Obesity. Some heat but not enough light.
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Adipose Tissue↗
Biomedical subjects
J Hirsch
Publications and source records attributed to J Hirsch.
The beta-D-xylosidase of Trichoderma reesei is a multifunctional beta-D-xylan xylohydrolase.
An extracellular multifunctional beta-D-xylan xylohydrolase, previously described as beta-xylosidase, was purified from Trichoderma reesei RUT C-30 to physical homogeneity. The active enzyme was a 100 (+/-5) kDa glycosylated monomer that exhibited a pl of 4.7. Its activity was optimal at pH 4 and it was stable between pH 3 and 6. Its temperature-stability was moderate (70 degrees zero of activity remaining after 60 min at 50 degrees C) and optimal activity was observed at 60 degrees C. It is capable of hydrolysing beta-1.4-xylo-oligosaccharides [degree of polymerization (DP) 2-7], the apparent Vmax increasing with increasing chain length. The enzyme also attacked debranched beech-wood (Lenzing) xylan and 4-O-methylglucuronoxylan, forming xylose as the only end product. The K(m) for xylan was 0.7 g/l. For this reason we consider the enzyme to be a beta-D-xylan xylohydrolase. The enzyme also exhibits alpha-L-arabinofuranosidase activity on 4-nitrophenyl alpha-L-arabinofuranoside, and evidence is presented that this is not caused by an impurity in the enzyme preparation. The beta-D-xylan xylohydrolase exhibits glycosyltransferase activity with xylo-oligosaccharides and at high concentrations of 4-nitrophenyl beta-D-xylopyranoside (4-Nph-beta-Xyl). The enzyme hydrolyses beta-1, 4-linkages preferentially to beta-1,3-linkages, and beta-1,2-linked xylo-oligosaccharides are not hydrolysed at all. The enzyme liberates terminal beta-1,4-xylopyranose residues linked to a 2-O-substituted xylopyranose residue, but not that linked to a 3-O-substituted xylopyranose residue. The enzyme does not attack methyl, methyl 1-thio-benzyl or butyl l-thio-beta-D-xylopyranosides and 4-naphthyl, 2-naphthyl and phenyl beta-D-xylopyranosides.
Amino Acid Sequence↗
Cardiac autonomic nervous system activity in obese and never-obese young men.
Autonomic nervous system (ANS) activity in age-matched, weight-stable, free-living, ad libitum-fed, obese (OB) and never-obese (NO) young men (body mass index means [SD], 38.5 [3.9] and 22.0 [1.7], respectively) was evaluated by sequential blockade of cardiac autonomic innervation with weight-adjusted doses of parasympathetic (atropine) and sympathetic (esmolol) blockers so as to produce maximal effects on heart rate. Change in heart period (interbeat interval) from baseline, induced by atropine, defined parasympathetic control (PC), and the subsequent change, after esmolol administration, defined sympathetic control (SC). The heart period, after PC and SC blockade, defined intrinsic heart period (I). In the OB group, baseline heart period and PC were lower, and SC and I were higher, than in the NO group. The results in the OB, relative to the NO subjects, are similar to those reported in a previous study of NO subjects who had undergone a 10% weight gain by overfeeding. These findings suggest that the ANS of individuals with obesity is chronically altered in a way that would tend to oppose their excessive adiposity, and that these autonomic changes are more likely to be responses to other forces that induce obesity, rather than being primary agents in the production of the disease.
Adult↗
Y-chromosome effects on Drosophila geotaxis interact with genetic or cytoplasmic background.
Previously, all of the major fruit fly, Drosophila melanogaster, chromosomes (I, II and III) have been shown to be associated with geotaxis, but the Y chromosome has not. Using two methods (back-crossing and chromosome substitution), Y chromosomes from lines that have evolved stable, extreme expressions of geotaxis were placed into different genetic and cytoplasmic backgrounds to test the resulting males for geotaxis. The results of the back-crossing do not support the interpretation of Y-chromosome effects on geotaxis. These tests do not have sufficient statistical power, however, to detect small genetic effects. In the chromosome substitution experiment, the geotaxis-line Y chromosomes were placed into high- and low-selected lines, Canton-S and Champaign wild-type backgrounds. The results of the chromosome substitution experiment provide evidence for a Y-chromosome effect on geotaxis in selected geotaxis lines, but not in wild-type stock, backgrounds. These results suggest that the Y chromosome has a small effect on geotaxis, whose detection depends on genetic and/or cytoplasmic background. The implications of these results are discussed for behaviour genetic analysis of D. melanogaster and for issues of statistical power in detecting small genetic effects.
