shukoor65/lab-rag-model huggingface dataset:
Repressor to activator switch by mutations in the first Zn finger of the glucocorticoid receptor: is direct DNA binding necessary? Transfection of HeLa cells with cDNA vectors expressing the wild-type human glucocorticoid receptor (GR) enabled dexamethasone to strongly repress cytokine- and second messenger-induced expression of cotransfected chimeric reporter genes containing transcription regulatory DNA elements from the human interleukin 6 (IL-6) promoter. Deletion of the DNA-binding domain or of the second Zn finger or a point mutation in the Zn catenation site in the second finger blocked the ability of GR to mediate repression of the IL-6 promoter. Unexpectedly, deletion of the first Zn finger, a point mutation in the Zn-catenation site in the first finger, or one in the steroid-specificity domain at the base of the first finger converted GR into a dexamethasone-responsive activator that enhanced basal and interleukin 1-induced IL-6 promoter function. These first-finger mutants of GR also mediated dexamethasone-responsive enhancement of expression of the herpesvirus thymidine kinase-chloramphenicol acetyltransferase (TK-105-CAT and TK-80-CAT) reporter genes but not of the murine mammary tumor virus long terminal repeat-CAT or the c-fos-CAT (pFC700) reporter genes. Wild-type GR was able to specifically bind to DNA fragments containing glucocorticoid response element sequences in both the murine mammary tumor virus and IL-6 promoters, albeit weakly to the latter, in a sequential DNA-binding immunoprecipitation assay. The first-finger mutants of GR, however, were inactive in this assay. Thus, mutations in the first Zn finger unmask unusual promoter-specific activation properties of GR that may not require direct high-affinity binding of the mutant GR to target DNA.
Radiation exposure of pediatric patients and physicians during cardiac catheterization and balloon pulmonary valvuloplasty. Thermoluminescent dosimeters were applied to various areas of 61 pediatric patients and physicians to measure radiation doses during routine cardiac catheterization and during 4 cases of balloon pulmonary valvuloplasty. Radiation doses were measured during chest roentgenography, fluoroscopy and cineangiography. Average skin dose to the chest was 121 microGy during chest x-ray, 5,182 microGy during catheterization and 641 mGy during valvuloplasty. For the eyes, thyroid and gonads of the patients, the exposure during routine catheterization was equal to 0.4, 6 and 0.2 chest x-rays, respectively. Radiation dose of the operator was 3 microGy for the eyes and 6 miCroGy in the thyroid. About 56% of the operator's dose could be reduced by thyroid shields, and 80% by lead aprons. The assistant received only 1 microGy outside the thyroid shield. Therefore, we have concluded that the patients' dose during routine catheterization is largely based on our experimental results, but the dose is acceptable based on the risk factor analysis. The skin dose to the right lateral chest of the patient during valvuloplasty is extremely high, perhaps as high as the equivalent of 1,000 chest x-rays. Besides the clinical benefits of valvuloplasty, the long-term radiation-related hazards to the patient should be carefully monitored.
Variables controlling the secretion of insulin-like growth factor binding protein-2 in normal human subjects. Insulin-like growth factor binding protein-2 (IGFBP-2) is one of a family of IGFBPs that are present in extracellular fluids, and binds both IGF-II and IGF-I with high affinity. These studies were conducted to determine the nutritional and hormonal variables that regulate plasma IGFBP-2 concentrations in humans. The mean plasma IGFBP-2 concentration for 38 normal adult subjects was 150 +/- 61 micrograms/L and was 4.7-fold greater than their mean fasting IGFBP-1 value. Mean IGFBP-2 values in cord sera of 26 normal term infants was 3.8-fold greater than the normal adult mean value. Likewise, the mean value for 44 hypopituitary adults was increased 2-fold compared to normal. There was no suppression of IGFBP-2 values in acromegaly. Normal adult subjects showed minimal fluctuations (less than 2-fold changes) in plasma IGFBP-2 concentrations during a 48-h sampling period. These changes were significantly less than the changes that occurred in plasma IGFBP-1 during the same interval. Plasma IGFBP-2 did not change significantly post prandially or after a glucose infusion. Extreme insulin deficiency, after 9 days of fasting, was associated with a 1.7-fold increase in plasma IGFBP-2. Administration of GH, which is known to cause a major decrease in plasma IGFBP-1 and in IGFBP-2 in hypophysectomized animals, did not result in a change in calorically restricted normal adult subjects, suggesting that a normal caloric intake is required for GH to suppress IGFBP-2. In summary, these results show that plasma IGFBP-2 is regulated differently than IGFBP-1. Acute stimulation of insulin secretion does not suppress IGFBP-2, and there is much less daily fluctuation compared to IGFBP-1. These findings suggest that plasma IGFBP-2 levels are more stable than IGFBP-1, and therefore IGFBP-2 may serve as a larger reservior that is available for IGF transport.
