Improving stable isotopic interpretations made from human hair through reduction of growth cycle error.

A recent trend in stable isotopic analysis involves the reconstruction of short-term variations in diet using hair segments. However, bulk hair samples typically contain a growth cycle error, which may conceal or confound the most recently incorporated isotopic information. It is assumed that, at any given time, ∼85-90% of scalp hairs are actively growing, while the remaining 10-15% have transitioned into a resting or inactive phase, which lasts up to 4 months before hairs are shed. This study uses growth phase to determine the effects of age, sex, and health status on carbon and nitrogen isotopic ratios of hair analyzed in sequential segments. For this study, we selected archaeological hair samples from 10 individuals from Dakhleh Oasis, Egypt. Isotopic analyses of actively growing hair segments were compared to those for mixed growth phase segments from each individual. These data demonstrate the presence of growth cycle error and show that an understanding of structural-functional relationships is essential for interpreting normal versus pathological changes in hair follicle and fiber production. In situations where diet change and mobility produce variations in an individual's isotopic composition, elimination of positional-temporal error in sequential segment hair analyses can facilitate greater understanding of intraindividual metabolic reactions and changes in hair growth cycles. Phase identification may aid in determining the presence of pathological conditions in individuals, especially in those lacking skeletal indications, and provide a more precise estimation of seasonal dietary patterns, access to changing food resources, and metabolic equilibration to a new locality.

A quantitative MRI study of posterior fossa development in velocardiofacial syndrome.

BACKGROUND: Velocardiofacial syndrome (VCFS) has been identified as a risk factor for developing schizophrenia. Qualitative neuroimaging studies indicated that VCFS was frequently associated with abnormal development of structures in the posterior fossa of the brain. The objective of this investigation was to identify the specific structures affected in the posterior fossa and investigate the association of these neuroanatomic variations with behaviors potentially related to later-onset psychiatric disorders. METHODS: Twenty-four children and adolescents with VCFS individually matched for age and gender with 24 control subjects received magnetic resonance imaging scans. Analysis of covariance models were used to investigate regional brain differences. Association between brain areas and behaviors measured on the Child Behavior Checklist (CBCL) were assessed using simple regression models. RESULTS: Children with VCFS had significantly smaller size of vermal lobules VI--VII and the pons after adjusting for overall brain size. There were no significant associations between scores on the CBCL and measures of neuroanatomic variation within the VCFS group. CONCLUSIONS: Structural alterations of the posterior fossa in VCFS are specifically limited to cerebellar vermis lobules VI--VII and pons. Previous literature has suggested that the vermis is involved in social cognition, and alteration of lobules VI--VII could therefore partially explain the neurobehavioral profile associated with VCFS.

Children and adolescents with velocardiofacial syndrome: a volumetric MRI study.

OBJECTIVE: Velocardiofacial syndrome is a common genetic condition often accompanied by mild cognitive impairment. Children and adolescents with velocardiofacial syndrome also are at greater risk for developing serious neuropsychiatric disorders in adulthood, particularly schizophrenia-like disorders. The purpose of this preliminary study was to 1) elucidate through brain imaging the neurobiological basis of cognitive and neuropsychiatric problems in velocardiofacial syndrome, and 2) consider the association between variations in neuroanatomy in velocardiofacial syndrome subjects and the associated neurobehavioral phenotype. METHOD: Fifteen children and adolescents with velocardiofacial syndrome were matched by age and gender with 15 comparison subjects. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of specified brain tissues and regions. Rater-blind morphometric analyses were conducted to examine tissue volumes of the four lobes and the cerebellum. RESULTS: Total brain volume was approximately 11% smaller in the children with velocardiofacial syndrome. Gray matter volume was reduced to a lesser extent (7.5%) than white matter volume (16.3%). Multivariate analyses of variance indicated a distinct pattern of regional morphological variation among the children with velocardiofacial syndrome. Specifically, frontal lobe tissue tended to be enlarged relative to the overall reduction in brain volume. Normal symmetry of parietal lobe tissue observed in the comparison group was not evident in the velocardiofacial syndrome group. This loss of symmetry was attributable to a significant reduction of gray matter in the left parietal lobe. CONCLUSIONS: Aberrant brain morphology is associated with velocardiofacial syndrome. These changes are potentially related to the language and learning deficits associated with the syndrome and may provide clues about neurodevelopmental pathways associated with schizophrenia.

