shukoor65/lab-rag-model huggingface dataset:
Single and multiple dose pharmacokinetics of methionyl growth hormone in children with idiopathic growth hormone deficiency. The pharmacokinetics (PK) of methionyl GH (metGH) were characterized in 20 newly diagnosed GH-deficient children (19 males; 12.9 +/- 3.3 yr old; initial height, 138.8 +/- 16.2 cm; weight, 32.1 +/- 13.1 kg) after the first dose (FD) of metGH and again after 4-5 weeks of multiple dosing (MD). All subjects received a total metGH dose of 0.3 mg/kg.week by sc administration, but were randomized to receive the drug daily (D; n = 12; dose, 0.043 mg/kg) or three times per week (TIW; n = 8; dose, 0.1 mg/kg). After drug administration, repeated blood samples (n = 14) were obtained over a 10-h period. Concentrations of metGH from each sample were determined using a monoclonal antibody radiometric assay (range of linearity, 0.5-40.0 ng/ml; coefficient of variation, less than 4%). Plasma concentration vs. time data were curve fit using a nonlinear weighted least squares algorithm which permitted calculation of the following PK parameters (mean +/- SEM; FD vs. MD group): elimination rate constant (0.23 +/- 0.04 vs. 0.25 +/- 0.04 h-1), absorption rate constant (0.43 +/- 0.05 vs. 0.48 +/- 0.04 h-1), elimination half-life (t1/2; 3.01 vs. 2.77 h), total plasma clearance (CL/F; 0.32 +/- 0.02 vs. 0.54 +/- 0.09 L/h.kg), and apparent volume of distribution (VDss/F; 2.2 +/- 0.14 vs. 3.15 +/- 0.28 L/kg). Both the CL/F and VDss/F of metGH were significantly greater when data from the entire study population were compared on the basis of FD vs. MD administration. With the exception of a larger VDss/F in subjects who received daily (3.6 +/- 0.4 L/kg) vs. TIW metGH (2.4 +/- 0.2 L/kg), no significant differences were found for the PK parameters between the D and TIW dosing groups. In all subjects, absorption of metGH was slow, with an average time to reach maximum concentration (Tmax) of 4.4 h and an absorption t1/2 that ranged from 1.4-1.8 h. Proportionality was also found between the dose and the area under the plasma concentration vs. time curve, suggesting dose-independent PK of metGH. Our data demonstrate that the PK of metGH after sc administration to children are markedly different from those previously reported in adults and, also, do not vary as a consequence of dosing schedule (i.e. D vs. TIW). The apparent increase in CL/F and VDss/F for met GH with multiple dosing may reflect concentration-dependent changes in plasma binding of the drug or, alternatively, represent the effect of increased body mass on the pharmacokinetics of GH.
The renin-angiotensin system: renal actions and blood pressure regulation. The RAS is part of an extremely powerful feedback system for long-term control of blood pressure and volume homeostasis. Disturbances that tend to lower blood pressure, such as heart failure, cirrhosis, and peripheral vasodilation, cause sodium and water retention until blood pressure returns to normal due, in large part, to the combined actions of ANGII and reduced arterial pressure. In response to increased sodium intake, decreased ANGII formation greatly amplifies the effectiveness of pressure natriuresis, thereby preventing large increases in body fluid volumes and blood pressure. In circumstances in which the RAS is inappropriately activated, the sodium retaining effects of ANGII necessitate increased blood pressure to maintain sodium balance via pressure natriuresis. Because the RAS is so powerful in regulating blood pressure, blockade of the system with ACE inhibitors offers a powerful therapeutic tool in diseases such as hypertension and congestive heart failure. The control of sodium excretion and blood pressure by ANGII is exerted through multiple intrarenal as well as extrarenal effects, including stimulation of aldosterone secretion, which can influence renal excretion. Current evidence suggests that the intrarenal effects of ANGII are quantitatively more important than those mediated by aldosterone in controlling blood pressure and renal excretion. The most important intrarenal effects of ANGII include efferent arteriolar constriction as well as direct effects on sodium transport. The constrictor effect on efferent arterioles also is important in preventing reductions in GFR in circumstances associated with impaired renal perfusion. Therefore blockade of ANGII formation in circumstances such as renal artery stenosis may caused marked reductions in GFR. However, in many patients efferent arteriolar vasodilation caused by ANGII blockade may not lower GFR markedly because of other autoregulatory mechanisms that compensate by causing parallel reductions in afferent arteriolar resistance. In these individuals, chronic ACE inhibition may prove to be beneficial in slowing the progression of renal disease because a reduction in glomerular hydrostatic pressure may help to prevent glomerular damage.
