Antioxidant intervention attenuates oxidative stress in children and teenagers with Down syndrome

We previously demonstrated that systemic oxidative stress is present in Down syndrome (DS) patients. In the present study we investigated the antioxidant status in the peripheral blood of DS children and teenagers comparing such status before and after an antioxidant supplementation. Oxidative stress biomarkers were evaluated in the blood of DS patients (n = 21) before and after a daily antioxidant intervention (vitamin E 400 mg, C 500 mg) during 6 months. Healthy children (n = 18) without DS were recruited as control group. The activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), gamma-glutamyltransferase (GGT), glucose-6-phosphate dehydrogenase (G6PD) and myeloperoxidase (MPO), as well as the contents of reduced glutathione (GSH), uric acid, vitamin E, thiobarbituric acid reactive substances (TBARS), and protein carbonyls (PC) were measured. Before the antioxidant therapy, DS patients presented decreased GST activity and GSH depletion; elevated SOD, CAT, GR, GGT and MPO activities; increased uric acid levels; while GPx and G6PD activities as well as vitamin E and TBARS levels were unaltered. After the antioxidant supplementation, SOD, CAT, GPx, GR, GGT and MPO activities were downregulated, while TBARS contents were strongly decreased in DS. Also, the antioxidant therapy did not change G6PD and GST activities as well as uric acid and PC levels, while it significantly increased GSH and vitamin E levels in DS patients. Our results clearly demonstrate that the antioxidant intervention with vitamins E and C attenuated the systemic oxidative damage present in DS patients.     

In vitro evidence that sulfite impairs glutamatergic neurotransmission and inhibits glutathione metabolism-related enzymes in rat cerebral cortex

Sulfite oxidase (SOX) deficiency is an inherited neurometabolic disorder biochemically characterized by tissue accumulation and high urinary excretion of sulfite and thiosulfate. Affected patients present severe neurological dysfunction accompanied by seizures, whose pathophysiology is poorly known. In the present study we evaluated the in vitro effects of sulfite and thiosulfate on important parameters of glutamatergic neurotransmission and redox homeostasis in rat cerebral cortex slices. We verified that sulfite, but not thiosulfate, significantly decreased glutamate uptake when cerebral cortex slices were exposed during 1 h to these metabolites. We also observed that thiosulfate inhibited glutamine synthetase (GS) activity. A pronounced trend toward GS inhibition induced by sulfite was also found. Regarding redox homeostasis, sulfite, at the concentration of 10 μM, increased thiobarbituric acid-reactive substances and decreased glutathione concentrations after 1 h of exposure. In contrast, thiosulfate did not alter these parameters. We also found that 500 μM sulfite increased sulfhydryl group content in rat cerebral cortex slices and increased GSH levels in a medium containing oxidized GSH (GSSG) and devoid of cortical slices, suggesting that sulfite reacts with disulfide bonds to generate sulfhydryl groups. Moreover, sulfite and thiosulfate did not alter the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PDH) after 1 h of incubation. However, sulfite inhibited the activities of GPx, GST and G6PDH when cortical slices were exposed for 3 h to sulfite. We finally verified that sulfite did not induce cell death after 1 h of incubation. Our data show that sulfite impairs glutamatergic neurotransmission and redox homeostasis in cerebral cortex. Therefore, it may be presumed that these pathomechanisms contribute, at least in part, to the seizures observed in patients affected by SOX deficiency.     

Biobehavioral and neuroendocrine correlates of antioxidant enzyme activity in ovarian carcinoma

Increased levels of reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxide have been reported in many cancer cells and they have been implicated in carcinogenesis and tumor progression. Antioxidant enzymes, such as Manganese Superoxide Dismutase (MnSOD or SOD2) and Glutathione Peroxidase-1 (GPx1), act coordinately to neutralize ROS. These enzymes are also thought to contribute to cancer cell resistance to conventional radio-chemo-therapies. Although some relationships have been reported between psychosocial factors and the regulation of antioxidant enzymes, little is known about these relationships in the context of cancer progression.The current study investigated the levels of MnSOD and GPx1in confirmed serous, high-grade tumor tissue from 60 ovarian cancer patients, and explored the relationship between the activity of these enzymes, the levels of tumor norepinephrine (NE), and patient mood as determined via pre-operative questionnaires. MnSOD activity was positively related to depressed mood (p = 0.025) and tumor NE (p = 0.023). In contrast, GPx1 activity was inversely related to fatigue (p = 0.015) and tumor NE (p = 0.009), and was positively associated with vigor (p = 0.024). These findings suggest that psychological state and adrenergic signaling are linked with antioxidant enzyme activity in ovarian cancer and may have implications for patient treatments and outcomes.     