Velocardiofacial syndrome: are structural changes in the temporal and mesial temporal regions related to schizophrenia?

OBJECTIVE: Velocardiofacial syndrome results from a microdeletion on chromosome 22 (22q11.2). Clinical studies indicate that more than 30% of children with the syndrome will develop schizophrenia. The authors sought to determine whether neuroanatomical features in velocardiofacial syndrome are similar to those reported in the literature on schizophrenia by measuring the volumes of the temporal lobe, superior temporal gyrus, and mesial temporal structures in children and adolescents with velocardiofacial syndrome. METHOD: Twenty-three children and adolescents with velocardiofacial syndrome and 23 comparison subjects, individually matched for age and gender, received brain magnetic resonance imaging (MRI) scans. Analysis of covariance models were used to compare regional brain volumes. Correlations between residualized brain volumes and age were standardized and compared with the Fisher r-to-z transformation. RESULTS: Children with velocardiofacial syndrome had significantly smaller average temporal lobe, superior temporal gyrus, and hippocampal volumes than normal comparison children, although these differences were commensurate with a lower overall brain size in the affected children. In a cross-sectional analysis, children with velocardiofacial syndrome exhibited aberrant volumetric reductions with age that were localized to the temporal lobe and left hippocampal regions. CONCLUSIONS: Abnormal temporal lobe and hippocampal development in velocardiofacial syndrome is potentially concordant with MRI findings in the schizophrenia literature. Temporal lobe and mesial temporal structures may represent a shared substrate for the effects of the 22q11.2 deletion and for the complex etiological pathways that lead to schizophrenia. Longitudinal research may help determine which children with velocardiofacial syndrome are at risk for serious psychiatric illness in adulthood.

Functional neuroanatomy of visuospatial working memory in fragile X syndrome: relation to behavioral and molecular measures.

OBJECTIVE: Fragile X syndrome is a neurogenetic disorder that is the most common known heritable cause of neurodevelopmental disability. This study examined the neural substrates of working memory in female subjects with fragile X syndrome. Possible correlations among behavioral measures, brain activation, and the FMR1 gene product (FMRP expression), as well as between IQ and behavioral measures, were investigated. METHOD: Functional magnetic resonance imaging was used to examine visuospatial working memory in 10 female subjects with fragile X syndrome and 15 typically developing female subjects (ages 10-23 years). Subjects performed standard 1-back and 2-back visuospatial working memory tasks. Brain activation was examined in four regions of the cortex known to play a critical role in visuospatial working memory. Correlations between behavioral, neuroimaging, and molecular measures were examined. RESULTS: Relative to the comparison group, subjects with fragile X syndrome performed significantly worse on the 2-back task but not on the 1-back task. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, comparison subjects showed significantly increased brain activation between the 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. Significant correlations were found in comparison subjects between activation in the frontal and parietal regions and the rate of correct responses on the 2-back task, but not on the 1-back task. In subjects with fragile X syndrome, significant correlations were found during the 2-back task between FMRP expression and activation in the right inferior and bilateral middle frontal gyri and the bilateral supramarginal gyri. CONCLUSIONS: Subjects with fragile X syndrome are unable to modulate activation in the prefrontal and parietal cortex in response to an increasing working memory load, and these deficits are related to a lower level of FMRP expression in fragile X syndrome subjects than in normal comparison subjects. The observed correlations between biological markers and brain activation provide new evidence for links between gene expression and cognition.