Type I transforming growth factor-beta receptors on neutrophils mediate chemotaxis to transforming growth factor-beta. Participation of human polymorphonuclear neutrophils in the inflammatory response is mediated, in part, by soluble factors such as chemotactic peptides and cytokines. Although the cytokine, transforming growth factor beta (TGF-beta), has been shown to recruit monocytes and promote the inflammatory process, its effects on neutrophils are unknown. In this investigation, [125I]TGF-beta 1 affinity binding studies were employed to show that neutrophils express TGF-beta receptors (350 +/- 20 receptors/cell), which exhibit high affinity for the ligand (dissociation constant, 50 pM). Affinity cross-linking studies identified the receptors to be primarily of the type I class. In contrast to the receptors on monocytes, neutrophil TGF-beta receptors were not down-regulated by exposure to specific inflammatory mediators. Additional studies examined whether exposure of neutrophils to TGF-beta could enhance specific functions, as occurs with monocytes. TGF-beta was shown to cause directed migration of neutrophils at femtomolar concentrations, thus it is the most potent neutrophil chemotactic factor yet identified. Neutrophil production of reactive oxygen intermediates was not stimulated by TGF-beta, nor did TGF-beta enhance or depress subsequent PMA- or FMLP-stimulated superoxide production. However, the stable expression of neutrophil TGF-beta receptors, and the capacity of this cytokine to stimulate neutrophil chemotaxis, suggest that the pro-inflammatory effects of TGF-beta are mediated by neutrophils in addition to monocytes.
Bone modulation in sustained hematopoietic stimulation in mice. To understand the etiology of bone modulation and hypercalcemia observed in granulocytosis of a tumor-bearing animal model and to gain insight into the implication of sustained hematopoietic stimulation on the bone tissue, in vivo responses of normal mouse hematopoietic and bone tissues to long-term injections of recombinant human and murine granulocyte colony-stimulating factor (G-CSF), murine granulocyte-macrophage CSF (GM-CSF), and human erythropoietin were quantitatively analyzed. Osteoclast activation was estimated by the osteoclast-endosteal ratio, determined by morphometric analyses of femoral sections. Medullary and bone areas were measured on transverse ground bone sections of the tibia. Recombinant murine G-CSF provoked marked granulocytosis associated with significant increases in the number of marrow granulocytes and their progenitors, and caused expansion of granulopoietic marrow into fatty marrow. The bone of G-CSF-treated mice showed a significant increase in endosteal osteoclast numbers with medullary area enlargement and a reduction in the bone thickness; indicative of endosteal bone resorption. Although GM-CSF had little effect on granulopoiesis, it caused peritoneal macrophages to increase and induced similar bone changes as those observed in G-CSF treatment. Enhanced erythropoiesis stimulated by erythropoietin was also associated with evidence of endosteal bone resorption. Bone changes induced by these growth factors were not associated with hypercalcemia. These animal studies document association of bone modulation in sustained stimulation of hematopoiesis, and implicate important physiologic effects of hematopoietic growth factors on skeletal tissue in vivo.
Clinical application of PET for the evaluation of brain tumors. The combination of FDG and PET has demonstrated clinical utility in the evaluation of patients with brain tumors. At the time of diagnosis, FDG PET provides information concerning the degree of malignancy and patient prognosis. After therapy, FDG PET is able to assess persistence of tumor, determine degree of malignancy, monitor progression, differentiate recurrence from necrosis, and assess prognosis. Other studies using PET provide information that may be clinically useful. Determination of tumor blood flow and permeability of the blood-brain barrier may help in the selection of appropriate therapy. Amino acid imaging using 11C-methionine is being evaluated in patients with brain tumors and provides different information than FDG imaging.
P300 response to tones and speech sounds after cochlear implant: a case report. P300 potentials evoked by tones and spoken words were recorded from a 20-year-old man with a House-3M single-channel cochlear implant. Three months after cochlear implantation, there was a slight appearance of P300 response to both pure-tone stimuli and spoken-word stimuli; 6 months later, clearly identifiable P300 response to both pure-tone stimuli and spoken-word stimuli were obtained. These results are consistent with an encoding improvement for re-establishment of information processing after auditory rehabilitation.
