bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal fertility problems and risk for transient neonatal diabetes mellitus
Authors: Hargreave Marie , Kjaer Susanne Krüger , Jørgensen Marit Eika , Jensen Allan
Published: July 2017

Aims: The study of imprinting disorders in the context of infertility and its treatment is important, as studies have indicated an increased risk. In this study, we evaluated the risk of transient neonatal diabetes mellitus (TNDM), defined here as diabetes mellitus presenting within the first six weeks of life, in children born to women with fertility problems. Methods: This nationwide register-based cohort study comprised all 2,107,837 children born in Denmark between 1977 and 2010. Of these, 121,044 (5.7%) children were born to women with fertility problems. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between maternal fertility status and the risk for TNDM. Results: A total of 103 children developed TNDM during the follow-up period. Children born to women with fertility problems had an elevated risk for TNDM, after adjustment for birth year, maternal age at birth and parental history of diabetes, although this was not statistically significant (HR = 1.49; 95% CI 0.73–3.03). The risk of children born in the period 1994–2010 (a period with more comprehensive information on maternal fertility problems and with more invasive fertility treatment procedures) was increased almost twofold (HR = 1.92; 95% CI 0.92–4.00) but was still not statistically significant. Conclusions: Our results indicate that children born to women with fertility problems, particularly after 1993, may be at an elevated risk for TNDM. As the increased risks were not statistically significant, however, the finding may be due to chance.
Scoping the meaning of ‘critical’ in mathematical thinking for Initial Teacher Education
Authors: Furness Jane , Cowie Bronwen , Cooper Beverley
Published: July 2017

Current strong emphasis on literacy and numeracy in New Zealand educational policy, as elsewhere, reverberates in different ways in institutions charged with children’s and adults’ learning. A common response is to locate literacy and numeracy centrally in programmes aimed at preparing children for and enhancing adult participation in 21st century life and work. These agendas overlap in preservice teacher education. Preservice teachers enter Initial Teacher Education (ITE) programmes as adult learners engaged in building literacy and numeracy capability for teaching across the curriculum, working with student achievement data and administrative tasks, aspects of which may also be useful in their wider lives. These activities involve making judgements that require critical thinking, another key policy focus in New Zealand and internationally for children’s and adults’ learning. This article explores meanings of ‘critical’ in the context of mathematical thinking in ITE programmes. Given that mathematically based arguments can have both helpful and harmful consequences for humanity, we propose that development in preservice teachers’ capacity for critical mathematical thinking is crucial. In these times of significant global change we advocate for development of the kind of critical mathematical thinking that facilitates teachers working actively in pursuit of a socially just and sustainable world.
The Influence of Positioning of the Nellix Endovascular Aneurysm Sealing System on Suprarenal and Renal Flow: An In Vitro Study
Authors: Boersen Johannes T. , Groot Jebbink Erik , Van de Velde Lennart , Versluis Michel , Lajoinie Guillaume , Slump Cornelius H. , de Vries Jean-Paul P. M. , Reijnen Michel M. P. J.
Published: July 2017

Purpose: To examine the influence of device positioning and infrarenal neck diameter on flow patterns in the Nellix endovascular aneurysm sealing (EVAS) system. Methods: The transition of the aortic flow lumen into two 10-mm-diameter stents after EVAS creates a mismatched area. Flow recirculation may affect local wall shear stress (WSS) profiles and residence time associated with atherosclerosis and thrombosis. To examine these issues, 7 abdominal aortic aneurysm flow phantoms were created, including 3 unstented controls and 3 stented models with infrarenal neck diameters of 24, 28, and 32 mm. Stents were positioned within the instructions for use (IFU). Another 28-mm model was created to evaluate lower positioning of the stents outside the IFU (28-mm LP). Flow was visualized using optical particle imaging velocimetry (PIV) and quantified by time-averaged WSS (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT) in the aorta at the anteroposterior (AP) midplane, lateral midplane, and renal artery AP midplane levels. Results: Flow in the aorta AP midplane was similar in all models. Vortices were observed in the stented models in the lateral midplane near the anterior and posterior walls. In the 32-mm IFU and 28-mm LP models, a steady state of vortices appeared, with varying location during a cycle. In all models, a low TAWSS (<10−2 Pa) was observed at the anterior wall of the aorta with peak OSI of 0.5 and peak RRT of 104 Pa−1. This region was more proximally located in the stented models. The 24- and 28-mm IFU models showed flow with a higher velocity at the renal artery inflow compared to controls. TAWSS in the renal artery was lower near the orifice in all models, with the largest area in the 24-mm IFU model. OSI and RRT in the renal artery were near zero for all models. Conclusion: EVAS enhances vorticity proximal to the seal zone, especially with lower positioning of the device and in larger neck diameters. Endobags just below the renal artery affect the flow profile in a minor area of this artery in 24- and 28-mm necks, while lower stent positioning does not influence the renal artery flow profile.
Determination of Aerobic Capacity via Cycle Ergometer Exercise Testing in Alzheimer’s Disease
Authors: Bronas Ulf G. , Salisbury Dereck , Kelly Kaitlin , Leon Arthur , Chow Lisa , Yu Fang
Published: July 2017

Background:

Older adults with Alzheimer’s disease (AD) may be unable to perform treadmill testing due to balance issues. We investigated whether older adults with AD could successfully complete a peak cycle ergometer test.

