Role of Recurrent Hypoxia-Ischemia in Preterm White Matter Injury Severity

Objective

Although the spectrum of white matter injury (WMI) in preterm infants is shifting from cystic necrotic lesions to milder forms, the factors that contribute to this changing spectrum are unclear. We hypothesized that recurrent hypoxia-ischemia (rHI) will exacerbate the spectrum of WMI defined by markers of inflammation and molecules related to the extracellular matrix (hyaluronan (HA) and the PH20 hyaluronidase) that regulate maturation of the oligodendrocyte (OL) lineage after WMI.

Methods

We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. The response to rHI was compared against corresponding early or later single episodes of HI. An ordinal rating scale of WMI was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microglial activation. Late oligodendrocyte progenitors (preOLs) were quantified by stereology. Analysis of hyaluronan and the hyaluronidase PH20 defined the progressive response of the extracellular matrix to WMI.

Results

rHI resulted in a more severe spectrum of WMI with a greater burden of necrosis, but an expanded population of preOLs that displayed reduced susceptibility to cell death. WMI from single episodes of HI or rHI was accompanied by elevated HA levels and increased labeling for PH20. Expression of PH20 in fetal ovine WMI was confirmed by RT-PCR and RNA-sequencing.

Conclusions

rHI is associated with an increased risk for more severe WMI with necrosis, but reduced risk for preOL degeneration compared to single episodes of HI. Expansion of the preOL pool may be linked to elevated hyaluronan and PH20.     

Enrichment of HIV-1 Subtype AD Recombinants in a Ugandan Cohort of Severely Septic Patients

Background

Several population-wide HIV-1 subtype distribution studies in Uganda have evaluated relatively healthy clinic patients. Given the differences in HIV-1 disease progression based on subtype, we examined HIV-1 subtype distribution and disease outcomes among hospitalized patients with severe sepsis.

Methods

Patients with severe sepsis were enrolled at two hospitals in Uganda. Data collected included demographics, Karnofsky scores, highly active antiretroviral therapy (HAART) use, HIV-1 serostatus, CD4+ T cell concentration, whole blood lactate concentration, and blood cultures. HIV-1 subtypes were determined by sequencing parts of the gag and env genes, followed by phylogenetic analysis.

Results

Of the 267 patients evaluated, 228 (85.4%) were HIV infected. The predominant HIV-1 subtypes were A (46%), D (17%), and AD recombinants (30%). HIV-1 subtypes B, C, and other recombinants were uncommon. Patients infected with HIV-1 subtypes A, D and AD viruses were similar in demographics, CD4⁺ T cell concentration, HAART use, Karnofsky scores, whole blood lactate concentration, and positive blood cultures. There was no difference in 30-day mortality from severe sepsis between the 3 groups (p = 0.99).

Conclusion

A high proportion of HIV-1 subtypes A and AD recombinants was observed in this cohort of severely septic patients. The proportion of AD recombinants was higher in this cohort than in previous cohorts of Ugandan HIV-1 patients. No difference in baseline demographics, clinical factors or 30-day mortality was seen across HIV-subtypes.     

A Quantitative Method to Analyze Drosophila Pupal Eye Patterning

Background

The Drosophila pupal eye has become a popular paradigm for understanding morphogenesis and tissue patterning. Correct rearrangement of cells between ommatidia is required to organize the ommatidial array across the eye field. This requires cell movement, cell death, changes to cell-cell adhesion, signaling and fate specification.

Methodology

We describe a method to quantitatively assess mis-patterning of the Drosophila pupal eye and objectively calculate a ‘mis-patterning score’ characteristic of a specific genotype. This entails step-by-step scoring of specific traits observed in pupal eyes dissected 40–42 hours after puparium formation and subsequent statistical analysis of this data.

Significance

This method provides an unbiased quantitative score of mis-patterning severity that can be used to compare the impact of different genetic mutations on tissue patterning.     

Treatment of Sleep Disordered Breathing Liberates Obese Hypoxemic Patients from Oxygen

Background

Obese hypoxemic patients have a high prevalence of sleep disordered breathing (SDB). It is unclear to what extent treatment of SDB can improve daytime hypoxemia.

