Cardiovascular Components Research Articles

Mannitol is an independent risk factor of acute kidney injury after cerebral trauma: a case–control study

We retrospectively studied a random cohort of patients with cerebral trauma to investigate the risk factors of acute kidney injury (AKI) following cerebral trauma. AKI was determined using the RIFLE (risk, injury, failure, loss, or end-stage kidney) staging criteria. About 171 patients were chosen in the study, with 53 patients in AKI group and 118 patients without AKI in non-AKI group. By logistic regression analysis, univariate analysis revealed that age, hypertension, emergent surgery, systemic inflammatory response syndrome (SIRS), Glasgow coma score (GCS), sequential organ failure assessment (SOFA) score, the respiration, coagulation, and cardiovascular components of the SOFA score, mechanical ventilation time, red blood cell transfusion, plasma transfusion, and the accumulative doses of furosemide, torsemide, and mannitol were significantly related to AKI after cerebral trauma. Logistic multivariate regression analysis showed that SOFA score [odds ratio (OR) = 1.516, 95% confidence interval (CI) 1.222–1.881, p < 0.001], the accumulative doses of torsemide (OR = 0.016, 95% CI 1.002–1.031, p = 0.016), and the accumulative doses of mannitol (OR = 2.687, 95% CI 1.062–6.800, p = 0.037) were independent risk factors of AKI. This model had a good discrimination for AKI with an area under the receiver operating characteristic (ROC) curve of 0.901 (p < 0.001). The accumulative doses of mannitol as a risk factor of AKI were identified by propensity score match (PSM) method. We concluded that AKI was a common complication in patients with cerebral trauma. SOFA score and the accumulative doses of torsemide and mannitol were independent risk factors of AKI following cerebral trauma.

Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout

For many years, the relationship between cardiovascular disease risk and gout, though strong and consistent, was suspected of being coincidental rather than causative. In recent years, compelling epidemiological and clinical data have increasingly favoured an aetiological connection. However, that connection is notably complex, involving a multifaceted model that includes interactions between inflammatory processes, oxidative stress and potential genetic influences, as well as cardiovascular and renal components that remain only partly explained. Urate appears to be able to activate the immune response, and in that context has a mediating role in the inflammatory process via the inflammasome. This interaction of urate and inflammation is central to the inflammatory cascade associated with gout flares. In the arena of oxidative stress, urate has both antioxidant and pro-oxidant properties, and while potentially beneficial in scavenging free radicals, it can also impair endothelial function and thereby give rise to atherosclerotic risk. Human and animal studies have revealed associations between hyperuricaemia and a host of atherosclerotic risk factors, whereas a reduction in urate levels is frequently associated with improvement or even resolution of such risk factors. The degree to which reduction of serum urate can reliably improve cardiovascular risk remains uncertain. It is hoped that the introduction of newer urate-lowering agents may help to clarify this picture and improve treatment options for both gout and atherosclerosis.

Growth Curves for Cardio-Metabolic Risk Factors in Children and Adolescents

This study developed percentile curves for anthropometric (waist circumference) and cardiovascular (lipid profile) risk factors for US children and adolescents. A representative sample of US children and adolescents from the National Health and Nutrition Examination Survey from 1988 to 1994 (NHANES III) and the current national series (NHANES 1999-2006) were combined. Percentile curves were constructed, nationally weighted, and smoothed using the Lambda, Mu, and Sigma method. The percentile curves included age- and sex-specific percentile values that correspond with and transition into the adult abnormal cut-off values for each of these anthropometric and cardiovascular components. To increase the sample size, a second series of percentile curves was also created from the combination of the 2 NHANES databases, along with cross-sectional data from the Bogalusa Heart Study, the Muscatine Study, the Fels Longitudinal Study and the Princeton Lipid Research Clinics Study. These analyses resulted in a series of growth curves for waist circumference, total cholesterol, LDL cholesterol, triglycerides, and HDL cholesterol from a combination of pediatric data sets. The cut-off for abnormal waist circumference in adult males (102 cm) was equivalent to the 94(th) percentile line in 18-year-olds, and the cut-off in adult females (88 cm) was equivalent to the 84(th) percentile line in 18-year-olds. Triglycerides were found to have a bimodal pattern among females, with an initial peak at age 11 and a second at age 20; the curve for males increased steadily with age. The HDL curve for females was relatively flat, but the male curve declined starting at age 9 years. Similar curves for total and LDL cholesterol were constructed for both males and females. When data from the additional child studies were added to the national data, there was little difference in their patterns or rates of change from year to year. These curves represent waist and lipid percentiles for US children and adolescents, with identification of values that transition to adult abnormalities. They could be used conditionally for both epidemiological and possibly clinical applications, although they need to be validated against longitudinal data.