Methods:

Peak oxygen consumption (peak [Formula: see text]) assessed via a cycle ergometer test in 44 participants with AD (age 78.4 ± 6.8). Physical function was assessed via the incremental shuttle walk, 6-minute walk, and the Short Physical Performance Battery (SPPB).

Results:

All participants completed the cycle ergometer test successfully. Peak [Formula: see text] was correlated with SPPB ( r = .35, P = .023), shuttle walk ( r = .35, P = .024), 6-minute walk ( r = .31, P = .05), and inversely with age ( r = −.4, P = .009). There was no correlation between peak [Formula: see text] and cognition.

Conclusion:

Older adults with AD are able to safely complete a peak cycle ergometer exercise testing protocol. We provide an individualized cycle ergometer test for determining aerobic capacity in older adults with AD who may be unable to perform treadmill testing due to balance or gait issues.
Escape-Motivated Bathroom Visits: Effects of Activity Scheduling, Cuing, and Duration-Fading in an Adult With Intellectual Disability
Authors: Luiselli James K. , Sobezenski Timothy
Published: July 2017

We report the case of a woman who had intellectual disability, made frequent bathroom requests, and spent excessive time in the bathroom at a day-habilitation center. Functional behavioral assessment suggested that frequency and duration of bathroom requests were escape-motivated. Intervention was directed at reducing the reinforcing effects of visiting the bathroom through (a) activity scheduling, (b) cuing the woman to exit the bathroom according to a fixed time limit, and (c) gradually reducing the time limit to an acceptable duration. Compared with a baseline phase, intervention was associated with decreased bathroom requests and duration of bathroom visits that were maintained at 2-month follow-up. We discuss clinical implications of these findings and recommendations to practitioners.
Nuclear Lipid Signaling: Novel Role of Eicosanoids
Authors: Gilmour R. Stewart , Mitchell Murray D.
Published: July 2017

Nuclear lipid signaling is an established, widespread mechanism that operates in multiple cellular processes including proliferative and differentiative responses to a variety of stimuli. In this literature review with key references highlighted, we put forward the hypothesis that differential flow through various intracrine mechanisms can dictate resultant cellular actions such as mitosis, differentiation, or apoptosis.
Insulin Resistance: Cellular and Clinical Concepts
Authors: Cefalu William T.
Published: July 2017

Insulin resistance is defined as a clinical state in which a normal or elevated insulin level produces an attenuated biologic response. Specifically, the biologic response most studied is insulin-stimulated glucose disposal, yet the precise cellular mechanism responsible is not yet known. However, the presence of insulin resistance is observed many years before the onset of clinical hyperglycemia and the diagnosis of Type 2 diabetes. Insulin resistance at this stage appears to be significantly associated with a clustering of cardiovascular risk factors predisposing the individual to accelerated cardiovascular disease. An overview of insulin resistance and the associated clinical insulin resistant state will be discussed.
The Effect of Diabetes and Sex on Nitric Oxide–Mediated Cardiovascular Dynamics
Authors: Martínez-Nieves Brenda , Dunbar Joseph C.
Published: July 2017

Diabetes is associated with impaired cardiovascular responses that are especially prominent in females. Since nitric oxide (NO)–mediated effects on cardiovascular dynamics are altered in diabetes, we evaluated the effect of L-NAME, a nitric oxide synthase (NOS) antagonist, on mean arterial pressure (MAP), heart rate (HR), and selective vascular flows in both male and female normal and diabetic rats as an index of NO activity. Rats were made diabetic using streptozotocin and maintained for 5–6 weeks. Following anesthesia with urethane/α-chloralose, the femoral artery and vein were cannulated for recording and sampling, and flow probes were placed on the iliac, renal, and superior mesenteric arteries. A bolus infusion of L-NAME (10mg/kg) resulted in a rapid +52% and +68% increase in MAP in normal female and male rats, respectively. However, diabetic females' and males' responses were significantly lower (44% and 45%, respectively) when compared with their normal counterparts. The decreased HR in response to the peak pressor effect of L-NAME was more prominent in normal females compared with normal males (–14% vs 2%). The results in diabetic females and males were equivalent (–6% vs −9%, respectively). L-NAME decreased the conductance (flow/MAP) an average of 65% in all three vascular beds in normal female rats. In diabetic females, the iliac and superior mesenteric responses to L-NAME were less, and the renal conductance was contrastingly increased 23%. The response to L-NAME was comparable (-62%) in the renal and superior mesenteric and less (–40%) in the iliacs of normal versus diabetic males. We concluded that diabetes is associated with a decreased pressor response to NOS inhibition. And the impaired constriction response of the renal vessels noted in female diabetic rats may provide a basis for the increased renal pathology observed in diabetic humans.
Effect of Pre-Loading Oral Glucosamine HCl/Chondroitin Sulfate/Manganese Ascorbate Combination on Experimental Arthritis in Rats
Authors: Beren Joel , Hill Susan L. , Diener-West Marie , Rose Noel R.
Published: July 2017

The therapeutic effect of a nutritional supplement consisting of a combination of glucosamine hydrochloride (FCHG49), purified sodium chondroitin sulfate (TRH122), and manganese ascorbate (GCM)3 was investigated in the rat model of collagen-induced autoimmune arthritis (CIA). The GCM compound was mixed with a palatable nutritional paste (Nutri-cal® [NC]). Oral administration of the NC/GCM compound was initiated in 26 rats 10 days before immunization and continued until the day of sacrifice. One group of 12 control rats was given no oral agents; a second group of 12 control rats received NC only. Evaluations included arthritis index (AI) scoring by three independent evaluators, histologic index (HI) scoring of lesions, T-cell proliferation, and serological studies for antibody classes and subclasses. Both the AI and HI criteria showed a statistically significant reduction in the prevalence of CIA in rats pretreated with the NC/GCM (54%) compared to the combined control groups (96%, χ2 analysis P < 0.001). Rats fed the NC/GCM also exhibited a significant decrease in the severity of autoimmune arthritis in both the AI and HI compared to control Group 2 (immunized-NC) (χ2 analysis P < 0.05). Histological studies verified the decreased incidence of arthritis in the NC/GCM group compared to control Group 2.