Animals↗
The coming of genetics in the control of ingestion.
The study of appetitive behavior in relation to obesity is now being enriched by molecular-genetic findings in experimental animals with genetic obesity and associated "feeding disorders". The opinion is expressed that the mutual enrichment of the disciplines of behavior and molecular biology will place the study of human ingestive behavior on a firm scientific base.
Eating↗
Fast and localized event-related optical signals (EROS) in the human occipital cortex: comparisons with the visual evoked potential and fMRI.
Localized evoked activity of the human cortex produces fast changes in optical properties that can be detected noninvasively (event-related optical signal, or EROS). In the present study a fast EROS response (latency approximately 100 ms) elicited in the occipital cortex by visual stimuli showed spatial congruence with fMRI signals and temporal correspondence with VEPs, thus combining subcentimeter spatial localization with subsecond temporal resolution. fMRI signals were recorded from striate and extrastriate cortex. Both areas showed EROS peaks, but at different latencies after stimulation (100 and 200-300 ms, respectively). These results suggest that EROS manifests localized neuronal activity associated with information processing. The temporal resolution and spatial localization of this signal make it a promising tool for studying the time course of activity in localized brain areas and for bridging the gap between electrical and hemodynamic imaging methods.
Adult↗
Some history of heredity-vs-environment, genetic inferiority at Harvard (?), and The (incredible) Bell Curve.
This article discusses some historical and intellectual roots of American behaviorism in psychology and its anti-heredity, environmentalist bias, as well as the early 'justification' for pure line theory in genetics and some interrelations between the two fields. Next, I discuss the heritability concept, its promotion, its critique and the importance of distinguishing it from, rather than confusing or conflating it with, the heredity concept. Then, briefly I consider some of the history and problems associated with the intelligence concept, as well as the capital importance of biological controls in studies of human heredity. And finally, I document the incredibility of the The Bell Curve and the appalling inadequacy of its reception.
Environment↗
Fatty acid composition of adipose tissue, an indication of dietary fatty acids, and breast cancer prognosis.
PURPOSE: Fatty acid composition of adipose tissue is an indicator of the long-term ingestion pattern of several specific fatty acids. There is good correlation of antecedent diet with the essential fatty acids, and there is reflection of the diet with the fatty acids that can be synthesized. The relationship between the fatty acid levels and lymph node status and clinical outcome was examined. METHODS: At the time of diagnostic surgery, 161 women with clinical stage T1NO breast cancer had subcutaneous adipose tissue (breast and abdominal) aspirated. The concentrations of 35 fatty acids, seven summed classes, and six fatty acid groups were measured by capillary gas chromatography. Lymph node status was determined with axillary dissection, and patients were followed-up (mean, 7.3 years) for clinical outcome. RESULTS: There was no significant association of any adipose tissue fatty acids with overall survival, although few (16 of 161 women) died of breast cancer. However, the odds of having positive lymph nodes (57 of 161 women) were significantly higher for women with a greater adipose tissue proportion of oleic acid (odds ratio [OR], 7.56; 95% confidence interval [CI], 1.78 to 32.1) or total saturated acids (OR, 8.43; 95% CI, 1.48 to 40.0) and significantly lower with a higher proportion of trans fatty acids (OR, 0.24; 95% CI, 0.07 to 0.77), as assessed by multivariate logistic regression. CONCLUSION: These data support previous research with dietary questionnaire methodology, suggesting that specific dietary fatty acids may be associated with breast cancer promotion. Further research with long-term clinical follow-up is necessary to investigate these observations in large, diverse populations before dietary recommendations can be envisioned.
Abdomen↗
Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma.