Solitary pulmonary nodule: high-resolution CT and radiologic-pathologic correlation. Edge and internal characteristics of pulmonary nodules evaluated with high-resolution computed tomography (HRCT) were correlated with the pathologic specimens in 93 patients. Speculation correlated pathologically with irregular fibrosis, localized lymphatic spread of tumor, or an infiltrative tumor growth pattern and was observed in six of 11 benign nodules (55%) and 74 of 85 malignant nodules (87%). Pleural tags were observed in three benign nodules (27%) and 49 malignant lesions (58%); pathologically, these represented fibrotic bands usually associated with juxta-cicatricial pleural retraction. Bubblelike areas of low attenuation within the nodule were observed in 21 malignant lesions (25%) and only one benign nodule (9%). They were observed most commonly in bronchioloalveolar carcinomas (seven of 14) and were due either to patent small bronchi or small, cystic spaces within neoplastic glands. Malignant nodules as a group were larger than benign lesions (P = .02) and more commonly demonstrated a spiculated contour (P less than .05), lobulation (P less than .001), and inhomogeneous attenuation (P less than .05).
The association of bullous pemphigoid and malignant disease: a case control study. In a case control study, the incidence of malignant disease in 84 patients with bullous pemphigoid (BP) was compared with 168 controls. The rate of malignant disease (past, concurrent or during follow-up) in BP patients was 17.9% compared to 5.3% in the controls. A number of the malignancies occurring in the BP group may be of doubtful significance, being either temporally very remote or partially attributable to treatment. The rate of concurrent BP and malignancy (within 8 weeks) was 6.0% suggesting that there is probably a slight excess of malignancy in BP, but insufficient to warrant extensive investigation in pursuit of cancer. Comparison of the BP patients with and without cancer identified no clinical or immunopathological subgroups in whom investigations would be indicated. Three patients with both BP and malignancy were HLA-DR 13 positive, which may point to an immunogenetic predisposition to both diseases.
Oxygen transport during steady-state submaximal exercise in chronic hypoxia. Arterial O2 delivery during short-term submaximal exercise falls on arrival at high altitude but thereafter remains constant. As arterial O2 content increases with acclimatization, blood flow falls. We evaluated several factors that could influence O2 delivery during more prolonged submaximal exercise after acclimatization at 4,300 m. Seven men (23 +/- 2 yr) performed 45 min of steady-state submaximal exercise at sea level (barometric pressure 751 Torr), on acute ascent to 4,300 m (barometric pressure 463 Torr), and after 21 days of residence at altitude. The O2 uptake (VO2) was constant during exercise, 51 +/- 1% of maximal VO2 at sea level, and 65 +/- 2% VO2 at 4,300 m. After acclimatization, exercise cardiac output decreased 25 +/- 3% compared with arrival and leg blood flow decreased 18 +/- 3% (P less than 0.05), with no change in the percentage of cardiac output to the leg. Hemoglobin concentration and arterial O2 saturation increased, but total body and leg O2 delivery remained unchanged. After acclimatization, a reduction in plasma volume was offset by an increase in erythrocyte volume, and total blood volume did not change. Mean systemic arterial pressure, systemic vascular resistance, and leg vascular resistance were all greater after acclimatization (P less than 0.05). Mean plasma norepinephrine levels also increased during exercise in a parallel fashion with increased vascular resistance. Thus we conclude that both total body and leg O2 delivery decrease after arrival at 4,300 m and remain unchanged with acclimatization as a result of a parallel fall in both cardiac output and leg blood flow and an increase in arterial O2 content.