GCM treatment failed to alter T-cell proliferation and antibody production to bovine type-II collagen, indicating that its effects are not due to alteration of the antigen-specific immune response.
Effect of L-Tryptophan Supplementation on Eosinophils and Eotaxin in Guinea Pigs
Authors: Stahl James L. , Cook Ellen B. , Pariza Michael A. , Cook Mark E. , Graziano Frank M.
Published: July 2017

Eosinophilie Myalgia Syndrome is a hypereosinophilic disorder that appears to result from the ingestion of the dietary supplement L-tryptophan by susceptible individuals. It is unclear if this disease results from tryptophan, contaminants found in tryptophan, individual predisposition (such as immune status and allergies), or some combination of effects. To evaluate effects of L-tryptophan on eosinophil migration, guinea pigs were compared with or without supplemental tryptophan (0. g/kg/day), with or without immune sensitization, and with or without immune challenge. Eosinophil counts were obtained from bone marrow, blood, lung, and bronchial alveolar lavage fluid (BAL). Lung cells were obtained to measure eotaxin concentrations in supernates and lysates with or without antigen and calcium ionophore challenge using direct ELISA. Skin biopsies were taken from both non-injected and antigen injection sites. The tryptophan supplemented, antigen-sensitized/antigen-challenged guinea pigs showed a significant decrease in blood eosinophils, compared to control (cellulose) supplemented antigen-sensitized/antigen-challenged guinea pigs [(0.086 ± 0.023) × 106vs (0.147 ± 0.021) × 106eoslnophils/ml recovered, respectively] with a significant increase in BAL eosinophils [(0.052 ± 0.008) × 106vs (0.033 ± 0.005) × 10seosinophils/ml recovered, respectively]. Unchallenged lung cell lysates from tryptophan-supplemented guinea pigs contained significantly less eotaxin compared to cellulose-supplemented guinea pigs regardless of whether they were sensitized (0.006 ± 0.002 vs 0.027 ± 0.008 ng/106cells, respectively). No differences were observed in skin biopsies between cellulose and tryptophan groups. These results suggest that L-tryptophan-supplemented guinea pigs have altered eotaxin regulation, a potential mechanism by which human overconsumption of tryptophan dietary supplements could lead to hypereosinophilic disorders in susceptible individuals.
VLCD-Induced Weight Loss Improves Heart Rate Variability in Moderately Obese Japanese
Authors: Akehi Yuko , Yoshimatsu Hironobu , Kurokawa Mamoru , Sakata Toshiie , Eto Hiroshi , Ito Sukenobu , Ono Junko
Published: July 2017

To evaluate the effects of weight reduction on the autonomic nervous system in obese patients, we investigated heart rate variability (HRV) based on 24-hr ambulatory electrocardiogram (ECG) recordings before and after weight reduction. To aim for weight reduction, 16 obese patients were treated with the very-low-calorie conventional Japanese diet (VLCD-CJ) therapy combined with behavior therapy. Percent weight reduction was 17.8% ± 1.5% (means ± SEM), but mean blood pressure did not change significantly after VLCD-CJ therapy. The mean normal R-R interval (mNN) of the 24-hr ECG and all other five time-domain indices increased after weight reduction. Spectral analysis revealed that weight reduction increased the high frequency (HF) component, but decreased the ratio of low to high (LF/HF) components. Rate of change in mNN or HF correlated positively with reduction rate of body mass index, but not that in LF/HF. Analysis of daily fluctuations in each HRV parameter showed that significant improvement after weight loss occurred mainly during the nocturnal period, but an HF component was improved throughout the day and night periods. These findings indicate that functional impairment of the autonomic nervous system in obese subjects, particularly in the nocturnal period, is improved by effective weight reduction after VLCD-CJ therapy.
Agouti Signaling Protein Stimulates Islet Amyloid Polypeptide (Amylin) Secretion in Pancreatic β-Cells
Authors: Xue Bingzhong , Zemel Michael B.
Published: July 2017

Ectopic overexpression of the murine agouti gene results in yellow coat color, obesity, hyperinsulinemia, and type II diabetes. We have shown the human homologue of agouti (agouti signaling protein; ASP) to regulate human adipocyte metabolism and lipid storage via a Ca2+-dependent mechanism. We have also demonstrated agouti expression in human pancreas, and that ASP stimulates insulin release via a similar Ca2+-dependent mechanism. Plasma amylin is also elevated in agouti mutant mice. Amylin is cosecreted with insulin from β-cells, and overexpression of human amylin in β-cells in yellow agouti mutant mice resulted in accelerated pancreatic amyloid deposition, severely impaired β-cell function, and a diabetic phenotype. We report here that ASP stimulates amylin release in both the HIT-T15 β-cell line and human pancreatic islets in the presence of a wide range of glucose concentrations (0–16.7 mmol/L), similar to its effect on insulin release; this effect was blocked by 30 μmol/L nitrendipine, confirming a Ca2+-dependent mechanism. Accordingly, ASP stimulation of amylin release may serve as a compensatory system to regulate blood glucose in yellow agouti mutants.
Cadmium Effects on Hypothalamic-Pituitary-Testicular Axis in Male Rats
Authors: Lafuente Anunciación , Márquez Nuria , Pérez-Lorenzo María , Pazo David , Esquifino Ana I.
Published: July 2017

