Compensatory State Research Articles

Downregulation of Tnf-α and Cat Expression in a Wistar Rat Diabetic Model during Diabetes Onset.

Diabetes Mellitus (DM) is a metabolic disorder characterized by persistent hyperglycemia and/or insulin resistance. If left uncontrolled, it can lead to a combination of cardiac and renal alterations known as cardiorenal syndrome. Additionally, oxidative stress and inflammation contribute to tissue damage, thereby reducing the life expectancy of individuals with diabetes. The aim of this study was to identify early molecular markers associated with cardiorenal syndrome, oxidative stress, and inflammation, and to investigate their correlation with the duration of exposure to DM. An experimental DM model was employed using Wistar rats. The rats were divided into four groups: diabetic rats at 7 days (DM7), diabetic rats at 30 days (DM30), control sham at 7 days (CS7), and control sham at 30 days (CS30). Blood and brain tissue from the brainstem region were collected at 7 and 30 days after confirming DM induction. Gene expression analysis of Bnp, Anp, Cat, Gpx, Sod, Tnf-α, and Il-6 was performed. The analysis revealed lower expression values of Cat in the brainstem tissue of the DM7 group compared to the NDS7 group. Moreover, diabetic animals exhibited statistically lower levels of Tnf-α in their peripheral blood compared to the control animals. This study concluded that DM alters the oxidative balance in the brainstem after 7 days of DM induction, resulting in lower Cat expression levels. Although some genes did not show statistical differences after 30 days of DM induction, other genes exhibited no expression values, indicating possible gene silencing. The study identified an imbalance in the studied pathways and concluded that the organism undergoes a compensatory state in response to the initial metabolic alterations caused by DM.

The Metabolic Functional Feature of Gut Microbiota in Mongolian Patients with Type 2 Diabetes.

The accumulating evidence substantiates the indispensable role of gut microbiota in modulating the pathogenesis of type 2 diabetes. Uncovering the intricacies of the mechanism is imperative in aiding disease control efforts. Revealing key bacterial species, their metabolites and/or metabolic pathways from the vast array of gut microorganisms can significantly contribute to precise treatment of the disease. With a high prevalence of type 2 diabetes in Inner Mongolia, China, we recruited volunteers from among the Mongolian population to investigate the relationship between gut microbiota and the disease. Fecal samples were collected from the Volunteers of Mongolia with Type 2 Diabetes group and a Control group, and detected by metagenomic analysis and untargeted metabolomics analysis. The findings suggest that Firmicutes and Bacteroidetes phyla are the predominant gut microorganisms that exert significant influence on the pathogenesis of type 2 diabetes in the Mongolian population. In the disease group, despite an increase in the quantity of most gut microbial metabolic enzymes, there was a concomitant weakening of gut metabolic function, suggesting that the gut microbiota may be in a compensatory state during the disease stage. β-Tocotrienol may serve as a pivotal gut metabolite produced by gut microorganisms and a potential biomarker for type 2 diabetes. The metabolic biosynthesis pathways of ubiquinone and other terpenoid quinones could be the crucial mechanism through which the gut microbiota regulates type 2 diabetes. Additionally, certain Clostridium gut species may play a pivotal role in the progression of the disease.

Dynamic change of vestibular function and the long-term prognosis of vestibular neuritis.

