Nocturnal hypoglycaemias in type 1 diabetic patients : what can we learn with continuous glucose monitoring ?

Rapport de synthèse : Hypoglycémies nocturnes chez les patients diabétiques de type 1 : que pouvons-nous apprendre de la mesure de la glycémie en continu ? But : les hypoglycémies nocturnes sont une complication majeure du traitement des patients diabétiques de type 1; des autocontrôles de la glycémie capillaire sont donc recommandés pour les détecter. Cependant, la majorité des hypoglycémies nocturnes ne sont pas décelées par un autocontrôle glycémique durant la nuit. La mesure de la glycémie en continu (CGMS) est une alternative intéressante. Les buts de cette étude rétrospective étaient d'évaluer la véritable incidence des hypoglycémies nocturnes chez des patients diabétiques de type 1, la meilleure période pour effectuer un autocontrôle permettant de prédire une hypoglycémie nocturne, la relation entre les hyperglycémies matinales et les hypoglycémies nocturnes (phénomène de Somogyi) ainsi que l'utilité du CGMS pour réduire les hypoglycémies nocturnes. Méthode : quatre-vingt-huit patients diabétiques de type 1 qui avaient bénéficié d'un CGMS ont été inclus. Les indications au CGMS, les hypoglycémies nocturnes et diurnes ainsi que la corrélation entre les hypoglycémies nocturnes et les hyperglycémies matinales durant le CGMS ont été enregistrées. L'efficacité du CGMS pour réduire les hypoglycémies nocturnes a été évaluée six à neuf mois après. Résultats : la prévalence des hypoglycémies nocturnes était de 67% (32% non suspectées). La sensibilité d'une hypoglycémie à prédire une hypoglycémie nocturne était de 37% (OR = 2,37, P = 0,001) lorsqu'elle survient au coucher (22-24 h) et de 43% lorsqu'elle survient à 3 h (OR = 4,60, P < 0,001). Les hypoglycémies nocturnes n'étaient pas associées à des hyperglycémies matinales, mais à des hypoglycémies matinales (OR = 3.95, P < 0.001). Six à neuf mois après le CGMS, les suspicions cliniques d'hypoglycémies nocturnes ont diminué de 60% à 14% (P < 0.001). Abstract : Aim. - In type 1 diabetic patients (TIDM), nocturnal hypoglycaemias (Nlï) are a serious complication of T1DM treatment; self-monitoring of blood glucose (SMBG) is recommended to detect them. However, the majority of NH remains undetected on an occasional SMBG done during the night. An alternative strategy is the Continuous glucose monitoring (CGMS), which retrospectively shows the glycaemic profile. The aims of this retrospective study were to evaluate the true incidence of NH in TiDM, the bèst SMBG time to predict NH, the relationship between morning hyperglycaemia and N$ (Somogyi phenomenon) and the utility of CGMS to reduce NH. Methods. -Eighty-eight T1DM who underwent a CGMS exam were included. Indications for CGMS evaluarion, hypoglycaemias and correlation with morning hyperglycaemias were recorded. The efficiency of CGMS to reduce the suspected NH was evaluated after 6-9 months. Results. -The prevalence of NH was 67% (32% of them unsuspected). A measured hypoglycaemia at bedtime (22-24 h) had a sensitivity of 37% to detect NH (OR = 2.37, P = 0.001), while a single measure <_ 4 mmol/l at 3-hour had a sensitivity of 43% (OR = 4.60, P < 0.001). NH were not associated with morning hyperglycaemias but with morning hypoglycaemias (OR = 3.95, P < 0.001). After 6-9 months, suspicions of NH decreased from 60 to 14% (P < 0.001). Conclusion. - NH were highly prevalent and often undetected. SMBG at bedtime, which detected hypoglycaemia had sensitivity almost equal to that of 3-hour and should be preferred because it is easier to perform. Somogyi phenomenon was not observed. CGMS is useful to reduce the risk of NH in 75% of patients.

