'Alternative cancer cures': looking for common ground.
Explore the source record for details and available documents.
Complementary Therapies↗
Biomedical subjects
J Diamond
Publications and source records attributed to J Diamond.
Luminal and systemic signals trigger intestinal adaptation in the juvenile python.
Juvenile pythons undergo large rapid upregulation of intestinal mass and intestinal transporter activities upon feeding. Because it is also easy to do surgery on pythons and to maintain them in the laboratory, we used a python model to examine signals and agents for intestinal adaptation. We surgically isolated the middle third of the small intestine from enteric continuity, leaving its mesenteric nerve and vascular supply intact. Intestinal continuity was restored by an end-to-end anastomosis between the proximal and distal thirds. Within 24 h of the snake's feeding, the reanastomosed proximal and distal segments (receiving luminal nutrients) had upregulated amino acid and glucose uptakes by up to 15-fold, had doubled intestinal mass, and thereby soon achieved total nutrient uptake capacities equal to those of the normal fed full-length intestine. At this time, however, the isolated middle segment, receiving no luminal nutrients, experienced no changes from the fasted state in either nutrient uptakes or in morphology. By 3 days postfeeding, the isolated middle segment had upregulated nutrient uptakes to the same levels as the reanastomosed proximal and distal segments, but it still lacked any appreciable morphological response. These contrasting results for the reanastomosed intestine and for the isolated middle segment suggest that luminal nutrients and/or pancreatic biliary secretions are the agents triggering rapid upregulation of transporters and of intestinal mass and that systemic nerve or hormonal signals later trigger transporter regulation but no trophic response.
Adaptation, Physiological↗
Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes.
OBJECTIVE: Lifetime rates of full and partial anorexia nervosa and bulimia nervosa were determined in first-degree relatives of diagnostically pure proband groups and relatives of matched, never-ill comparison subjects. METHOD: Rates of each eating disorder were obtained for 1,831 relatives of 504 probands on the basis of personal structured clinical interviews and family history. Best-estimate diagnoses based on all available information were rendered without knowledge of proband status and pedigree identity. Only definite and probable diagnoses were considered. RESULTS: Whereas anorexia nervosa was rare in families of the comparison subjects, full and partial syndromes of anorexia nervosa aggregated in female relatives of both anorexic and bulimic probands. For the full syndrome of anorexia nervosa, the relative risks were 11.3 and 12.3 in female relatives of anorexic and bulimic probands, respectively. Bulimia nervosa was more common than anorexia nervosa in female relatives of comparison subjects, but it, too, aggregated in the families of ill probands; the corresponding relative risks for bulimia nervosa were 4.2 and 4.4 for female relatives of anorexic and bulimic probands, respectively. When partial syndromes of anorexia nervosa and bulimia nervosa were considered, relative risks fell by one-half in each group of ill probands. CONCLUSIONS: Both anorexia nervosa and bulimia nervosa are familial. Their cross-transmission in families suggests a common, or shared, familial diathesis. The additional observation that familial aggregation and cross-transmission extend to milder phenotypes suggests the validity of their inclusion in a continuum of familial liability.
Adolescent↗
Intraspinal and behavioral consequences of nerve growth factor-induced nociceptive sprouting and nerve growth factor-induced hyperalgesia compared in adult rats.
Intraspinal and behavioral events were studied in adult rats with nociceptive nerves that were undergoing collateral sprouting into adjacent denervated skin. This sprouting, which is driven by endogenous nerve growth factor (NGF), did not cause hyperalgesia. For comparison, we studied an exogenous NGF administration that induced hyperalgesia but was too brief to evoke sprouting. When nociceptive nerves sprouted in skin, back-labeling with wheat germ agglutinin-conjugated horseradish peroxidase revealed that their projections sprouted in the cord. The sprouted peripheral nerves now activated more c-Fos-containing interneurons, which stimulus-response studies showed was not due to an increased afferent discharge. We attribute the interneuron recruitment to synaptogenesis following the intraspinal sprouting. Nociceptive stimulation of dorsal skin reflexly activates underlying cutaneous trunci muscle (CTM). When a nociceptive field expanded by nerve sprouting, so did the area of the evoked CTM reflex: this implies a recruitment of CTM motoneurons. We interpret this "matching" of response to stimulus as an adaptive phenomenon ensured by an adaptive intraspinal sprouting of the nociceptive projections. Neither the intraspinal changes nor the reflex changes occurred if peripheral sprouting was blocked by systemic anti-NGF treatment, indicating that the role of endogenous NGF was only in that sprouting. No comparable adaptive events occurred during NGF-induced hyperalgesia. Neither nociceptive fields nor CTM reflexes were affected; however there was a recruitment of c-Fos-expressing interneurons. This recruitment was not explained by peripheral sensitization, and, because sprouting was not involved here, we attribute the recruitment to "synaptic unmasking," i.e., an increased effectiveness of the preexisting excitatory circuitry.