To comprehensively evaluate the dynamic change of vestibular function during long-term follow-up of vestibular neuritis, as well as the co-relationship with the outcomes of vestibular neuritis (VN), which provides the recommendations for vestibular function tests during the course of VN. A prospective cohort study was conducted on 16 patients with acute VN. Caloric test, vHIT, rotatory chair tests, VEMP, dizziness handicap inventory (DHI) score, and dynamic dizzy scales (VAS-DD) was first performed within 7 days of neuritis onset, which were further re-evaluated during the 6-12 months of follow-up. The dynamic changes on multiple objective vestibular examinations were analyzed during the acute and recovery stage of VN. We further evaluated the co-relationship between the vestibular dysfunction scales and the prognosis of VN. In more than 6 months of follow-up, 44% of the ultralow frequency, 94% of the low-to-mid frequency, and 44% of the high-frequency function of the horizontal semicircular canal returned to normal (p < 0.05). The change degree in symmetry of the rotatory chair test was correlated with the gain of the horizontal semicircular canal on the vHIT and the unilateral weakness (UW) value on the caloric test (p < 0.05). The change in DHI score was correlated with the phase; change in VAS-DD level correlated with the symmetry and TC of the rotatory chair test at VN recovery stage (p < 0.05). There was no significant correlation between the change in DHI score or change in VAS-DD and the degree of vestibular function recovery (p > 0.05). In general, vestibular function improved during the course of VN. The rotatory chair test can be used to evaluate the overall function of the vestibular system and the compensatory state in patients with VN.

Enhancing the clinical value of single-phase computed tomography angiography in the assessment of collateral circulation in acute ischemic stroke: A narrative review.

Acute ischemic stroke (AIS) condition assessment and clinical prognosis are significantly influenced by the compensatory state of cerebral collateral circulation. A standard clinical test known as single-phase computed tomography angiography (sCTA) is useful for quickly and accurately assessing the creation or opening of cerebral collateral circulation, which is crucial for the diagnosis and treatment of AIS. To improve the clinical application of sCTA in the clinical assessment of collateral circulation, we examine the present use of sCTA in AIS in this work.

Assessment of neurofunctional activity in patients with vibration disease caused of local vibration

Introduction. The stressful effect of local vibration contributes to the development of cerebral dysfunction with the formation of a sensorineural deficit in patients with vibration disease associated with exposure to local vibration.&#x0D; The study aims to identify the features of changes in somatosensory evoked potentials, neuroenergocarting and neuropsychological testing in patients with local vibration.&#x0D; Materials and methods. Scientists examined 103 patients with local vibration (group one), 35 healthy men (comparison group). We used methods of registration of somatosensory evoked potentials (SSEP), constant potential level (CPL), neuropsychological testing.&#x0D; Results. The authors revealed in the first group, in comparison with the other group, a significant increase in cerebral energy metabolism in the form of an increase in the level of constant potential in the frontal right and left (Fd, Fs), central (Cd, Cz, Cs), parietal (Pd, Pz, Ps), occipital (Oz), right and central temporal (Td, Tz) brain regions, increased latency of peaks N10, N11, N13, N30, peak interval N13–N18 at p&lt;0.04, cognitive dysfunction with mild damage to prefrontal frontal lobes, inferior temporal and inferior parietal regions, parietal-temporal-occipital zone of the left hemisphere, as well as subcortical structures. The data of the correlation analysis indicate that the slowing down of the ascending somatosensory flow from the level of the brachial plexus ganglia to the ventroposterolateral nucleus of the thalamus contributes to the emergence of a compensatory state in the form of an increase in energy processes in the frontal-central and parietal parts of the cerebral cortex, causing the development of cognitive disorders.&#x0D; Limitations. The limitations of the study were the lack of studying the effects of local vibration on cerebral hemodynamics and the state of efferent pathways of the central nervous system in patients with local vibration.&#x0D; Conclusion. Signs of impaired neurofunctional activity in local vibration are an increase in the duration of peak intervals N10–N13 and N11–N13, the latency of peak N10, the level of constant potential of the frontal right and central left leads, the level of constant potential of interhemispheric relations in the central department, a decrease in categorical and conceptual thinking, short-term (auditory) memory, visual gnosis, expressive speech.&#x0D; Ethics. The study was conducted in compliance with Ethical standards developed in accordance with the Helsinki Declaration of the World Medical Association "Ethical principles of conducting scientific medical research with human participation" as amended in 2000 and "Rules of Clinical Practice in the Russian Federation" approved by Order of the Ministry of Health of the Russian Federation No. 266 dated 06/19/2003. Informed consent was received from each person to participate in the survey, approved in accordance with the established procedure by the Local Ethics Committee.

