The origins of neuromuscular fatigue post-stroke.

Fatigue post-stroke is a disabling and persistent symptom affecting many stroke survivors. Despite its high prevalence, the pathophysiology underlying this phenomenon remains obscure. The aim of the present study was to investigate the origins of neuromuscular fatigue post-stroke. Ten chronic stroke survivors and 10 controls sustained an isometric contraction at 30% of maximal voluntary contraction (MVC) with the ankle dorsiflexors. Motor evoked potential (MEP), cortical silent period (SP), voluntary activation, M wave and contractile properties were evaluated before, during and after fatigue among the paretic, non-paretic and control limbs. The pattern of response to fatigue in the non-paretic and control limbs was comparable; therefore, results are presented between the paretic and non-paretic limbs. Before fatigue, reduced MVC peak torque and MEP amplitude were observed on the paretic side in comparison with the non-paretic side. During fatigue, the cortical SP duration increased significantly in both limbs, whereas the MEP amplitude significantly increased only in the non-paretic limb. After fatigue, MVC peak torque decreased significantly in both limbs. Significant reductions in M wave and twitch peak torque were observed in both limbs, pointing to the development of peripheral fatigue. However, central fatigue, evident by a significant reduction in voluntary activation, was greater in the paretic than in the non-paretic limb. After stroke, an inability to increase central excitability in response to an increased cortical inhibition associated with the fatiguing contraction may contribute to central fatigue observed in the paretic limb, which may also be linked to increased self-reported fatigue during activities of daily living. These findings advance our understanding of the neuromuscular basis of fatigue post-stroke.

Polymorphonulcear leukocyte chemotaxis toward oxidized lipid components of cell membranes.

Polymorphonuclear leukocyte chemotaxis has been elicited by oxidized arachidonic acid and other oxidized polyenoic lipids in the Boyden micropore filter assay system. This chemotactic activity was observed in the absence of serum and chemotactic proteins. The esterfied arachidonic acid present in plasma membranes may be a precursor of chemotactic messages as well as prostaglandins in vivo.

Relationship between adverse childhood experiences and perceived discrimination in adulthood.

BACKGROUND: Adverse Childhood Experiences (ACEs) and perceived discrimination impact health overtime, however little is known about their association. METHODS: Data for 6,325 participants in the Midlife in the US (MIDUS) study were analyzed across three waves of data. ACEs included emotional or physical abuse, household dysfunction, or financial strain in childhood. Generalized Linear Models with Generalized Estimating Equation approach was used to test the unadjusted and adjusted associations for ACEs and perceived discrimination and perceived inequality. RESULTS: Individuals with ACEs reported significantly higher perceived inequality in work (ß=0.05, 95%CI 0.02-0.07), in home (ß=0.06, 95%CI 0.04-0.09), in family relationships (ß=0.09, 95%CI 0.06-0.11), perceived daily discrimination (ß=0.77, 95%CI 0.58-0.96), and perceived lifetime discrimination (ß=0.24, 95%CI 0.18-0.30). ACE types were significantly associated with more perceived inequality and perceived discrimination. . Abuse was independently associated with all outcomes after adjusting for household dysfunction, financial strain, age, sex, race/ethnicity, education, marital status, and income. LIMITATIONS: Findings cannot speak to the temporal relationship between ACEs and discrimination. It should not be assumed that ACEs cause perceived discrimination, but rather that there is an important association that warrants further investigation. CONCLUSIONS: These findings represent the first step in better understanding the relationship between ACEs and perceived discrimination. As both influence health across the lifespan, understanding the relationship, mechanisms, and pathways for intervening are of great importance from a population health perspective. Efforts to incorporate discussions on experiences with discrimination and inequality may be warranted as a part of treatment for ACEs to address psychosocial stressors across the lifespan.

The expression of protoporphyrinogen oxidase in human tissues.