Socio-economic status, cortisol and allostatic load: a review of the literature

The notion that chronic stress contributes to health inequalities by socio-economic status (SES) through physiological wear and tear has received widespread attention. This article reviews the literature testing associations between SES and cortisol, an important biomarker of stress, as well as the summary index of allostatic load (AL). A search of all published literature on the PubMed and ISI Web of Knowledge literature search engines was conducted using broad search terms. The authors reviewed abstracts and selected articles that met the inclusion criteria. A total of 26 published studies were included in the review. Overall, SES was not consistently related to cortisol. Although several studies found an association between lower SES and higher levels of cortisol, many found no association, with some finding the opposite relationship. Lower SES was more consistently related to a blunted pattern of diurnal cortisol secretion, but whether this corresponded to higher or lower overall cortisol exposure varied by study. Approaches to collecting and analysing cortisol varied widely, likely contributing to inconsistent results. Lower SES was more consistently related to higher levels of AL, but primarily via the cardiovascular and metabolic components of AL rather than the neuroendocrine markers. Current empirical evidence linking SES to cortisol and AL is weak. Future work should standardize approaches to measuring SES, chronic stress and cortisol to better understand these relationships.

Ability of physical activity measurements to assess health-related risks

The aim of this study is to evaluate if two different physical activity (PA) questionnaires have similar ability to rank individuals, and to examine associations with cardiovascular-metabolic risk factors, compared to an objective measure. In a random sample (n=369, age: 65+/-6 years) from the population-based 'Malmö Diet and Cancer' (MDC) cohort, PA was measured by a leisure-time comprehensive questionnaire (MDC-score), a simple leisure-time questionnaire and by accelerometer-monitoring (CSA). Moderate correlations were observed between MDC-score and CSA in men and women (r=0.35 and 0.24, respectively). In men, both questionnaires and CSA were inversely associated with waist circumference, insulin resistance and metabolic syndrome. In women, the MDC-score was positively associated with high-density lipoprotein-cholesterol, and the simple questionnaire inversely associated with anthropometric indexes, but no association was seen between PA estimates and cardiovascular components. We conclude that both PA questionnaires distinguish health risks associated with anthropometric-metabolic risk factors, particularly in men.

Trans fat feeding results in higher serum alanine aminotransferase and increased insulin resistance compared with a standard murine high-fat diet

Diets high in trans fats are associated with an increased risk of cardiovascular disease and components of the metabolic syndrome. The influence of these toxic fatty acids on the development of nonalcoholic fatty liver disease has not been significantly examined. Therefore, we sought to compare the effect of a murine diet high in trans fat to a standard high-fat diet that is devoid of trans fats but high in saturated fats. Male AKR/J mice were fed a calorically identical trans fat diet or standard high-fat diet for 10 days, 4 wk, and 8 wk. Serum alanine aminotransferase (ALT), lipid, insulin, and leptin levels were determined and the quantitative insulin-sensitivity check index (QUICKI) was calculated as a measure of insulin resistance. Additionally, hepatic triglyceride content and gene expression of several proinflammatory genes were assessed. By 8 wk, trans fat-fed mice exhibited higher ALT values than standard high-fat-fed mice (126 +/- 16 vs. 71 +/- 7 U/l, P < 0.02) despite similar hepatic triglyceride content at each time point. Trans fat-fed mice also had increased insulin resistance compared with high-fat-fed mice at 4 and 8 wk with significantly higher insulin levels and lower QUICKI values. Additionally, hepatic interleukin-1beta (IL-1beta) gene expression was 3.6-fold higher at 4 wk (P < 0.05) and 5-fold higher at 8 wk (P < 0.05) in trans fat-fed mice compared with standard high-fat-fed mice. Trans fat feeding results in higher ALT values, increased insulin resistance, and elevated IL-1beta levels compared with standard high-fat feeding.