Adaptation, Physiological↗
The nitric oxide donors, SNAP and DEA/NO, exert a negative inotropic effect in rat cardiomyocytes which is independent of cyclic GMP elevation.
The role of guanosine 3',5'-cyclic monophosphate (cGMP) in the regulation of cardiac contractility remains controversial. The present study has examined the effects of high concentrations of the nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine (SNAP) and 1,1-diethyl-2-hydroxy-2-nitroso-hydrazine (DEA/NO), on cGMP levels and isoproterenol-induced increases in contractility in rat cardiomyocytes before and after selective inhibition of soluble guanylyl cyclase with 1 H -[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). In control myocytes, 100 microm SNAP or 100 microm DEA/NO increased cGMP levels by more than 15-fold at 2 and 6 min and produced marked attenuations of isoproterenol-mediated increases in maximal cell shortening over the same time period. The NO donors had no significant effect on basal cell shortening (in the absence of isoproterenol). Pretreatment of myocytes with 25 microm ODQ for 30 min resulted in a complete blockade of the SNAP- or DEA/NO-induced increases in cGMP with no reversal of negative inotropy. ODQ did not affect basal contractility, basal cGMP levels or isoproterenol-induced increases in cell shortening. Furthermore, myocytes exposed to the cGMP analog, 8-bromo-cGMP (100 microm), did not exhibit significant differences in basal contractility or isoproterenol-induced increases in cell shortening. These results suggest that attenuation of cardiac contractility by NO donors in rat cardiomyocytes occurs by a mechanism independent of increases in cGMP levels.
Animals↗
An updated two-dimensional gel electrophoresis technique for the detection of drug-induced changes in protein phosphorylation in intact smooth muscle.
Two-dimensional gel electrophoresis is widely used in many areas of scientific research. The necessity for greater resolution and more sensitive protein detection with this technique have resulted in a steadily changing methodology. Complete descriptions of some aspects of two-dimensional gel electrophoresis are available in the earlier literature. However, simplified methods incorporating recent advances specifically designed to use two-dimensional gel electrophoresis for the measurement of protein phosphorylation in intact tissue are lacking. This report describes, in detail, each of the steps involved in carrying out such measurements including intact tissue labeling with 32P, homogenization and protein sample preparation, two-dimensional gel electrophoresis using isoelectric focusing followed by vertical second-dimension SDS-PAGE, staining, autoradiography, and quantitative analysis of changes in phosphorylation of specific proteins. This method incorporates a number of modifications taken from other published sources and includes several novel changes developed in our laboratory. To illustrate the utility of this technique we have included a set of results analyzing the phosphorylation patterns induced by the addition of a nitric oxide donor, sodium nitroprusside, to intact strips of rat aorta. We were able to demonstrate SNP-induced phosphorylation of a number of proteins, several of which have not been previously described in earlier reports in which the patterns of PKG-mediated phosphorylation were investigated.
Animals↗
Corneal biopsy with tissue micro-homogenisation for isolation of organisms in bacterial keratitis.
PURPOSE: To evaluate a novel two-stage technique to increase yield of bacteria isolated from infected corneal ulcers. METHODS: A new blade was designed to remove friable material from infected corneal ulcers. The new blade was used in combination with standard tissue micro-homogenisation equipment in a two-stage technique intended to distribute biopsy samples evenly between relevant agar plates. Patients with presumed-bacterial corneal ulcers underwent sequential corneal sampling using the new two-stage technique and a scalpel blade, used without micro-homogenisation (the order of sampling was varied between two groups). Bacterial isolation rates were compared using the chi-squared test. RESULTS: Twenty-four patients with presumed-bacterial corneal ulcers were studied. The overall positive bacterial isolation rate was 88%, with identical bacterial isolation rates for the new two-stage technique and the scalpel blade (71%). The new technique isolated bacteria from three ulcers that had initially been 'sterile' when sampled with a scalpel blade. Polymicrobial infections were identified in two ulcers with the new blade where only a single organism had been identified using the scalpel blade (not significantly different). CONCLUSIONS: The new two-stage technique shows promise for improving bacterial isolation rates from presumed-bacterial corneal ulcers.
Bacteria↗
Paracellular glucose transport plays a minor role in the unanesthetized dog.