Hemodialysis for cefepime intoxication: A case report

Introduction: We report a case of cefepime intoxication with acute severe neurologic symptoms, which was treated by temporary hemodialysis. Patients (or Materials) and Methods: Cefepime 2 g BID for endovascular prosthesis infection was prescribed to a frail, chronically ill 88-year-old woman with a serum creatinine of 199 μmol/L and an estimated creatinine clearance of 13 mL/min (Cockroft formula). Two days later, she was transferred to a neurocritical care unit because of acute aphasia, myoclonic jerks, and delirium with a Glasgow coma scale score of 12/15. The following day, in the absence of other causes, cefepime intoxication was hypothesized, and cefepime was withdrawn after a total of 7 doses = 14 g. Over the next 24 hours, two 3-hour hemodialysis (HD) sessions were performed under cefepime concentration monitoring. Results: Cefepime plasma levels were measured by liquid chromatography/ mass spectrometry. There is no validated reference range, but a study (Chapuis T et al, Critical Care, 2010) found a 50% risk of neurotoxicity with residual levels > 15 mg/L. In our patient, levels were 83.3 mg/L 10 hours after last dose, 24.1 mg/L immediately after the first HD session, 13.4 mg/L immediately before the second HD session, and 2.5 mg/L immediately after the second HD session. The patient made a full clinical recovery over the next 48 hours. The 70% to 80% fall in plasmatic levels observed during each HD session is in accordance with literature data (Schmaldienst S et al, Eur J Clin Pharmacol, 2000, and Manyor LM et al, Pharmacotherapy, 2008). According to kinetic simulation, cefepime dropped at a concentration < 15 mg/L 15 hours earlier with HD than it would have without. Conclusion: Neuropsychiatric adverse effects of beta-lactam antibiotics can be easily overlooked by clinicians. One should be especially cautious with their use in very old and frail patients in whom plasma creatinine poorly estimates renal function and cognitive impairment is highly prevalent. Temporary hemodialysis effectively clears cefepime, but its role in hastening clinical recovery may be limited.

Cell death and autophagy after severe hypoxic-ischemic encephalopathy in term newborns

Introduction: Various studies from hypoxic-ischemic animals haveinvestigated neuroprotection by targeting necrosis and apoptosis with inconclusive results. Three types of cell death have been described: apoptosis, necrosis and more recently, autophagic cell death. While autophagy is a physiological process of degradation of cellular components, excessive autophagy may be involved in cell death. Recent studies showed that inhibition of autophagy is neuroprotective in rodent neonatal models of cerebral ischemia. Furthermore, neonatal hypoxia-ischemia strongly increased neuronal autophagic flux which is linked to cell death in a rat model of perinatal asphyxia. Following our observations in animals, the aim of the present study was to characterize the different neuronal death phenotypes and to clarify whether autophagic cell death could be also involved in neuronal death in the human newborns after perinatal asphyxia. Methods: we selected retrospectively and anonymously all newborns who died in our unit of neonatology between 2004 and 2009, with the following criteria: gestational age >36 weeks, diagnosis of perinatal asphyxia (Apgar <5 at 5 minutes, arterial pH <7.0 at 1 hour of life and encephalopathy Sarnat III) and performed autopsy. The brain of 6 cases in asphyxia group and 6 control cases matching gestational age who died of pulmonary or other malformations were selected. On histological sections of thalamus, frontal cortex and hippocampus, different markers of apoptosis (caspase 3, TUNEL), autophagosomes (LC3-II) and lysosomes (LAMP1, Cathepsin D) were tested by immunohistochemistry. Results: Preliminary studies on markers of apoptosis (TUNEL, caspase 3) and of autophagy (Cathepsin D, LC3II, LAMP1) showed an expected increase of apoptosis, but also an increase of neuronal autophagic flux in the selected areas. The distribution seems to be region specific. Conclusion: This is the first time that autophagic flux linked with cell death is shown in brain of human babies, in association with hypoxicischemic encephalopathy. This work leads to a better understanding of the mechanisms associated with neuronal death following perinatal asphyxia and determines whether autophagy could be a promising therapeutic target.