Methods

We performed a retrospective cohort study of obese hypoxemic individuals, all of whom underwent polysomnography, arterial blood gas analysis, and subsequent initiation of positive airway pressure (PAP) therapy for SDB. Patients were followed for one year for change in partial pressure of arterial oxygen and the need for supplemental oxygen.

Results

One hundred and seventeen patients were treated with nocturnal PAP and had follow-up available. Adherence to PAP was satisfactory in 60%, and was associated with a significant improvement in daytime hypoxemia and hypercapnea; 56% of these patients were able to discontinue supplemental oxygen. Adherence to PAP therapy and the baseline severity of OSA predicted improvement in hypoxemia, but only adherence to PAP therapy predicted liberation from supplemental oxygen.

Conclusions

The identification and treatment of SDB in obese hypoxemic patients improves daytime hypoxemia. It is important to identify SDB in these patients, since supplemental oxygen can frequently be discontinued following treatment with PAP therapy.     

Hypoglycemia and the Origin of Hypoxia-Induced Reduction in Human Fetal Growth

Background

The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.

Methods

Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated.

Principal Findings

The maternal arterial – venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced.

Conclusion/Significance

Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia.     

Self-Reported Pain Intensity with the Numeric Reporting Scale in Adult Dengue

Background

Pain is a prominent feature of acute dengue as well as a clinical criterion in World Health Organization guidelines in diagnosing dengue. We conducted a prospective cohort study to compare levels of pain during acute dengue between different ethnicities and dengue severity.

Methods

Demographic, clinical and laboratory data were collected. Data on self-reported pain was collected using the 11-point Numerical Rating Scale. Generalized structural equation models were built to predict progression to severe disease.

Results

A total of 499 laboratory confirmed dengue patients were recruited in the Prospective Adult Dengue Study at Tan Tock Seng Hospital, Singapore. We found no statistically significant differences between pain score with age, gender, ethnicity or the presence of co-morbidity. Pain score was not predictive of dengue severity but highly correlated to patients’ day of illness. Prevalence of abdominal pain in our cohort was 19%. There was no difference in abdominal pain score between grades of dengue severity.

Conclusion

Dengue is a painful disease. Patients suffer more pain at the earlier phase of illness. However, pain score cannot be used to predict a patient’s progression to severe disease.     

A Randomized Pilot Study of L-Arginine Infusion in Severe Falciparum Malaria: Preliminary Safety,Efficacy and Pharmacokinetics

Background

Decreased nitric oxide (NO) and hypoargininemia are associated with severe falciparum malaria and may contribute to severe disease. Intravenous L-arginine increases endothelial NO in moderately-severe malaria (MSM) without adverse effects. The safety, efficacy and pharmacokinetics of L-arginine or other agents to improve NO bioavailability in severe malaria have not been assessed.

Methods

In an open-label pilot study of L-arginine in adults with severe malaria (ARGISM-1 Study), patients were randomized to 12 g L-arginine hydrochloride or saline over 8 hours together with intravenous artesunate. Vital signs, selected biochemical measures (including blood lactate and L-arginine) and endothelial NO bioavailability (using reactive hyperemia peripheral arterial tonometry [RH-PAT]) were assessed serially. Pharmacokinetic analyses of L-arginine concentrations were performed using NONMEM.

Results

Six patients received L-arginine and two saline infusions. There were no deaths in either group. There were no changes in mean systolic (SBP) and diastolic blood pressure (DBP) or other vital signs with L-arginine, although a transient but clinically unimportant mean maximal decrease in SBP of 14 mmHg was noted. No significant changes in mean potassium, glucose, bicarbonate, or pH were seen, with transient mean maximal increases in plasma potassium of 0.3 mmol/L, and mean maximal decreases in blood glucose of 0.8 mmol/L and bicarbonate of 2.3 mEq/L following L-arginine administration. There was no effect on lactate clearance or RH-PAT index. Pharmacokinetic modelling (n = 4) showed L-arginine concentrations 40% lower than predicted from models developed in MSM.