A hybrid hierarchical decision support system for cardiac surgical intensive care patients. Part II. Clinical implementation and evaluation

Patients emerging from cardiac surgery can display varying degrees of cardiovascular instability arising from potentially complex, multi-factorial and interlinked causes. Stabilization and control of the cardiovascular system are currently managed by healthcare experts using experiential knowledge, and, in some centers, manually inputted decision pathway algorithms. This paper describes a clinical trial undertaken to determine the basic functioning of a clinical decision support system (CDSS) designed and constructed by the authors to facilitate the control of the major cardiovascular components in the early post-operative phase. Part II follows Part I's description of the software and simulation testing of the CDSS, and describes the hardware setup of a patient monitoring and CDSS. The system is evaluated on three post-cardiac surgery intensive care patients whom had all undergone cardio-pulmonary bypass. The study was approved by the Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust Research Ethics Committee and conducted at the North Trent cardio-thoracic surgical unit and cardiac intensive care unit (CICU), Northern General Hospital, Sheffield (UK). Patients considered as 'very likely' to require active intervention to support the cardiovascular function following routine cardiac surgery were recruited during pre-operative surgical and anesthetic assessment, giving written informed consent when admitted for their operation. These patients underwent routine induction and maintenance of anesthesia by a non-study consultant anesthetist and the operation performed. There were no restrictions placed on the types of invasive monitoring used, on the use of trans-oesophageal echocardiography, drug selection, or the anesthetic agents selected by the clinicians performing the operations. All patients had full, routine invasive and non-invasive monitoring applied, including electrocardiography, central venous and peripheral arterial catheterisation, urine outputs and central temperature. After chest closure the patients were transferred to the CICU, sedated and ventilated, and the study commenced by the study anesthetist (1st author). The patients were in a clinically stable condition when admitted to the unit, and were attended by the treating clinicians until the handover to the study anesthetist occurred. The LiDCOplus (lithium dilution cardiac output) monitor (LiDCO Limited, Flowers Building, Granta Park, Cambridge CB1 6GU, United Kingdom) was calibrated after attachment to the patient's arterial line, and the patient's beat-to-beat hemodynamic data transferred to the host laptop computer. The CDSS graphical interface displays the patient's clinical details and specific cardiovascular data and prompts the anesthetist to input the target ranges for each parameter, and select a suitable advisor frequency. This is the frequency with which the therapeutic advice is displayed on screen with an audible prompt for a control inputs from the anesthetist. In each case this was selected to be 30s. When the study anesthetist agreed with the CDSS advice (administration of fluid, commencing a drug, altering the drug infusion rate) the syringe motif on the "Advisor Infusion Rates" panel of the graphical interface was 'clicked' on and the infusion rate immediately and manually inputted to Graseby 3400 pumps. If any disagreement between the anesthetist and the computer's advice arose, the syringe motif on the "Expert Infusion Rates" panel of the preferred drug was 'clicked' on and the expert's therapeutic decision (e.g. infusion rate) was entered in the corresponding data field and then applied to the pump. During all trials, data was stored for off-line analysis. The CDSS successfully selected suitable drug therapies for each case and advised reasonable and appropriate infusion rates such that the study anesthetist did not have to override the suggested CDSS instructions and infusion rates. Under differing clinical conditions the system was able to maintain clinically appropriate and stable control of the cardiovascular system (CVS), with good profiles under noisy physiological measurements, and was readily able to regain control following transient deterioration of the patient hemodynamic parameters (coughing, or during blood sampling).

Surface properties and blood compatibility of commercially available diamond‐like carbon coatings for cardiovascular devices

The aim of this study was to determine the relationships between the surface properties and blood compatibility of in-use diamond-like carbon (DLC) coatings for cardiovascular components. Commercially available DLC films were characterized with respect to surface topography and wettability, protein adsorption from human plasma, and platelets adhesion/activation. Fibrinogen (Fng) and human serum albumin (HSA) adsorbed onto the sample surfaces were in particular quantified as two of the main proteins involved in blood compatibility. A low tendency of platelets to spread and form aggregates onto the DLC-coated surfaces has been described and related to a low Fng-to-HSA adsorption ratio. This study provides evidence that the rapid and tenacious binding of albumin molecules to DLC materials tends to passivate the surfaces and to inhibit Fng adsorption, thus imparting thromboresistance to the carbon coatings by rendering the surfaces less adhesive and activating for platelets. Albumin preferential adsorption was ascribed to high chemical heterogeneity of the DLC sample surfaces. The DLC films tested present a favorable behavior as regards blood compatibility with respect to platelet thrombus formation by reason of their surface properties.