Traditionally, intestinal glucose absorption was thought to occur through active, carrier-mediated transport. However, proponents of paracellular transport have argued that previous experiments neglected effects of solvent drag coming from high local concentrations of glucose at the brush-border membrane. The purpose of this study was to evaluate glucose absorption in the awake dog under conditions that would maximize any contribution of paracellular transport. Jejunal Thiry-Vella loops were constructed in six female mongrel dogs. After surgical recovery, isotonic buffers containing L-glucose as the probe for paracellular permeability were given over 2-h periods by constant infusion pump. At physiological concentrations of D-glucose (1-50 mM), the fractional absorption of L-glucose was only 4-7% of total glucose absorption. Infusion of supraphysiological concentrations (150 mM) of D-glucose, D-maltose, or D-mannitol yielded low-fractional absorptions of L-glucose (2-5%), so too did complex or nonabsorbable carbohydrates. In all experiments, there was significant fractional water absorption (5-19%), a prerequisite for solvent drag. Therefore, with even up to high concentrations of luminal carbohydrates in the presence of significant water absorption, the relative contribution of paracellular glucose absorption remained low.
Absorption↗
Ontogeny of intestinal safety factors: lactase capacities and lactose loads.
We measured intestinal safety factors (ratio of a physiological capacity to the load on it) for lactose digestion in developing rat pups. Specifically, we assessed the quantitative relationships between lactose load and the series capacities of lactase and the Na+-glucose cotransporter (SGLT-1). Both capacities increased significantly with age in suckling pups as a result of increasing intestinal mass and maintenance of mass-specific activities. The youngest pups examined (5 days) had surprisingly high safety factors of 8-13 for both lactase and SGLT-1, possibly because milk contains lactase substrates other than lactose; it also, however, suggests that their intestinal capacities were being prepared to meet future demands rather than just current ones. By day 10 (and also at day 15), increased lactose loads resulted in lower safety factors of 4-6, values more typical of adult intestines. The safety factor of SGLT-1 in day 30 (weanling) and day 100 (adult) rats was only approximately 1.0. This was initially unexpected, because most adult intestines maintain a modest reserve capacity beyond nutrient load values, but postweaning rats appear to use hindgut fermentation, assessed by gut morphology and hydrogen production assays, as a built-in reserve capacity. The series capacities of lactase and SGLT-1 varied in concert with each other over ontogeny and as lactose load was manipulated by experimental variation in litter size.
Aging↗
Magnitude of functional adaptation after intestinal resection.
Intestinal adaptation after resection has been much studied, but rarely examined in an integrative context. Hence we assessed the effects of resection and subsequent adaptation on the quantitative relationship between dietary glucose load and gut capacity to transport glucose. The ratio of capacity to load is termed the "safety factor." Our objectives were to determine 1) the time course of intestinal adaptation after resection, 2) whether adaptation is quantitatively complete, 3) whether survival requires maintaining a safety factor of at least 1.0 for glucose transport, 4) the effect of altered energy demands on adaptation, and 5) the relationship between the amount of tissue removed and the magnitude of functional adaptation. We performed 80% resection of the small intestine on Sprague-Dawley rats and measured small intestinal glucose uptake capacity, dietary glucose load, and gut gross morphology at 1, 5, and 10 wk postsurgery. Nearly all aspects of adaptation were complete by 1 wk postsurgery. After resection, remnant small intestine mass increased by over fivefold within 1 wk, to reach 50-70% of its preresection value. However, mass-specific glucose uptake activity was reduced, so that intestinal regeneration restored uptake capacity to only 33% of control values. Increased energetic demands had only modest effects on intestinal adaptation. Although the safety factor for small intestinal glucose uptake remained <1.0 (i.e., capacity < load) after adaptation to resection, nearly all rats survived. Hindgut fermentation of nonabsorbed nutrients appeared to contribute to that survival, despite inadequate small intestinal capacity. After less massive resection surgeries (25, 50, and 75% resections), the percent increase in glucose uptake capacity increased with the amount of tissue removed.
Adaptation, Physiological↗
A vertebrate model of extreme physiological regulation.
Investigation of vertebrate regulatory biology is restricted by the modest response amplitudes in mammalian model species that derive from a lifestyle of frequent small meals. By contrast, ambush-hunting snakes eat huge meals after long intervals. In juvenile pythons during feeding, there are large and rapid increases in metabolism and secretion, in the activation of enzymes and transporter proteins, and in tissue growth. These responses enable an economic hypothesis concerning the evolution of regulation to be tested. Combined with other experimental advantages, these features recommend juvenile pythons as the equivalent of a squid axon in vertebrate regulatory biology.