This study analyzes cadmium effects at the hypothalamic-pituitary-testicular axis. Male rats were given cadmium during puberty or adulthood. Cadmium exposure through puberty increased norepinephrine content in all hypothalamic areas studied, but not in the median eminence. Metal exposure increased serotonin turnover in median eminence and the anterior hypothalamus, while decreased it in mediobasal hypothalamus. Also, decreased plasma levels of testosterone were found. Cadmium exposure during adulthood increased norepinephrine content in posterior hypothalamus and decreased the neurotransmitter content in anterior and mediobasal hypothalamus. Decreased circulating levels of luteinizing hormone (LH) and testosterone and increased plasma follicle stimulating hormone (FSH) levels were also observed. Cadmium accumulated in all analyzed tissues. Various parameters showed age-dependent changes. These data suggest that cadmium globally effects hypothalamic-pituitary-testicular axis function by acting at the three levels analyzed and that an interaction between cadmium exposure and age emerge.
Erythrocytic Glutathione and Plasma Cysteine Status of Human Immunodeficient Patients
Authors: Lang Calvin A. , Huang Anna , Ramirez Julio A. , Liu Marcia C.
Published: July 2017

Both deficient and normal blood levels of glutathione (GSH) and cysteine (Cys) have been reported in HIV patients, a discrepancy that has been attributed to different methodologies. The goal of this study was to apply our analytical method to this problem. Blood samples from HIV patients and healthy subjects were collected, immediately stabilized, and quantified using high performance liquid chromatography with dual electrochemical detection. The results showed that the erythrocytic GSH levels were the same in healthy subjects and in HIV patients regardless of their CD4 lymphocyte level. Only those with the lowest CD4 level plus opportunistic infections had subnormal GSH concentrations (P < 0.001). GSH plus glutathione disulfide (GSSG) levels also were normal in patients. However, the Cys contents were higher in patients than in controls (P < 0.05). These findings demonstrated that HIV patients have normal erythrocytic GSH concentrations and supranormal Cys levels.
Effect of Modified Diabetic Splenocytes on Mice Injected with Splenocytes from Multiple Low-Dose Streptozotocin Diabetic Donors
Authors: Arata Mabel , Bruno Lidia , Pastorale Claudia , Pagliero Fabiola , Basabe Juan Carlos
Published: July 2017

Etiological agents of autoimmune processes that have been made nonvirulent by several treatments, i.e., mitomycin C (Mit C), can be used as a vaccine to protect against disease. In this work we studied the effects of splenocytes from diabetic mice on animals that had been injected with modified splenocytes (Mit C-treated splenocytes from multiple low-dose streptozotocin [mld-sz] mice) 15 days before. Splenocytes from mld-sz diabetic donors altered i.p. glucose tolerance and the first peak of insulin secretion pattern when injected into normal singeneic recipients. These effects can be prevented partially (one injection in a vaccine form) or completely (two injections with a 15-day interval) by a previous injection of Mit C-treated mononuclear splenocytes (MS) from mld-sz mice. The fact that control splenocytes previously treated with Mit C were not able to achieve similar results indicates that donor splenocytes have to be diabetic to prevent the disease. On the other hand, Mit retreated diabetic MS were not effective in preventing the alterations in glucose tolerance and in the pattern of insulin secretion when injected into athymic mice. This suggests that the preventive effect of Mit C-treated diabetic MS injection also implies an active role of the T cells from the recipient mice. Mit C-treated diabetic splenocytes are preferentially trapped by the pancreas and the lymph nodes from recipient mice. Our results show that the impairment in glucose tolerance and in the insulin secretion pattern produced by diabetic splenocyte transfer can be prevented by one or two previous injections of Mit C-modlfied diabetic splenocytes.
Evidence for the Existence of a Distinct SO–4-OH– Exchange Mechanism in the Human Proximal Colonic Apical Membrane Vesicles and Its Possible Role in Chloride Transport
Authors: Tyagip Sangerta , Kavilaveettil Reena J. , Alrefai Waddah A. , Alsafwah Shadwan , Ramaswamy Krishnamurthy , Dudeja Pradeep K.
Published: July 2017