Диагностическая лапароскопия в современной хирургии (обзор литературы)

The research presents a review of the current state of the method of diagnostic laparoscopy in modern clinical practice. In modern medicine, there is a tendency to minimize injuries to the patient in diagnostic search to achieve a compensatory state as soon as possible, to improve the quality of life, and to maintain working capacity. All these conditions meet the requirements of the method of diagnostic laparoscopy. The purpose of this research is to assess the current state of the scope and prevalence of diagnostic laparoscopy in modern surgery. Materials and methods: the search was carried out in the open electronic scientific databases PubMed and the databases of the Russian scientific electronic library eLibrary using keywords and phrases: laparoscopy, diagnostic laparoscopy, surgical intervention, current trends, abdominal cavity. Results. In modern surgical practice, diagnostic laparoscopy is considered as a highly informative preoperative method for detecting intra-abdominal pathologies and postoperative complications. This technique is widely used in gynecological practice, oncogynecology, in acute and chronic surgical pathologies in patients of various ages in order to assess the state of the intra-abdominal space and determine the correct tactics and extent of surgical intervention in the earliest possible time. In urgent abdominal pathology, laparoscopy remains the leading minimally invasive technique that allows assessing the extent and prevalence of the process. Conclusion: the vector of development of modern clinical medical practice creates all the conditions for the regular development and active growth of the possibilities of carrying out the presented diagnostic technique in various areas of surgical profiles.

Postsurgical Latent Pain Sensitization Is Driven by Descending Serotonergic Facilitation and Masked by µ-Opioid Receptor Constitutive Activity in the Rostral Ventromedial Medulla.

Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory µ-opioid receptor constitutive activity (MORCA) in the dorsal horn of the spinal cord. To demonstrate LS, we conducted plantar incision in mice and then waited 3-4 weeks for hypersensitivity to resolve. At this time (remission), systemic administration of the opioid receptor antagonist/inverse agonist naltrexone reinstated mechanical and heat hypersensitivity. We first tested the hypothesis that LS extends to serotonergic neurons in the rostral ventral medulla (RVM) that convey pronociceptive input to the spinal cord. We report that in male and female mice, hypersensitivity was accompanied by increased Fos expression in serotonergic neurons of the RVM, abolished on chemogenetic inhibition of RVM 5-HT neurons, and blocked by intrathecal injection of the 5-HT3R antagonist ondansetron; the 5-HT2AR antagonist MDL-11 939 had no effect. Second, to test for MORCA, we microinjected the MOR inverse agonist d-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) and/or neutral opioid receptor antagonist 6β-naltrexol. Intra-RVM CTAP produced mechanical hypersensitivity at both hindpaws; 6β-naltrexol had no effect by itself, but blocked CTAP-induced hypersensitivity. This indicates that MORCA, rather than an opioid ligand-dependent mechanism, maintains LS in remission. We conclude that incision establishes LS in descending RVM 5-HT neurons that drives pronociceptive 5-HT3R signaling in the dorsal horn, and this LS is tonically opposed by MORCA in the RVM. The 5-HT3 receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.SIGNIFICANCE STATEMENT Surgery leads to latent pain sensitization and a compensatory state of endogenous pain control that is maintained long after tissue healing. Here, we show that either chemogenetic inhibition of serotonergic neuron activity in the RVM or pharmacological inhibition of 5-HT3 receptor signaling at the spinal cord blocks behavioral signs of postsurgical latent sensitization. We conclude that MORCA in the RVM opposes descending serotonergic facilitation of LS and that the 5-HT3 receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.

P53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction

BackgroundHeart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF.Methods and ResultsHFpEF dietary regimen (high‐fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second‐generation and third‐generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second‐generation telomerase RNA component knockout (at 6 weeks) and third‐generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial‐specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF.ConclusionsHere we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride challenged murine model.