Conclusion

In the first clinical trial of an adjunctive treatment aimed at increasing NO bioavailability in severe malaria, L-arginine infused at 12 g over 8 hours was safe, but did not improve lactate clearance or endothelial NO bioavailability. Future studies may require increased doses of L-arginine.

Trial Registration

ClinicalTrials.gov NTC00616304     

Comparative Effectiveness of Cognitive Therapies Delivered Face-to-Face or over the Telephone: An Observational Study Using Propensity Methods

Objectives

To compare the clinical and cost-effectiveness of face-to-face (FTF) with over-the-telephone (OTT) delivery of low intensity cognitive behavioural therapy.

Design

Observational study following SROBE guidelines. Selection effects were controlled using propensity scores. Non-inferiority comparisons assessed effectiveness.

Setting

IAPT (improving access to psychological therapies) services in the East of England.

Participants

39,227 adults referred to IAPT services. Propensity score strata included 4,106 individuals; 147 pairs participated in 1∶1 matching.

Intervention

Two or more sessions of computerised cognitive behavioural therapy (CBT).

Main outcome measures

Patient-reported outcomes: Patient Health Questionnaire (PHQ-9) for depression; Generalised Anxiety Disorder questionnaire (GAD-7); Work and Social Adjustment Scale (WSAS). Differences between groups were summarised as standardised effect sizes (ES), adjusted mean differences and minimally important difference for PHQ-9. Cost per session for OTT was compared with FTF.

Results

Analysis of covariance controlling for number of assessments, provider site, and baseline PHQ-9, GAD-7 and WSAS indicated statistically significantly greater reductions in scores for OTT treatment with moderate (PHQ-9: ES: 0.14; GAD-7: ES: 0.10) or small (WSAS: ES: 0.03) effect sizes. Non-inferiority in favour of OTT treatment for symptom severity persisted as small to moderate effects for all but individuals with the highest symptom severity. In the most stringent comparison, the one-to-one propensity matching, adjusted mean differences in treatment outcomes indicated non-inferiority between OTT versus FTF treatments for PHQ-9 and GAD-7, whereas the evidence was moderate for WSAS. The per-session cost for OTT was 36.2% lower than FTF.

Conclusions

The clinical effectiveness of low intensity CBT-based interventions delivered OTT was not inferior to those delivered FTF except for people with more severe illness where FTF was superior. This provides evidence for better targeting of therapy, efficiencies for patients, cost savings for services and greater access to psychological therapies for people with common mental disorders.     

Arterial Stiffness and Pulse Wave Reflection Are Increased in Patients Suffering from Severe Periodontitis

Aim

This single blind cross-sectional study compared the vascular health of subjects suffering from severe chronic periodontitis, severe aggressive periodontitis and periodontal healthy controls by evaluating pulse wave velocity (PWV), augmentation index (AIx) and pulse pressure amplification (PPA).

Material and Methods

In a total of 158 subjects, 92 suffering from severe periodontitis and 66 matched periodontal healthy controls, PWV, AIx, central and peripheral blood pressure were recorded using an oscillometric device (Arteriograph).

Results

Subjects suffering from severe chronic or aggressive periodontitis exhibited significantly higher PWV (p = 0.00004), higher AIx (p = 0.0049) and lower PPA (p = 0.028) than matched periodontal healthy controls.

Conclusions

The results of this study confirm the association between periodontal inflammation and increased cardiovascular risk shown by impaired vascular health in case of severe periodontitis. As impaired vascular health is a common finding in patients suffering from severe periodontal disease a concomitant routine cardiovascular evaluation may be advised.     

A Study of Cytological Changes in the Bone Marrow of Patients with Severe Fever with Thrombocytopenia Syndrome

Background

Peripheral blood leucopenia and thrombocytopenia are the main manifestations in severe fever with thrombocytopenia syndrome (SFTS) patients. However, the underlying causes are poorly understood. Therefore, we aimed to investigate cytology of bone marrow samples collected from SFTS patients.