Recent studies have demonstrated that mutations in human downregulated in adenoma gene (DRA) result in congenital chloride diarrhea (CLD), and that DRA may be involved in chloride transport across the intestinal apical domains. DRA is highly homologous to sulfate transporters, but not to any member of the anion exchanger gene family (AEs). Our previous studies have characterized the existence of a distinct CI–-OH– (HCO3–) exchanger, with minimal affinity for sulfate in the human colonic apical membrane vesicles (AMV). However, the mechanism(s) of sulfate movement across the colonocyte plasma membranes in the human colon is not well understood. Current studies were undertaken to elucidate sulfate transport pathways in AMVs of human proximal colon. Purified AMV and rapid filtration 35SO–4 uptake techniques were used. Our results demonstrate the presence of a pH gradient-driven carrier-mediated SO–4-OH– exchange process in the human proximal colonic luminal membranes based on the following: a marked increase in the SO–4 uptake in the presence of an outwardly directed OH- gradient; a significant inhibition of SO–4 uptake by the membrane anion transport inhibitor, DIDS; demonstration of saturation kinetics (Km for SO–4 0.80 ± 0.17 mM and Vmax 649 ± 74 pmol/mg protein/10 sec); competitive inhibition of SO–4-OH– exchange by oxalate; SO–4 uptake was insensitive to alterations in the membrane potential; and inwardly directed Na+ gradient under non-pH gradient conditions did not stimulate SO–4 uptake. SO–4 uptake was significantly inhibited by increasing concentrations of chloride (1–10 mM) in the incubation media with a Ki, for CI– of 9.3 ± 1.4 mM. In contrast, OH–/HCO3– gradient-driven 36CI– uptake into these vesicles was unaffected by increasing concentrations of sulfate (10–50 mM). The above data indicate that two distinct transporters may be involved in SO–4 and CI– transport In the human intestinal apical membranes: an anion exchanger with high affinity for SO–4 and oxalate but low affinity for CI–, and a distinct CI–-OH– (HCO3–) exchanger with low affinity for SO–4.
Asymmetrical Response of p38 Kinase Activation to Volume Changes in Primary Rat Astrocytes
Authors: Xu Dazhong , Wang Ling , Olson James E. , Lu Luo
Published: July 2017

Activation of p38 kinase by osmotic stress has been documented in many cells; however, no report has distinguished the effects of cell volume on p38 activity from the effects of the altered osmotic condition per se. Here we report asymmetrical activation of astrocyte p38 mitogen-activated protein (MAP) kinase in response to volume increases and volume decreases. We separate effects of cell volume changes from the effects of osmotic exposure on p38 activation. Exposure to 400, 500, or 600 mOsm phosphate-buffered saline (PBS) caused cell shrinkage and an osmolality-dependent increase in p38 activity to 175%, 409%, or 518%, respectively, compared with cells maintained in control conditions (290 mOsm). Likewise, hyposmotic conditions ranging from 250 to 57 mOsm PBS caused the same activation of p38 (approximately 300% of the control value within 10 min). The activity in hyposmotic conditions did not diminish over 30 min despite cell volume recovery, indicating a dependence of extracellular osmolality or ionic strength rather than cell volume. Cells that were returned to isosmotic conditions following 30 min in 250, 150, or 57 mOsm PBS shrunk to 73%, 39%, or 26% of the control cell volume, respectively. In these cells, the activity of p38 increased further from approximately 300% of the control values in each hyposmotic condition to as much as 500% of the control activity as a function of the degree of cell shrinkage. Thus, p38 may be activated by cell shrinkage in hyperosmotic or in isoosmotic conditions, indicating reduced cell volume is a more important determinant of this enzyme activity than extracellular osmolality. Our results indicate distinct mechanisms of p38 activation in astrocytes exposed to hyperosmotic or hyposmotic PBS.
Hepatotoxicity of Prenatal and Postnatal Exposure to Nicotine in Rat Pups
Authors: Sheng Hwai-Ping , Yuen Siu Tsan , Leung So Hau , Cho Chi Hin
Published: July 2017

Prenatal and postnatal exposure to nicotine have been shown to affect developing tissues in growing animals. Rat pups were exposed to nicotine prenatally and/or postnatally for 10 days by feeding pregnant and lactating rat dams water containing 0, 54, or 108 μM of nicotine. Nicotine exposure did not affect either litter sizes or body weights at birth and at 10 days of age. Exposure to 108 μM of nicotine prenatally increased significantly the incidence of focal necrosis at birth, and the liver damage was still evident at 10 days of age even after the pups were allowed to suckle dams not exposed to any nicotine during the study period. Continuation of nicotine exposure postnatally increased the incidence and severity of focal and confluent necrosis. Postnatal exposure to 108 μM of nicotine to pups not previously exposed also increased the incidence of mild focal and confluent necrosis, although not significantly. Exposure to nicotine prenatally did not affect liver malondialdehyde (MDA) levels at birth. However, liver MDA was significantly lower in rat pups exposed to nicotine prenatally when they were 10 days of age irrespective of whether there were further exposure to nicotine postnatally. Reasons for the late onset of the low MDA levels need further investigation. Postnatal nicotine exposure to either 54 or 108 μM of nicotine to pups not previously exposed fails to affect liver MDA at 10 days of age. The significant decrease in hepatic superoxide dismutase (SOD) levels reflects those of hepatic injury, indicating the possibility of a nicotine-induced downregulation of SOD enzyme production.
Nicotine Inhibition of Apoptosis in Murine Immune Cells
Authors: Hakki Amal , Pennypacker Keith , Eidizadeh Shabnam , Friedman Herman , Pross Susan
Published: July 2017