Oxygen consumption of Litopenaeus vannamei juveniles in heterotrophic medium with zero water exchange

This work aimed at determining the dissolved oxygen consumption rate of Litopenaeus vannamei juveniles maintained in a microbial biofloc raceway system at high density with no aeration. Three 4 L bottles were filled for each treatment, sealed hermetically, and placed in an enclosed greenhouse raceway system. Four shrimp (13.2±1.42 g) were assigned to two sets of the bottles, which underwent the following treatments: light conditions with no shrimp; dark conditions with no shrimp; light conditions with shrimp; and dark conditions with shrimp. Dissolved oxygen content was measured every 10 min for 30 min. A quadratic behavior was observed in dissolved oxygen concentration over time. Significant differences for oxigen consumption were observed only at 10 and 20 min between shrimp maintained in the dark and those under light conditions. At 10 min, a higher value was observed in shrimp maintained under light, and at 20 min, in the dark. Significant differences between 10 and 20 min and between 10 and 30 min were observed when oxygen consumption was analyzed over time in the presence of light. Under dark conditions there were significant differences only between 20 and 30 min. Lethal oxygen concentration (0.65 mg L-1) would be reached in less than one hour either under light or dark conditions with no aeration.

Temporary Speed Hump Impact Evaluation, 2002

The main objective of this research was to evaluate the impact of temporary speed humps and speed tables on vehicle speeds, vehicle speed profiles, and traffic volumes along local and/or collector streets in several rural Iowa cities. A 25 mile per hour (mph) temporary speed hump and a 30 mph temporary speed table, both made of recycled rubber, were purchased to test the impact of temporary devices. Two cities volunteered and the speed hump/table was installed on two test streets in the city of Atlantic (Roosevelt Drive and Redwood Drive) and one test street in the city of Le Claire (Canal Shore Drive). The speed hump was installed first and then converted to a speed table. Each device was installed for a period of at least two weeks at the same location. Speed, volume, and resident opinion data were then collected and evaluated.

Efficacy of a dilemma-focused intervention for unipolar depression: study protocol for a multicenter randomized controlled trial

Background Depression is one of the more severe and serious health problems because of its morbidity, disabling effects and for its societal and economic burden. Despite the variety of existing pharmacological and psychological treatments, most of the cases evolve with only partial remission, relapse and recurrence. Cognitive models have contributed significantly to the understanding of unipolar depression and its psychological treatment. However, success is only partial and many authors affirm the need to improve those models and also the treatment programs derived from them. One of the issues that requires further elaboration is the difficulty these patients experience in responding to treatment and in maintaining therapeutic gains across time without relapse or recurrence. Our research group has been working on the notion of cognitive conflict viewed as personal dilemmas according to personal construct theory. We use a novel method for identifying those conflicts using the repertory grid technique (RGT). Preliminary results with depressive patients show that about 90% of them have one or more of those conflicts. This fact might explain the blockage and the difficult progress of these patients, especially the more severe and/or chronic. These results justify the need for specific interventions focused on the resolution of these internal conflicts. This study aims to empirically test the hypothesis that an intervention focused on the dilemma(s) specifically detected for each patient will enhance the efficacy of cognitive behavioral therapy (CBT) for depression. Design A therapy manual for a dilemma-focused intervention will be tested using a randomized clinical trial by comparing the outcome of two treatment conditions: combined group CBT (eight, 2-hour weekly sessions) plus individual dilemma-focused therapy (eight, 1-hour weekly sessions) and CBT alone (eight, 2-hour group weekly sessions plus eight, 1-hour individual weekly sessions). Method Participants are patients aged over 18 years meeting diagnostic criteria for major depressive disorder or dysthymic disorder, with a score of 19 or above on the Beck depression inventory, second edition (BDI-II) and presenting at least one cognitive conflict (implicative dilemma or dilemmatic construct) as assessed using the RGT. The BDI-II is the primary outcome measure, collected at baseline, at the end of therapy, and at 3- and 12-month follow-up; other secondary measures are also used. Discussion We expect that adding a dilemma-focused intervention to CBT will increase the efficacy of one of the more prestigious therapies for depression, thus resulting in a significant contribution to the psychological treatment of depression. Trial registration ISRCTN92443999; ClinicalTrials.gov Identifier: NCT01542957.

Biology and morphometrics of the immature stages of Epinotia aporema on artificial diet

The objective of this work was to establish a life table for the immature stages of Epinotia aporema, as part of a wider investigation on its biological control. Insects were reared on an artificial diet at 25±1ºC and a 16:8 (light:dark) hour photoperiod. For the identification of larval instars for the study of pathogen-insect interactions under laboratory conditions, head capsule widths (HCWs) were also determined. The egg incubation period was 4.13±0.30 days, larval stage took 11.64±0.49 days, and the development time of the pupal phase was sex-dependent with 8.51±0.69 days for the females and 9.41±0.65 days for the males. Five larval instars were identified.