Animals↗
A method for assaying intestinal brush-border sucrase in an intact intestinal preparation.
Small intestinal brush-border hydrolases usually are assayed in intestinal mucosal homogenates resuspended in solutions of unphysiological ionic composition. Thus, extrapolation of measured Vmax values (maximal reaction rates at high substrate concentrations) to in vivo conditions, hence comparison with physiological substrate loads, is uncertain. We therefore have developed a sucrase assay in an intact preparation of mouse small intestine, an everted intestinal sleeve incubated in a physiological Ringer's solution. As in homogenate studies, sucrase is assayed by glucose production measured colorimetrically, but uptake of liberated glucose into the intestinal sleeve is prevented by the transport inhibitor phlorizin. The coefficient of variation of Vmax is 16% for sleeves from the same mouse and 8% for mean values from different mice. Sleeve sucrase activity is abolished by the inhibitor castanospermine. Activity in sleeves and homogenates proves to be the same when measured under identical solution conditions, but variations in assay conditions cause large activity changes from values measured in physiological solutions.
Animals↗
Evolutionary matches of enzyme and transporter capacities to dietary substrate loads in the intestinal brush border.
Safety factors of enzymes and transporters are defined as the ratio of Vmax (maximal reaction rates at high substrate concentrations) to the reaction rate under actual physiological conditions. Although corresponding safety factors have been measured for macroscopic biological structures and for human-engineered structures, safety factors have been little studied at the molecular level. Some evolutionary considerations suggest that safety factors should be modestly in excess of 1.0 ("enough but not too much") and should tend to be similar for the various steps of a pathway consisting of two or more elements arranged in series. Hence we used a preparation of intact mouse small intestine to measure Vmax values (capacities) of brush-border sucrase (yielding glucose plus fructose) and of the brush-border glucose transporter, for comparison with each other and with dietary sucrose loads. Load was manipulated by varying dietary sucrose level or by studying lactating mice with increased energy requirements. Capacities both of sucrase and the glucose transporter increased with sucrose load (i.e., both proteins are inducible) and remained approximately matched to each other except on a carbohydrate-free diet. Their safety factors decreased from ca. 2.7 at low load to 1.0 at high load. Thus, neither sucrase nor the glucose transporter is the rate-limiting step for sucrose digestion; both steps are equally limiting. The modest safety factors and matched capacities must be genetically programmed through natural selection, with benefits of excess capacities being balanced against costs of biosynthetic energy and limited membrane space.
Adaptation, Physiological↗
Glucose uptake in dilated small intestine.
BACKGROUND/PURPOSE: The development of dilated small intestine in patients with short bowel syndrome results in increased mucosal surface area. This study examines whether the incremental increase in surface area leads to a proportional increase in absorptive function of the small intestine. METHODS: Partial obstruction of the small intestine was created in rats by placing an intussusception valve in the proximal jejunum. Rats that underwent sham operations served as controls. One week postoperatively, the small intestine proximal and distal to the valve was removed. The intestinal diameter proximal and distal to the obstruction was measured. The rate of glucose uptake was measured by the everted sleeve technique. The results were analyzed by analysis of variance (ANOVA). RESULTS: The intestine proximal to the valve was significantly dilated and thickened when compared with the intestine distal to the valve. The wet mass per centimeter of the dilated segment was 2.5 times that of the control group (P<.001). The glucose uptake capacity of the dilated segment was slightly higher than that of the control group (540 v 420 nmol/min/cm, P<.05). However, the specific glucose uptake rate was reduced significantly in the intestine proximal to the valve (247 v 335 nmol/min/cm2, P<.01). CONCLUSIONS: Although the partial obstruction of small intestine resulted in a substantial increase in the intestinal surface area, the absorptive capacity of the dilated intestine per unit surface area was decreased significantly. This translated ultimately into a slight increase in the overall functional absorptive capacity of glucose in the small intestine. These results suggest that dilated small intestine may not enhance mucosal absorption.
Analysis of Variance↗
Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania.
