Biomedical subjects
J Diamond
Publications and source records attributed to J Diamond.
Dinosaurs, dragons, and dwarfs: the evolution of maximal body size.
Among local faunas, the maximum body size and taxonomic affiliation of the top terrestrial vertebrate vary greatly. Does this variation reflect how food requirements differ between trophic levels (herbivores vs. carnivores) and with taxonomic affiliation (mammals and birds vs. reptiles)? We gathered data on the body size and food requirements of the top terrestrial herbivores and carnivores, over the past 65,000 years, from oceanic islands and continents. The body mass of the top species was found to increase with increasing land area, with a slope similar to that of the relation between body mass and home range area, suggesting that maximum body size is determined by the number of home ranges that can fit into a given land area. For a given land area, the body size of the top species decreased in the sequence: ectothermic herbivore > endothermic herbivore > ectothermic carnivore > endothermic carnivore. When we converted body mass to food requirements, the food consumption of a top herbivore was about 8 times that of a top carnivore, in accord with the factor expected from the trophic pyramid. Although top ectotherms were heavier than top endotherms at a given trophic level, lower metabolic rates per gram of body mass in ectotherms resulted in endotherms and ectotherms having the same food consumption. These patterns explain the size of the largest-ever extinct mammal, but the size of the largest dinosaurs exceeds that predicted from land areas and remains unexplained.
Responses of python gastrointestinal regulatory peptides to feeding.
In the Burmese python (Python molurus), the rapid up-regulation of gastrointestinal (GI) function and morphology after feeding, and subsequent down-regulation on completing digestion, are expected to be mediated by GI hormones and neuropeptides. Hence, we examined postfeeding changes in plasma and tissue concentrations of 11 GI hormones and neuropeptides in the python. Circulating levels of cholecystokinin (CCK), glucose-dependent insulinotropic peptide (GIP), glucagon, and neurotensin increase by respective factors of 25-, 6-, 6-, and 3.3-fold within 24 h after feeding. In digesting pythons, the regulatory peptides neurotensin, somatostatin, motilin, and vasoactive intestinal peptide occur largely in the stomach, GIP and glucagon in the pancreas, and CCK and substance P in the small intestine. Tissue concentrations of CCK, GIP, and neurotensin decline with feeding. Tissue distributions and molecular forms (as determined by gel-permeation chromatography) of many python GI peptides are similar or identical to those of their mammalian counterparts. The postfeeding release of GI peptides from tissues, and their concurrent rise in plasma concentrations, suggests that they play a role in regulating python-digestive responses. These large postfeeding responses, and similarities of peptide structure with mammals, make pythons an attractive model for studying GI peptides.
Archaeology. Tree trail to Chaco Canyon.
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Metabolic rate and environmental productivity: well-provisioned animals evolved to run and idle fast.
Even among vertebrate species of the same body mass and higher-level taxonomic group, metabolic rates exhibit substantial differences, for which diverse explanatory factors-such as dietary energy content, latitude, altitude, temperature, and rainfall-have been postulated. A unifying underlying factor could be food availability, in turn controlled by net primary productivity (NPP) of the animal's natural environment. We tested this possibility by studying five North American species of Peromyscus mice, all of them similar in diet (generalist omnivores) and in gut morphology but differing by factors of up to 13 in NPP of their habitat of origin. We maintained breeding colonies of all five species in the laboratory under identical conditions and consuming identical diets. Basal metabolic rate (BMR) and daily ad libitum food intake both increased with NPP, which explained 88% and 90% of their variances, respectively. High-metabolism mouse species from high-NPP environments were behaviorally more active than were low-metabolism species from low-NPP environments. Intestinal glucose uptake capacity also increased with NPP (and with BMR and food intake), because species of high-NPP environments had larger small intestines and higher uptake rates. For metabolic rates of our five species, the driving environmental variable is environmental productivity itself (and hence food availability), rather than temporal variability of productivity. Thus, species that have evolved in the presence of abundant food run their metabolism "fast," both while active and while idling, as compared with species of less productive environments, even when all species are given access to unlimited food.
Males with anorexia nervosa: a controlled study of eating disorders in first-degree relatives.
OBJECTIVE: To compare lifetime rates of full and partial anorexia nervosa and bulimia nervosa in first-degree relatives of males with anorexia nervosa and in relatives of never-ill comparison subjects. METHODS: Rates of eating disorders were obtained for 747 relatives of 210 probands from personal structured clinical interviews and family history. Best-estimate diagnoses were determined blind to proband diagnosis and pedigree status. RESULTS: Full and partial syndromes of anorexia nervosa aggregated in female relatives of ill probands. For the full syndrome of anorexia nervosa, the crude relative risk was 20.3 among female relatives and for partial syndrome anorexia nervosa, the crude relative risk was 3.3. In contrast, bulimia nervosa was relatively uncommon among relatives of ill probands. CONCLUSION: Although anorexia nervosa in males is exceedingly rare, there is a pattern of familial aggregation that is highly similar to that observed in recent family studies of affected females. On the basis of these findings, there is no evidence that familial-genetic factors distinguish the occurrence of anorexia nervosa in the two sexes.
