glucose tolerance test according to the new criteria. The secondary outcomes are changes in blood pressure, lipid profile, insulin sensitivity, cardiovascular events, and morphometric profile. RESULTS: Screening was performed in a high-risk population. As of 1 March 1997, 4,424 subjects had been screened, and data were available for 3,919 (88.5%) subjects. Of these subjects, 1,200 (30.6%) had glucose intolerance. Of the subjects with glucose intolerance, 521 (13.3%) had previously undetected type 2 diabetes, and 679 (17.3%) had IGT. Of the IGT population, 412 (60.7%) subjects were eligible for the study This population had the following characteristics: the mean age was 54.8 years, 52% of the subjects were female, 53% had more than one risk factor for type 2 diabetes, >90% had a family history of diabetes, 78.2% had a BMI > or =27 kg/m2, 47.5% had high blood pressure, 51.2% had dyslipidemia, and 22.8% of the women had a history of gestational diabetes. CONCLUSIONS: Screening of a high-risk population yields one eligible subject per every 10 volunteers screened. This study should definitely answer the question of whether acarbose can prevent or delay the progression of IGT to type 2 diabetes mellitus.     

Phlebotomus papatasi sand fly salivary gland lysate down-regulates a Th1, but up-regulates a Th2, response in mice infected with Leishmania major

A vertebrate host becomes infected with Leishmania major when the sand fly vector injects parasites into skin along with saliva. Previous studies showed that salivary gland lysate of the New World sand fly Lutzomyia longipalpis markedly enhanced L. major infection in CBA mice. However, L. major is an Old World parasite transmitted in nature by the Old World sand fly Phlebotomus papatasi. Here we examine the ability of P. papatasi salivary gland lysate to enhance infection (lesion size and parasite burden) by L. major. In addition, we examine the effects of salivary gland lysate on the immune response to L. major by monitoring the levels of cytokine mRNA from the lymph nodes draining cutaneous lesions. We found that P. papatasi salivary gland lysate dramatically exacerbated lesion development in disease-resistant CBA mice. This exacerbation of disease correlated with inhibition of the production of Thl cytokines and associated factors (IFN-gamma, IL-12, and inducible nitric oxide synthase), but with enhancement of the Th2 cytokine IL-4, whereas no changes in the levels of IL-10 and TGF-beta were noted. Importantly, salivary gland lysate directly up-regulated expression of IL-4 mRNA in mice in the absence of infection with L. major.     

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.     

Dentine hypersensitivity: a clinical trial to compare 2 strontium densensitizing toothpastes with a conventional fluoride toothpaste

Sixty-nine patients, aged 63-98 years and admitted at the Geneva Geriatric Hospital, were included in the present retrospective study. They received clomipramine orally, 50 or 75 mg/day. Blood concentrations of clomipramine were measured as part of a routine drug monitoring program. Comparison with a reference population of patients aged < or = 65 years indicated that elderly patients with concomitant somatic diseases reach higher dose-normalized concentrations of clomipramine and increased parent drug to demethylated metabolite ratios, as a consequence of impaired demethylation (approximately 50%) and hydroxylation (approximately 25%). Sixty-five percent of patients showed clinical improvement, with a maximum rate of satisfactory response observed in major depression. Severe side effects, such as symptomatic hypotension or confusion, were seen in 20% of patients. Because of 10- and 15-fold interindividual variations in the concentrations of clomipramine and its metabolite, respectively, therapeutic drug monitoring can provide valuable assistance to clinical judgment in individual dose adjustment for patients whose old age, associated somatic diseases, and comedication necessitate additional precautions.     

Temporal aggregation and spurious instantaneous causality in multiple time series models

Large aggregation interval asymptotics are used to investigate the relation between Granger causality in disaggregated vector autoregressions (VARs) and associated contemporaneous correlation among innovations of the aggregated system. One of our main contributions is that we outline various conditions under which the informational content of error covariance matrices yields insight into the causal structure of the VAR. Monte Carlo results suggest that our asymptotic findings are applicable even when the aggregation interval is small, as long as the time series are not characterized by high levels of persistence.     

Correlation between lymphocyte-induced donor-specific tolerance and donor cell recirculation. Role of class I and class II major histocompatibility complex

Intravenous infusion of mice with viable allogeneic lymphocytes can produce donor-specific enhancement of skin graft survival, but only if the injected lymphocytes can persist in the host's recirculating lymphocyte pool for at least 3 days. We have investigated the relative roles of class I and class II MHC for C57BL/6 mice infused with lymphoid cells from co-isogenic strains mutated at class I MHC (bm1) or class II MHC (bm12), and for A.TH lymphoid cells infused into C3H (class I different, class II identical) or A.TH (class II different, class I identical). Injected cells differing from the host at class I MHC, but not at class II MHC, can be rapidly removed by host natural immune mechanisms (probably NK cells). Persistence is favored if the injected cells also carry host class I MHC, i.e., tolerance is more readily induced by injecting F1 (A x B) into A rather than B into A, consistent with the "missing self" hypothesis of NK recognition, with class I MHC being the relevant self-marker. Injected cells differing from the host at class II MHC but not at class I MHC always persist for at least 3 days, even when class I-different cells are being actively removed.     

Effects of subject- versus experimenter-selected reinforcers on the behavior of individuals with profound developmental disabilities

Results from a number of studies have shown that individuals with profound developmental disabilities often show differential approach behavior to stimuli presented in a variety of formats, and that such behavior is a reasonably good predictor of reinforcement effects when these "preferred" stimuli are used subsequently in a contingent arrangement. Recent data suggest that reinforcement effects may be enhanced further by allowing individuals to select, just prior to training sessions, which (of several) preferred stimuli would be used as reinforcers, but whether this method is superior to one based on selection by a teacher or therapist has not been adequately addressed. We compared the effects of these two methods of reinforcer selection on rates of responding on a free-operant task, using stimuli previously identified as potential reinforcers. Results obtained with 4 subjects indicated little or no difference in reinforcement effects when stimuli were selected by subjects rather than experimenters. Implications of these results with respect to choice and its relation to reinforcement are discussed.     

Symptomatic subclavian steal syndrome four decades after operation for dysphagia lusoria

Congenital abnormalities of the aortic arch may lead to signs and symptoms of tracheal and esophageal obstruction secondary to a restrictive vascular ring. There are many case reports and monographs concerning the surgical management of dysphagia lusoria. This case provides the first example of long-term follow-up of surgical intervention for relief of dysphagia lusoria. A 45-year-old laborer presented with a several year history of episodic bilateral blindness and a more recent onset of "drop attacks." Notably this patient had presented at the age of 18 months with difficulty breathing and eating since birth. The patient also had frequent upper respiratory infections and episodes of pneumonia. Workup revealed a right-sided aortic arch with a left ligamentum arteriosum. When he was first seen in our clinic, history and physical examination revealed claudication and diminished pulses in the left upper extremity. Arteriography and duplex studies confirmed reversal of flow in the patient's left vertebral artery. The arteriogram demonstrated the presence of a right-sided aortic arch and descending aorta along with the proximal stump of the previously ligated left subclavian artery. He underwent left carotid to left axillary artery bypass for the treatment of symptomatic subclavian steal syndrome. His symptoms have resolved with return of antegrade vertebral flow and the presence of normal pulses in the left arm. Congenital aortic abnormalities that lead to tracheal and esophageal compromise are numerous and varied. Surgical management requires a thorough understanding of the person's anatomy and preoperative planning. The life expectancy of patients with dysphagia lusoria necessitates consideration of the long-term consequences of surgical intervention.