Methods

10 SFTS patients were identified by typical clinical manifestations, detection of peripheral blood leucopenia and thrombocytopenia, and nucleic acid-based detection of the newly identified bunyavirus. SFTS patients, along with 10 participants with acute aplastic anemia and 10 healthy volunteers were enrolled in this study after written informed consent to undergo bone marrow cytological examination.

Results

We observed similar bone marrow properties in SFTS patients and healthy volunteers, significantly different from the characteristics observed in acute aplastic anemia patients.

Conclusion

Similarities between bone marrow samples collected from SFTS patients and healthy volunteers suggest that peripheral blood leucopenia and thrombocytopenia do not result from bone marrow cell plasticity.     

In vivo bioimaging as a novel strategy to detect doxorubicin-induced damage to gonadal blood vessels

Introduction

Chemotherapy may induce deleterious effects in normal tissues, leading to organ damage. Direct vascular injury is the least characterized side effect. Our aim was to establish a real-time, in vivo molecular imaging platform for evaluating the potential vascular toxicity of doxorubicin in mice.

Methods

Mice gonads served as reference organs. Mouse ovarian or testicular blood volume and femoral arterial blood flow were measured in real-time during and after doxorubicin (8 mg/kg intravenously) or paclitaxel (1.2 mg/kg) administration. Ovarian blood volume was imaged by ultrasound biomicroscopy (Vevo2100) with microbubbles as a contrast agent whereas testicular blood volume and blood flow as well as femoral arterial blood flow was imaged by pulse wave Doppler ultrasound. Visualization of ovarian and femoral microvasculature was obtained by fluorescence optical imaging system, equipped with a confocal fiber microscope (Cell-viZio).

Results

Using microbubbles as a contrast agent revealed a 33% (P<0.01) decrease in ovarian blood volume already 3 minutes after doxorubicin injection. Doppler ultrasound depicted the same phenomenon in testicular blood volume and blood flow. The femoral arterial blood flow was impaired in the same fashion. Cell-viZio imaging depicted a pattern of vessels'' injury at around the same time after doxorubicin injection: the wall of the blood vessels became irregular and the fluorescence signal displayed in the small vessels was gradually diminished. Paclitaxel had no vascular effect.

Conclusion

We have established a platform of innovative high-resolution molecular imaging, suitable for in vivo imaging of vessels'' characteristics, arterial blood flow and organs blood volume that enable prolonged real-time detection of chemotherapy-induced effects in the same individuals. The acute reduction in gonadal and femoral blood flow and the impairment of the blood vessels wall may represent an acute universal doxorubicin-related vascular toxicity, an initial event in organ injury.     

Lactate-Modulated Induction of THBS-1 Activates Transforming Growth Factor (TGF)-beta2 and Migration of Glioma Cells In Vitro

Background

An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by lactic acid, is a key pathophysiological factor in glioblastoma, leading to increased invasion and severe local immunosuppression after proteolytic cleavage from its latency associated peptide. In this study we tested the hypothesis, that lactate regulates TGF-beta2 expression and glioma cell migration via induction of Thrombospondin-1 (THBS-1), a TGF-beta activating protein.

Methods

Lactate levels were reduced by knockdown of LDH-A using specific small interfering RNA (siRNA) and competitive inhibition of LDH-A by sodium oxamate. Knockdown of THBS-1 was performed using specific siRNA. Western Blot, qRT-PCR, and ELISA were used to investigate expression levels of LDH-A, LDH-B, TGF-beta2 and THBS-1. Migration of cells was examined by Spheroid, Scratch and Boyden Chamber assays.

Results

Knockdown of LDH-A with subsequent decrease of lactate concentration leads to reduced levels of THBS-1 and TGF-beta2 in glioma cells. Lactate addition increases THBS-1 protein, leading to increased activation of TGF-beta2. Inhibition of THBS-1 reduces TGF-beta2 protein and migration of glioma cells. Addition of synthetic THBS-1 can rescue reduced TGF-beta2 protein levels and glioma cell migration in siLDH-A treated cells.

Conclusion

We define a regulatory cascade between lactate, THBS-1 and TGF-beta2, leading to enhanced migration of glioma cells. Our results demonstrate a specific interaction between tumor metabolism and migration and provide a better understanding of the mechanisms underlying glioma cell invasion.     