Predicting METs from the heart rate index in persons with Down syndrome

Persons with Down syndrome (DS) have altered heart rate modulation and very low aerobic fitness. These attributes may impact the relationship between metabolic equivalent units (METs) and the heart rate index (HR_index—the ratio between heart rate during activity and resting heart rate), thereby altering the HR_index thresholds for moderate- and vigorous-intensity physical activity. This study examined whether the relationship between METs and HR_index differs between persons with and without DS and attempted to develop thresholds for activity intensity based on the HR_index for persons with DS. METs were measured with portable spirometry and heart rate with a monitor in 18 persons with DS (25 ± 7 years; 10 women) and 18 persons without DS (26 ± 5 years; 10 women) during 6 over-ground walking trials, each lasting 6 min, at the preferred walking speed and at 0.5, 0.75, 1.0, 1.25, and 1.5 m/s. The relationship between METs and HR_index in the two groups was analyzed with multi-level modeling with random intercepts and slopes. Group, HR_index, and the square of HR_index were significant predictors of METs (p < 0.001; R² = 0.65). Absolute percent error did not differ significantly between groups across speeds (DS: 19.6 ± 14.4%; non-DS: 21.0 ± 14.5%). Bland–Altman plots demonstrated somewhat greater variability in the difference between actual and predicted METs in participants with than without DS. The HR_index threshold for moderate-intensity activity was 1.32 and 1.20 for persons with and without DS, respectively. The HR_index threshold for vigorous-intensity activity was 1.80 and 1.65 for persons with and without DS, respectively. Persons with DS have an altered relationship between METs and HR_index and higher HR_index thresholds for moderate- and vigorous-intensity physical activity.     

Serum uric acid level in patients with relapsing-remitting multiple sclerosis

Uric acid (UA) is a hydrophilic antioxidant product associated with multiple sclerosis (MS). We conducted a randomized case-control study to evaluate the serum level of UA in different phases of MS in comparison with levels in a healthy control population. Serum UA was checked in 130 patients with relapsing-remitting MS (85 patients in remitting and 45 patients in relapsing phase) and 50 age-matched controls using a quantitative enzyme-linked immunosorbent assay (ELISA). The mean concentrations of UA in serum was 6.41(±3.18) mg/dL in patients with remitting MS, 4.76(±1.66) mg/dL in patients with relapsing MS and 6.33(±2.94) mg/dL in controls. There was a significant difference between mean UA concentration in relapsing MS and remitting MS (p < 0.001), and between patients with relapsing MS and controls (p = 0.002); however, the difference between levels for patients in the remitting phase of MS and the control group was not significant (p = 0.87). It seems probable that UA has a role in the prevention of disease activity in MS.     

Arterial stiffness response to exercise in persons with and without Down syndrome

This study compared arterial stiffness and wave reflection at rest and following maximal exercise between individuals with and without Down syndrome (DS), and the influence of body mass index (BMI), peak oxygen uptake (VO₂peak) on changes in arterial stiffness. Twelve people with DS (26.6 ± 2.6 yr) and 15 healthy controls (26.2 ± 0.6 yr) completed this study. Intima-media thickness (IMT) and stiffness of common carotid artery was examined. Hemodynamic and arterial variables were measured before and 3-min after exercise. Persons with DS had higher BMI and lower VO₂peak than controls. IMT did not differ between groups. At rest, carotid β stiffness was significantly higher in persons with DS (P < 0.05) but there was no difference in between groups for any of the other arterial stiffness measures. After exercise, persons with DS exhibited attenuated arterial stiffness responses in AIx-75, carotid β stiffness and Ep in contrast with controls (significant group-by-time interactions). When controlling for BMI and VO₂peak, the interactions disappeared. In both groups combined, BMI was correlated significantly with carotid Ep and β at rest. VO₂peak correlated significantly with AIx-75 and its pre-post change (r = ?0.45, P = 0.029; r = 0.47, P = 0.033, respectively). The arterial stiffness responses to maximal exercise in persons with DS were blunted, potentially reflecting diminished vascular reserve. Obesity and particularly VO₂peak influenced these findings. These results suggest impaired vascular function in people with DS.     

