shukoor65/lab-rag-model huggingface dataset:
Inhibition of promoter activity by methylation: possible involvement of protein mediators. To study the relationship between DNA methylation and promoter activity we have methylated in vitro the promoters of the mouse metallothionein I gene and the herpes simplex virus thymidine kinase gene. We have transiently transfected these promoters fused to the human growth hormone in their methylated or unmethylated state into mouse L or F9 cells. Promoters methylated by methylase (M.) Hpa II and M.Hha I caused inhibition of reporter gene expression in L cells but not in F9 cells, while methylation of all CpGs by M.Sss I caused inhibition in both cell lines. Repression of promoter activity by M.Hpa II and M.Hha I methylation, but not by M.Sss I methylation, could be alleviated by cotransfection with an excess of untranscribable DNA methylated with M.Sss I. The methylated sites in nuclei isolated from the transfected L cells, but not F9 cells, were found to be protected from Msp I digestion. Taken together these results suggest that a factor present in L cells and missing in F9 cells mediates the methylation-directed inhibition of promoter activity. The ability of methylated DNA to overcome the inhibition seems to reflect competition for the mediator factor. Interestingly, treatment with Zn2+ ions brought about activation of the methylated promoter of the metallothionein gene. Similarly, butyrate could override the repression of the thymidine kinase methylated promoter. These activations were not accompanied by demethylation of the promoter or displacement of the mediator factor.
6-mercaptopurine therapy in selected cases of corticosteroid-dependent Crohn's disease. Nineteen patients (12 children and 7 adults) with severe Crohn's disease, all of whom were dependent on corticosteroids, were treated with 6-mercaptopurine. All patients received a daily dose of 6-mercaptopurine of 50 mg; in two pediatric patients with a poor response after 2 months, the dosage was increased to 75 mg/day. A complete or partial response to 6-mercaptopurine therapy was noted in 47% of patients, and therapy failed in 53%. The age of the patients, prior resection, or initial symptoms did not influence the response. The clinical response was better in male than in female patients and in patients with involvement of both the small intestine and the colon than in those with only enteritis. 6-Mercaptopurine is a possible alternative to long-term corticosteroid therapy or surgical treatment in selected patients with severe Crohn's disease.
Incentive spirometry versus routine chest physiotherapy for prevention of pulmonary complications after abdominal surgery We entered 876 patients into a clinical trial aimed at preventing pulmonary complications after abdominal surgery. Patients either received conventional chest physiotherapy or were encouraged to perform maximal inspiratory manoeuvres for 5 min during each hour while awake, using an incentive spirometer. The incidence of pulmonary complications did not differ significantly between the groups: incentive spirometry 68 of 431 (15.8%, 95% CI 14.0-17.6%), and chest physiotherapy 68 of 445 (15.3%, CI 13.6-17.0%). Nor was there a difference between the groups in the incidence of positive clinical signs, pyrexia, abnormal chest radiographs, pathogens in sputum, respiratory failure (PO2 less than 60 mm Hg), or length of stay in hospital. We conclude that prophylactic incentive spirometry and chest physiotherapy are of equivalent clinical efficacy in the general management of patients undergoing abdominal surgery.
Gastric emptying in patients with severe reflux esophagitis. The pathogenesis of gastroesophageal reflux (GER) is not fully understood. There have been reports that delayed gastric emptying is a contributing factor in some patients. To determine whether delayed gastric emptying plays a role in the genesis of GER, we correlated gastric-emptying measures obtained by scintigraphic techniques with the degree of acid reflux assessed by esophageal pH monitoring. Ten patients, all of whom had evidence of esophageal mucosal disease and severe acid reflux, were studied. Four of the 10 patients with reflux had prolongation in the lag phase of gastric solid emptying, and one of the four showed prolonged gastric-emptying t1/2. There was no significant difference, however, in the mean gastric-emptying t1/2 between a control group and the patient group. Furthermore, there was no correlation between gastric-emptying measures and degree of acid reflux. We conclude that in this group of 10 patients with severe GER, delayed gastric emptying does not play an important role in the development of gastroesophageal reflux.