Thirst Perception and Osmoregulation of Vasopressin Secretion Are Altered During Recovery From Septic Shock

Objective

Vasopressin (AVP) secretion during an osmotic challenge is frequently altered in the immediate post-acute phase of septic shock. We sought to determine if this response is still altered in patients recovering from septic shock.

Design

Prospective interventional study

Setting

Intensive care unit (ICU) at Raymond Poincaré and Etampes Hospitals.

Patients

Normonatremic patients at least 5 days post discontinuation of catecholamines given for a septic shock.

Intervention

Osmotic challenge involved infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 minutes.

Measurements and main results

Plasma AVP levels were measured 15 minutes before the infusion and then every 30 minutes for two hours. Non-responders were defined as those with a slope of the relation between AVP and plasma sodium levels less than < 0.5 ng/mEq. Among the 30 included patients, 18 (60%) were non-responders. Blood pressure and plasma sodium and brain natriuretic peptide levels were similar in both responders and non-responders during the course of the test. Critical illness severity, hemodynamic alteration, electrolyte disturbances, treatment and outcome did not differ between the two groups. Responders had more severe gas exchange abnormality. Thirst perception was significantly diminished in non-responders. The osmotic challenge was repeated in 4 non-responders several months after discharge and the abnormal response persisted.

Conclusion

More than half of patients recovering from septic shock have an alteration of osmoregulation characterised by a dramatic decrease in vasopressin secretion and thirst perception during osmotic challenge. The mechanisms of this alteration but also of the relationship between haematosis and normal response remain to be elucidated.     

Defining Normal Liver Stiffness Range in a Normal Healthy Chinese Population without Liver Disease

Background

For patients with chronic liver disease, different optimal liver stiffness cut-off values correspond to different stages of fibrosis, which are specific for the underlying liver disease and population.

Aims

To establish the normal ranges of liver stiffness in the healthy Chinese population without underlying liver disease.

Methods

This is a prospective cross sectional study of 2,528 healthy volunteers recruited from the general population and the Red Cross Transfusion Center in Hong Kong. All participants underwent a comprehensive questionnaire survey, measurement of weight, height, and blood pressure. Fasting liver function tests, glucose and cholesterol was performed. Abdominal ultrasound and transient elastography were performed on all participants.

Results

Of the 2,528 subjects, 1,998 were excluded with either abnormal liver parenchyma on ultrasound, chronic medical condition, abnormal blood tests including liver enzymes, fasting glucose, fasting cholesterol, high body mass index, high blood pressure, or invalid liver stiffness scan. The reference range for the 530 subjects without known liver disease was 2.3 to 5.9 kPa (mean 4.1, SD 0.89). The median liver stiffness was higher in males compared with females (4.3 vs 4.0 kPa respectively, p<0.001). There was also a decline in median Lliver stiffness in the older age group, from 4.2 kPa in those <25 years to 3.4 kPa for those >55 years (p=0.001).

Conclusions

The healthy reference range for liver stiffness in the Chinese population is 2.3 to 5.9 kPa. Female gender and older age group was associated with a lower median liver stiffness.     

Diabetes,Glucose Metabolism,and Glaucoma: The 2005–2008 National Health and Nutrition Examination Survey

Background

Diabetes may affect vascular autoregulation of the retina and optic nerve and may be associated with an increased risk of glaucoma,but the association of prediabetes, insulin resistance, markers of glucose metabolismwith glaucoma has not beenevaluated in general population samples.

Objective

To examine the relation between diabetes, pre-diabetes, metabolic syndrome and its components and the levels of fasting glucose, HbA1c and HOMA-IR with the prevalence of glaucoma in the general U.S. population.

Methods

Cross-sectional study of 3,299 adult men and women from the 2005–2008 National Health and NutritionExamination Survey (NHANES). The presence of diabetes, prediabetes, the metabolic syndrome and its individual components and biomarkers of glucose metabolisms were based on standardized questionnaire and physical exam data and laboratory tests. The history of glaucoma was assessed through questionnaire during the home interview.