Saving Democracy from Rent‐Seeking Economic and Political Behavior Robert F. Durant, Building the Compensatory State. An Intellectual History and Theory of American Administrative Reform (New York/London: Routledge, 2020). 358 pp (including index). $39.95 (hardback), ISBN: 978‐0‐367‐34844‐1

Saving Democracy from Rent‐Seeking Economic and Political Behavior Robert F. Durant, <i>Building the Compensatory State. An Intellectual History and Theory of American Administrative Reform</i> (New York/London: Routledge, 2020). 358 <i>pp (including index). $39.95 (hardback), ISBN: 978‐0‐367‐34844‐1</i>

Diabetic bladder dysfunction in T2D KK-Ay mice and its changes in the level of relevant gene expression

ObjectiveDiabetic bladder dysfunction (DBD) is one of the most common and bothersome complications of diabetes mellitus (DM). The purpose of the present study is to investigate DBD in KK-Ay mice, and to identify the expression of relative genes. MethodTotally twenty-seven KK-Ay mice and thirty C57BL/6 J mice, respectively, were randomly divided into 12-, 18-, and 25-week old groups. The weight, water intake, voided volume, the frequency of micturition, fasting blood glucose (FBG), oral glucose tolerance test (OGTT) were measured at varying time points. Maximum bladder volume (MBC), residual volume (RV), bladder compliance (BC), micturition efficiency (VE) and maximum micturition pressure (MVP) were assessed by urodynamic test, and contractile responses to α, β‐methylene ATP, KCl, electrical‐field stimulation, carbachol were performed by detrusor smooth muscle strips contractility test. The bladders were stained with hematoxylin and eosin (H&E) and Masson’s trichrome to determine bladder wall thickness. Additionally, the mRNA expression of Myosin Va, SLC17A9, P2X1, M3 and M2 were then verified by qRT-PCR. ResultThe weight, water intake, voided volumes, micturition frequency, FBG, the blood glucose AUC0-2h of KK-Ay mice were significantly increased at three time points. MBC, RV and BC were significantly increased; VE was significantly lower at the age of 18 and 25 weeks in KK-Ay mice; MVP was significantly increased at the age of 25 weeks in KK-Ay mice. In DSM strips contractility test, the amplitude of the spontaneous activity in KK-Ay mice significant increased at 12 weeks and 18 weeks, while both the amplitude and frequency were significantly decreased at the age of 25 weeks. The level of Myosin Va, SLC17A9 and M3 receptor significantly decreased in KK-Ay mice at 12 weeks, while Myosin Va markedly increased at 18 weeks; P2X1 and M2 receptors of KK-Ay mice was significantly increased at all three time points. ConclusionTaken together, this study demonstrates that KK-Ay mice can be a proper model to investigate DBD whose transformation from compensatory state to decompensated state may ascribe to the time-dependent alternations of Myosin Va, SLC17A9, P2X1, M3 and M2 expression levels.

Cardiogenic Shock in Patients with Advanced Chronic Heart Failure.

Patients with end-stage heart failure (HF) who have failed optimal medical therapy provide a unique set of challenges compared to the more prevalent population of patients with cardiogenic shock (CS) due to ST-segment elevation myocardial infarction. Progression from "preshock" into a refractory state of CS is associated with a dismal outcome due to difficulties with the patient's recognition, response to interventions, and candidacy for salvage options. Challenges include heterogeneity of CS (eg, different phenotypes, etiologies, duration, acuity of onset, hemodynamics, end-organ effects), lack of a universal definition of CS that is applicable to this patient population, and blunted hemodynamic response given the patient's prolonged compensatory state. Individuals with advanced HF in CS require a multidisciplinary team-based assessment regarding when to escalate from medical therapy into temporary mechanical circulatory support, and they need an eligibility evaluation to determine their candidacy for advanced therapy. In this review, we discuss the definition and clinical phenotypes of CS, classification of CS in advanced HF patients, the utility of temporary mechanical circulatory support, and the role of the CS team.