Protoporphyrinogen oxidase is the penultimate enzyme in the haem biosynthetic pathway. In this study, the expression of protoporphyrinogen oxidase in a variety of human organs has been documented by immunohistochemical means at the light microscopy level in order to shed light on its inter- and intra-organ distribution. The expression varied amongst organs and the various cell types within an organ. The pattern of staining generally reflected presumed metabolic functionality and haem demand. Strongest staining was noted in hepatocytes, proximal convoluted tubules of the kidney, serous cells of the peribronchial gland in the lung, parietal cells of the stomach, tips of the villi in the small intestine and interstitial cells of the testis. Our results suggest that there are some significant sites of haem synthesis in addition to the liver and bone marrow, and should be borne in mind in studies related to haem or porphyrin dynamics and flux.

The differential impact of adverse childhood experiences in the development of pre-diabetes in a longitudinal cohort of US adults.

BACKGROUND: ACEs have a dose-response relationship with diabetes. The relationship between ACEs and pre-diabetes is not well known and may represent an effective area for prevention efforts. METHODS: Data from 1054 participants from two waves of the longitudinal MIDUS study were used. Multivariate general linear regression models assessed the relationship between ACEs and biomarker outcomes. Correlation tests and mediation models investigated the relationship between ACE and pre-diabetes. RESULTS: Individuals reporting ACEs were statistically significantly more likely to have higher BMI (1.13 (0.34-1.92)), higher waist circumference (2.74 (0.72-4.76)), elevated blood fasting insulin levels (2.36 (0.71-4.02)) and higher insulin resistance (HOMA-IR (0.57 (0.08-1.06)). BMI/waist circumference and insulin resistance did not maintain independent relationships with ACEs once HOMA-IR was included in the dichotomized ACE model (p = 0.05 and p = 0.06, respectively), suggesting the relationship between BMI and ACEs may be mediated by insulin resistance. CONCLUSIONS: These results represent one of the first studies to examine the differential impact of ACEs on a diverse set of clinical pre-diabetes measures. Findings suggest sexual and physical abuse, and financial strain during childhood are important factors associated with higher risk for pre-diabetes, and should be considered during intervention development.

Tumorigenesis and genotoxicity of ethyl carbamate and vinyl carbamate in rodent cells.

Vinyl carbamate (VC) is a suspect metabolic intermediate in ethyl carbamate (EC) carcinogenesis. In the present studies, EC and VC were evaluated for their relative abilities to induce adenomas and sister chromatid exchanges (SCEs) in lung cells of A/J, C3HeB/FeJ, and C57BL/6J strain mice. For both end points, animals were administered a single i.p. injection of the test chemical. Percentage of mice with adenomas and number of adenomas per mouse were compared among the three strains 24 weeks following exposure to EC or VC. Although the relative order of strain sensitivity was the same for both chemicals: A/J greater than C57BL/6J greater than C3HeB/FeJ, VC was much more potent than EC. For SCE analysis of primary lung cells cultured from treated animals, EC and VC showed potency differences similar to those observed for tumorigenesis. All three mouse strains revealed significant dose-dependent increases in SCE frequency. However, there was no strain specificity for this effect. SCE persistence over time was also compared in treated A/J and C57BL/6J mice. Although EC- and VC-induced SCE frequencies declined over a 2-week observation period, again, there was no strain specificity for this effect. VC was also tested for enhancement of SA7 virus transformation of Syrian hamster embryo cells. Significant concentration-dependent increases in cell transformation frequency were observed.

Diverse approaches to the health economic evaluation of bariatric surgery: a comprehensive systematic review.

BACKGROUND: Health economic evaluations inform healthcare resource allocation decisions for treatment options for obesity including bariatric/metabolic surgery. As an important advance on existing systematic reviews, we aimed to capture, summarize and synthesize a diverse range of economic evaluations on bariatric surgery. METHODS: Studies were identified by electronic screening of all major biomedical/economic databases. Studies included if they reported any quantified health economic cost and/or consequence with a measure of effect for any type of bariatric surgery from 1995 to September 2015. Study screening, data extraction and synthesis followed international guidelines for systematic reviews. RESULTS: Six thousand one hundred eighty-seven studies were initially identified. After two levels of screening, 77 studies representing 17 countries (56% USA) were included. Despite study heterogeneity, common themes emerged, and important gaps were identified. Most studies adopted the healthcare system/third-party payer perspective; reported costs were generally healthcare resource use (inpatient/shorter-term outpatient). Out-of-pocket costs to individuals, family members (travel time, caregiving) and indirect costs due to lost productivity were largely ignored. Costs due to reoperations/complications were not included in one-third of studies. Body-contouring surgery included in only 14%. One study evaluated long-term waitlisted patients. Surgery was cost-effective/cost-saving for severely obese with type 2 diabetes mellitus. Study quality was inconsistent. DISCUSSION: There is a need for studies that assume a broader societal perspective (including out-of-pocket costs, costs to family and productivity losses) and longer-term costs (capture reoperations/complications, waiting, body contouring), and consequences (health-related quality-of-life). Full economic evaluation underpinned by reporting standards should inform prioritization of patients (e.g. type 2 diabetes mellitus with body mass index 30 to 34.9 kg/m(2) or long-term waitlisted) for surgery. © 2016 World Obesity.