Results

Diabetes was strongly associated with prevalent glaucoma.In fully adjusted models, the odds ratiofor glaucoma comparing participants with diabetes with participants in the reference group with neither pre-diabetes nor diabetes was 2.12 (95% CI: 1.23, 3.67). The corresponding odd ratio comparing participants with pre-diabetes to those in the reference group was 1.01 (95% CI: 0.57, 1.82). Patients with 5 or more years of diabetes duration hadan OR for glaucoma of 3.90 (95% CI: 1.63, 9.32) compared with patients with <5 years of diabetes duration. We also found a hockey-stick shaped associations between biomarkers of glucose metabolisms and the prevalence of glaucoma.

Conclusions

Diabetes was associated with higher risk of glaucoma. Participants without diabetes but at the higher levels of fasting glucose, fasting insulin, HbA1c and HOMA-IR spectrum may also be at greater risk of glaucoma.     

Relationships between HDL-C,hs-CRP,with Central Arterial Stiffness in Apparently Healthy People Undergoing a General Health Examination

Background

Some cardiovascular risk factors have been confirmed to be positively correlated with arterial stiffness. However, it is unclear whether HDL-C, a well-established anti-risk factor, has an independent association with arterial stiffness. The aim of this study was to evaluate the relationship between HDL-C levels and arterial stiffness and the possible role of high-sensitivity C-reactive protein (hs-CRP) in this potential correlation in apparently healthy adults undergoing a general health examination in China.

Materials and Methods

This was a cross-sectional survey. In total, 15,302 participants (age range, 18–82 years; mean, 43.88±8.44 years) were recruited during routine health status examinations. A questionnaire was used and we measured the body mass index, systolic and diastolic blood pressure, and fasting glucose, and serum lipid, uric acid, hs-CRP, and serum creatinine levels of each participant. Central arterial stiffness was assessed by carotid–femoral pulse wave velocity (cf-PWV).

Results

HDL-C levels decreased as cf-PWV increased. Pearson’s correlation analysis revealed that HDL-C levels were associated with cf-PWV (r=−0.18, P<0.001). hs-CRP levels were positively associated with cf-PWV (r=0.13). After adjustment for all confounders, HDL-C was inversely independently associated with all quartiles of cf-PWV. Furthermore, HDL-C was associated with cf-PWV in different quartiles of hs-CRP, and the correlation coefficients (r) gradually decreased with increasing hs-CRP levels (quartiles 1–4).

Conclusions

HDL-C is inversely independently associated with central arterial stiffness. The anti-inflammatory activity of HDL-C may mediate its relationship with cf-PWV. Further, long-term follow-up studies are needed to evaluate whether high HDL-C levels are protective against central artery stiffening through the anti-inflammatory activity of HDL-C.     

Metabolomic Profile of Umbilical Cord Blood Plasma from Early and Late Intrauterine Growth Restricted (IUGR) Neonates with and without Signs of Brain Vasodilation

Objectives

To characterize via NMR spectroscopy the full spectrum of metabolic changes in umbilical vein blood plasma of newborns diagnosed with different clinical forms of intrauterine growth restriction (IUGR).

Methods

23 early IUGR cases and matched 23 adequate-for-gestational-age (AGA) controls and 56 late IUGR cases with 56 matched AGAs were included in this study. Early IUGR was defined as a birth weight <10^th centile, abnormal umbilical artery (UA) Doppler and delivery <35 weeks. Late IUGR was defined as a birth weight <10^th centile with normal UA Doppler and delivery >35 weeks. This group was subdivided in 18 vasodilated (VD) and 38 non-VD late IUGR fetuses. All AGA patients had a birth weight >10^th centile. ¹H nuclear magnetic resonance (NMR) metabolomics of the blood samples collected from the umbilical vein at delivery was obtained. Multivariate statistical analysis identified several metabolites that allowed the discrimination between the different IUGR subgroups, and their comparative levels were quantified from the NMR data.