PURPOSE: A phase II randomized trial of gallium nitrate/fluorouracil (5-FU) versus dose-intense methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was performed in poor-risk patients with advanced urothelial tract tumors. The efficacy and toxicity of these regimens were compared. Assessment of dose-intense M-VAC as salvage treatment in patients who failed to respond to the gallium nitrate/5-FU regimen was also performed. PATIENTS AND METHODS: Thirty-four patients who had not received prior systemic chemotherapy were randomized to either arm of the study. All patients had one or more clinical features predicting a low likelihood of durable complete response to standard chemotherapy, ie, weight loss, visceral metastases, and low performance status. Gallium nitrate and 5-FU were each administered by continuous 5-day infusions every 28 days. M-VAC was recycled every 21 days, with prophylactic recombinant human granulocyte colony-stimulating factor (rh-G-CSF). RESULTS: Two of 17 patients (12%; 95% confidence interval [CI], 1.4% to 36.4%) had a major response to gallium nitrate/5-FU. Sixteen of 17 patients treated with M-VAC (94%; 95% CI, 71.3% to 99.8%) demonstrated a major response. Five of 12 patients who failed to respond to the gallium nitrate/5-FU combination responded to M-VAC as second-line therapy (42%; 95% CI, 15.2% to 72.3%). Median survival for the gallium nitrate and 5-FU arm was 19 versus 17 months for the M-VAC arm, with a median follow-up duration of 35 months (range, 2 to 51) for all patients. Dose-intense M-VAC was associated with a greater incidence of neutropenia and thrombocytopenia. CONCLUSION: Dose-intense M-VAC is superior to gallium nitrate/5-FU in poor-risk patients (P < .0001). Despite the overall high response rate, the median survival for patients with M-VAC remained unsatisfactory. Similar survival distributions were observed for patients who received investigational therapy followed by cisplatin-based therapy and patients treated with initial cisplatin-based therapy.
Adult↗
Effects of weight change on plasma leptin concentrations and energy expenditure.
Circulating concentrations of leptin are closely correlated with body fat mass, and may thus constitute an afferent limb of a system regulating body fatness, with efferent limbs that affect energy expenditure and food intake. We studied 50 subjects (27 males, 23 premenopausal females; 31 never-obese, 19 obese) at usual body weight during active weight loss or weight gain and during the maintenance of body weights 10% above usual (WT + 10%) and 10% and/or 20% below usual body weight (Wt -10% and Wt -20%) to test the hypotheses that the dynamic process of weight change and the maintenance of an altered body weight are associated with significant changes in circulating concentrations of leptin and/or the relationship between fat mass and leptin, and such changes in the plasma concentration of leptin are related to changes in energy expenditure at altered body weight. Subjects were admitted to the Rockefeller University Hospital, and energy metabolism (24-h energy expenditure, resting energy expenditure, thermic effect of feeding, and nonresting energy expenditure) and circulating concentrations of leptin and insulin were examined at various weight plateaus (usual body weight, 10% above usual body weight, 10% below usual body weight, and 20% below usual body weight). Plasma leptin was also measured in some subjects during dynamic periods of weight gain or loss. Though both plasma leptin concentrations and fat mass were significantly correlated with resting energy expenditure, only the correlation of fat mass and energy expenditure remained significant in a multiple stepwise linear regression analysis. Neither absolute nor relative changes in plasma leptin between weight plateaus were significantly correlated with any of the observed changes in energy expenditure. Plasma leptin concentrations were significantly lower during weight loss than during weight maintenance at the same body composition. Plasma leptin concentrations, normalized to fat mass, were significantly lower during the maintenance of a reduced body weight in females and higher during the maintenance of an elevated body weight in males than in the same subjects at usual body weight. At all weight plateaus, plasma leptin concentrations normalized to fat mass were significantly higher in females than in males, but gender was not a significant covariate of the relationship between leptin and energy expenditure. Postabsorptive serum concentrations of insulin was a significant covariate of plasma leptin concentration in males, but not females, at Wt initial and Wt + 10%. Although plasma leptin is significantly reduced during dynamic weight loss compared with static weight maintenance at the same body weight, the lack of correlation between changes in plasma leptin and changes in energy expenditure between weight plateaus suggests that leptin is not the primary signal that mediates the changes of energy expenditure that accompany the maintenance of an altered body weight in humans.
Body Composition↗
A multinational investigation of the impact of subcutaneous sumatriptan. I: Design, methods and clinical findings.
