Adiponectin gene therapy ameliorates high-fat,high-sucrose diet-induced metabolic perturbations in mice

Background and Design:

Adiponectin is an adipokine secreted primarily from adipose tissue that can influence circulating plasma glucose and lipid levels through multiple mechanisms involving a variety of organs. In humans, reduced plasma adiponectin levels induced by obesity are associated with insulin resistance and type 2 diabetes, suggesting that low adiponectin levels may contribute the pathogenesis of obesity-related insulin resistance.

Methods and Results:

The objective of the present study was to investigate whether gene therapy designed to elevate circulating adiponectin levels is a viable strategy for ameliorating insulin resistance in mice fed a high-fat, high-sucrose (HFHS) diet. Electroporation-mediated gene transfer of mouse adiponectin plasmid DNA into gastrocnemius muscle resulted in elevated serum levels of globular and high-molecular weight adiponectin compared with control mice treated with empty plasmid. In comparison to HFHS-fed mice receiving empty plasmid, mice receiving adiponectin gene therapy displayed significantly decreased weight gain following 13 weeks of HFHS diet associated with reduced fat accumulation, and exhibited increased oxygen consumption and locomotor activity as measured by indirect calorimetry, suggesting increased energy expenditure in these mice. Consistent with improved whole-body metabolism, mice receiving adiponectin gene therapy also had lower blood glucose and insulin levels, improved glucose tolerance and reduced hepatic gluconeogenesis compared with control mice. Furthermore, immunoblot analysis of livers from mice receiving adiponectin gene therapy showed an increase in insulin-stimulated phosphorylation of insulin signaling proteins.

Conclusion:

Based on these data, we conclude that adiponectin gene therapy ameliorates the metabolic abnormalities caused by feeding mice a HFHS diet and may be a potential therapeutic strategy to improve obesity-mediated impairments in insulin sensitivity.     

Occult splenic rupture with cardiovascular collapse: a report of three cases in critically ill patients

Three cases of splenic rupture causing cardiovascular collapse in critically ill patients are discussed. The first patient had received cardiopulmonary resuscitation (CPR) in the days before the collapse, the second patient was recovering from severe sepsis and the third patient was recovering from severe sepsis, had received CPR and had undergone percutaneous endoscopic gastrostomy (PEG). The diagnosis was made at post mortem in two of the patients, the third patient, who bled following PEG, survived after prompt surgical intervention. Splenic rupture should be considered as part of the differential diagnosis of unexpected cardiovascular collapse in patients who have received CPR or who are recovering from sepsis.     

Nasal carriage of Staphylococcus aureus on admission to intensive care: incidence and prognostic significance

We retrospectively studied the prevalence of the nasal carriage of methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) on admission to a medical surgical intensive care unit (ICU). We also compared the intensive care survival of MSSA carriers with non-carriers. Records of 678 patients admitted over a 24-month period were retrospectively reviewed. Nasal swabs were taken from 565 patients on admission to the ICU. MSSA was isolated from the anterior nares of 126 (22%) patients, MRSA was isolated in 16 (3%) patients and 423 (75%) patients had no nasal carriage identified. MSSA carriers were more likely to have been admitted to the ICU after less than 24 h hospital stay (28% non-carriers, 44% MSSA carriers) and were significantly younger (mean age of 50 years) than non-carriers (mean age 55 years). The median survival (with confidence intervals (CI)) was 29 days (CI 14-44) in non-carriers, 16 days (CI 10-22) in MSSA carriers and 6 days (CI 4-8) for the MRSA carriers. This difference was significant when MSSA carriers were compared with non-carriers ( p=0.003). The ICU mortality was also significantly higher ( p=0.004) in MSSA carriers (88 of the 423 (21%) non-carriers and 40 of 126 (32%) MSSA carriers died prior to ICU discharge).     

Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior

Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety.     

Hypothermic and antipyretic effects of ACTH (1-24) and alpha-melanotropin in guinea-pigs

Intracerebroventricular administration of adrenocorticotropin (ACTH 1-24) and alpha-melanotropin (alpha-MSH), peptides which occur naturally in brain induced dose-related hypothermia in guinea-pigs at room temperature (21 degrees C) and also produced greater hypothermia at low (10 degrees C) ambient temperature. However, when the experiments were repeated in a warm (30 degrees C) environment, no effect on body temperature was observed. These results indicate that the peptides did not reduce the central set-point of temperature control. The hypothermia induced by ACTH and alpha-MSH was not mediated via histamine H1- or H2-receptors and serotonin since the H1-receptor antagonist, mepyramine, the H2-receptor antagonist, cimetidine, and the serotonin antagonist, methysergide, had no antagonistic effects. The peptides were antipyretic since they reduced pyrogen-induced-fever and hyperthermia due to prostaglandin E2, norepinephrine and dibutyryl cAMP, at a dose which did not affect normal body temperature. The powerful central effects of these peptides on normal body temperature, fever and hyperthermia, together with their presence of the brain regions important to temperature control, suggest that they participate in thermoregulation.     