Hypoxia: unique myocardial morphology?

OBJECTIVE: The objective of this study was to investigate the effects of chronic and intermittent hypoxia on myocardial morphology. METHODS: Rats randomly divided into 3 groups (n = 14 per group) were exposed to room air (Fio(2) = 0.21), chronic hypoxia (Fio(2) = 0.10), and intermittent hypoxia (chronic hypoxia with 1 hour per day of room air) for 2 weeks. Weight, blood gas analysis, hematocrit, hemoglobin, red cells, and right and left ventricular pressures were measured. Hearts excised for morphologic examination were randomly divided into 2 groups (9 per group for gross morphologic measurements and 5 per group for histologic and morphometric analysis). The weight ratio of right to left ventricles plus interventricular septum, myocyte diameter, cross-sectional area, and free wall thickness in right and left ventricles were measured. RESULTS: Despite the same polycythemia, the right ventricle pressure (P <.05) and ratio of right to left ventricle pressures (P <.02) were higher after chronic hypoxia than intermittent hypoxia. The ratio of heart weight to total body weight and the ratio of right to left ventricles plus interventricular septum was higher (P <.01) in chronic and intermittent hypoxia than in normoxia. Myocyte diameter was not different between the right and left ventricles in normoxia, whereas right ventricle myocytes were larger than left ventricle myocytes in chronic hypoxia (P <.05) and intermittent hypoxia (P <.0005). There was marked dilatation of right ventricle size (P <.001) and marked reduction of left ventricle (P <.001) size in chronic and intermittent hypoxia compared with normoxia. The total ventricular area (right ventricle plus left ventricle area) remained the same in all groups. The wall thickness ratio in chronic hypoxia and intermittent hypoxia was increased (P <.001) compared with normoxia in the right ventricle but not in the left ventricle. CONCLUSIONS: Intermittent reoxygenation episodes do not induce a lesser ventricular hypertrophic response than observed with chronic hypoxia. The functional myocardial preconditioning consequence of intermittent reoxygenation is not supported by structural differences evident with the available techniques.

J-shaped association between serum glucose and functional outcome in acute ischemic stroke.

BACKGROUND AND PURPOSE: Hyperglycemia after stroke is associated with larger infarct volume and poorer functional outcome. In an animal stroke model, the association between serum glucose and infarct volume is described by a U-shaped curve with a nadir ≈7 mmol/L. However, a similar curve in human studies was never reported. The objective of the present study is to investigate the association between serum glucose levels and functional outcome in patients with acute ischemic stroke. METHODS: We analyzed 1446 consecutive patients with acute ischemic stroke. Serum glucose was measured on admission at the emergency department together with multiple other metabolic, clinical, and radiological parameters. National Institutes of Health Stroke Scale (NIHSS) score was recorded at 24 hours, and Rankin score was recorded at 3 and 12 months. The association between serum glucose and favorable outcome (Rankin score ≤2) was explored in univariate and multivariate analysis. The model was further analyzed in a robust regression model based on fractional polynomial (-2-2) functions. RESULTS: Serum glucose is independently correlated with functional outcome at 12 months (OR, 1.15; P=0.01). Other predictors of outcome include admission NIHSS score (OR, 1.18; P<0001), age (OR, 1.06; P<0.001), prestroke Rankin score (OR, 20.8; P=0.004), and leukoaraiosis (OR, 2.21; P=0.016). Using these factors in multiple logistic regression analysis, the area under the receiver-operator characteristic curve is 0.869. The association between serum glucose and Rankin score at 12 months is described by a J-shaped curve with a nadir of 5 mmol/L. Glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome. A similar curve was generated for the association of glucose and 24-hour NIHSS score, for which glucose values between 4.0 and 7.2 mmol/L are associated with a NIHSS score <7. Discussion-Both hypoglycemia and hyperglycemia are dangerous in acute ischemic stroke as shown by a J-shaped association between serum glucose and 24-hour and 12-month outcome. Initial serum glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome.

Extended access cocaine self-administration differentially activates dorsal raphe and amygdala corticotropin-releasing factor systems in rats.