This report describes the design, methods and clinical results of a prospective sequential multinational (5 countries) study conducted to evaluate the effects of subcutaneous sumatriptan on health-related quality of life, workplace productivity, clinical parameters and patient satisfaction. Adult patients with moderate to severe migraine initially received customary therapy for migraine episodes for 12 weeks, followed by 24 weeks' treatment with self-administered subcutaneous sumatriptan 6 mg. Demographic, baseline, health-related quality of life and patient satisfaction rating data were collected during visits to the clinic. Data relating to migraine symptoms, migraine therapy, work productivity and non-work activity time were collected on diary cards filled out by the patients. 749 patients were recruited to the study and 637 received at least 1 dose of sumatriptan. Overall, 75.5% of migraines were successfully treated within 2 hours with sumatriptan compared with 31.9% with customary therapy; 36% of patients reported complete relief at 2 hours with sumatriptan treatment compared with 1% of patients receiving customary therapy. 69% of patients successfully treated 70% of their migraines with sumatriptan within 2 hours, compared with 12% of patients with customary therapy. No serious adverse events were reported; 50% of patients reported an adverse event during the 12-week customary therapy phase and 89% of patients during the 24-week sumatriptan phase. These clinical results, which are consistent with those reported in randomised blinded studies of subcutaneous sumatriptan, suggest that relief of migraine symptoms occurs more often, and in less time, in patients receiving subcutaneous sumatriptan rather than customary therapy as their primary medication.
Adolescent↗
A multinational investigation of the impact of subcutaneous sumatriptan. II: Health-related quality of life.
The aim of this prospective sequential multinational (5 countries) study was to concurrently evaluate the effects of subcutaneous sumatriptan on clinical parameters, health-related quality-of-life (HRQOL) measures, workplace productivity and patient satisfaction. This report presents the HRQOL results. 582 patients (aged 18 to 65 years) with moderate to severe migraine received their customary antimigraine therapy for 12 weeks and then subcutaneous sumatriptan for 24 weeks. The Short Form-36 Health Survey and the Migraine-Specific Quality of Life Questionnaire were completed at a screening visit (base-line), at the end of the 12-week customary therapy phase, and at 12 and 24 weeks of the sumatriptan phase. Scores for most of the Short Form-36 dimensions improved significantly (p < 0.05) after 12 and 24 weeks of sumatriptan therapy compared with 12 weeks of customary therapy, in each country. Similarly, scores on all Migraine-Specific Quality of Life Questionnaire dimensions were significantly (p < 0.05; paired t-test) improved after 12 weeks (in all countries) and 24 weeks (in 4 of 5 countries) of sumatriptan therapy compared with 12 weeks of customary therapy. This study demonstrates that, in 5 countries, treatment of migraine attacks with subcutaneous sumatriptan compared with customary therapy was associated with improvements in HRQOL, as measured by both general health status and disease-specific instruments.
Adolescent↗
A multinational investigation of the impact of subcutaneous sumatriptan. III: Workplace productivity and non-workplace activity.
This report presents the workplace productivity and non-workplace activity results of a multinational study of the effects of subcutaneous sumatriptan 6 mg in the acute treatment of migraine compared with patient's customary therapy. Patients diagnosed with migraine treated their symptoms for 24 weeks with subcutaneous sumatriptan after a 12-week period of treating symptoms with their customary (non-sumatriptan) therapy. Patients used diary cards to record information concerning the effects of migraine on workplace productivity and non-workplace activity time. The average workplace productivity time lost was 23.4 hours per patient during 12 weeks of customary therapy, compared with 7.2 and 5.8 hours per patient during the first and second 12-week periods of sumatriptan therapy, respectively. An average of 9.3 hours of non-workplace activity time was lost per patient during the customary therapy phase, compared with 3.2 and 2.8 hours during the first and second 12-week periods of sumatriptan therapy, respectively. Treatment of migraine with subcutaneous sumatriptan compared with customary therapy was associated with an average gain per patient of approximately 16 hours of workplace productivity time and 6 hours of non-workplace activity time, over a 3-month period.
Adolescent↗
Perception of a border defined by rapidly reversing luminance contrast.