Results

The NMR-based analysis showed increased unsaturated lipids and VLDL levels in both early and late IUGR samples, decreased glucose and increased acetone levels in early IUGR. Non-significant trends for decreased glucose and increased acetone levels were present in late IUGR, which followed a severity gradient when the VD and non-VD subgroups were considered. Regarding amino acids and derivatives, early IUGR showed significantly increased glutamine and creatine levels, whereas the amounts of phenylalanine and tyrosine were decreased in early and late-VD IUGR samples. Valine and leucine were decreased in late IUGR samples. Choline levels were decreased in all clinical subforms of IUGR.

Conclusions

IUGR is not associated with a unique metabolic profile, but important changes are present in different clinical subsets used in research and clinical practice. These results may help in characterizing comprehensively specific alterations underlying different IUGR subsets.     

Behavioral and Cardiorespiratory Responses to Bilateral Microinjections of Oxytocin into the Central Nucleus of Amygdala of Wistar Rats,an Experimental Model of Compulsion

Introduction

The central nucleus of amygdala plays an important role mediating fear and anxiety responses. It is known that oxytocin microinjections into the central nucleus of amygdala induce hypergrooming, an experimental model of compulsive behavior. We evaluated the behavioral and cardiorespiratory responses of conscious rats microinjected with oxytocin into the central nucleus of amygdala.

Methods

Male Wistar rats were implanted with guide cannulae into the central nucleus of amygdala and microinjected with oxytocin (0.5 µg, 1 µg) or saline. After 24 h, rats had a catheter implanted into the femoral artery for pulsatile arterial pressure measurement. The pulsatile arterial pressure was recorded at baseline conditions and data used for cardiovascular variability and baroreflex sensitivity analysis. Respiratory and behavioral parameters were assessed during this data collection session.

Results

Microinjections of oxytocin (0.5 µg) into the central nucleus of amygdala produced hypergrooming behavior but did not change cardiorespiratory parameters. However, hypergrooming evoked by microinjections of oxytocin (1 µg) into the central nucleus of amygdala was accompanied by increase in arterial pressure, heart rate and ventilation and augmented the power of low and high (respiratory-related) frequency bands of the systolic arterial pressure spectrum. No changes were observed in power of the low and high frequency bands of the pulse interval spectrum. Baroreflex sensitivity was found lower after oxytocin microinjections, demonstrating that the oxytocin-induced pressor response may involve an inhibition of baroreflex pathways and a consequent facilitation of sympathetic outflow to the cardiovascular system.

Conclusions

The microinjection of oxytocin (1 µg) into the central nucleus of amygdala not only induces hypergrooming but also changes cardiorespiratory parameters. Moreover, specific oxytocin receptor antagonism attenuated hypergrooming but did not affect pressor, tachycardic and ventilatory responses to oxytocin, suggesting the involvement of distinct neural pathways.     

Prevalence of Type 2 Diabetes among High-Risk Adults in Shanghai from 2002 to 2012

Objective

The objective of this study was to evaluate the trend and prevalence of prediabetes and diabetes among high-risk adults in Shanghai from 2002 to 2012.

Methods

From 2002 to 2012, 10043 subjects with known risk factors for diabetes participated in the diabetes-screening project at the Shanghai Sixth People’s Hospital of Shanghai Jiao Tong University. All participants were asked to complete a nurse-administered standard questionnaire concerning age, sex, smoking status, and personal and family histories of diabetes, cardiovascular disease, stroke, hypertension and other diseases. The participants’ body mass index scores, blood pressures and blood glucose levels at 0, 30, 60, 120 and 180 min were measured in response to a 75 g oral glucose tolerance test.

Results

The overall prevalence of diabetes increased from 27.93% to 34.78% between 2002 and 2012 in high-risk subjects. The study also showed that the prevalence increased much faster in male compared to female subjects. Specifically, an increased rate was seen in middle-aged men, with no change observed in middle-aged females over the eleven-year period.

Conclusion

This study showed that sex, age, parental diabetic history, and being overweight were associated with an increased risk for diabetes in high-risk people. Therefore, as prediabetes and diabetes are highly prevalent in people with multiple diabetes risk factors in Shanghai, screening programs targeting these individuals may be beneficial.