Cytokeratin 20 is not a reliable molecular marker for occult breast cancer cell detection in hematological tissues.
Cytokeratins are potential markers for epithelial cell detection in hematological tissues. Thus, we developed a nested reverse transcriptase-polymerase chain reaction (RT-PCR) strategy to detect cytokeratin 20 (CK20) mRNA and studied its sensitivity and specificity as a molecular marker of occult breast cancer cells. In cell dilution experiments with human breast cancer cell lines, the limit of detection was 1 tumor cell in 1,000 hematological cells. In RNA dilution experiments of breast cancer cells' RNA in E. Coli tRNA, the CK20 transcript was only detectable when at least 1 ng of total tumor RNA was present in a total of 1 microg of RNA mixture. In parallel experiments using colorectal cancer specimens, CK20 mRNA was detected with as little as 1 pg of total tumor RNA, suggesting a low level of CK20 mRNA expression in breast cancer cells. The CK20 transcript was detected in all six tumors and five hematological samples of breast cancer patients but in none of nine hematological cell lines. However, CK20 transcript was also detected in unfractionated nucleated cell population of hematological samples from 23 of 31 (74%) healthy volunteers and from 12 of 24 (50%) patients with hematological malignancies. When mononucleated and polymorphonucleated cell populations of hematological samples from these control groups were screened separately, CK20 expression was detected in 94% of polymorphonucleated cell fractions and in 44% of mononucleated cell subpopulations. Thus, we conclude that the low sensitivity and specificity of RT-PCR detection of CK20 mRNA limits its usefulness for breast cancer cell detection in hematological products.
Effect of NO donors on protein phosphorylation in intact vascular and nonvascular smooth muscles.
It is generally well accepted that nitrovasodilator-induced relaxation of vascular smooth muscle involves elevation of cGMP and activation of a specific cGMP-dependent protein kinase [protein kinase G (PKG)]. However, the protein targets of PKG and the underlying mechanisms by which this kinase leads to a relaxant response have not been elucidated. Several types of smooth muscle, including rat myometrium and vas deferens, are not relaxed by sodium nitroprusside, even at concentrations that produce marked elevation of cGMP and activation of PKG. The main objective of our studies was to compare PKG-mediated protein phosphorylation in intact rat aorta, rat myometrium, and rat vas deferens using two-dimensional gel electrophoresis. In intact rat aorta, seven PKG substrates were detected during relaxation of the tissue. None of the PKG substrates identified in the rat aorta appeared to be phosphorylated in the myometrium or vas deferens after administration of various cGMP-elevating agents. Thus the failure of the rat myometrium and rat vas deferens to relax in the face of cGMP elevation and PKG activation may be due to a lack of PKG substrate phosphorylation.
Health, environment, and transgenic agriculture.
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The PML-RAR alpha transcript in long-term follow-up of acute promyelocytic leukemia patients.
BACKGROUND AND OBJECTIVES: Detection of PML-RAR alpha transcripts by RT-PCR is now established as a rapid and sensitive method for diagnosis of acute promyelocytic leukemia (APL). Although the majority of patients in long-term clinical remission are negative by consecutive reverse transcription polymerase chain reaction (RT-PCR) assays, negative tests are still observed in patients who ultimately relapse. Conversion from negative to positive PCR has been observed after consolidation and found to be a much stronger predictor of relapse. This study reports on 47 APL patients to determine the correlation between minimal residual disease (MRD) status and clinical outcome in our cohort of patients. DESIGN AND METHODS: The presence of PML-RAR alpha t transcripts was investigated in 47 APL patients (37 adults and 10 children) using a semi-nested reverse transcriptase-polymerase chain reaction to evaluate the prognostic value of RT-PCR tests. RESULTS: All patients achieved complete clinical remission (CCR) following induction treatment with all-trans retinoic acid (ATRA) and chemotherapy (CHT) or ATRA alone. Patients were followed up between 2 and 117.6 months (median: 37 months). Relapses occurred in 11 patients (9 adults and 2 children) between 11.4 and 19 months after diagnosis (median: 15.1 months) while 36 patients (28 adults and 8 children) remained in CCR. Seventy-five percent of patients carried the PML-RAR alpha long isoform (bcr 1/2) which also predominated among the relapsed cases (9 of 11) but did not associate with any adverse outcome (p= 0.37). For the purpose of this analysis, minimal residual disease tests were clustered into four time-intervals: 0-2 months, 3-5 months, 6-9 months and 10-24 months. INTERPRETATION AND CONCLUSIONS: Children showed persisting disease for longer than adults during the first 2 months of treatment. At 2 months, 10 (50%) of 20 patients who remained in CCR and 4 (80%) of 5 patients who subsequently relapsed were positive. Patients who remained in CCR had repeatedly negative results beyond 5.5 months from diagnosis. A positive MRD test preceded relapse in 3 of 4 tested patients. The ability of a negative test to predict CCR (predictive negative value, PNV) was greater after 6 months (>83%), while the ability of a positive test to predict relapse (predictive positive value, PPV) was most valuable only beyond 10 months (100%). This study (i) highlights the prognostic value of RT-PCR monitoring after treatment of APL patients but only from the end of treatment, (ii) shows an association between conversion to a positive test and relapse and (iii) suggests that PCR assessments should be carried out at 3-month intervals to provide a more accurate prediction of hematologic relapses but only after the end of treatment.