Cocaine-induced neuroadaptation of stress-related circuitry and increased access to cocaine each putatively contribute to the transition from cocaine use to cocaine dependence. The present study tested the hypothesis that rats receiving extended versus brief daily access to cocaine would exhibit regional differences in levels of the stress-regulatory neuropeptide corticotropin-releasing factor (CRF). A secondary goal was to explore how CRF levels change in relation to the time since cocaine self-administration. Male Wistar rats acquired operant self-administration of cocaine and were assigned to receive daily long access (6 hours/day, LgA, n = 20) or short access (1 hour/day, ShA, n = 18) to intravenous cocaine self-administration (fixed ratio 1, ∼0.50 mg/kg/infusion). After at least 3 weeks, tissue CRF immunoreactivity was measured at one of three timepoints: pre-session, post-session or 3 hours post-session. LgA, but not ShA, rats showed increased total session and first-hour cocaine intake. CRF immunoreactivity increased within the dorsal raphe (DR) and basolateral, but not central, nucleus of the amygdala (BLA, CeA) of ShA rats from pre-session to 3 hours post-session. In LgA rats, CRF immunoreactivity increased from pre-session to 3 hours post-session within the CeA and DR but tended to decrease in the BLA. LgA rats showed higher CRF levels than ShA rats in the DR and, pre-session, in the BLA. Thus, voluntary cocaine intake engages stress-regulatory CRF systems of the DR and amygdala. Increased availability of cocaine promotes greater tissue CRF levels in these extrahypothalamic brain regions, changes associated here with a model of cocaine dependence.

Atorvastatin-loaded hydrogel affects the smooth muscle cells of human veins.

Intimal hyperplasia (IH) is the major cause of stenosis of vein grafts. Drugs such as statins prevent stenosis, but their systemic administration has limited effects. We developed a hyaluronic acid hydrogel matrix, which ensures a controlled release of atorvastatin (ATV) at the site of injury. The release kinetics demonstrated that 100% of ATV was released over 10 hours, independent of the loading concentration of the hydrogel. We investigated the effects of such a delivery on primary vascular smooth muscle cells isolated from human veins. ATV decreased the proliferation, migration, and passage of human smooth muscle cells (HSMCs) across a matrix barrier in a similar dose-dependent (5-10 µM) and time-dependent manner (24-72 hours), whether the drug was directly added to the culture medium or released from the hydrogel. Expression analysis of genes known to be involved in the development of IH demonstrated that the transcripts of both the gap junction protein connexin43 (Cx43) and plasminogen activator inhibitor-1 (PAI-1) were decreased after a 24-48-hour exposure to the hydrogel loaded with ATV, whereas the transcripts of the heme oxygenase (HO-1) and the inhibitor of tissue plasminogen activator were increased. At the protein level, Cx43, PAI-1, and metalloproteinase-9 expression were decreased, whereas HO-1 was upregulated in the presence of ATV. The data demonstrate that ATV released from a hydrogel has effects on HSMCs similar to the drug being freely dissolved in the environment.

In vitro organogenesis from internodal segments of adult sweet orange plants

The objective of this work was to optimize in vitro plant regeneration via organogenesis from tissues of adult 'Hamlin', 'Pêra', and 'Valência' sweet orange plants. Explants were grown in EME culture medium with different concentrations of 6-benzylaminopurine (BAP) and naphthaleneacetic acid (NAA), at 27ºC in the absence of light for 50 days, followed by a 16-hour photoperiod for 20 days. Regeneration was assessed 50 and 70 days after in vitro culture. Organogenesis in cultivars Hamlin and Valência was promoted by EME supplemented with BAP, while NAA showed no apparent effect.