Enteral nutrition feeding alters antioxidant activity in unstimulated whole saliva composition of patients with neurological disorders

Patients with neurological disorders have an increased risk of oral and systemic diseases due to compromised oral hygiene. If patients lose the ability to swallow and chew food as a result of their disorder, enteral nutrition is often utilized. However, this type of feeding may modify salivary antioxidant defenses, resulting in increased oxidative damage and the emergence of various diseases. The aim of this study was to evaluate the effects of enteral nutrition on biochemical parameters in the unstimulated whole saliva composition of patients with neurological disorders. For this, enzymatic (superoxide dismutase – SOD; glutathione peroxidase – GPx) and non-enzymatic (uric acid; ferric ion reducing antioxidant power – FRAP) antioxidant activity, as well as a marker for oxidative damage (thiobarbituric acid reactive substances – TBARS) were analyzed. Unstimulated whole saliva was collected from 12 patients with neurological disorders and tube-feeding (tube-fed group – TFG), 15 patients with neurological disorders and normal feeding via the mouth (non-tube-fed group – NTFG), and 12 volunteers without neurological disorders (control group – CG). The daily oral hygiene procedures of TFG and NTFG patients were similar and dental care was provided monthly by the same institution's dentist. All patients exhibited adequate oral health conditions. The salivary levels of FRAP, uric acid, SOD, GPx, TBARS, and total protein were compared between studied groups. FRAP was increased (p < 0.05) in the NTFG (4651 ± 192.5 mmol/mL) and the TFG (4743 ± 116.7 mmol/mL) when compared with the CG (1844 ± 343.8 mmol/mL). GPx values were lower (p < 0.05) in the NTGF (8.24 ± 1.09 mmol/min/mg) and the TFG (8.37 ± 1.60 mmol/min/mg) than in the CG (15.30 ± 2.61 mmol/min/mg). Uric acid in the TFG (1.57 ± 0.23 mg/dL) was significantly lower than in the NTFG (2.34 ± 0.20 mg/dL) and the CG (3.49 ± 0.21 mg/dL). Protein was significantly lower in the TFG (5.35 ± 0.27 g/dL) than in the NTFG (7.22 ± 0.57 g/dL) and the CG (7.86 ± 0.54 g/dL). There was no difference in the salivary flow rate and SOD between groups. Enteral nutrition in patients with neurological disorders was associated with lower oxidative damage, resulting in increased salivary antioxidant capacity. These results emphasize the importance of oral care for this population to prevent oral and systemic diseases.     

Age assessment based on dental calcification in individuals with Down syndrome

It is important to estimate both chronological age (CA) and maturational age of an individual, in order to perform orthopedic treatment or surgery, and in cases of lost documentation. Use of dental age (DA) for these purposes has been widely studied; however, the literature is scarce with regard to individuals with Down syndrome (DS), a prevalent condition worldwide. In this study the chronology of dental maturation was evaluated by analyzing the DA of individuals with DS based on the Chronological Mineralization Table proposed by Nolla (1960). Thus, second molars were evaluated in 57 panoramic radiographs of male and female individuals with DS, between 5 and 16 years-old. These data were compared with a control group of 191 nonsyndromic individuals of the same age group. Correlation between CA and DA was ascertained using Pearson's correlation coefficient (r), and the difference between these variables was measured using Student's t-test for paired samples and the method proposed by Bland and Altman. The difference between DA and CA was compared between the control and DS groups using Student's t-test for independent samples (α = 0.05). DA was slightly lower than the CA; however, this difference was only significant for females. The difference between DA and CA was not significant between individuals with DS and control group (both genders, p = 0.945; males, p = 0.542; females, p = 0.381). We concluded that dental maturation in individuals with DS occurs similarly to that of nonsyndromic individuals.     