Influence of ractopamine hydrochloride and days on feed on feedlot performance and red meat yield in thin cull beef cows targeted for a lean market

Thin, beef, cull cows [n = 144; initial body weight (BW) = 465.8 ± 56.9 kg, initial body condition score (BCS) = 2.13 ± 0.68] were serially slaughtered to evaluate the relationship between ractopamine hydrochloride (RH) administration and days on feed (DOF) on feedlot performance and carcass cutout value in a lean cow market. Cows were organized into a 3 × 2 factorial arrangement of treatments (48 pens, 8 pens per treatment, 3 cows per pen) and blocked by BW nested within pregnancy status. Treatment pens were top-dressed 400 mg per cow per day of RH (Actogain 45; Zoetis, Parsippany, NJ) for the final 28 d prior to slaughter to cows spending 28, 42, or 56 DOF. Pen served as the experimental unit, for all calculations. No RH × DOF interactions were detected (P ≥ 0.11), indicating that despite a majority of compensatory gain occurring during the first 28 d of the trial, the magnitude of the RH response was not affected by DOF. Compared to controls, RH incited improvements in feedlot performance, but had a greater extent on carcass weight gain and efficiency. Specifically, RH improved average daily gain (ADG) by 13.7% (P = 0.04) and carcass ADG by 16.9% (P = 0.02) Cattle fed RH displayed a 15.5% improved gain to feed ratio (P = 0.02) and a 20% improved carcass gain to feed ratio (P = 0.05). Inclusion of RH in the finishing diet increased hot carcass weight by 4.5% (P = 0.05; 12.9 kg). However, supplementation of RH did not alter red meat yield (P ≥ 0.16), but provoked a 11.1% improvement in lean maturity (P < 0.01). Evaluation of the main effect of DOF provided insight into the compensatory state of beef cull cows on a high-concentrate diet. Serial slaughter offal weights presented confounding results. With additional DOF, a numerical increase in liver weights (P = 0.20) suggested that organ tissue replenishment occurred throughout the trial, and cattle experienced compensatory gain during the entire feeding phase. In contrast, lung and heart weights were not altered, while kidney tended to decrease linearly (P = 0.08) despite additional DOF. Furthermore, extending DOF generated a linear increase in dry matter intake (P < 0.01) yet a tendency for a decline in ADG (P = 0.10), reinforcing the premise that most of compensatory gain occurred during the first 28 d of the trial. If thin (BCS ≤ 4), healthy candidates can be finished, feeders can reap the benefits of an additive relationship between compensatory gain and RH.

Dynamic Changes in Brain Glucose Metabolism and Neuronal Structure in Rats with Heart Failure

Patients with heart failure (HF) are more susceptible to cognitive impairment, but the mechanism is still unclear. This study aimed to observe the dynamic changes in brain glucose metabolism and neuronal structure in different stages of HF. An HF rat model was established by ligating the anterior descending branch of the left coronary artery. To simulate acute heart failure (AHF) and chronic heart failure (CHF) in the clinic, relevant laboratory indexes were detected 10 and 60 days after ligation. The results showed that the model rats had systolic HF. Cognitive function was not obviously impaired in 10-day rats with HF, while the memory and learning functions were significantly impaired in 60-day rats with HF. The brain glucose metabolism in 10-day rats compensatorily increased in the prefrontal cortex (PFC), medial PFC (mPFC), cingulate gyrus, and basal ganglia (BG). In contrast, the metabolism of 60-day rats reduced in the PFC and BG. Meanwhile, the neuronal structure slightly changed in 10-day rats with HF, but neuronal karyopyknosis, reduced Nissl bodies, and swollen organelles were found in 60-day rats with HF. In conclusion, brain glucose metabolism and neuronal structure showed a dynamic evolution. Rats with AHF were in a compensatory state for increased glucose metabolism and slight neuronal damage. As a result, no significant cognitive impairment was observed. However, rats with CHF had significantly decreased cerebral glucose metabolism and neuronal degeneration, contributing to the cognitive function after HF.