Accuracy of Sequential Organ Failure Assessment (SOFA) scoring in clinical practice

The Sequential Organ Failure Assessment (SOFA) score is used to quantify the severity of illness daily during intensive care. Our aim was to evaluate how accurately SOFA is recorded in clinical practice, and whether this can be improved by a refresher course in scoring rules. The scores recorded by physicians in a university hospital intensive care unit (ICU) were compared with the gold standard determined by two expert assessors. Data concerning all consecutive patients during two 6-week-long observation periods (baseline and after the refresher course) were compared. SOFA was accurate on 75/158 (48%) patient days at baseline. The cardiovascular, coagulation, liver, and renal component scores showed excellent accuracy (>or=82%, weighted kappa >or=0.92), while the neurological score showed only moderate (70%, weighted kappa 0.51) and the respiration score showed good accuracy (75%, weighted kappa 0.79). After the refresher course, the number of >or=2 point errors decreased (P<0.01). Sedation precluded neurological evaluation on 135/311 (43%) days. The accuracy of the assumed neurological scores was lower than those based on timely data: 89/135 (66%, weighted kappa 0.55) vs. 125/176 (71%, weighted kappa 0.81) (P<0.01). Only half of the SOFA scores were accurate. In most cases, they were accurate enough to allow the recognition of organ failure and detection of change. The component scores showed good to excellent accuracy, except the neurological score. After the refresher course, the results improved slightly. The moderate accuracy of the neurological score was not amended. A simpler neurological classification tool than the Glasgow Coma Scale is needed in the ICU.

Role of 5-HT 1A receptors in the lower brainstem on the cardiovascular response to dorsomedial hypothalamus activation

The dorsomedial hypothalamus (DMH) is an essential brain region for the integration of the physiological response to psychological stressors. The cardiovascular components of the response include increases in blood pressure, heart rate and the activity of sympathetic nerves to the kidney, skin, brown adipose tissue, and heart. Neurons in the rostral ventrolateral medulla (RVLM) and in the region of the medullary raphe are important components of the descending pathways that mediate the cardiovascular response to the DMH activation. Activation of 5-hydroxytryptamine 1A (5-HT 1A) receptors in the brain leads to a suppression of the cardiac and sympathetic vasomotor components of the DMH-evoked response and of the response to acute psychological stress. In this study we showed that intracisternal injection of a low dose (1 µg/kg) of the 5-HT 1A receptor agonist, 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), significantly reduced the increases in heart rate and renal sympathetic nerve activity evoked by disinhibition of the DMH, but had no effect on these responses when injected intravenously. Subsequent intracisternal administration of the 5-HT 1A receptor antagonist WAY-100635 restored the DMH-evoked cardiovascular responses to levels observed before 8-OH-DPAT administration. Bilateral microinjections of 8-OH-DPAT (200pmol on each side) into the RVLM, however, did not significantly affect the cardiovascular response to disinhibition of the DMH. These observations demonstrate that activation of 5-HT 1A receptors within the lower brainstem, but not in the RVLM, can powerfully suppress the cardiovascular response evoked from the DMH.

Laser microfabrication of L605 cobalt-chromium cardiovascular stent implants with modulated pulsed Nd:YAG laser

Photonics modulation techniques can be effectively used for the laser microfabrication of biomedical implants to achieve better flexibility and control of the available optical power. These enable the processing and manufacturing of biomedical implants like cardiovascular stents and micro-metallic components with reduced heat affected zone (HAZ) and extremely precise edge cutting. Our investigation deals with the study of acousto-optic modulation of a pulsed Nd:YAG laser beam and further profile cutting of thin cobalt-chromium tubes for cardiovascular stent manufacturing. The acousto-optic modulator used in the investigations is a Bragg diffraction device. During one piercing process, the focused laser power is gradually varied from a low value and reaches the maximum as the beam goes deeper into the material. The optimum value for dwell time during which the laser piercing is occurring is found as 58 ms. A 14-step staircase modulating voltage with a maximum AC component of 900 mV was used, and the laser power was 4.4 W in TEM00 operation. Pulsed Nd:YAG laser modulated using an acousto-optic device in the Bragg regime is capable of cutting extremely complex geometries of stents on L605 tubing. Laser cutting resulted in a kerf width of 22.5±0.5 µm. Precise strut dimensions of 112±15 µm for the subsidiary strut, 140±15 µm for the main strut, and 140±15 µm for the link were also obtained. Scanning electron microscopy (SEM) images of L605 stents illustrate the higher strength Co-Cr alloy L605 with the same ductility, its ability to be translated into thinner struts, and improved deliverability. L605 also exhibits enhanced radio visibility thanks to its tungsten content and exceptional work hardening rate for a uniform expansion with minimal recoil.

Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects

Data on the effectiveness of sleeve gastrectomy in improving or resolving type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MS) are scarce. A twelve-month prospective study on the changes in glucose homeostasis and the MS in 91 severely obese T2DM subjects undergoing laparoscopic SG (SG; n = 39) or laparoscopic Roux-en-Y gastric bypass (GBP; n = 52), matched for DM duration, type of DM treatment, and glycemic control was conducted. At 12 months after surgery, subjects undergoing SG and GBP lost a similar amount of weight (%EBL: SG: 63.00 +/- 2.89%, BPG: 66.06 +/- 2.34%; p = 0.413). On that evaluation, T2DM had resolved, respectively, in 33 out of 39 (84.6%) and 44 out of 52 (84.6%) subjects after SG and GBP (p = 0.618). The rate of resolution of the MS (SG: 62.2%, BPG: 67.3%; p = 0.392) was also comparable. A shorter DM duration (p < 0.05), a DM treatment not including pharmacological agents (p < 0.05), and a better glycemic control (p < 0.05), were significantly associated with T2DM resolution in both surgical groups. Weight loss was not associated with T2DM resolution after SG or GBP, but was associated with resolution of the MS following the two surgical procedures (p < 0.05). Our data show that at 12 months after surgery, SG is as effective as GBP in inducing remission of T2DM and the MS. Furthermore, our data suggest that SG and GBP represent a successful an integrated strategy for the management of the different cardiovascular risk components of the MS in subjects with T2DM.

The role of the paratrigeminal nucleus in the pressor response to sciatic nerve stimulation in the rat

The paratrigeminal nucleus (Pa5), an input site for spinal, trigeminal, vagus and glossopharyngeal afferents, is a recognized site for orofacial nociceptive sensory processing. It has efferent connections to brain structures associated with nociception and cardiorespiratory functions. This study aimed at determining the function of the Pa5 on the cardiovascular component of the somatosensory reflex (SSR) to sciatic nerve stimulation (SNS) in paralyzed and artificially-ventilated rats following Pa5 chemical lesions (ibotenic acid), synaptic transmission blockade (CoCl 2), local anaesthetics (lidocaine) or desensitization of primary afferent fibers (capsaicin). The pressor response to sciatic nerve stimulation at 0.6 mA and 20 Hz (14 ± 1 mm Hg) was strongly attenuated by contra- (− 80%) or bilateral (− 50%) paratrigeminal nucleus lesions. Ipsilateral Pa5 lesions only attenuated the response to 0.1 mA, 20 Hz SNS (− 55%). Cobalt chloride or lidocaine injected in the contralateral paratrigeminal nucleus also attenuated the SSR. In capsaicin-treated animals, the pressor responses to 0.1 mA were abolished, whereas the responses to SNS at 0.6 mA were increased from 65 to 100% depending on the stimulus frequency. The paratrigeminal nucleus receives both, excitatory and inhibitory components; the later apparently involving capsaicin-sensitive fiber inputs mostly to the ipsilateral site whereas the capsaicin insensitive excitatory components that respond to high or low frequency stimulation, respectively, target the contralateral and ipsilateral sites. Thus, the paratrigeminal nucleus mediates excitatory and inhibitory components of the somatosensory reflex, representing a primary synapse site in the brain for nociceptive inputs from the sciatic innervation field.