Behavioral treatment of dizziness secondary to benign positional vertigo following head trauma. Benign positional vertigo (BPV) represents a challenge to rehabilitation due to the subjective nature of the complaint of dizziness, frequent failure of pharmacologic intervention, and complicating psychologic factors. Behavioral therapy was used to treat a 26-year-old woman who complained of debilitating dizzy spells after mild head injury sustained in a motor vehicle accident. During a three-week baseline period before treatment, the patient reported a weekly average of 48 dizzy spells, which prevented participation in independent activities and kept her homebound and psychologically distressed. Nine-week behavioral treatment included biofeedback-assisted relaxation training, psychologic counseling, gaze-fixation practice, desensitization exercise, and generalization training. This protocol has been used successfully to train aviators to combat vertigo and nausea in flight. Our regimen included hourly recording of physical activity, notation of frequency of dizzy spells, and use of behavioral methods during nine weeks. The patient reported 90% reduction in dizzy spells and full resumption of independent activities including driving and athletics. Results are discussed in the context of behavioral problems associated with BPV and application of behavioral methods to the complaint of dizziness.
Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. The effects of interleukin-6 (IL-6) in vivo were assessed by inoculating Chinese hamster ovarian (CHO) cells which were transfected with the murine IL-6 gene in nude mice. Nude mice bearing CHO cells expressing IL-6 developed hypercalcemia. Tumor-bearing mice also showed increases in white cell count, platelet count, and decreases in body weight. In nude mice carrying CHO tumors which had not been transfected with the IL-6 gene, there were no changes in these parameters. These results suggest that increased circulating concentrations of IL-6 in patients with malignant disease may contribute to a number of paraneoplastic syndromes including hypercalcemia, cachexia, leukocytosis and thrombocytosis.
IFN-gamma inhibits inflammatory cell recruitment and the evolution of bacterial cell wall-induced arthritis. Localization of streptococcal cell wall Ag (SCW) in the synovial tissue of treated rats induces an influx of leukocytes and a cell-mediated immune response leading to arthritis and joint destruction. Systemic administration of the T cell product, IFN-gamma (10(6) U/kg/day), suppresses the recruitment of leukocytes into the synovium and effectively inhibits the inflammation and pathology characteristic of SCW-induced arthritis (articular index 10.4 +/- 0.6 for SCW vs 2.0 +/- 0.7 for SCW with IFN-gamma, p less than 0.005). Monocyte-macrophages from animals treated with IFN-gamma exhibited defective chemotactic responses when tested in vitro and furthermore, monocytes cultured with IFN-gamma (25 to 500 U/ml) in vitro had significantly suppressed chemotactic responses to the complement fragment C5a (p less than 0.005). The decreased ability to migrate to C5a was associated with decreased binding of fluorochrome-conjugated C5a indicative of reduced expression of C5a receptors. Based on these data, IFN-gamma that induces monocyte maturation as reflected by increased Ia expression conversely inhibits C5a receptor expression. Although locally elevated IFN-gamma levels may serve to inhibit recruitment away from an inflammatory site, systemic exposure to IFN-gamma appears to inhibit leukocyte recruitment to the inflammatory site by its ability to induce premature maturation and concomitant inability to respond to certain chemotactic ligands. Inasmuch as monocyte recruitment to the synovium is pivotal in the development of SCW-induced polyarthritis, the ability of IFN-gamma to inhibit this event effectively inhibits the synovial pathology.