Positron emission tomography for the assessment of myocardial viability. The detection of viable myocardium or ischemically injured myocardium with a reversible impairment of contractile function remains clinically important but challenging. Detection of reversible dysfunction and distinction from irreversible tissue injury by positron emission tomography is based on identification of preserved or even enhanced glucose metabolism with F-18 2-fluoro 2-deoxyglucose. Regional patterns of myocardial glucose utilization and blood flow, defined as perfusion-metabolism mismatches or matches, on positron emission tomography in patients with chronic or even acute ischemic heart disease are highly accurate in predicting the functional outcome after interventional revascularization. Compared with thallium-201 redistribution scintigraphy, positron emission tomography appears to be diagnostically more accurate, especially in patients with severely impaired left ventricular function. While larger clinical trials are needed for further confirmation, positron emission tomography has already proved clinically useful for stratifying patients with poor left ventricular function to the most appropriate therapeutic approach.
Enzymic control of the expression of the X determinant (CD15) in human myeloid cells during maturation: the regulatory role of 6-sialytransferase. To establish the basis for the reduced expression of the X determinant on leukemic blasts and the changes in antigenic expression that occur during myeloid maturation, the presence on myeloid cells of X and related structures was examined in conjunction with studies on the activities of the glycosyltransferases involved in their biosynthesis. Expression of X and sialyl-X was weak on blasts in comparison with neutrophils despite the presence of the requisite precursor structures. Much higher levels of 3-fucosyltransferase activity were found in blasts than in neutrophils when nonsialylated substrates were used, but, whereas the enzyme in neutrophils reacted equally well with 3'-sialylated and nonsialylated acceptors, the enzyme in blasts showed a marked preference for nonsialylated substrates. 6'-Sialyltransferase activity was strong in blasts but was not detectable in neutrophils, whereas a much lower level of 3'-sialyltransferase activity was present in both blasts and neutrophils. Dimethyl sulfoxide-induced maturation of HL60 cells was associated with (1) a decrease in both 6'-sialyltransferase and 3-fucosyltransferase activities, (2) a change in the substrate specificity of 3-fucosyltransferase towards that found in mature cells, and (3) increased cell surface expression of sialyl-X. These results suggest that the reduced expression of X in myeloblasts is related to the presence of the strong 6'-sialyltransferase, which uses the precursor substrate at the expense of the 3-fucosyltransferase and prevents the synthesis of X and sialyl-X. The developmental regulation of the levels of 3'- and 6'-sialyltransferases, and the level and specificity of the 3-fucosyltransferases, therefore controls the expression of X and its degree of sialylation.
Vitamin B6 and valproic acid in treatment of infantile spasms. Twenty patients with infantile spasms were treated with high doses of vitamin b6, valproic acid, or both. Three of 13 patients (23%) treated initially with high doses of vitamin B6 demonstrated a definite reduction in seizures; 2 patients had no improvement on electroencephalography. Vitamin B6 therapy alone was continued in a single patient (8%) who remained seizure-free during the 15-month follow-up period. Initial treatment with vitamin B6 and valproic acid improved the electroencephalogram significantly more (P less than 0.05) than initial vitamin B6 treatment alone. The group which had valproic acid added to vitamin B6 therapy had significantly fewer seizures (P less than 0.05) and better electroencephalograms (P less than 0.01) than did the group treated initially with vitamin B6 alone. There were no significant differences among the group treated initially with vitamin B6, the group treated initially with valproic acid, and the group in which valproic acid was substituted for vitamin B6. ACTH was more effective in abolishing seizures than was valproic acid or vitamin B6 and valproic acid. ACTH had an excellent effect on seizures in 86% of patients who did not respond well to vitamin B6, valproic acid, or both; however, many of these patients had later recurrence of infantile spasms. The combination of vitamin B6 and valproic acid is effective and safe in the treatment of infantile spasms.
Intensive therapy for small-cell lung cancer using carboplatin alternating with cisplatin, ifosfamide, etoposide, mid-cycle vincristine, and radiotherapy. Forty patients with small-cell lung cancer (31 patients with limited-stage [LS] disease, and nine patients with extensive-stage [ES] disease but of good performance status) have been treated with an intensive therapy composed of carboplatin alternating with cisplatin, ifosfamide, and etoposide with vincristine on day 14 of each carboplatin cycle. A maximum of six cycles were administered at 3 weekly intervals after the cisplatin combination and 4 weekly after the carboplatin combination. Prophylactic cranial irradiation was given with the first cycle of chemotherapy and thoracic irradiation with the third cycle. The median nadir for neutrophils was 0.47 x 10(9)/L and for platelets, 40 x 10(9)/L. Chemotherapy dosages were not reduced in response to myelosuppression, but treatment was delayed to allow blood count recovery. Sixty-eight percent of patients received all six cycles of chemotherapy, and there were four deaths associated with treatment-related neutropenia. Twenty-eight patients (70%) achieved a complete response (CR) when assessed 1 month after the end of treatment, and a further five patients (12.5%) had a partial response (PR). Median duration of CR was 16 months and of PR, 8 months. Cerebral metastases occurred in 20% of all patients and was the apparent sole site of relapse in 11% of the CR patients. The median survival of the total group was 14 months with an actual 2-year survival of 30% and a minimum follow-up of 28 months.