Association of calcemia and serum vitamin D with 24H-urinary calcium excretion in a swiss population-based study

Background: Elevated urinary calcium excretion is associated with reduced bone mineral density. Population-based data on urinary calcium excretion are scarce. We explored the association of serum calcium and circulating levels of vitamin D (including 25(OH)D2 and 25(OH)D3) with urinary calcium excretion in men and women in a population-based study. Methods: We used data from the "Swiss Survey on Salt" conducted between 2010 and 2012 and including people aged 15 years and over. Twenty-four hour urine collection, blood analysis, clinical examination and anthropometric measures were collected in 11 centres from the 3 linguistic regions of Switzerland. Vitamin D was measured centrally using liquid chromatography - tandem mass spectrometry. Hypercalciuria was defined as urinary calcium excretion >0.1 mmol/kg/24h. Multivariable linear regression was used to explore factors associated with 24-hour urinary calcium excretion (mmol/24h) squared root transformed, taken as the dependant variable. Vitamin D was divided into monthspecific tertiles with the first tertile having the lowest value and the third tertile having the highest value. Results: The 669 men and 624 women had mean (SD) age of 49.2 (18.1) and 47 (17.9) years and a prevalence of hypercalciuria of 8.9% and 8.0%, respectively. In adjusted models, the association of urinary calcium excretion with protein-corrected serum calcium was (β coefficient } standard error, according to urinary calcium squared root transformed) 1.125 } 0.184 mmol/L per square-root (mmol/24h) (P<0.001) in women and 0.374 } 0.224 (P=0.096) in men. Men in the third month-specific vitamin D tertile had higher urinary calcium excretion than men in the first tertile (0.170 } 0.05 nmol/L per mmol/24h, P=0.001) and the corresponding association was 0.048 } 0.043, P= 0.272 in women. Conclusion: About one in eleven person has hypercalciuria in the Swiss population. The positive association of serum calcium with urinary calcium excretion was steeper in women than in men, independently of menopausal status. Circulating vitamin D was associated positively with urinary calcium excretion only in men. The reasons underlying the observed sex differences in the hormonal control of urinary calcium excretion need to be explored in further studies.

Genome-wide RNA polymerase II profiles and RNA accumulation reveal kinetics of transcription and associated epigenetic changes during diurnal cycles.

Interactions of cell-autonomous circadian oscillators with diurnal cycles govern the temporal compartmentalization of cell physiology in mammals. To understand the transcriptional and epigenetic basis of diurnal rhythms in mouse liver genome-wide, we generated temporal DNA occupancy profiles by RNA polymerase II (Pol II) as well as profiles of the histone modifications H3K4me3 and H3K36me3. We used these data to quantify the relationships of phases and amplitudes between different marks. We found that rhythmic Pol II recruitment at promoters rather than rhythmic transition from paused to productive elongation underlies diurnal gene transcription, a conclusion further supported by modeling. Moreover, Pol II occupancy preceded mRNA accumulation by 3 hours, consistent with mRNA half-lives. Both methylation marks showed that the epigenetic landscape is highly dynamic and globally remodeled during the 24-hour cycle. While promoters of transcribed genes had tri-methylated H3K4 even at their trough activity times, tri-methylation levels reached their peak, on average, 1 hour after Pol II. Meanwhile, rhythms in tri-methylation of H3K36 lagged transcription by 3 hours. Finally, modeling profiles of Pol II occupancy and mRNA accumulation identified three classes of genes: one showing rhythmicity both in transcriptional and mRNA accumulation, a second class with rhythmic transcription but flat mRNA levels, and a third with constant transcription but rhythmic mRNAs. The latter class emphasizes widespread temporally gated posttranscriptional regulation in the mouse liver.

Changes in the isoflavone profile and in the chemical composition of tempeh during processing and refrigeration

The objective of this work was to analyze changes in the isoflavone profile, determined by high performance liquid chromatography, at different processing stages and after refrigeration of tempeh. For tempeh production, clean soybean grains from cultivars BR 36 (low isoflavone content) and IAS 5 (high) were dehulled, and the separated cotyledons were hydrated and then cooked in boiling water for 30 min. Spores of the fungus Rhizopus microsporus var. oligosporus were inoculated in the cooked and cooled cotyledons, and incubated at 32ºC for 6, 12, 18, and 24 hours in perforated polypropylene bags, for fermentation. The resulting tempeh was stored at 4ºC for 6, 12, 18, and 24 hours. After 24-hour fermentation, isoflavone glucosides were 50% reduced, and the aglycone forms in the tempeh from both cultivars was increased. The malonyl forms reduced 83% after cooking. Less than 24 hours of refrigeration did not affect the isoflavone profile of tempeh from either cultivar, which is a good indicator of its quality. The tempeh maintains the high and low isoflavone content of the cultivars, which indicates that cultivar differences in this trait should be considered when processing tempeh.