Preliminary evidence of widespread morphological variations of the brain in dyslexia.

The MR images of 16 men with dyslexia and 14 control subjects were compared using a voxel-based analysis. Evidence of decreases in gray matter in dyslexic subjects, most notably in the left temporal lobe and bilaterally in the temporoparietooccipital juncture, but also in the frontal lobe, caudate, thalamus, and cerebellum, was found. Widely distributed morphologic differences affecting several brain regions may contribute to the deficits associated with dyslexia.

Functional optimization of arithmetic processing in perfect performers.

Lesion and imaging studies to date have not clarified which sub-regions of the parietal lobe are specialized for arithmetic processing, and which perform supporting functions. We used functional magnetic resonance imaging to investigate parietal lobe function during arithmetic processing. Functional optimization was examined by analyzing regional differences in brain activation between perfect (100% accuracy) and imperfect performers. Perfect performers had significantly less activation only in the left angular gyrus, a finding that may be associated with skill mastery and long-term practice effects. The present results provide the first direct evidence of localized functional optimization for arithmetic processing in the human brain.

Alterations in myocardial signal transduction due to aging and chronic dynamic exercise.

Normal aging without disease leads to diminished chronotropic and inotropic responses to catecholamine stimulation, resulting in depressed cardiac function with stress. The purpose of this study was to determine molecular mechanisms for decrements in adrenergic responsiveness of the left ventricle (LV) due to aging and to study the effects of chronic dynamic exercise on signal transduction. We measured beta-adrenergic receptor (beta-AR) density, adenylyl cyclase (AC) activity, and G-protein content and distribution in LV from 66 male Fischer 344 rats from three age groups that were either sedentary or treadmill trained (60 min/days, 5 days/wk, 10 wk at 75% of the maximal capacity). Final ages were 7 mo (young), 15 mo (middle-age), and 25 mo (old). There was no significant difference in beta-AR density among groups as a function of age or training. AC production of adenosine 3',5'-cyclic monophosphate (cAMP) with the use of five pharmacological stimulations revealed that old sedentary myocardium had depressed basal, receptor-dependent, G-protein-dependent, and AC catalyst stimulation (30-43%) compared with hearts from young and middle-age sedentary rats. Training did not alter AC activity in either middle-age or old groups but did increase G-protein-dependent cAMP production in young myocardium (12-34%). Immunodetectable concentrations of stimulatory and inhibitory G proteins (Gs and Gi, respectively) showed 43% less total Gs with similar Gi content in hearts from old sedentary compared with middle-age sedentary rats. When compared with young sedentary animals, Gi content was 39 and 50% higher in middle-age sedentary and old sedentary myocardium, respectively. With age, there was a significant shift in the alpha-subunit of Gs distribution from cytosolic fractions of LV homogenates to membrane-bound fractions (8-12% redistribution in middle-age sedentary vs. old sedentary). The most significant training effect was a decrease in Gi content in hearts from old trained rats (23%), which resulted in values comparable with young sedentary rats and reduced the Gi/Gs ratio by 27% in old-rat LV. We report that age-associated reductions in cardiovascular beta-adrenergic responsiveness correspond with alterations in postreceptor adrenergic signaling rather than with a decrease in receptor number. Chronic dynamic exercise partially attenuates these reductions through alterations in postreceptor elements of cardiac signal transduction.

Application of an automated parcellation method to the analysis of pediatric brain volumes.