Restoration of spinal bone in osteoporotic men by treatment with human parathyroid hormone (1-34) and 1,25-dihydroxyvitamin D.

Daily subcutaneous injection of a synthetic human parathyroid hormone fragment, combined with daily ingestion of 1,25(OH)2 vitamin D, significantly increased trabecular bone density in the spine (p less than .01), and improved intestinal calcium and phosphorus absorption and total body retention of dietary calcium and phosphorus in middle-aged men with idiopathic osteoporosis. The increases in spinal bone mineral were marked and progressive during a year of treatment. These results indicate that increasing intestinal absorption of dietary calcium while simultaneously stimulating new bone formation with small doses of parathyroid hormone can restore spinal bone in osteoporotic men.

Malnutrition studies in Macaca mulatta. V. Effect on biochemical and cytochemical composition of major organs.

The effects of control, dilute, and low-protein duets on organ development were evaluated in infant rhesus monkeys. Both experimental duets resulted in growth failure of the cerebral hemisphere, lung, liver, kidney, and muscle and, with few exceptions, in their total organ contents of water, protein, lipid, glycogen, DNA, and RNA. Calculation of the various ratios for biochemical indices per mg of DNA indicates that with the exception of increased glycogen:DNA ratios in lung of animals fed the dilute diet, increased lipid:DNA ratios in liver, and reduced glycogen:DNA ratios in muscle of animals fed the low-protein diet, all other biochemical profiles of the cellular populations of organs were comparable to control values. Accordingly, the small organ size and reduced organ content of the various biochemical indices of growth appear primarily due to the reduced cellular populations of these organs. The reduced cellular populations reflect failure of the normal miotic processes of infancy to occur, with or without loss of cells already present at the onset of the malnutrition phase. If no cell loss is involved, it is speculated that normal indices of organ growth may still be possible through the processes of "catch up" growth which accompany nutritional rehabilitation.

Pain laterality in relation to site of pain and diagnosis.

A retrospective study of pain laterality was performed on a sample of 1006 patients suffering from chronic pain attending the Centre for Pain Relief, Walton Hospital, Liverpool, U.K. 769 patients reported unilateral pain. There was no significant difference in the numbers presenting with right-sided and left-sided pain. When the data for different sites of pain were analysed separately a similar picture emerged. No statistically significant differences in the frequency of left- and right-sided pain were found at any site. Similarly, when the data for different diagnoses were examined, there were no significant differences in the laterality of the pain found in any diagnostic category. This study fails to support the general hypothesis that pain, when lateralised, occurs more frequently on the left.

Administration of sucralfate prolongs survival of animals with experimental peptic ulceration.

Ligation of the pig bile duct (BDL) results in 100% incidence of pars esophageal ulceration within 48 hours of the procedure. Usually such ulceration is uniformly fatal unless a highly selective vagotomy is performed simultaneously with the BDL. The administration of sucralfate to pigs with BDL prolonged their survival for up to 7 days, with evidence of healing of the ulcer on macroscopic and histologic observations. An increase in cell proliferation in the squamous epithelium of the ulcerated area was also seen in this sucralfate group. These features were not seen in controls, pigs with BDL only, or pigs with BDL and with magaldrate (Riopone), colloidal bismuth subcitrate (DeNol), or carbenoxolone. Analysis by Sepharose 2B gel filtration showed that there was no significant difference in the amounts of polymeric mucin in any group, with a wide scatter of the data seen especially for pigs in the untreated BDL-only group. This study suggests that sucralfate may enhance healing in this experimental pig ulcer model via a mechanism independent of the stimulation of mucus secretion. We propose that coating the mucosa with sucralfate provides a temporary substitute barrier that creates a microenvironment conducive to wound repair by mucosal proliferation.