Physical activity: The present in the context of the past

In the broad sense, modern humans have lived in an environment in which physical activity and associated movement skills were central, especially in the context of physical competition with other animals. The physically active lifestyle of earlier human populations has been emphasized, especially the cardiovascular endurance component and energy expenditure, but less attention has been devoted to the gross and fine motor skills that are essential components of this lifestyle. Motor skills developed through practice are important determinants of success and survival in preindustrial societies. In industrial and postindustrial societies, on the other hand, the role of physical activity is different, with prowess in certain areas of physical expertise (e.g., accuracy with projectiles, muscular strength, among others) and prolonged exertion (i.e., cardiovascular endurance) less important for survival. The combined effects of the transition to a sedentary lifestyle and attendant dietary changes have resulted first an epidemic of coronary heart disease and more recently an epidemic of overweight/obesity in postindustrial societies. Although mortality associated with coronary heart disease has declined, due largely to biomedical advances, overweight and obesity have increased concomitantly with population reduction in physical activity (energy expenditure) and increased calorie (energy) consumption. The current scenario begs several questions which have implications for contemporary human biology related to sustaining the pace of cultural change on a biological base that is increasingly being compromised by physical inactivity, overweight, and obesity.

Cardiovascular and behavioral responses to conditioned fear after medullary raphe neuronal blockade

Conditioned fear to context in the rat leads to a host of sympathetically mediated physiological changes, including a marked rise in mean arterial pressure, a delayed rise in heart rate and a marked cutaneous vasoconstriction, along with the behavioral responses of freezing and ultrasonic vocalization. In this study we examine the role of the rostral ventromedial medulla (RVM), which includes raphe nuclei pallidus and magnus, in the expression of these changes. RVM is a major premotor sympathetic and somatic center and an important integrating center in the descending emotional motor system. To evaluate its role, conditioned fear was tested after temporary blockade with microinjections (0.4 μl) of the GABA-A receptor agonist muscimol (0.2 mM) or the glutamate receptor antagonist kynurenic acid (0.1 M). Changes in mean arterial pressure, heart rate and activity were recorded by radio-telemetry. Cutaneous vasoconstriction in the tail was recorded indirectly by infrared thermography. Muscimol and kynurenic acid had different, almost complementary effects. Muscimol abolished the skin vasoconstrictor response and significantly reduced the tachycardic response, but did not reduce the pressor response significantly and had little effect on the somatic motor components, freezing and ultrasonic vocalization. In contrast, kynurenic acid abolished ultrasonic vocalization and significantly reduced freezing but had no effect on the cardiovascular components. The results show that neurons in the rostral ventromedial medulla are implicated in the expression of some of the cardiac, vascular and somatic motor components of conditioned fear. Most importantly, these cardiovascular components are not under local glutamatergic control whereas the somatic motor components are.

Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature

Vascular dysfunction has been reported in human cases of anthrax, in mammalian models of Bacillus anthracis, and in animals injected with anthrax toxin proteins. To examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits in vivo imaging and evaluation of vasculature and cardiovascular function. Vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. We demonstrated increased endothelial permeability as an early consequence of toxin action by tracking the extravasation of fluorescent microspheres in toxin-injected embryos. Lethal toxin did not induce a significant amount of cell death in embryonic tissues or blood vessels, as shown by staining with acridine orange, and endothelial cells in lethal toxin-injected embryos continued to divide at the normal rate. Vascular permeability is strongly affected by the VEGF/vascular permeability factor (VPF) signaling pathway, and we were able to attenuate anthrax lethal toxin effects with chemical inhibitors of VEGFR function. Our study demonstrates the importance of vascular permeability in anthrax lethal toxin action and the need for further investigation of the cardiovascular component of human anthrax disease.

Neural Pathways Underlying Lactate-Induced Panic

Panic disorder is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as 0.5 M sodium lactate infusions. Although studied for four decades, the mechanism of lactate sensitivity in panic disorder has not been understood. The dorsomedial hypothalamus/perifornical region (DMH/PeF) coordinates rapid mobilization of behavioral, autonomic, respiratory and endocrine responses to stress, and rats with disrupted GABA inhibition in the DMH/PeF exhibit panic-like responses to lactate, similar to panic disorder patients. Utilizing a variety of anatomical and pharmacological methods, we provide evidence that lactate, via osmosensitive periventricular pathways, activates neurons in the compromised DMH/PeF, which relays this signal to forebrain limbic structures such as the bed nucleus of the stria terminalis to mediate anxiety responses, and specific brainstem sympathetic and parasympathetic pathways to mediate the respiratory and cardiovascular components of the panic-like response. Acutely restoring local GABAergic tone in the DMH/PeF blocked lactate-induced panic-like responses. Autonomic panic-like responses appear to be a result of DMH/PeF-mediated mobilization of sympathetic responses (verified with atenolol) and resetting of the parasympathetically mediated baroreflex. Based on our findings, DMH/PeF efferent targets such as the C1 adrenergic neurons, paraventricular hypothalamus, and the central amygdala are implicated in sympathetic mobilization; the nucleus of the solitary tract is implicated in baroreflex resetting; and the parabrachial nucleus is implicated in respiratory responses. These results elucidate neural circuits underlying lactate-induced panic-like responses and the involvement of both sympathetic and parasympathetic systems.