Authoritarian populism and neo-extractivism in Bolivia and Ecuador: the unresolved agrarian question and the prospects for food sovereignty as counter-hegemony

ABSTRACTThe new economic flows ushered in across the South by the rise of China in particular have permitted some to circumvent the imperial debt trap, notably the ‘pink tide’ states of Latin America. These states, exploiting this window of opportunity, have sought to revisit developmentalism by means of ‘neo-extractivism’. The populist, but now increasingly authoritarian, regimes in Bolivia and Ecuador are exemplars of this trend and have swept to power on the back of anti-neoliberal sentiment. These populist regimes in Bolivia and Ecuador articulate a sub-hegemonic discourse of national developmentalism, whilst forging alliances with counter-hegemonic groups, united by a rhetoric of anti-imperialism, indigenous revival, and livelihood principles such as buen vivir. But this rhetorical ‘master frame’ hides the class divisions and real motivations underlying populism: that of favouring neo-extractivism, principally via sub-imperial capital, to fund the ‘compensatory state’, supporting small scale commercial farmers through reformism whilst largely neglecting the counter-hegemonic aims, and reproductive crisis, of the middle/lower peasantry, and lowland indigenous groups, and their calls for food sovereignty as radical social relational change. These tensions are reflected in the marked shift from populism to authoritarian populism, as neo-extractivism accelerates to fund ‘neo-developmentalism’ whilst simultaneously eroding the livelihoods of subaltern groups, generating intensified political unrest. This paper analyses this transition to authoritarian populism particularly from the perspective of the unresolved agrarian question and the demand by subaltern groups for a radical, or counter-hegemonic, approach to food sovereignty. It speculates whether neo-extractivism’s intensifying political and ecological contradictions can foment a resurgence of counter-hegemonic mobilization towards this end.

THERAPEUTIC MISADVENTURE WITH A BETA BLOCKER DURING A THYROID STORM

SESSION TITLE: Critical Care and Pediatrics SESSION TYPE: Global Case Reports PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM INTRODUCTION: Thyroid storm (TS) has a high mortality rates, whether treated 20% [2] or untreated 50%-90% [1,2]. Immediate goals are to decrease synthesis, prevent release, decrease peripheral action with beta blockers, support circulation and treat the precipitating condition (3). Caution against beta blocker is warranted in patients with heart failure, although it may be beneficial when tachycardia is a significant precipitant to decompensated cardiac function (4). We present a case of thyroid storm with right heart failure and exaggerated response to propranolol leading to circulatory collapse secondary to cardiogenic shock. CASE PRESENTATION: 48-year-old female with untreated hypertension presented to emergency for progressively worsening dyspnea, cough and diarrhea with elevated white count and fever. Treatment was initiated per sepsis protocol and PE was ruled out with contrasted CT. Shortly afterward, GCS deteriorated from 14 to 6 and she was intubated for airway protection. Lab work revealed an undetectable TSH with elevated free T4 and T3. Upon revaluation, her Burch-Wartofsky Point Scale was 95, elevated from 55 on arrival. She received glucocorticoids, propylthiouracil and oral propranolol. She developed bradycardia and cardiac arrest. Post ROSC echocardiogram showed right heart failure with flattened ventricular septum and EF of 45%. A second cardiac arrest ensued despite glucagon and transcutaneous pacing attempts. She was stabilized with crystalloids, vasopressors and bicarbonate drip. Central venous and bladder pressures were 34 and 26, minutes before a third cardiac arrest that ended with an emergency bedside laparotomy for decompression of abdominal compartment syndrome. Her hospital course was further complicated by coagulopathy, blood loss and renal failure requiring dialysis. DISCUSSION: The concept of thyrocardiac disease must be kept in mind when managing a TS. In long standing hyperthyroidism, the resulting cardiomyopathy is compensated by tachycardia and increased sensitivity to catecholamines [3]. This compensation depends on excess adrenergic drive to maintains adequate cardiac output. Failure to consider this led to our therapeutic misadventure. Current management of TS includes propranolol to lessen the adrenergic effect on the heart and to inhibit peripheral conversion of T4 to T3. This patient’s experience suggested that abrupt disruption of this compensatory state with beta blockade puts the body at risk for cardiovascular collapse. CONCLUSIONS: It is imperative to for clinicians to avoid beta blockers or use short acting beta blockers with extreme caution when managing TS Reference #1: Nayak B1, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am. 2006 Dec;35(4):663-86, vii Reference #2: Richard Carroll and Glenn Matfin Endocrine and metabolic emergencies: thyroid storm Ther Adv Endocrinol Metab. 2010 Jun; 1(3): 139–145. Reference #3: Singhal, A., & Campbell, D. "Thyroid storm." 2003. www.emedicine.com/ped/topic2247.htm (16 Dec. 2004) DISCLOSURES: No relevant relationships by Emmanuel Addo-Yobo, source=Web Response No relevant relationships by Nanette Bentley, source=Web Response No relevant relationships by Diana Trofimovitch, source=Web Response No relevant relationships by Karthik Vijayan, source=Web Response No relevant relationships by Gabriel Zaietta, source=Web Response