Complement activation during bypass in acquired C1 esterase inhibitor deficiency. Serial complement estimations during cardiopulmonary bypass are reported in a patient with acquired C1 esterase inhibitor deficiency. Although the extent of classic and alternative pathway activation appeared appropriate, exaggerated common pathway activation with massive increase in the C3d:C3 ratio occurred. A fatal hemostatic disorder, pulmonary edema, and circulatory collapse ensued despite prophylaxis and therapy.
Myeloablative combination chemotherapy without total body irradiation for neuroblastoma. Myeloablative treatment intensification in 25 patients diagnosed when older than 12 months of age with stage IV neuroblastoma included sequential delivery of cisplatin 120 mg/m2 x 1, hyperfractionated radiation (2,100 cGy) to the primary site and adjacent lymph nodes, carmustine (BCNU) 200 mg/m2 x 1, melphalan 60 mg/m2/d x 3 (n = 13) or thiotepa 300 mg/m2/d x 3. (n = 12), and etoposide (VP 16) 300 mg/m2/d x 3. Seventy-two hours after the last dose of VP 16, histologically tumor-free and 4-hydroperoxycyclophosphamide (4-HC; 100 mumol/L)-purged autologous bone marrow (ABMT) was infused. Acute toxicities included grade 3 to 4 oral mucositis, grade 1 to 2 diarrhea, and fevers. No patient required infusion of unpurged reserve autografts. At ABMT, 16 patients (group I) were progression-free 6.5 months to 14 months (median, 9 months) from diagnosis: seven remain progression-free 20 months to 46 months (median, 39 months) off therapy, six relapsed 4 months to 17 months post-ABMT, and three died of toxicity (candidiasis, metabolic derangement, and venoocclusive disease [VOD]). The event-free survival of group I patients is 44% at 24 months post-ABMT. Nine patients (group II) were in second remission at ABMT, including three who had relapsed after other transplant procedures: two are progression-free 24 months and 41 months off therapy, four relapsed 3 months to 12 months post-ABMT, and three died of toxicity (aspergillosis, hemorrhagic cystitis, VOD). Only one of 10 relapses involved a primary site, suggesting a beneficial effect of local radiation. In terms of survival or toxicity, an advantage for melphalan or thiotepa was not evident. Regimens such as this may prolong the survival of selected patients with poor-risk neuroblastoma, but concerns over late relapses and toxicity mandate continuing efforts to devise alternative, less risky, and more clearly beneficial approaches for definitive ablation of neuroblastoma.
Enalapril prevents cardiac fibrosis and arrhythmias in hypertensive rats. To evaluate the effects of hypertension on cardiac hypertrophy, on myocardial structure, and on ventricular arrhythmias, 27 3-month-old spontaneously hypertensive rats were treated with enalapril (10 mg/kg) daily for 11 months and compared with 26 untreated control rats. Systolic arterial pressure was significantly decreased in treated rats, and at the end of the experiment, it was 199 +/- 3 mm Hg (treated) versus 237 +/- 3 mm Hg (controls) (p less than 0.001). At this time, spontaneous arrhythmias and induced arrhythmias either by programmed electrical stimulation (train of stimuli +1 or 2 extrastimuli) or by trains of eight stimuli at decreasing coupling intervals were observed in isolated heart preparations. Comparing enalapril-treated and control rats, spontaneous arrhythmias (9 of 27 versus 20 of 26, respectively; p less than 0.01), programmed stimulation-induced arrhythmias (3 of 26 versus 12 of 23, respectively; p less than 0.01), and trains of stimuli-induced arrhythmias (4 of 26 versus 14 of 19, respectively, p less than 0.001) were less frequent in the enalapril group. Left ventricular weight was decreased in treated rats by 18% (p less than 0.001). Enalapril administration diminished the fraction of myocardium occupied by foci of replacement fibrosis normally occurring in control rats by 59% (p less than 0.001). Finally, a significant correlation was found between left ventricular weight, the extent of myocardial fibrosis, and the occurrence of ventricular fibrillation. It was concluded that chronic treatment with enalapril, which resulted in attenuation of systemic arterial pressure by limiting cardiac hypertrophy and myocardial fibrosis, decreases the propensity of the heart of hypertensive rats to arrhythmogenesis.