Nicotine, the addictive component of tobacco, is thought to be at least partially responsible for the deleterious effects of smoking such as heart disease and cancer. Evidence shows that nicotine is an immunomodulator and that one of its possible mechanisms is regulation of apoptosis, or programmed cell death, in immune cells. This study examined the effects and the mechanisms of action of nicotine on dexamethasone (DEX)-induced apoptosis in murine immune cells by examining the expression of levels of the 17-kDa active caspase-3, a marker of apoptosis. Thymocytes and splenocytes from adult BALB/c female mice were Incubated with concentrations of nicotine correlating to those found in the blood and tissue of smokers (0.01 μg/ml [0.022 μM] and 1 μg/ml [2.2 μM]), concurrently with 100 nM DEX, to induce apoptosis. Cytosolic protein fractions were analyzed by Western blotting with polyclonal antibodies that recognize the active form of caspase-3. The data showed that nicotine significantly blocked the formation of the DEX-induced 17-kDa caspase-3 subunit expression. This downregulation ranged from 65% to 100% of the active caspase-3 expressed in cultures treated with DEX alone. Addition of d-tubocurarine chloride (dTC), a general nicotinic receptor antagonist, inhibited nicotine downregulation of the DEX-lnduced active caspase-3 expression, providing evidence that this action of nicotine was receptor-mediated. These data support that nicotine is an important immunomodulator at the level of immune cell apoptosis, a process thought to be a contributory mechanism of autoimmunity, cardiovascular disease, and carcinogenesis.
Brain Pathways Controlling Food Intake and Body Weight
Authors: Schwartz Michael W.
Published: July 2017

Evidence has existed for more than 50 years in support of the hypothesis that body energy stored in the form of fat is homeostatically regulated. Implicit in this concept is the existence of a biological system that operates dynamically over time to match cumulative energy intake to energy expenditure. For example, to compensate for weight loss induced by energy restriction, animals must enter a period of positive energy balance (i.e., energy intake greater than energy expenditure) that is sustained for as long as it takes to correct the deficit in body fat stores. Having reached this point, the animal must return to a state of neutral energy balance if stable fat mass is to be maintained. The identification of neuronal circuits in the hypothalamus that, when activated, exert potent, unidirectional effects on energy balance provides a cornerstone of support for this model. The additional finding that these central effector pathways are regulated by humoral signals generated in proportion to body fat stores, including the hormones insulin and leptin, helps to round out the picture of how energy homeostasis is achieved. The goal of this overview is to highlight the evidence that specific subsets of hypothalamic neurons containing specific signaling molecules participate in this dynamic regulatory process, and to put these observations in the larger context of a biological system that controls body adiposity.
Dietary Protein Peptic Hydrolysates Stimulate Cholecystokinin Release via Direct Sensing by Rat Intestinal Mucosal Cells
Authors: Nishi Takashi , Hara Hirosh , Hira Tohru , Tomita Fusao
Published: July 2017

We previously demonstrated that a peptic hydrolysate of guanidinated casein strongly stimulates exocrine pancreatic secretion in chronic bile-pancreatic juice-diverted rats and cholecystokinin (CCK) release from dispersed rat intestinal mucosal cells. These results reveal that the chemically modified protein hydrolysate stimulates CCK secretion and increases pancreatic secretion by a luminal trypsin-independent direct action on the small intestine. In the present study, we examined the direct effect of peptic hydrolysates of naturally occurring dietary proteins, casein, soybean protein isolate (SPI), egg white, and wheat gluten on CCK release under in vitro trypsin-independent conditions. All protein hydrolysates significantly stimulated CCK release from dispersed rat intestinal mucosal cells. Among the hydrolysates treated, SPI hydrolysate was the most effective in stimulating CCK release. The potential of SPI hydrolysate to stimulate CCK release was increased by long-term peptic digestion. However, an SPI-like amino acid mixture did not effect CCK release. In conclusion, peptic hydrolysates of commonly ingested dietary proteins stimulate CCK release via trypsin-independent direct sensing by intestinal mucosal cells.
Calorie Restriction Influences Cell Cycle Protein Expression and DNA Synthesis during Liver Regeneration
Authors: Cuenca Alex G. , Cress W. Douglas , Good Robert A. , Marikar Yasmin , Engelman Robert W.
Published: July 2017

Calorie restriction without essential nutrient deficiency (calorie restriction, CR) abrogates experimental carcinogenesis and extends healthful life span. To test whether CR influences cell-cycle protein expression during the hepatocellular proliferation induced by 70% partial hepatectomy (PH), BALB/c mice were separated into two groups, fed comparable semi-purified diets for 10 weeks that differed 40% in caloric offering, and were then subjected to PH. When PH was performed, CR mice weighed 36% less than ad libitum (AL)-fed mice (P < 0.01), but liver-to-body weight ratios were similar. During the regenerative hyperplasia, hepatocytes of CR mice demonstrated evidence of accelerated entrance and passage through G1 and S phases, and an earlier exit from the cell cycle. The first peak of DNA synthesis occurred 6 hr earlier, and the second peak was significantly greater among CR mice with 38% ± 13% bromodeoxyuridine (BrdU)-positive hepatocytes, compared with 14% ± 4% in AL mice (P < 0.01). More E2F-1 expression was induced at the hepatic G1/S boundary just prior to each peak of DNA synthesis in regenerating livers of CR mice (P < 0.01), and 8 hr earlier among CR mice. More hyperphosphorylated retinoblastoma p110 was detected during hepatic G1 and the G1-S transition among CR mice, coincident with the early hepatocellular proliferative wave. Cyclin A was induced during the first peak of DNA synthesis 4 hr earlier among CR mice, and it continued 4 hr longer in AL mice, indicating an earlier post-replicative exit by hepatocytes in CR mice. p21 was induced during the G1 phase at 4 hr post-PH, and was maximally expressed during and after peak DNA synthesis in both dietary groups. These results indicate that CR influences cell cycle protein expression levels, causing hepatocytes to enter into S phase earlier and exit abruptly from the cell cycle, and they support the premise that CR enhances induced cell responsiveness by influencing cell cycle regulatory controls.
Lingering Doubts about Spongiform Encephalopathy and Creutzfeldt-Jakob Disease
Authors: Narang Harash K.
Published: July 2017