Synthesis and anticonvulsant activity of some new 2-substituted 3-aryl-4(3H)-quinazolinones.

A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3) were synthesized and evaluated for anticonvulsant activity. Preliminary screening of these compounds revealed that 2-[2-oxo-2-(4-pyridyl)ethyl]-3-aryl-4(3H)-quinazolinones 6l and 8i, 8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity. Compounds 6l and 8i possessing 3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low neurotoxicity after intraperitoneal administration in mice. They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50) and the median lethal dose (LD50). Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats, they were also more neurotoxic. This neurotoxicity was particularly acute in oral tests with rats, which resulted in marginal protective indices. In drug differentiation tests, compound 6l was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some protection against picrotoxin-induced seizures.

Synthesis of C-11 iodoantipyrine for positron emission tomography.

We have developed a method for the synthesis of C-11 iodoantipyrine. Carbon-11-labeled methyl iodide, prepared from 11CO2, was used to methylate 3-methyl-1-phenyl-2-pyrazolin-5-one to form C-11 antipyrine. Following silica-gel column chromatography and iodination, radiochemical purity of the C-11 iodoantipyrine was more than 99.5%, with a 10% yield and a specific activity of 30 mCi/mumol. Preliminary animal studies showed complete cerebral extraction and local cerebral blood-flow values that were within 4.6% of those obtained using C-14 iodoantipyrine. The C-11 analog, with positron emission tomography, will facilitate local cerebral blood-flow studies in human subjects.

A biomechanical study of suture pullout in linea alba.

The relationship of suture bite size, suture diameter, and fascial thickness to strength of wound closure was studied in cadaveric linea alba. All soft tissue was removed from the fascia of 12 abdominal walls that were cut into 346 test sections. A single suture loop was placed in each section, simulating laparotomy closure with interrupted technique. Suture bite size (0.3, 0.6, 0.9, 1.2, 1.5, and 1.8 cm) and gauge (00, 0, 1, and 2) were randomly assigned. The force and energy required to pull out suture loops were measured. Mean linea alba thickness was greater above the linea semicircularis than below (1.19 vs 0.77 mm; p less than 0.001). Similarly, mean pullout force was greater above the linea semicircularis (58.2 vs 31.6 N; p less than 0.001). Regression analysis found that fascial thickness and bite size accounted for 68% of observed variability in pullout force. Suture diameter was unrelated to pullout force. Optimum security was obtained with bites of at least 1.2 to 1.5 cm.

A radioisotopic method for the simultaneous quantitation of regional cerebral blood flow and glucose utilization in small dissected samples: validation studies and values in the nitrous oxide-anesthetized rat.

A method is described for the simultaneous determination of the rates of regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCMRgl) in 6-7 mg brain samples dissected from multiple areas of interest. The method utilizes [131I]iodoantipyrine ([131I]IAP) to measure rCBF by indicator fractionation, and [14C]2-deoxyglucose to measure rCMRgl. [131I]IAP was synthesized with specific activity exceeding 350 Ci/mmol and radiochemical purity greater than 99.5% by the radioiodination of antipyrine with Na131I. A triple-counting strategy was developed to quantitate 14C activity of the dissected brain samples in the presence of 131I. The factors contributing to the propagated error of the double-label separation strategy were defined and optimal assay parameters were determined. The separation strategy was validated by measuring rCBF simultaneously with both [131I]IAP (x) and [14C]IAP (y) in a series of rats. The equation of the regression line was y = 1.025 x -0.065 (correlation coefficient 0.985), denoting excellent agreement. In another series of 5 normocapnic rats anesthetized with nitrous oxide, rCBF and rCMRgl were measured simultaneously. In individual animals, the rates of rCBF within 14-16 brain areas were closely coupled to their respective rates of glucose metabolism. For the group data, the linear regression equation relating rCBF (y) to rCMRgl (x) was y = 1.76 x + 0.13 (correlation coefficient 0.93, P less than 0.001). These studies provide direct evidence, based upon data obtained in the same brain, of a close coupling of regional metabolic rate and blood flow.