Recurrence of oropharyngeal carcinoma after radiotherapy. Two-hundred-and-twenty-one patients with squamous carcinoma of the oropharynx treated by irradiation are presented. The primary recurrence rate at five years in the previously untreated patients was 27%, but was dictated by neither host factors (age, sex and general condition) nor tumour factors (site, T-stage and histological grade). Pre-operative histological diagnosis had a very high sensitivity but a low specificity, indicating that false positives are common but false negatives unusual. Twenty per cent of patients with a recurrent primary tumour were untreatable. The five year survival after a primary recurrence was 31 per cent. Sixty-eight per cent of patients undergoing major surgery recovered without a major complication, and the hospital mortality rate was three per cent, due entirely to major medical catastrophes. The major complication rate in those undergoing flap repair after major resection was seven per cent. The metastatic rate in lymph nodes was 44 per cent at five years, and again this did not depend on any host or tumour factors. The survival at five years after node recurrence was a mere 19 per cent, and the length of survival was related to the primary site of the original tumour and the presence of extranodal disease. Two-thirds of patients had advanced disease (N2 and N3) when node recurrence was diagnosed and about 15 per cent were unsuitable for surgery.
Cerebral infarction verified by cranial computed tomography and prognosis for survival following transient ischemic attack. Of 564 consecutive patients with transient ischemic attack, 350 (62%) had cranial computed tomography performed. Except for date of admission and smoking history, there were few differences between the patients evaluated with computed tomography and the 214 who were not. Cerebral infarcts were found in 59 (17%) of the 350 tomographic evaluations. Previous clinically diagnosed stroke, older age, and male sex were all significantly associated with the occurrence of tomographically verified infarcts (p less than 0.05). After controlling for stroke history and other important covariates, patients with tomographically verified infarcts had significantly shorter survival times than did patients without evidence of infarction on computed tomography (p = 0.035). Thus, cranial computed tomography findings appear to have important prognostic value for estimating survival following transient ischemic attack.
A1-adenosine receptor inhibition of adenylate cyclase in failing and nonfailing human ventricular myocardium. BACKGROUND. Receptors that couple via the stimulatory G protein, Gs, to adenylate cyclase and to a positive inotropic response have been extensively investigated in falling human heart. In contrast, much less is known about receptors, such as the A1-adenosine receptor, that couple to adenylate cyclase via the inhibitory G protein, Gi, to give a negative inotropic response. Activation of such Gi-coupled receptors might worsen heart failure. Furthermore, alpha Gi is increased in failing human ventricular myocardium, which may enhance inhibitory receptor coupling to adenylate cyclase. METHODS AND RESULTS. A1-Adenosine receptor inhibition of adenylate cyclase was examined in crude particulate preparations derived from 12 nonfailing and 12 failing human left ventricles. Experimental conditions were designed for maximal inhibitory responses. Dose-response curves were performed with the selective A1-adenosine receptor agonist R-phenylisopropyl-adenosine (R-PIA). No differences in nonfailing versus failing heart were observed for basal adenylate cyclase activity (49.0 +/- 4.1 versus 45.7 +/- 2.6 pmol cyclic AMP/min/mg), maximal R-PIA-mediated inhibition (31.1 +/- 2.6 versus 30.2 +/- 1.6 pmol cyclic AMP/min/mg), ED50 (R-PIA x 10(-7) 1.28 +/- 0.10 versus 1.36 +/- 0.08), or slope (1.06 +/- 0.06 versus 1.03 +/- 0.10), respectively. Furthermore, fluoride, forskolin, and manganese adenylate cyclase activation were not different in failing heart, which is consistent with no change in the catalytic unit of adenylate cyclase. The inhibitory G protein alpha Gi, as quantitated by pertussis toxin-catalyzed ADP-ribosylation, was increased in failing heart (105.7 +/- 5.8 versus 132.7 +/- 3.4 optical density units, p less than 0.003). Basal adenylate cyclase activity was reduced in failing heart (7.8 +/- 0.8 versus 4.5 +/- 0.4 pmol cyclic AMP/min/mg, p less than 0.005) with assay conditions designed to assess G protein effects. CONCLUSIONS. The A1-adenosine receptor pathway exerts a major inhibitory effect on human myocardial adenylate cyclase activity. Although alpha Gi was increased in failing heart, A1-adenosine receptor inhibition of adenylate cyclase was not altered in preparations of failing versus nonfailing human ventricular myocardium.
Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. An overview. Evidence is accumulating that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is linked to ulceration of the stomach and duodenum and can cause significant, life-threatening ulcer complications. The mechanism of action seems to be both topical damage to the mucosal barrier and the systemic effect of a reduction in levels of mucosal prostaglandins. Patients especially at risk are the elderly, those with concomitant debilitating disease, those with a history of ulcers, and those taking corticosteroids. Histamine2 blockers are reported to significantly reduce the incidence of NSAID-induced duodenal ulcer, and misoprostol (Cytotec) has been shown to significantly reduce the incidence of NSAID-induced gastric ulcer. Prophylaxis with these agents should be considered for high-risk patients who need NSAID therapy to maintain a reasonable life-style.
Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers Recent studies have suggested the existence of a tumor suppressor gene located at chromosome region 5q21. DNA probes from this region were used to study a panel of sporadic colorectal carcinomas. One of these probes, cosmid 5.71, detected a somatically rearranged restriction fragment in the DNA from a single tumor. Further analysis of the 5.71 cosmid revealed two regions that were highly conserved in rodent DNA. These sequences were used to identify a gene, MCC (mutated in colorectal cancer), which encodes an 829-amino acid protein with a short region of similarity to the G protein-coupled m3 muscarinic acetylcholine receptor. The rearrangement in the tumor disrupted the coding region of the MCC gene. Moreover, two colorectal tumors were found with somatically acquired point mutations in MCC that resulted in amino acid substitutions. MCC is thus a candidate for the putative colorectal tumor suppressor gene located at 5q21. Further studies will be required to determine whether the gene is mutated in other sporadic tumors or in the germ line of patients with an inherited predisposition to colonic tumorigenesis.
Urethrovaginal fistula repair with Martius labial fat pad graft. Most urethrovaginal fistulas are iatrogenic and, like other urinary fistulas, significantly reduce the quality of the affected individual's life. The Martius labial fat pad graft facilitates the urologic care of these women.
Free and supported stance in Parkinson's disease. The effect of posture and 'postural set' on leg muscle responses to perturbation, and its relation to the severity of the disease. Upright stance and its reflex control were studied in parkinsonian patients and in age-matched normal subjects. They stood unperturbed on a force-measuring surface (static conditions), or were displaced by movement of a supporting platform (dynamic conditions). During quiet stance the following variables were analysed, with eyes open or closed: position of the centre of foot pressure (CFP), average sway area, length of sway path, amplitude and distribution of tonic leg muscle EMG activity. Perturbations of stance were induced by toe-up or toe-down rotations, and by backward or forward translations of the platform. Amplitude of short, medium and long-latency EMG responses to displacement were measured in the tibialis anterior (TA) and in the three heads of the triceps surae (TS) muscle. The perturbations were produced during both free and supported stance (holding onto a stable structure), under which condition normal subjects suppress medium and long-latency responses. Under static conditions, the only significant finding in parkinsonians was represented by a shift in the position of the CFP. This was correlated with the severity of the disease (Webster scale), the less affected patients being shifted backwards and the more affected patients forwards, with respect to normals. Under dynamic conditions, the reflex responses to perturbations of free stance were similar in both groups. Only the medium-latency burst of gastrocnemius lateralis and the long-latency burst TA evoked by TS stretch were larger in parkinsonians. The amplitude of these responses, as well as of all the others, was not related to the Webster score. Within the patients' group, a relationship between position of CFP and area of EMG burst was found for both medium and long-latency TA responses evoked by forward translation and toe-up rotation, respectively. Under supported conditions, the capability to suppress all medium and long-latency muscle responses to any perturbation was lost or impaired in the parkinsonians. The degree of impairment was unrelated to the position of the CFP, but was significantly related to the severity of the disease. The suppression to 40% (supported/nonsupported), of TA response to toe-down rotation is proposed as the point of separation between normals and parkinsonians. The forward projection of the CFP, occurring in the severe stages of the disease, and the increase in amplitude of some responses to perturbations of free stance might be a compensatory adaptation to the anomalous upright posture.(ABSTRACT TRUNCATED AT 400 WORDS).