Bilateral carcinoma of the external auditory meatus. A 65-year-old woman had suffered for two months from bilateral tinnitus and discharge, pain in the right ear, and loss of hearing. Biopsy showed carcinoma of the squamous type on both sides. Tomography revealed bone destruction on the right. The patient was treated with radiotherapy. Two months after treatment, tomography showed tumour regression on the right side, but progression on the left. The literature on this subject is reviewed.
Stroke in a young adult with Fletcher trait. We have reported the case of a young woman with prekallikrein deficiency who had a cerebral infarction despite a prolonged APTT. She had bleeding complications with heparin administration. From the limited information in the literature, anticoagulation may be hazardous in these patients, and it should be undertaken with caution.
Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis. Gonadotropin-releasing hormone agonists induce a reversible hypogonadotropic hypogonadal environment. Leiomyomas are common, estrogen-sensitive, benign neoplasms that decrease in size by 40% to 50% during gonadotropin-releasing hormone agonist treatment. During gonadotropin-releasing hormone agonist therapy most women are amenorrheic. After discontinuation of gonadotropin-releasing hormone agonist treatment, uterine and myoma size increase and a return to pretreatment menstrual patterns often occurs. Concerns about the safety of long-term hypoestrogenism have made long-term gonadotropin-releasing hormone agonist administration an undesirable treatment strategy. This article focuses on the use of gonadotropin-releasing hormone agonists as preoperative therapy in selected women undergoing hysterectomy or myomectomy and the combination of a gonadotropin-releasing hormone agonist with estrogen-progestin "add-back" treatment as a potential long-term medical therapy for women with symptomatic leiomyomas. Finally, an estrogen threshold hypothesis to assess the effects of circulating estrogen concentrations on different tissues, is presented.
Cardiac tamponade and hydrothorax as complications of central venous parenteral nutrition in infants. The recent use of soft catheters made of silastic polymeric silicone or polyurethane has decreased the incidence of perforation of great veins or right-sided heart chambers but has not eliminated it as had been hoped. Two premature infants who presented with cardiac tamponade more than 24 hr after the insertion of a 23-gauge silastic catheter for total parenteral nutrition (TPN) administration are described. In one infant, bilateral hydrothorax preceded the occurrence of cardiac tamponade. Osmotic injury to great vessels and/or myocardium seems to be the common mechanism but which these complications of intraluminal catheters are produced. Review of the pediatric literature revealed a proportion of low birth weight infants among the reported cases. Despite a prohibitively high mortality rate, early recognition can prevent a fatal outcome.
Clipping of an aneurysm 20 years after encasement with methyl methacrylate. Case report. A variety of agents have been used to coat aneurysms as an alternative to clipping. These agents were employed more frequently prior to the routine use of the operating microscope and the presently available variety of aneurysm clips. One such coating agent is methyl methacrylate. This report describes a patient with an anterior communicating aneurysm that rebled 20 years after being encased in methyl methacrylate. At operation, the pulsating aneurysm had eroded the adjacent layer of methyl methacrylate, creating a small intervening space. This space allowed removal under the microscope (with a high-speed air drill and a diamond bit) of the methyl methacrylate from the anterior cerebral arteries and aneurysm, exposing it for definitive clip placement. The feasibility of clipping encased aneurysms is discussed.
Tumor necrosis factor. Tumor necrosis factor is important in systemic and cutaneous defense, homeostasis, and many disease states. The numerous and diverse effects of tumor necrosis factor are best understood when considered as concentration-dependent, with normal homeostasis progressing to defense followed by toxic effects. Understanding tumor necrosis factor is important for the dermatologist as more studies appear in our literature and potential clinical uses of tumor necrosis factor (and possible anti-tumor necrosis factor agents) are realized.