New techniques in quantitative imaging are needed to accelerate understanding of brain development and function in children. In this study we evaluate the reliability and validity of an automated parcellation method for the measurement of large and small brain regions in normal and developmentally disabled children. We utilized an adaptation of the Talairach atlas to semi-automatically quantify brain volumes from 10 children with fragile X syndrome, 10 age- and gender-matched controls and 10 adult controls comparing them to 'gold standard' manually delineated regions. Excellent sensitivity, specificity, intra-class correlation and positive predictive value were achieved for large structures although results were less satisfactory for smaller structures, illustrating the limits of resolution of the method. Statistically significant differences in regional brain volumes were shown between males and females, children and adults, and individuals with fragile X and matched controls. This study demonstrates an automated method which rapidly and accurately quantifies large neuroanatomical structures, but not smaller structures. This method is sufficiently accurate to demonstrate some known anatomical differences in individuals with fragile X; the results suggest that this method could be applied to the assessment of brain volume in other neurodevelopmental disabilities.

Corneal virulence of LasA protease--deficient Pseudomonas aeruginosa PAO1.

PURPOSE: Pseudomonas aeruginosa PAO1 deficient in LasA protease was reported to be ocularly avirulent. However, the avirulence of this mutant could not attributed to the loss of LasA protease. The purpose of this study was to define the mechanism for such a mutant's inability to cause corneal disease. METHODS: A LasA protease--deficient mutant of P. aeruginosa PAO1 was constructed by allelic exchange. Virulence of this mutant in mouse and rabbit models of keratitis was assessed by scoring for ocular disease and quantitating viable bacteria from infected corneas. Adherence to scarified mouse corneal tissue was determined with an organ culture assay. RESULTS: In the mouse eye, the LasA protease--deficient mutant was not virulent, despite being as adherent as its parent strain. Virulence of the mutant was also significantly reduced in the rabbit eye. Complementation with lasA did not restore virulence in either model of infection. Neither the mutant nor the mutant complemented with lasA grew well in ocular tissue. An analysis of the mutant showed that it was auxotrophic for leucine. CONCLUSION: These data show that the mutant's avirulence in the eye is caused by poor growth in the ocular environment and not the loss of a functional lasA gene.

Pseudomonas aeruginosa LasA protease and corneal infections.

PURPOSE: A mutant strain of Pseudomonas aeruginosa deficient in LasA protease (staphylolytic protease) has been described as having reduced ocular virulence, suggesting that LasA is a major virulence factor. This study was undertaken to provide further genetic analysis of the role of P. aeruginosa LasA protease in ocular infections. METHODS: LasA protease-deficient mutants of P. aeruginosa PAO1-V and ATCC 19660 were constructed by allelic replacement. Mutants and their respective wild type parent strains were evaluated for virulence and growth in the eye using mouse scarification and rabbit intrastromal injection models of keratitis. RESULTS: LasA protease-deficient mutants of both strains were as virulent as wild type strains, growing to 4 to 6 log10 CFU/cornea and causing significant ocular pathology in the mouse (P > 0.42) and rabbit (P > 0.53). CONCLUSIONS: These data show that LasA protease is not a major corneal virulence factor, suggesting that the main mechanism of corneal damage has yet to be definitively identified.

A conscious baboon model for evaluation of hemodynamics in altered gravity.

A model was developed for evaluation of cardiovascular parameters in conscious baboons exposed to altered gravitational environments. Baboons were trained to sit quietly in a confinement chair of unique design which allowed a range of normal physical activity. They were then instrumented with high-fidelity blood pressure transducers in the aorta and left ventricle, electromagnetic flow probes encircling the proximal ascending aorta, left and right atrial fluid catheters, left ventricular sonomicrometer crystals in a 3-axis configuration, and a hydraulic occluder cuff encircling the inferior vena cava. Catheters and transducer wires were exteriorized at the midscapular region of the back. Viability of percutaneous exit sites was enhanced by use of velour cuffs on the transducer wires, providing a scaffold for wound healing. Pressure transducers and flow probes were calibrated and balanced during postoperative cardiac catheterization procedures. This instrumentation allowed measurement of beat-to-beat stroke volume and cardiac output not reliant on thermodilution techniques. Postoperative longevity was from 1 to 10 months. Instrumentation failure included endocardial trapping of ventricular pressure transducers, corrosion of ventricular sonomicrometer crystals, and catheter tip thrombosis. Acquisition of high quality data was possible with this model in several different environments of altered gravitational stress, allowing characterization of aortic flow and ventricular performance.