Factors that affect the uptake of ammonia by the brain: the blood-brain pH gradient.

The brain uptake index (BUI) for [13N]ammonia was measured in 7 areas of the rat brain at 8 different pH values ranging from 6.58 to 7.73. When the regional BUI was plotted as a function of the pH of the test bolus, a significant linear correlation was found for each region (P less than 0.001). The highest slope was observed in the thalamus-basal ganglia complex (0.392 +/- 0.018) (S.D.), and the lowest in the ventral pons (0.143 +/- 0.011). These studies indicate that the brain-blood pH gradient plays a major role in determining the forward flux of ammonia from the blood into the brain in the physiological pH range. Regional differences in the slope may be due to metabolic factors. This pH effect may be important in clinical conditions characterized by hyperammonemia such as hepatic encephalopathy, and in the interpretation of [13N]ammonia emission tomographic images of the brain.

The effects of acrylamide on mouse germ-line and somatic cell chromosomes.

The industrial chemical acrylamide is suspected to induce potentially heritable genetic damage. While several studies in rodents have indicated that this substance can damage spermiogenic cells, resulting in dominant lethals and heritable translocations, cytogenetic assessments of premeiotic and meiotic cells after exposure have produced equivocal results. In the present study, various cytogenetic endpoints in both somatic and germ-line cells from acrylamide-treated mice were evaluated. Sister chromatid exchanges and micronuclei, but not chromosome aberrations, were induced in spleen cells; synaptonemal complex irregularities (asynapsis), but not chromosome aberrations, were induced in germ cells.

Arrest of folliculogenesis and inhibition of ovulation in the monkey following weekly administration of progestins.

Studies were undertaken in the rhesus monkey to determine whether development of a dominant ovarian follicle could be repeatedly arrested by the administration of a progestin on day 7 of the menstrual cycle, and then every 7 days thereafter regardless of menstrual bleeding history. Progesterone (7.5 mg), norethisterone (1.5 mg), and 17 alpha-ethinyl-17 beta-methoxy-7 alpha-methyl-4-estren-3-one (1.0 or 1.5 mg) effectively inhibited ovulation when injected intramuscularly once a week for 8 weeks. Orally administered STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-4,9-estradien-3-one, 1.0 mg) also inhibited ovulation. Two structurally related steroids (17 beta-methoxy-4-estren-3-one, 1.0 mg; and 17 beta-methoxy-7 alpha-methyl-4-estren-3-one, 1.5 mg) did not inhibit ovulation when given intramuscularly at the indicated doses. Although weekly administration of certain progestins effectively arrested follicular development and inhibited ovulation in the primate, the treatment was accompanied by disturbances in menstrual bleeding patterns.

Experimental spinal epidural abscess: a pathophysiological model in the rabbit.

To define the pathophysiology of spinal cord dysfunction associated with spinal epidural abscess formation, we developed an experimental model. Spinal epidural abscesses were produced in rabbits by injecting Staphylococcus aureus into the posterior thoracolumbar epidural space under direct vision. Progressive neurological deficits were detected in 18 of 20 animals; severe paraparesis or paraplegia occurred in 75%, and sphincter dysfunction occurred in 55%. Clinical data, including the results of plain spine roentgenography, myelography, and biochemical and bacteriological examination of the cerebrospinal fluid, were recorded. Epidural abscesses with varying degrees of spinal cord compression were confirmed pathologically in 95% of the experimental group. Spinal cord white matter changes included vacuolization, loss of myelin, and axonal swelling. The gray matter of the spinal cords was relatively preserved. There was no microscopic evidence of thrombosis or vasculitis in the major blood vessels supplying the spinal cords. Histopathological changes detected in the spinal cords were more consistent with direct compression of neural tissue than with infarction. The progressive clinical course and the histopathological changes in the spinal cord after compression by abscess closely resembled those of experimental compression of the spinal cord by epidural neoplasm.