Activation of S6 signaling is associated with cell survival and multinucleation in hyperplastic skin after epidermal loss of AURORA-A Kinase

The role of mitosis in the progression of precancerous skin remains poorly understood. To address this question, we deleted the mitotic Kinase Aurora-A (Aur-A) in hyperplastic mutant p53 mouse skin as an experimental tool to study the G2/M transition in precancerous keratinocytes and AUR-A's role in this process. Epidermal Aur-A deletion (Aur-AepiΔ) led to marked keratinocyte enlargement, pleomorphism, multinucleation, and attenuated induction of cell death. This phenotype was characteristic of slippage after a stalled mitosis. We also observed altered or impaired epidermal differentiation, indicative of a partial skin barrier defect. The upregulation of mTOR/PI3K signaling was implicated as a mechanism by which keratinocytes may evade cell death after AUR-A deficiency. This was evidenced by the ectopic expression of the pathway readout, p-S6, in the basal layer of Aur-AepiΔ skin and its mitotic upregulation in isolated keratinocytes. We further tested whether our findings were extended to skin carcinoma cells. The chemical inhibition of AUR-A led to a similar mitotic delay, polyploidy/multinucleation, and attenuated cell death in skin cancer cell lines. Moreover, inhibition of mTOR/PI3K signaling ameliorated the effects caused by the deficiency of AUR-A activity but was also associated with the persistence of mitotic p-S6 detection in surviving cancer cells. These results show the induction of multinucleation/polyploidy may be a compensatory state in keratinocytes that allows for cellular survival and maintenance of partial barrier function in face of aberrant cell division or differentiation. Moreover, mTOR/PI3K signaling is active in the mitosis of hyperplastic keratinocytes expressing mutant p53 and is further enhanced by stalled mitosis, indicating a potential resistance mechanism to the use of anti-mitotic drugs in the treatment of skin cancers.

Personal carbon allowances: A revised model to alleviate distributional issues

Personal Carbon Allowances (PCAs) are a policy proposal designed to facilitate carbon emissions reduction and engender carbon consciousness: they were investigated by the UK government in 2006–2008 but subsequently shelved. With continuing growth of atmospheric CO2 concentrations and increasing interest in behaviour change agendas PCAs are worthy of fresh development.Wide variation in energy usage between households of similar incomes implies that under the ‘standard’ model of PCAs significant numbers of low-income high-emitters would have to purchase top-up allowances. If PCAs penalise some of the worst off in society it creates a major political obstacle to their introduction.Solving this distributional problem by allocating additional allowances to certain groups or offering compensatory state benefits has been investigated and appears costly and only partially effective. This paper proposes a new ‘Mean & Max’ PCA model whereby higher usage is necessary before purchase of top-up allowances is required; potentially highly effective but consequently the volumes and values of surplus and top-up allowances become significantly different. This difference renders free market carbon allowance trading unworkable, potentially eliminating a hallmark (but publicly unpopular) PCA feature. The new model potentially offers the first solution to the distributional problem since it was highlighted in 2008.

Dendritic remodeling of hippocampal neurons is associated with altered NMDA receptor expression in alcohol dependent rats.