The differential effects of biofeedback in the treatment of menstrual and nonmenstrual migraine. The aim of the present study was to investigate the effects of biofeedback training in the treatment of menstrual and nonmenstrual migraine. Accordingly, 39 female patients suffering from both migraine associated, and migraine not associated, with menstrual periods were drawn from a pool of research volunteers enrolled in a biofeedback treatment program for migraine headaches. All patients were required to complete 5 weeks of daily self-monitoring of headache and menstruation activity immediately before and after treatment, and again at 6-month follow-up. Within-subjects comparisons of the effects of biofeedback on menstrual and nonmenstrual migraine, and between-subjects comparisons of the effects of biofeedback on patients suffering predominantly from either menstrual or nonmenstrual migraine showed that biofeedback is just as effective in reducing menstrual migraine as it is in reducing nonmenstrual migraine. Questions as to whether or not these conclusions can apply to patients who experience migraine headaches only during, or shortly before or after, menstruation, are raised.
Medullary carcinoma of the thyroid presenting as multifocal bronchial carcinoid tumour. A 21 year old man presented with diarrhoea and flushing after meals and later developed miliary shadowing on his chest radiograph. Multifocal bronchial carcinoid tumour was diagnosed initially, but at necropsy metastatic medullary carcinoma of the thyroid was found. Multifocal bronchial carcinoid tumour should not be accepted as a primary diagnosis without first excluding medullary carcinoma of the thyroid because of the need to screen relatives of affected patients.
Descending thoracic aorta-splenic artery graft for occlusive disease of the celiac axis. A new procedure is presented for the restoration of normal blood flow to the celiac axis in cases of orifice lesions of the celiac artery. The operation consists of inserting a graft between the descending thoracic aorta end-to-side and the divided splenic artery end-to-end.
Pseudohypacusis. This article provides the basis for the techniques and interpretation of audiologic tests useful in evaluation of the patient with pseudohypacusis. Differences between the childhood and adult forms of the problem are discussed. The indications for currently popular conventional and special tests are presented. These include both behavioral and electrophysiologic measures for assessing auditory function.
The impact of ulcerogenic drugs on surgery for the treatment of peptic ulcer disease. To investigate the impact of ulcerogenic drugs on surgery for the treatment of peptic ulcer disease, we reviewed 150 surgical cases. Ulcerogenic drug use (steroids and/or nonsteroidal anti-inflammatory agents, including aspirin) increased from 15% between 1972 and 1977 to 37% between 1983 and 1988. While there was no correlation between ulcerogenic drug use and hemorrhage, obstruction, or intractable pain, 16 (52%) of the 31 perforations and 26 (38%) of the 69 emergency operations were associated with use of ulcerogenic drugs. The overall mortality rate was 11%. Death was correlated with age greater than 65 years and emergency operation, but not with ulcerogenic drug use or other variables. Of 12 patients with histories of peptic ulcer disease who were treated with ulcerogenic drugs without concomitant antiulcer prophylaxis, 11 (92%) required emergency operation to treat perforation or massive hemorrhage. Standard antiulcer medications or misoprostol should be prescribed to elderly patients and to those with histories of ulcers who require ulcerogenic drug therapy.
Usefulness of esmolol in unstable angina pectoris. European Esmolol Study Group. Esmolol is a new cardioselective beta blocker with unique pharmacokinetic properties resulting in a half-life of only 9 minutes. The present multicenter, randomized, placebo-controlled study examined the hemodynamic and antiischemic effects of this compound given as an adjunctive to conventional medical therapy in 113 patients with unstable angina. Fifty-nine patients received esmolol and 54 received matching placebo infusions. Esmolol was titrated in a step-wise manner at dosages of 2 to 24 mg/min until a 25% reduction in the double product was achieved; thereafter, esmolol was continuously infused for up to 72 hours. Esmolol caused a significant and persistent decline in heart rate and blood pressure throughout the entire study period. Clinical events, such as development of acute myocardial infarction or the need for urgent revascularization, occurred in 3 esmolol compared with 9 placebo patients (p = 0.06). There was also a trend toward reduction of silent ischemia as judged by Holter monitoring (mean [+/- standard deviation] duration/patient/24 hours, 21 +/- 81 minutes in the esmolol and 35 +/- 128 minutes in the placebo groups). Esmolol-related adverse effects were mostly cardiovascular in origin and could be managed promptly by downward dose titration or cessation of drug infusion. Thus, esmolol appears to be a safe and effective drug for patients with unstable angina because it permits a large degree of flexibility in adapting the desired level of beta blockade to the patient's changing clinical presentation.