We compared the response to acute lithium therapy in 30 adolescents, 13-17 years of age, with mania and a prior history of early childhood attention deficit hyperactivity disorder (ADHD) to a sex- and age-matched control group of adolescent manics without premorbid psychiatric illness. Response to treatment was assessed daily over the course of 28 days using measures of global clinical improvement and severity ratings on the Bech-Rafaelsen Mania Scale (BRMS). BRMS scores decreased by a mean of 24.3 in the subgroup without prior ADHD compared to 16.7 in patients with ADHD (P = 0.0005). The average percent drop in BRMS scores over the study period in these two subgroups was 80.6% and 57.7%, respectively (P = 0.0005). Time to onset of sustained global clinical improvement was also assessed using Kaplan-Meier survival methods and possible covariates of time to improvement were tested in a Cox proportional hazards model. Median time to onset of sustained improvement was lengthened significantly in patients with early ADHD (23 days) compared to those without it (17 days; log rank chi2 = 7.2, P = 0.007). The results suggest that early childhood ADHD defines an important source of heterogeneity in bipolar illness with developmental, clinical, and neuropharmacogenetic implications.
Adolescent↗
Evidence that spontaneous contractile activity in the rat myometrium is not inhibited by NO-mediated increases in tissue levels of cyclic GMP.
1. There is conflicting evidence in the literature concerning the role of cyclic GMP in the regulation of myometrial contractility and the importance of hormonal status on the uterine response to cyclic GMP-elevating agents. The objective of the present study was to investigate further the importance of cyclic GMP in the control of uterine contractility, by monitoring the effects of cyclic GMP-elevating agents on spontaneous contractions and cyclic GMP levels in myometrial strips from pregnant rats and from ovariectomized rats under the influence of oestrogen and/or progesterone. 2. Sodium nitroprusside (SNP) 5 mM, atrial natriuretic peptide (ANP) 100 nM, L-arginine 1 mM and 8-bromo-cyclic GMP 100 mM had no relaxant effect on the spontaneous contractions of myometria from pregnant rats or from ovariectomized rats under the influence of oestrogen or progesterone. 3. Tissue levels of cyclic GMP were significantly elevated by SNP in all treatment groups, including pregnant animals. For example, in ovariectomized, progesterone-treated rats, SNP raised cyclic GMP levels approximately 8 fold from a basal level of 2.9 +/- 0.4 pmol mg(-1) protein to 24.8 +/- 4.0 pmol mg(-1) protein. ANP increased cyclic GMP levels approximately 2 fold in all treatment groups, except in the pregnant animals. L-Arginine elevated cyclic GMP significantly only in ovariectomized, vehicle-treated myometria. 4. The activity of cyclic GMP-dependent protein kinase (PKG) was significantly increased (3 fold) in myometria exposed to SNP (5 mM). Thus, the inability of SNP to relax uterine preparations was not due to a failure of SNP-elevated cyclic GMP to activate PKG. 5. The more potent NO donor, S-nitroso-N-acetylpenicillamine (SNAP), at a concentration of 100 microM was able to inhibit spontaneous contractions significantly in myometrial preparations from both non-ovariectomized and ovariectomized rats treated with oestrogen or progesterone. 6. Tissue levels of cyclic GMP were markedly increased by SNAP at concentrations of 10, 30 and 100 microM. At 100 microM, cyclic GMP levels increased from 1.9 +/- 0.2 pmol mg(-1) protein to 74.0 +/- 18.0 pmol mg(-1) protein. However, complete or partial blockade of SNAP-induced increases in cyclic GMP levels by the soluble guanylyl cyclase inhibitor, ODQ (25 microM), had no effect on the relaxant response to SNAP. Thus, the relaxant effect of SNAP in this tissue appears to be mediated via a mechanism independent of cyclic GMP. 7. Taken as a whole, the results of the present study indicate that cyclic GMP does not play an important role in the control of contractility in the rat uterus.
Animals↗
African-American attitudes towards United States immigration policy.
Explore the source record for details and available documents.
Black or African American↗
Intensity and predictors of treatment received by adolescents with unipolar major depression prior to hospital admission.
We sought to characterize the type and intensity of treatment received in the community by 80 adolescents with unipolar major depressive disorder prior to hospital admission for this index episode of illness. Structured clinical interviews were used to rate the presence and severity of a wide range of depressive symptoms and to derive global measures of episode subtype and degree of impairment. Multiple sociodemographic and clinical variables were considered as predictors of level of antidepressant treatment exposure. Although the majority of patients sought help prior to admission, only 58% received antidepressant medication, and fewer than half of these treated patients received levels of treatment deemed adequate by conventional standards. More aggressive levels of pharmacotherapy were received by only a small minority of the sample, and overall severity of illness had little effect on intensity of treatment. Specific clinical features associated with endogeneity were the most robust predictors of more intense antidepressant pharmacotherapy. A disturbingly high proportion of adolescents with serious depressive illness receive less than optimally aggressive treatment in the community relative to the seriously handicapping nature of their illness. The potential implications of these observations are considered.
Adolescent↗