Preoperative radiation therapy followed by extrafascial hysterectomy in patients with stage II endometrial carcinoma. Seventy-four patients with Stage II endometrial cancer were treated by a combination of preoperative radiation therapy followed by extrafascial hysterectomy, bilateral salpingo-oophorectomy, and paraaortic lymph node sampling at the University of Kentucky Medical Center from 1967 to 1988. All patients had histologically confirmed endometrial cancer with involvement of the endocervix. The cell types and numbers of the tumors treated were as follows: adenocarcinoma, 58; adenoacanthoma, six; adenosquamous carcinoma, nine; and clear cell carcinoma, one. Preoperative radiation consisted of 4500 cGy external therapy followed by one intracavitary implant providing an additional 2000 cGy to point A. Surgery was done 4 to 6 weeks after completion of radiation therapy. Five patients (7.1%) had paraaortic lymph node metastases. Four were treated with extended-field radiation therapy and one with platinum-based combination chemotherapy. After treatment, the patients were followed at regular intervals from 2 to 22 years (mean, 5.4 years). Eleven patients (15%) had recurrent cancer, with the vagina and upper abdomen being the most common sites of spread. The estimated 5-year and 10-year disease-free survival rates of these patients are 88% and 76%, respectively. Cell type, depth of myometrial invasion, and lymph node status were the most important prognostic variables in the patients evaluated. These data confirm that the combination of preoperative radiation therapy and surgery produces excellent long-term survival in patients with Stage II endometrial cancer.
Carpal tunnel syndrome in the mucopolysaccharidoses and related disorders. Eighteen patients with various mucopolysaccharidoses or mucolipidosis III were studied electrophysiologically to determine the presence or absence of carpal tunnel syndrome. In 17 patients this was clearly demonstrated, the only exception being a boy with mucopolysaccharidosis II, age 6 months at testing. All patients had a remarkable lack of symptoms. Carpal tunnel syndrome is a very common complication of the mucopolysaccharidoses and mucolipidosis III and should be actively looked for in affected patients. Early diagnosis and treatment offer the best chance of a good response to surgery.
Expression of the c-myc protein is down-regulated at the terminal stages during in vitro differentiation of B-type chronic lymphocytic leukemia cells. The translocated c-myc oncogene in Burkitt's lymphoma (BL) and murine plasmacytoma (MPC) has been proposed to be expressed at a stage of differentiation at which the gene is normally silent, resulting in a continuous proliferation and an inhibited terminal differentiation. To determine whether c-myc is differently expressed at the various stages of the differentiation pathway, we used B-type chronic lymphocytic leukemia (B-CLL) cells, representing resting B lymphocytes, inducible to proliferation and/or differentiation in vitro. The c-myc protein, and Ig lambda-light chain and PCA-1 antigen as markers of B-cell maturation, were analyzed in single, morphologically defined cells by immunocytochemical double-staining. The proliferation of individual cells was determined by 3H-thymidine incorporation and by analysis of Ki-67 antigen expression. The results show that the level of c-myc expression correlates to the stage of differentiation and to the proliferative activity. Uninduced resting cells did not express c-myc. The c-myc protein was observed in the highest amount at the proliferative B-lymphoblast stage of maturation and was reduced in plasmablasts and undetectable in plasma cells. The results suggest that maturation of B cells into nonproliferative, terminally differentiated plasma cells is associated with a downregulated c-myc expression and thus support the view that the deregulated c-myc gene in BL and MPC is expressed at an inappropriate stage of maturation and thereby inhibits terminal differentiation.
Trigeminal neuralgia secondary to tumor with normal exam, responsive to carbamazepine. Trigeminal neuralgia is most commonly idiopathic, although it can be associated with multiple sclerosis. Tumors are rare causes of trigeminal neuralgia. A case is presented of trigeminal neuralgia with normal neurological examination and responsive to carbamazepine, secondary to a cerebellopontine angle meningioma. Literature relative to neoplastic etiologies of trigeminal neuralgia is reviewed. The role of electrodiagnostic testing in the evaluation of trigeminal neuralgia is considered. A normal neurological examination and responsiveness to carbamazepine do not exclude tumor as an etiology of trigeminal neuralgia.
Is laterality important in neck node metastases in head and neck cancer? We present a series of 2219 previously untreated squamous carcinomas of the head and neck, 141 (6.5%) of whom had bilateral nodes at presentation. Bilateral nodes became progressively less common with increasing age but were not related to other host factors. They were also strongly related to the site of the primary tumour, its T-stage and its histological grade, being more common in tumours of the oro or naso-pharynx, in poorly or moderately differentiated tumours, and in tumour stages T3 or T4 at presentation. There were also interactions between these tumour factors, and patients with all three factors had a 25% incidence of bilateral nodes. 126 of these patients could be matched for the main prognostic factors with 126 patients with unilateral neck node disease. The survival rate of the latter group was 9% better than that of the unilateral group. Further breakdown showed that the survival of patients with nodes smaller than 6 cm is not affected by laterality, whereas it is for patients with massive nodes.