Prolonged alcohol exposure has been previously shown to impair the structure and function of the hippocampus, although the underlying structural and biochemical alterations contributing to these deleterious effects are unclear. Also unclear is whether these changes persist into prolonged periods of abstinence. Previous work from our lab utilizing a clinically relevant rodent model of alcohol consumption demonstrated that alcohol dependence (induced by chronic intermittent ethanol vapor exposure or CIE) decreases proliferation and survival of neural stem cells in the hippocampal subgranular zone and hippocampal neurogenesis in the dentate gyrus, implicating this region of the cortex as particularly sensitive to the toxic effects of prolonged ethanol exposure. For this study, we investigated seven weeks of CIE-induced morphological changes (dendritic complexity and dendritic spine density) of dentate gyrus (DG) granule cell neurons, CA3, and CA1 pyramidal neurons and the associated alterations in biochemical markers of synaptic plasticity and toxicity (NMDA receptors and PSD-95) in the hippocampus in ethanol-experienced Wistar rats 3h (CIE) and 21days (protracted abstinence) after the last ethanol vapor exposure. CIE reduced dendritic arborization of DG neurons and this effect persisted into protracted abstinence. CIE enhanced dendritic arborization of pyramidal neurons and this effect did not persist into protracted abstinence. The architectural changes in dendrites did not correlate with alterations in dendritic spine density, however, they were associated with increases in the expression of pNR2B, total NR2B, and total NR2A immediately following CIE with expression levels returning to control levels in prolonged abstinence. Overall, these data provide the evidence that CIE produces profound changes in hippocampal structural plasticity and in molecular tools that maintain hippocampal structural plasticity, and these alterations may underlie cognitive dysfunction associated with alcohol dependence. In addition, the compensatory state concurrent with reduced plasticity during protracted abstinence could leave the hippocampus vulnerable to subsequent insult following chronic ethanol exposure.

Is there a cognitive signature for MS-related fatigue?

The compensatory approach of fatigue argues that it is a state caused by task load. The neuropsychiatric approach argues that fatigue is a trait (like depression), unrelated to environmental challenges. We propose that fatigue is an internal state that can be measured behaviorally only by applying specific cognitive tasks. PubMed was searched for articles concerning the relation between fatigue and cognitive performance or brain atrophy or functional MRI, distinguishing between the following cognitive domains: learning/memory, cognitive speed/selective attention, language, visuospatial processing, working memory, alerting/vigilance. Only tasks assessing alerting/vigilance are strongly related to fatigue. Areas with brain atrophy in fatigue patients overlap with brain regions activated in healthy controls performing alerting/vigilance tasks. Fatigue is not a compensatory state, nor a psychogenic trait. It is a feeling with behavioral effects that seems to be caused by brain atrophy or a neurochemical dysfunction of the alerting/vigilance system.

Glucose homeostasis in acromegaly: pathogenesis and effects of treatment

Acromegaly is a chronic debilitating disorder resulting from excessive secretion of growth hormone (GH) and consequent increase in insulin-like growth factor I (IGF-I), usually caused by a pituitary somatotroph adenoma. Effective treatment aims to ameliorate symptoms and signs of the disease and to lower mortality rate. In particular, high morbidity and mortality are partly related to the presence of insulin resistance due to the action of GH on liver, muscle and adipose tissue. Insulin resistance and/or reduced insulin sensitivity physiologically result in hypersecretion of insulin from the pancreas. This compensatory state of hyperinsulinemia is felt to be a first and more important marker for this condition. Adequate control of GH excess by surgery or pharmacotherapy is associated with decreased insulin resistance, resulting in reduced plasma insulin and glucose levels or improved glucose tolerance. Despite divergent effects of both somatostatin and somatostatin analogs on GH, insulin and glucagon secretion, and glucose absorption, treatment with the somatostatin analogs octreotide and lanreotide has only limited effects on glucose metabolism. However, glucose sensitivity has been formally examined using a hyperinsulinemic euglycemic clamp only in a minority of studies. Treatment with the GH-receptor antagonist pegvisomant improves insulin sensitivity, thus decreasing circulating fasting insulin and glucose levels. Assessment of insulin secretion and glucose levels in acromegalic patients during administration of the above compounds is thus mandatory.