We report a new visual illusion of a perceptual boundary visible between two contiguous regions of equal luminance when the intensity is modulated with a temporal frequency that is higher than the critical fusion rate. Measurements of the luminance threshold of the perceptual border with various slopes of the luminance gradient yielded a function suggestive of the range of ocular instability. These findings raise the possibility that this new border illusion may be influenced by involuntary ocular motion during fixation.
Adult↗
[Glutamatergic excitatory receptors and temporal lobe epilepsy].
Despite a considerable wealth of data, the mechanisms responsible for the generation of epileptic bursts in temporal lobe epilepsy (TLE) remain a mystery. Recently, research and therapy have focused on impairment of GABAergic inhibition in epilepsy. Several lines of evidence support this approach: 1-GABA is the main inhibitory neurotransmitter in the neuronal structures involved in TLE. 2-Enhancers of GABAergic inhibition (such as benzodiazepines or barbiturates) are commonly used as antiepileptic drugs. 3-Interictal discharges can be obtained following the pharmacological blockade of GABAA receptors. Since the axiom at the basis of epilepsy research states that the balance between inhibition and excitation is tipped toward excitation, we have addressed the following question: where are the loci most likely to be involved in such imbalance? We have limited our investigation to the excitatory side of the story. The main glutamatergic excitatory receptors (AMPA and NMDA) involved in TLE and their properties will be first addressed. We will focus on the excitatory synapses most likely involved in epileptogenesis. We have then specifically studied the effects of redox reagents on NMDA receptor-dependent epileptiform activity in a chronic animal model of TLE, the kainic acid lesioned rat hippocampus. We report that oxidizing drugs abolish evoked epileptiform discharges via a decrease by 50 p. 100 of NMDA receptor-mediated responses without affecting synaptic plasticity and thus memory and learning. The dormant cell hypothesis (i.e. the disconnection of inhibitory interneurons from their excitatory afferents) was also tested. We report that interneurons are not dormant in TLE and fire bursts of action potentials during spontaneous or evoked paroxismal activity.
Animals↗
Redox sites of NMDA receptors can modulate epileptiform activity in hippocampal slices from kainic acid-treated rats.
Using an animal model of temporal lobe epilepsy, the kainic acid lesioned rat hippocampus, we have evaluated the possibility of modulating glutamate N-methyl-D-aspartate (NMDA) receptor-dependent evoked epileptiform activity through the manipulation of NMDA receptor redox sites. Epileptiform activity was recorded extracellularly from hippocampal slices, in the stratum pyramidale of the CA1 area, and the effects of the oxidizing reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) and the reducing agent Tris(2-carboxy ethyl)phosphine (TCEP) on these responses were quantified. Epileptiform activity was substantially reduced in the presence of DTNB but was fully reinstated with the application of TCEP. The effects of both drugs persisted even after wash. Epileptiform activity was totally abolished in the presence of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid. These results suggest that epileptiform activity can be controlled by manipulation of the redox sites of NMDA receptors and raise the possibility of developing new anticonvulsant drugs which do not fully block NMDA receptor-mediated synaptic transmission.
Animals↗
Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet.
A new experimental approach was used to determine whether a eucaloric, low fat, high carbohydrate diet increases fatty acid synthesis. Normally volunteers consumed low fat liquid formula diets (10% of calories as fat and 75% as glucose polymers, n = 7) or high fat diets (40% of calories as fat and 45% as glucose polymers, n = 3) for 25 d. The fatty acid composition of each diet was matched to the composition of each subject's adipose tissue and compared with the composition of VLDL triglyceride. By day 10, VLDL triglyceride was markedly enriched in palmitate and deficient in linoleate in all subjects on the low fat diet. Newly synthesized fatty acids accounted for 44 +/- 10% of the VLDL triglyceride. Mass isotopomer distribution analysis of palmitate labeled with intravenously infused 13C-acetate confirmed that increased palmitate synthesis was the likely cause for the accumulation of triglyceride palmitate and "dilution" of linoleate. In contrast, there was minimal fatty acid synthesis on the high diet. Thus, the dietary substitution of carbohydrate for fat stimulated fatty acid synthesis and the plasma accumulation of palmitate-enriched, linoleate-deficient triglyceride. Such changes could have adverse effects on the cardiovascular system.
Adult↗