A method for repeated high-fidelity micromanometer measurement of intracardiac pressures.

Dial-tipped, high-fidelity micromanometers were inserted through polyurethane catheters to acutely measure blood pressures within the chambers of the heart and the great vessels of baboons, rhesus monkeys, and goats. Repeated measurements of atrial, ventricular, aortic, and pulmonary artery pressure were possible with this method, with calibration of micromanometers accomplished immediately prior to and after pressure recordings to assure data accuracy. All attempts to pass micromanometers into the atria in all species were successful. Passage of micromanometers from the left ventricle across the aortic valve and into the aorta was successful in 97% of the attempts in baboons, 100% for rhesus monkeys, and 75% for goats; while insertions into the pulmonary artery from the right ventricle were successful in 64% of the baboons, 40% of the rhesus monkeys, and 75% of the goats. Advantages of this technique are that a permanent conduit for cardiac vascular access is available and that high-fidelity pressure signals may be acquired.

Does dopamine modulate rate of decay of activation in the rostral brain?

The hypothesis that dopaminergic systems affect rate of decay of activation in at least some sites in the rostral brain involved in the selection and patterning of behaviours is explored. Behavioural evidence appears to support the hypothesis, but insufficient neurophysiological data are available to evaluate it directly.

The gynecologist's role in the treatment of breast carcinoma.

The treatment of early carcinoma of the breast remains contraversial. One hundred eleven cases of stage I and II carcinoma of the breast treated from January 1985 to November 1988 were reviewed. Given an informed choice, 13 of the 30 patients (43.3%) treated by the author chose breast conservation over mastectomy, in striking contrast to a 97.5% incidence of mastectomy in the 81 patients treated by the general surgeons on the hospital staff. The role of the gynecologist in the treatment of breast cancer can be to offer a different viewpoint and thus possibly to become a major force in the reduction in the number of mastectomies.

Expression of p53 in epithelial carcinoma of the ovary after chemotherapy.

OBJECTIVE: To compare the expression of p53 protein before and after chemotherapy in epithelial carcinoma of the ovary. STUDY DESIGN: Thirty patients were identified during a 10-year period with both their primary surgery and laparotomy after chemotherapy at the same institution. Tissue was processed from paraffin blocks, exposed to an antihuman p53 monoclonal antibody, then stained. Patient records were reviewed for survival data. RESULTS: Twelve of 30 (40%) patients' tissue initially stained positive for p53. Seventeen of 30 (56.7%) were negative, and one (3.3%) was mixed. Eight of 12 (66.7%) initially positive remained so after chemotherapy, 2 converted to negative, and 2 converted to mixed expression. One patient with mixed expression converted to positive after chemotherapy. Seventeen tissues initially negative remained unchanged. CONCLUSION: Chemotherapy did not permanently alter the expression of p53 detected by immunohistochemical staining in the majority (83.3%) of patients with epithelial ovarian cancer; 16.7% (all initially over-expressing p53) did show some decrease. This may have been due to deactivation of the mutated p53 gene, spontaneous mutation, selective growth within a heterogeneous population or alteration of p53 protein.

Cervical intraepithelial neoplasia extending to the margins of resection in conization of the cervix.

Conization of the cervix is still widely utilized under certain conditions for the diagnosis and treatment of cervical intraepithelial neoplasia (CIN). Little has been written about the management of disease extending to the margins of resection. Ninety-four patients underwent conization of the cervix for cervical intraepithelial neoplasia (CIN). Nineteen (20%) had positive margins of resection; 10 (56%) of them had no evidence of disease in follow-up of one to four years. The inflammatory response of healing may play a role in a cure. Positive margins of resection and persistent disease, noted in 44%, were positively associated with higher grades of CIN and smoking. Smoking was also a risk factor for recurrent disease in those with negative margins of resection.