Bovine spongiform encephalopathy (BSE) is an infectious disease and has been transmitted orally to many other animals, including humans. There is clear evidence of maternal transmission, although disagreement on the source of the BSE agent remains. The current theories link the origin of BSE to common scrapie in sheep. Twenty different strains of the scrapie agent have been isolated from sheep. A search of the literature indicates two distinct clinical syndromes in sheep, both of which have been called scrapie. I have designated these Type I (the common type), which exhibits itchiness and lose their wool, and Type II, which exhibits trembling and ataxia. Sheep inoculated with BSE develop Type II scrapie and they exhibit trembling. When cattle or mink are injected with the Type I strain, only a few will develop a clinical disease. By contrast, no clinical disease has so far been shown in cattle or mink by feeding them with Type I-infected sheep brains. However, either by injecting or feeding with the BSE strain, 100% of calves and mink develop the clinical disease. Evidence suggests that Type II is the cause of BSE. Identical clinical signs of Type II trembling are found in kuru and many of the recent cases of Creutzfeldt-Jakob disease. The BSE agent has caused spongiform encephalopathies (SEs) in domestic cats, tigers, and in some species of ruminants in zoos. The nature of the BSE agent remains unchanged when passaged through a range of species, irrespective of their genetic make up, demonstrating that variations in the host PrP gene are not a major factor in the susceptibility to the BSE agent. Since more than 85 zoo animals of many species have been diagnosed with SEs, from these studies it seems reasonable to conclude that the BSE agent can infect almost all mammalian species, including humans. For eradication of BSE and to reduce the risk of infection to humans, the development of a vaccine against BSE is suggested. Such a possibility should be fully explored.
Copper Control as an Antiangiogenic Anticancer Therapy: Lessons from Treating Wilson's Disease
Authors: Brewer George J.
Published: July 2017

The search for new anticopper drugs for Wilson's disease is culminating in two excellent new drugs: zinc for maintenance therapy and tetrathiomolybdate (TM) for initial therapy. Both are effective and nontoxic. TM is a very potent, fast-acting new anticopper drug and its properties may be useful well beyond Wilson's disease. Angiogenesis (new blood vessel growth) is required for tumor growth, and a sufficient level of copper appears to be required for angiogenesis. We hypothesize that there is a “window” to which the copper level can be reduced that inhibits angiogenesis in tumors, but does not interfere with vital cellular functions of copper. Using TM therapy, this approach has worked to slow or stabilize tumor growth in several animal tumor models, and preliminary results are also very encouraging in human patients with a variety of advanced and metastatic malignancies. A hypothesis is advanced that copper availability has played a fundamental role in growth regulation throughout evolution and that is the reason that so many angiogenic promoters appear to be dependent upon copper levels.
GnRH and Gonadotropin Release is Decreased in Chronic Nitric Oxide Deficiency
Authors: Barnes Maria J. , Lapanowski Karen , Rafols Jose A. , Lawson David M. , Dunbar Joseph C.
Published: July 2017

Nitric oxide synthetase (NOS), the conversion enzyme for nitric oxide (NO) is localized in the anterior pituitary of female rats, particularly in gonadotrophs and folliculo-stellate cells, suggesting that NO regulates the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary. The focus of this study was to determine the effect of chronic NO deficiency on the subsequent pituitary release of LH and FSH in vitro and the hypothalamic immunoexpression of GnRH in vivo. NO deficiency was induced by adding the NOS inhibitor, N-nitro-L-arginine (L-NNA, 0.6g/L) to the drinking water of female Wistar rats. After 8 weeks, the animals were euthanized, the pituitaries were removed, and they were incubated in vitro. Pituitaries were perfused for 4 hr in the presence of pulsatile gonadotropin release hormone (GnRH, 500 ng/pulse) every 30 min. S-Nitroso-L-acetyl penicillamine (SNAP, an NO donor, 0.1 mM) or L-nitro-argine methyl ester (L-NAME, a NOS inhibitor, 0.1 mM) was added to the media and perfusate samples were collected at 10-min intervals. LH and FSH levels in the perfusate were measured by double antibody radioimmunoassays. Pituitaries from the NO-deficient rats had a significantly smaller GnRH-stimulated release of LH and FSH compared with proestrous control rats. The addition of S-NAP to the perfusate resulted in decreased LH and FSH secretion in the control group, but increased LH secretion in the NO-deficient group. The addition of L-NAME to the perfusate suppressed LH secretion from control pituitaries, but not in pituitaries from NO-deficient animals. Immunohistochemistry of brain slices demonstrated that NO-deficient rats had a large qualitative decrease of GnRH in the median eminence compared with their controls. This decrease was particularly evident in the external capillary plexus of the median eminence. We concluded that chronic NO deficiency is associated with a decreased GnRH in neurosecretory terminals in the external capillary layer of the median eminence, accompanied by a decrease in LH and FSH release from the pituitaries.
Hormonal Modulation of Food Intake in Response to Low Leptin Levels Induced by Hypergravity
Authors: Moran Megan M. , Stein T. Peter , Wade Charles E.
Published: July 2017