Reduction in primary genu recurvatum gait after aponeurotic calf muscle lengthening during multilevel surgery

Knee hyperextension (genu recurvatum, GR) is often seen in children with bilateral spastic cerebral palsy (CP). Primary GR appears essential without previous treatment. As equinus deformity is suspected to be one of the main factors evoking primary GR, the purpose of this study was to determine whether lengthening the calf muscles to decrease equinus would decrease coexisting GR in children with bilateral spastic CP. In a retrospective study, 19 CP patients with primary GR (mean age: 9.4 years, 13 male, 6 female, 26 involved limbs) in whom an aponeurotic calf muscle lengthening procedure was performed during single-event multilevel surgery were included and investigated using three-dimensional gait analysis before and at a mean follow-up of 14 months after the procedure according to a standardized protocol. After calf muscle lengthening, a significant improvement in ankle dorsiflexion (9.5°) and a significant reduction (10.5°) in knee hyperextension (p < 0.001) were found during mid-stance of the gait cycle. Six limbs (23%) showed no improvement concerning knee hyperextension and were designated as nonresponders. In these patients no significant improvement in ankle dorsiflexion was found after surgery either. Improvement in ankle dorsiflexion and reduction in knee hyperextension in stance phase correlated significantly (r = 0.46; p = 0.019). These findings indicate that equinus deformity is a Major underlying factor in Primary GR and that calf muscle lengthening can effectively reduce GR in patients with CP.     

Effects of calcium and training on the development of bone density in children with Down syndrome

In this study we examined the effects of physical training and calcium intake on the development of bone mineral density (BMD) in children with Down syndrome (DS). A total of 48 children with DS (age 7–12 years old) matched for age and BMD were assigned to four groups exercise and calcium intake (Ex⁺Ca⁺), calcium intake-no-exercise (Ex^?Ca⁺), exercise no-calcium intake (Ex⁺Ca^?) and non-exercise-no-calcium intake (Ex^?Ca^?). The training protocol included 45 min of weight bearing exercise performed 3 sessions per week in addition to dietary calcium rich food intake of enriched cow milk with vitamin D containing 200 mg calcium per serving or no enriched dietary supplement for a duration of 4 months. Data analysis was performed on data by using t-test, one-way ANOVA analysis and Tukey post hoc tests to determine the main and combined effects of training and calcium regiment on BMD. All groups showed greater femoral neck BMD after 4 months. The increase in femoral neck BMD in the Ex⁺Ca⁺ group was 5.96% greater than the Ex⁺Ca^? group (p < 0.01). The effect of training was greater than calcium intake alone. The Ex⁺Ca^? group achieved 3.52% greater BMD than Ex^?Ca⁺ group (p < 0.01). In this study, all the experimental groups had greater BMD than the no-calcium-no-exercise group that served as the control group (p < 0.01). It was concluded that additional weight bearing exercise and calcium supplementation resulted in a greater increase in BMD in children with DS.     

Voluntary exercise training in mice increases the expression of antioxidant enzymes and decreases the expression of TNF-α in intestinal lymphocytes

Acute exercise in mice induces intestinal lymphocyte (IL) apoptosis. Freewheel running reduces apoptosis and forced exercise training increases splenocyte antioxidant levels. The purpose of this study was to examine the effect of freewheel running and acute exercise on mouse IL numbers and concentrations of apoptosis and antioxidant proteins and pro-inflammatory cytokines in IL. Female C57BL/6 mice had access to in-cage running wheels (RW) or cages without wheels (NRW) for 16 weeks and were randomized at the end of training to no exercise control (TC) or to treadmill exercise with sacrifice after 90 min of running (TREAD; 30 min, 22 m min^?1; 30 min, 25 m min^?1; 30 min, 28 m min^?1; 2° slope). IL were analyzed for pro-(caspase 3 and 7) and anti-(Bcl-2) apoptotic proteins, endogenous antioxidants (glutathione peroxidase: GPx; catalase: CAT) and the pro-inflammatory cytokine, TNF-α. RW mice had higher cytochrome oxidase (p < 0.001) and citrate synthase (p < 0.01) activities in plantaris and soleus muscles and higher GPx and CAT expression in IL (p < 0.05) (indicative of training) compared with NRW mice. TNF-α expression was lower (p < 0.05) and IL numbers higher (p < 0.05) in RW vs. NRW mice. No training effect was observed for apoptotic protein expression, although TREAD resulted in higher caspase and lower Bcl-2. These results suggest that freewheel running in mice for 16 weeks enhances antioxidant and reduces TNF-α expression in IL but does not reduce pro-apoptotic protein expression after acute exercise. Results are discussed in terms of implications for inflammatory bowel diseases where apoptotic proteins and TNF-α levels are elevated.     