Allopurinol pretreatment improves evoked response recovery following global cerebral ischemia in dogs. The reperfusion of previously ischemic tissue may lead to the formation of highly reactive free radicals that promote tissue injury. Xanthine oxidase has been implicated as one source of these free radicals. We examined the role of xanthine oxidase in brain injury using a cerebrospinal fluid compression model of global cerebral ischemia with 15 minutes of ischemia and 4 hours of reperfusion. Seven dogs were pretreated with the xanthine oxidase inhibitor allopurinol (50 mg/kg for 5 days). Neurophysiological recovery was monitored with cortical somatosensory evoked potentials. As an attempt to correlate brain recovery with the mechanism of protection, free brain malondialdehyde was measured at the end of reperfusion by high-performance liquid chromatography. Brain water content was measured by wet-dry weights. Compared with seven untreated control dogs, allopurinol pretreatment significantly improved recovery of somatosensory evoked potentials after 4 hours of reperfusion. However, the amount of free malondialdehyde in the allopurinol-treated dogs was 32% greater than that in the controls. Brain water content was similar in the two groups. These results suggest that xanthine oxidase contributes to brain injury after ischemia and reperfusion. However, tissue damage caused by xanthine oxidase may be mediated through mechanisms other than free radical production.
The mechanisms and prevention of intravascular fluid loss after occlusion of the supraceliac aorta in dogs. Mechanisms of intravascular fluid depletion after temporary occlusion of the supraceliac aorta were investigated in a canine model. During ischemia and reperfusion, hemodynamic parameters, superior mesenteric artery flow, intestinal mucosal perfusion, and mucosal permeability were monitored. After 12 hours of reperfusion, the volumes of intravenous electrolyte fluid required to maintain hemodynamic stability and fluid lost into the gastrointestinal tract and peritoneal cavity were measured. The distribution of total body water was analyzed by use of radionuclide dilution techniques. Group A animals underwent laparotomy only, group B had the supraceliac aorta occluded for 45 minutes, group C had superoxide dismutase administered after 45 minutes of aortic occlusion, and group D animals were exposed to mild hypothermia during a similar ischemia and reperfusion period. No significant difference was found in mean superior mesenteric artery flow or mucosal perfusion during ischemia among groups B, C, and D. During reperfusion superior mesenteric artery flow returned to values similar to control in all groups. Aortic occlusion increased mucosal permeability most significantly in group B (p less than 0.01). Mean intravenous fluid requirements (ml/mg) were the following: group A, 80 +/- 5; group B, 201 +/- 9 (p less than 0.01); group C, 116 +/- 7 (p less than 0.05); group D, 245 +/- 24 (p less than 0.05). Mean gastrointestinal fluid loss was highest in the hypothermic group and smallest if superoxide dismutase was given. Mean intracellular fluid volume was increased in groups B and D compared with group A (p less than 0.01).
Reversible thyroid dysfunction during treatment with GM-CSF. To investigate whether autoimmunity against thyroid antigens is induced or exacerbated by granulocyte-macrophage colony-stimulating factor, thyroid function and thyroid autoantibodies were studied in 14 patients with advanced breast cancer and 11 with soft-tissue sarcoma who received several cycles of doxorubicin and cyclophosphamide plus GM-CSF 250 micrograms/m2 intravenously daily for 10 days in every 21 day cycle. All patients had normal thyroid function before treatment. In 2 patients with pre-existing thyroid antibodies, thyroid dysfunction developed but disappeared after cessation of GM-CSF. No other autoimmune abnormalities appeared. Stimulation of antigen-presenting cells by GM-CSF may bring about this phenomenon.