Tetrahydrobiopterin and nitric oxide synthase dimer levels are not changed following hypoxia-ischemia in the newborn rat

The effect of hypoxia-ischemia on the nitric oxide synthase (NOS) cofactor tetrahydrobiopterin (BH4) and changes in the enzyme dimer state have not previously been studied. Cell-based studies have demonstrated the regulation of nitric oxide (NO) synthesis by intracellular BH4 levels. Activation of NOS requires two NOS polypeptides to form a homodimer. Dimerization results in the creation of high-affinity binding sites for BH4 and L-arginine. Our previous studies have indicated that nNOS activity falls 2 h post-hypoxia-ischemia in the immature rodent model. Thus, the objective of this study was to determine whether changes in nNOS dimeric state could be responsible for the decrease in nNOS activity. Using the immature rat model of HI in conjunction with LT-PAGE and Western blot analysis, we determined the effect of HI on NOS dimer state in hippocampus and cortex and the effects of pharmacologic modulation of NO levels during HI on dimer formation. Using high-performance liquid chromatography (HPLC) and electrospray tandem mass spectrometry (MS-MS), we measured BH4 and L-arginine levels respectively after HI under the same conditions. We found minimal or no changes in either BH4 levels or NOS dimer state at 2 h, 24 h and 7 day recovery from HI on postnatal day 7. In contrast, L-arginine levels were transiently increased in the hypoxic ischemic hemisphere. Thus, our data suggest that the previously described decrease in NOS activity after HI is not associated with depletion of the cofactor BH4, L-arginine substrate or changes in the NOS enzyme dimer state.     

Peptide and non-peptide opioid-induced hyperthermia in rabbits

Intracerebroventricular administration of all three prototype non-peptide opioid receptor (μ, χ and σ) agonists, morphine, ketocyclazocine and N-allyl-normetazocine (SKF 10, 047) induced hyperthermia in rabbits. Similar administration of peptide opioids like β-endorphin (BE), methionine-enkephalin (ME) and its synthetic analogue d-ala²-methionine-enkephalinamide (DAME) also caused hyperthermia. As expected, the synthetic enkephalin DAME was more potent than the parent enkephalin. Of the three anion transport systems (iodide, hippurate and liver-like or L) present in the choroid plexus, it is suggested that only the L transport system seems to be important to ventricular inactivation of BE and DAME since iodipamide (an inhibitor of the L transport system) augmented the hyperthermia produced by BE and DAME. Prostaglandins (PG) and norepinephrine (NE) were not involved in peptide and non-peptide opioid-induced hyperthermia because a PG synthesis inhibitor, indomethacin, and an α-adrenergic receptor blocker, phenoxybenzamine, had no thermolytic effect on them. Likewise cAMP was not required since a phosphodiesterase inhibitor, theophylline, did not accentuate the hyperthermia due to peptide and non-peptide opioids. Naloxone-sensitive receptors were involved in the induction of hyperthermia by morphine. BE, ME and DAME since naloxone attentuated them. In contrast, the hyperthermic response to ketocyclazocine and SKF 10, 047 were not antagonized by naloxone.     

The effect of community-acquired pneumonia on plasma esterases in older people

INTRODUCTION: Pneumonia is a major cause of morbidity and mortality in older people. The poor outcome of older pneumonia patients despite treatment is still not understood. OBJECTIVE: The aim of this study was to examine the effect of community-acquired pneumonia on enzymes of drug metabolism in older people. METHODS: Fifteen patients (median age 67 years) with a clinical and radiological diagnosis of community-acquired pneumonia and 14 healthy volunteers matched for age and gender (median age 75 years) were recruited. Plasma activities of benzoylcholinesterase, butyrylcholinesterase, acetylcholinesterase and aspirin esterase were determined spectrophotometrically at three time points in pneumonia patients--within 24 h of admission to hospital, 2 days later and 10 days later. Monocyte aryl hydrocarbon hydroxylase (AHH) activity was determined spectrofluorimetrically at the same time points. Enzyme activities were measured at one time point in healthy controls. RESULTS: Mean plasma benzoylcholinesterase activity was significantly lower in pneumonia patients on admission to hospital (mean +/- SEM 848 +/- 100) and after 10 days of treatment (mean +/- SEM 925 +/- 114) than in healthy controls (mean +/- SEM 1333 +/- 84, P < 0.05). Similarly, plasma acetylcholinesterase activity was significantly lower in pneumonia patients on admission (P = 0.007) and after 10 days of treatment (P = 0.01) than in controls. Butyrylcholinesterase activity was lower in pneumonia patients on admission (P = 0.029) than in healthy controls, but improved slightly after treatment so there was no longer a significant difference at 10 days compared with controls (P = 0.077). In contrast there were no significant differences in plasma aspirin esterase activity or induced monocyte AHH activity between pneumonia patients and healthy controls. The activities of benzoylcholinesterase (r = -0.536, P = 0.04), butyrylcholinesterase (r = -0.638, P = 0.01), acetylcholinesterase (r = -0.583, P = 0.022) and aspirin esterase (r = -0.624, P = 0.013) correlated inversely with the British Thoracic Society pneumonia poor prognostic index. CONCLUSION: The activities of several esterases are reduced in older pneumonia patients. Other enzymes including aspirin esterase and induced monocyte AHH activity are unaltered in pneumonia. There was a significant inverse relationship between the activities of all esterases studied and the British Thoracic Society pneumonia poor prognostic index.