Comparison of accuracy of transesophageal versus transthoracic echocardiography for the detection of mitral valve prolapse with ruptured chordae tendineae (flail mitral leaflet). The accuracy of transesophageal echocardiography was compared with that of transthoracic echocardiography in the detection of ruptured chordae tendineae (flail mitral leaflet) in 27 patients with mitral valve prolapse (MVP) who underwent valve repair or replacement for mitral regurgitation. Confirmation of the presence of ruptured chordae resulting in a flail leaflet was available at surgery in all cases. The echocardiographic studies were read blindly by 2 independent observers with any differences resolved by a third. Mean (+/- standard deviation) age was 63 +/- 13 years. Men (n = 20) outnumbered women (n = 7) (p less than 0.02), and tended to be younger (p = 0.06). Flail leaflets were identified in 20 of 27 patients. In 1 patient, both leaflets were involved and in the remaining 19 patients posterior leaflets (15 patients) were more frequently affected than anterior leaflets (4 patients). Transesophageal echocardiography correctly identified all 20 patients with flail leaflets, but 1 false positive study occurred among the 7 patients without a flail leaflet. In contrast, transthoracic echocardiography identified only 12 of 20 patients with flail leaflets, with no false positive studies. Transesophageal echocardiography was more accurate, correctly classifying 26 of 27 (96%) cases versus 19 of 27 (70%) by the transthoracic approach (p less than 0.01). This study suggests a higher incidence of chordal rupture to the posterior leaflet in patients with MVP and demonstrates improved accuracy of transesophageal over transthoracic echocardiography in the detection of flail leaflets.
Electrogram patterns predictive of successful catheter ablation of accessory pathways. Value of unipolar recording mode. BACKGROUND. Transcatheter electrical ablation has been used in the treatment of arrhythmias, and most experience has been obtained by ablating the normal atrioventricular conduction system. Less information is available on ablation of atrioventricular accessory pathways. METHODS AND RESULTS. Catheter ablation of overt accessory pathways was attempted in 135 patients with 142 distinct pathways, including 21 right parietal or anteroseptal, 47 posteroseptal, and 74 left lateral pathways. We sought to identify the type and value of electrophysiological parameters associated with successful ablation outcome. For this purpose, the unipolar recording mode was used in addition to bipolar anterograde and retrograde parameters. With a mean follow-up of 16 +/- 6 (mean +/- SD) months, fulguration was successful in eliminating preexcitation in 129 patients (96%), including all seven with two distinct accessory pathways. The first ablation attempt was successful in 110 patients, and two or more attempts were performed in 25 patients. Bipolar electrograms associated with success of fulguration showed a shorter atrioventricular conduction time (40 +/- 13 versus 53 +/- 17 msec, p less than 0.0001) and an earlier main ventricular deflection relative to delta wave onset (-1.7 +/- 10 versus 5 +/- 7 msec, p less than 0.001) than electrograms associated with unsuccessful outcome. The only parameter dealing with retrograde conduction (i.e., ventriculoatrial conduction time during reciprocating tachycardia) was not predictive (86 +/- 17 versus 93 +/- 17 msec). Neither was the atrial to ventricular electrogram amplitude ratio. Two unipolar parameters were found to be predictive of successful outcome: 1) The three different patterns PQS, P-QS, P-rS of unipolar waves recorded at the annulus were associated with respective success rates of 97%, 78%, and 55% (p less than 0.001). 2) Intrinsic deflection timing occurred -4 +/- 8 and 6 +/- 7 msec relative to delta wave onset in successful attempts and in failures, respectively (p less than 0.001). Logistic regression analysis revealed a single independent factor predictive of success, the unipolar pattern (p = 0.03), with an odds ratio of 7:1 (PQS pattern versus P-rS pattern). In the group of 18 patients who underwent a first unsuccessful but second successful attempt, comparison of electrograms revealed no difference in the ventriculoatrial conduction time but a significant improvement in anterograde parameters and unipolar pattern distribution. CONCLUSIONS. Some distinctive electrogram patterns concerning anterograde conduction are associated with success of accessory pathway fulguration. The unfiltered unipolar recording mode (PQS pattern) contributes significantly to optimizing the accuracy of accessory pathway localization.