Inflammatory cell infiltrate in the cervix as a predictor of residual cervical intraepithelial neoplasia after conization.

From January 1985 to January 1991, 112 patients underwent conization of the cervix for dysplasia. Twenty-one had incomplete resection, with cervical intraepithelial neoplasia (CIN) extending to the endocervical margins of resection. Only 10 had persistent CIN in follow-up. A decrease in the inflammatory cell infiltrate in the cervical stroma of the conization specimen was associated with persistent disease. A simple technique for quantitating this inflammatory cell infiltrate was used. Smoking was associated with a suppression of this local immune response in the cervix.

Varying presentations of methemoglobinemia: two cases.

The cases of two patients with methemoglobin levels approaching 30% are presented. No history of exposure to an oxidant was ever determined for the first case; the second patient had taken amyl nitrate orally along with alcohol as well as a self-injected narcotic and antihistamine. Due to their symptomatology, both patients were treated with methylene blue with good results; however, the patient described in case one had a brief episode of symptoms and pulse oximetry changes, not previously emphasized, consistent with the administration of methylene blue. The pathophysiology of methemoglobinemia, the utility of bedside diagnostic techniques, and the use of pulse oximetry are discussed.

Differences between syncope resulting from rapid onset acceleration and orthostatic stress.

BACKGROUND AND HYPOTHESIS: Orthostatically-induced syncope is accompanied by venous pooling and vasodilatation. Loss of consciousness during head-to-foot acceleration (G-LOC) in aviators may be caused by a different mechanism, as venous pooling should be prevented through the use of an anti-G suit. This research was conducted to test the hypothesis that in individuals wearing a well-fitted anti-G garment, no important changes occur in the volume of dependent regions during loss of consciousness resulting from rapid onset acceleration stress. Further, this work compares venous pooling patterns in G-LOC subjects to patterns seen during syncope in volunteers and patients subjected to orthostatic stress. We conducted the tilt/LBNP tests to establish what level of venous pooling was required to induce syncope in the absence of a hydrostatic component (other than 1 G) and to confirm that our equipment was sensitive enough to detect volume changes large enough to cause syncope. METHODS: Shifts in blood volume to the calf, thigh and abdominal segments were compared in subjects with G-LOC to those in subjects taken to presyncope with orthostatic stress created by upright tilt and lower body negative pressure (LBNP). Centrifuge subjects were exposed to a 15 s rapid onset (6 G.s-1) + 5 Gz exposure on the centrifuge while remaining relaxed and wearing a well-fitting anti-G suit, but with the anti-G suit pressure inactivated. RESULTS: Blood volume decreased an average of 14.9 +/- 22.1 ml in the calf segment; increased an average of 64.1 +/- 7.9 ml in the thigh segment, and decreased an average of 80.1 +/- 29.7 ml in the abdominal segment. The mean net change in volume of the three combined regions was not significantly different from zero. Presyncope was induced in subjects by a progressive exposure to upright tilt, and then addition of LBNP at -20 mm Hg and -40 mm Hg. In the tilt/LBNP group, there was a net increase of 1022 +/- 269.8 ml for the combined segments. Changes in all three segments were significantly different than the mean segmental volume changes seen in centrifuge subjects at G-LOC endpoints. Significant changes from baseline mean arterial pressure, but not heart rate were also seen within, but not between the 2 groups, with mean eye level blood pressures (ELBP) falling an average of 45.6 +/- 7.7 mm Hg in the tilt/LBNP group at syncope and 105.1 +/- 15.5 mm Hg in the centrifuge subjects at G-LOC. CONCLUSIONS: These differences suggest that G-LOC may be due entirely to hydrostatic effects, with venous pooling being prevented by the wearing of an ant-G garment, even when it remains uninflated.