Comparison of four echocardiographic techniques for measuring left ventricular ejection fraction.
Accurate quantitative measurement of left ventricular (LV) ejection fraction (EF) by 2-dimensional echocardiography is limited by subjective visual endocardial border detection. Both harmonic and precision contrast microbubbles provide better delineation of endocardial borders than fundamental imaging. The aim of this study was to correlate 2-dimensional echocardiographic quantification of LVEF measured by 4 currently available techniques with radionuclide angiography. A total of 50 patients who underwent radionuclide (EF) measurement (47 of 50 had technically difficult echocardiograms by fundamental imaging) underwent echocardiography by 4 methods: fundamental alone, fundamental with contrast, harmonic alone, and harmonic with contrast. Three echocardiologists measured the biplane 2-dimensional echocardiographic LVEF independently and were blinded to radionuclide angiography. The correlation of echocardiographic EF with radionuclide EF improved incrementally with each method. However, contrast with harmonic imaging provided the closest correlation (r = 0.95, 0.96, and 0.95 as assessed by the 3 independent analysts.
Defects in sensory nerve numbers and growth in mutant Kit and Steel mice.
The roles in the nervous system of the receptor tyrosine kinase Kit and its ligand, Steel factor, are unclear. We have now found first, that sensory nerve populations are reduced in mutant Kit and Steel mice, implicating Steel-Kit interactions in neuronal development. Second, sensory axonal regeneration (which occurs independently of nerve growth factor, or NGF) is impaired, while collateral sprouting (NGF dependent) is normal. Therefore, there is a selective involvement of Kit signal transduction pathways in nerve growth; supporting this, in wild-type animals Kit was up-regulated in regenerating, but unchanged in sprouting, sensory neurons. The receptor tyrosine kinase Kit thus contrasts with the receptor tyrosine kinase trkA, which is activated by the sprouting stimulus (NGF) but not by the axonal regeneration signal.
Archaeology. Blitzkrieg against the moas.
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An automated machine vision system for the histological grading of cervical intraepithelial neoplasia (CIN).
The histological grading of cervical intraepithelial neoplasia (CIN) remains subjective, resulting in inter- and intra-observer variation and poor reproducibility in the grading of cervical lesions. This study has attempted to develop an objective grading system using automated machine vision. The architectural features of cervical squamous epithelium are quantitatively analysed using a combination of computerized digital image processing and Delaunay triangulation analysis; 230 images digitally captured from cases previously classified by a gynaecological pathologist included normal cervical squamous epithelium (n=30), koilocytosis (n=46), CIN 1 (n=52), CIN 2 (n=56), and CIN 3 (n=46). Intra- and inter-observer variation had kappa values of 0.502 and 0.415, respectively. A machine vision system was developed in KS400 macro programming language to segment and mark the centres of all nuclei within the epithelium. By object-oriented analysis of image components, the positional information of nuclei was used to construct a Delaunay triangulation mesh. Each mesh was analysed to compute triangle dimensions including the mean triangle area, the mean triangle edge length, and the number of triangles per unit area, giving an individual quantitative profile of measurements for each case. Discriminant analysis of the geometric data revealed the significant discriminatory variables from which a classification score was derived. The scoring system distinguished between normal and CIN 3 in 98.7% of cases and between koilocytosis and CIN 1 in 76.5% of cases, but only 62.3% of the CIN cases were classified into the correct group, with the CIN 2 group showing the highest rate of misclassification. Graphical plots of triangulation data demonstrated the continuum of morphological change from normal squamous epithelium to the highest grade of CIN, with overlapping of the groups originally defined by the pathologists. This study shows that automated location of nuclei in cervical biopsies using computerized image analysis is possible. Analysis of positional information enables quantitative evaluation of architectural features in CIN using Delaunay triangulation meshes, which is effective in the objective classification of CIN. This demonstrates the future potential of automated machine vision systems in diagnostic histopathology.
'Alternative cancer cures': looking for common ground.
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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.
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.