Decreased Fibroblast and Increased Osteoblast Functions on Ionic Plasma Deposited Nanostructured Ti Coatings

Bioactive coatings are in high demand to control cellular functions for numerous medical devices. The objective of this in vitro study was to characterize for the first time fibroblast (fibrous scar tissue forming cells) adhesion and proliferation on an important polymeric biomaterial (silicone) coated with titanium using a novel ionic plasma deposition (IPD) process. Fibroblasts are one of the first anchorage-dependent cells to arrive at an implant surface during the wound healing process. Persistent excessive functions of fibroblasts have been linked to detrimental fibrous tissue formation which may cause implant failure. The IPD process creates a surface-engineered nanostructure (with features usually below 100 nm) by first using a vacuum to remove all contaminants, then guiding charged metallic ions or plasma to the surface of a medical device at ambient temperature. Results demonstrated that compared to currently used titanium and uncoated silicone, silicone coated with titanium using IPD significantly decreased fibroblast adhesion and proliferation. Results also showed competitively increased osteoblast (bone-forming cells) over fibroblast adhesion on silicone coated with titanium; in contrast, osteoblast adhesion was not competitively increased over fibroblast adhesion on uncoated silicone or titanium controls. In this manner, this study strongly suggests that IPD should be further studied for biomaterial applications in which fibrous tissue encapsulation is undesirable (such as for orthopedic implants, cardiovascular components, etc.).

Pathogenese des metabolischen Syndroms - Insulinresistenz, chronische Entzündungsreaktionen und Lipotoxizität stehen im Zentrum

Das metabolische Syndrom beruht nicht auf einem einzelnen pathogenetischen Prinzip - wie es Kritiker fordern, um von einem „Syndrom” im medizinischen Sinn sprechen zu können. Vielmehr resultiert es aus vielfältigen und komplizierten Interaktionen metabolischer, kardiovaskulärer, renaler und neurohumoraler Veränderungen, die auf dem Boden der abdominalen Adipositas entstehen. Eine Schlüsselstellung als pathogenetische Faktoren haben Insulinresistenz, chronische Entzündungsreaktionen und Lipotoxizität in Leber, Muskel, Fettgewebe, Pankreas, Herz und Gefäßen. Hinzu kommt die Sympathikusaktivierung, die in besonderer Beziehung zu den kardiovaskulären Manifestationen des metabolischen Syndroms steht. Neue Erkenntnisse zu Sekretionsprodukten des Fettgewebes, den Adipokinen, und zellulären Veränderungen wie der verringerten oxidativen Kapazität der Mitochondrien werden hier mit Blick auf ihre Rolle bei der Pathogenese des metabolischen Syndroms diskutiert.

Pharmacologic Therapy of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a multifaceted disorder that affects between 5% and 8% of women. As a syndrome, PCOS is comprised of reproductive, metabolic, and cardiovascular components. Hyperandrogenemia and hyperinsulinemia are central to the pathogenesis of PCOS and thus typically serve as the targets for treatment. The spectrum of therapeutic options is broad and ranges from lifestyle intervention to specific pharmacologic agents. This chapter details current pharmacologic treatments for women with PCOS using a symptom-specific approach with a special focus on the metabolic effects of each treatment. Generally, oligomenorrhea mandates regulation of menstrual cyclicity and protection of the endometrium against the development of dysplasia and carcinoma. Progestins, either alone or in combination with estrogen (in the form of an oral contraceptive) are the mainstay of treatment of oligomenorrhea. Insulin lowering therapies also improve menstrual regularity. When androgen excess is the main target for therapy, an antiandrogen and/or oral contraceptives is typically chosen. Metabolic concerns of PCOS include excess body weight and insulin resistance. Metformin and thiazolidenediones both improve hyperinsulinemia but their differential effects on body weight must be considered.