A loss in fat mass is a common response to centrifugation and it results in low circulating leptin concentrations. However, rats adapted to hypergravity are euphagic. The focus of this study was to examine leptin and other peripheral signals of energy balance in the presence of a hypergravity-induced loss of fat mass and euphagia. Male Sprague-Dawley rats were centrifuged for 14 days at gravity levels of 1.25, 1.5, or 2 G, or they remained stationary at 1 G. Urinary catecholamines, urinary corticosterone, food intake, and body mass were measured on Days 11 to 14. Plasma hormones and epididymal fat pad mass were measured on Day 14. Mean body mass of the 1.25, 1.5, and 2 G groups were significantly (P < 0.05) lower than controls, and no differences were found in food intake (g/day/100 g body mass) between the hypergravity groups and controls. Epididymal fat mass was 14%, 14%, and 21% lower than controls in the 1.25, 1.5, and 2.0 G groups, respectively. Plasma leptin was significantly reduced from controls by 46%, 45%, and 65% in the 1.25, 1.5, and 2 G groups, respectively. Plasma insulin was significantly lower in the 1.25, 1.5, and 2.0 G groups than controls by 35%, 38%, and 33%. No differences were found between controls and hypergravity groups in urinary corticosterone. Mean urinary epinephrine was significantly higher in the 1.5 and 2.0 G groups than in controls. Mean urinary norepinephrine was significantly higher in the 1.25, 1.5 and 2.0 G groups than in controls. Significant correlations were found between G load and body mass, fat mass, leptin, urinary epinephrine, and norepinephrine. During hypergravity exposure, maintenance of food intake is the result of a complex relationship between multiple pathways, which abates the importance of leptin as a primary signal.
Cholesterol-Lowering Effects of Maitake (Grifola frondosa) Fiber, Shiitake (Lentinus edodes) Fiber, and Enokitake (Flammulina velutipes) Fiber in Rats
Authors: Fukushima Michihiro , Ohashi Tetsu , Fujiwara Yukiko , Sonoyama Kei , Nakano Masuo
Published: July 2017

The effects of mushroom fibers on serum cholesterol and hepatic low-density lipoprotein (LDL) receptor mRNA in rats were investigated. Rats were fed a cholesterol-free diet with 50 g/kg cellulose powder (CP), 50 g/kg maitake (Grifola frondosa) fiber (MAF), 50 g/kg shiitake (Lentinus edodes) fiber (SF), or 50 g/kg enakitake (Flammulina velutipes) fiber (EF) for 4 weeks. There were no significant differences in the body weight, food intake, liver weight, cecum weight, and cecum pH among the groups. Cecal acetic acid, butyric acid, and total short-chain fatty acid (SCFA) concentrations in the SF and EF groups were significantly higher than those in the other groups. The serum total cholesterol concentration in the CP group was significantly higher than that in the MAF and EF groups. The very LDL (VLDL) + intermediate-density lipoprotein (IDL) + LDL-cholesterol concentration in the CP group was significantly higher than that in the MAF, SF, and EF groups, whereas the high-density lipoprotein (HDL)-cholesterol concentration in the EF group was significantly lower than that in the other groups at the end of the 4-week feeding period. The hepatic LDL receptor mRNA level in the EF group was significantly higher than that in the CP group. The fecal cholesterol excretion in the MAF, SF, and EF groups was significantly higher than that in the CP group. The results of this study demonstrate that MAF and EF lowered the serum total cholesterol level by enhancement of fecal cholesterol excretion, and in particular, by enhancement of hepatic LDL receptor mRNA in EF group.
Control of Coronary Blood Flow during Exercise
Authors: Tune Johnathan D. , Richmond Keith Neu , Gorman Mark W. , Feigl Eric O.
Published: July 2017

Under normal physiological conditions, coronary blood flow is closely matched with the rate of myocardial oxygen consumption. This matching of flow and metabolism is physiologically Important due to the limited oxygen extraction reserve of the heart. Thus, when myocardial oxygen consumption is increased, as during exercise, coronary vasodilation and increased oxygen delivery are critical to preventing myocardial underperfusion and Ischemia. Exercise coronary vasodilation is thought to be mediated primarily by the production of local metabolic vasodilators released from cardiomyocytes secondary to an increase in myocardial oxygen consumption. However, despite various investigations into this mechanism, the medlator(s) of metabolic coronary vasodilation remain unknown. As will be seen in this review, the adenosine, K+ATP channel and nitric oxide hypotheses have been found to be inadequate, either alone or in combination as multiple redundant compensatory mechanisms. Prostaglandins and potassium are also not important in steady-state coronary flow regulation. Other factors such as ATP and endothelium-derived hyperpolarizing factors have been proposed as potential local metabolic factors, but have not been examined during exercise coronary vasodilation. In contrast, norepinephrine released from sympathetic nerve endings mediates a feed-forward ß-adrenoceptor coronary vasodilation that accounts for -25% of coronary vasodilation observed during exercise. There is also a feed-forward α-adrenoceptor-mediated vasoconstriction that helps maintain blood flow to the vulnerable subendocardium when heart rate, myocardial contractility, and oxygen consumption are elevated during exercise. Control of coronary blood flow during pathophysiological conditions such as hypertension, diabetes mellitus, and heart failure is also addressed.