Menstrual cycle and reproductive aging alters immune reactivity,NGF expression,antioxidant enzyme activities,and intracellular signaling pathways in the peripheral blood mononuclear cells of healthy women

Reproductive senescence in women is a process that begins with regular menstrual cycles and culminates in menopause followed by gradual development of diseases such as autoimmune diseases, osteoporosis, neurodegenerative diseases, and hormone-dependent cancers. The age-associated impairment in the functions of neuroendocrine system and immune system results in menopause which contributes to subsequent development of diseases and cancer. The aim of this study is to characterize the alterations in immune responses, compensatory factors such as nerve growth factor (NGF) and antioxidant enzyme activities, and the molecular mechanisms of actions in the peripheral blood mononuclear cells (PBMCs) of young (follicular and luteal phases), middle-aged, and old healthy women. Peripheral blood mononuclear cells were isolated from young women in follicular and luteal phases of the menstrual cycle (n = 20; 22.6 ± 2.9 yrs), middle-aged women (n = 19; 47.1 ± 3.8 yrs; perimenopausal) and old (n = 16; 63.2 ± 4.7 yrs; post-menopausal) women and analyzed for Concanavalin (Con A)-induced proliferation of lymphocytes and cytokine (IL-2 and IFN-γ) production, expression of NGF, p-NF-κB, p-ERK, p-CREB, and p-Akt, antioxidant enzymes [superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), glutathione-S-transferase (GST)], extent of lipid peroxidation, and nitric oxide (NO) production. Serum gonadal hormones (17β-estradiol and progesterone) were also measured. A characteristic age- and menstrual cycle-related change was observed in the serum gonadal hormone secretion (estrogen and progesterone), T lymphocyte proliferation and IFN-γ production. Salient features include the age-related decline observed in target-derived growth factors (lymphocyte NGF expression), signaling molecules (p-ERK/ERK and p-CREB/CREB ratios) and compensatory factors such as the activities of plasma and PBMC antioxidant enzymes (SOD and catalase) and NO production. Further, an age-associated increase in p-NF-κB expression and lipid peroxidation was observed. Also, serum 17β-estradiol levels were positively correlated with IFN-γ production, SOD activity and NGF expression in the PBMCs. These results suggest that alterations in the levels of gonadal hormones are associated with immunosenescence characterized by decreased IFN-γ production and proliferation of T lymphocytes, decline in NGF expression, SOD and catalase activities, NO production, and signaling mechanisms and thus, may increase the incidence of diseases and cancer in women.     

Variability of cognitive development in children with Down syndrome: Relevance of good reasons for using the cluster procedure

The main goal of this cross-sectional study was to demonstrate that, in addition to a main change during childhood, the cognitive development of children with Down syndrome (DS) is characterized by interindividual variability in their cognitive functioning. Eighty-eight French children with DS took part in this experiment. They were divided into six chronological age groups: 6 years (N = 9), 7 years (N = 19), 8 years (N = 18), 9 years (N = 19), 10 years (N = 14) and 11 years (N = 9). They were assessed by means of the Differential Scales of Intellectual Efficiency. This test, composed of six independent scales, measures verbal abilities and nonverbal reasoning abilities. Initial analyses of the verbal and nonverbal subtest scores indicated a main change in cognitive skills. We then used a clustering approach to identify four cognitive profiles that distinguished the children with DS independently of age and gender. The results confirm that there is a growth in the cognitive skills of DS children. They also suggest that the cognitive functioning of DS children is characterized by different individual profiles. Implications for more fine-tuned research and intervention efforts are discussed.     

The influence of timing of knee recurvatum on surgical outcome in cerebral palsy

Recent reports have shown that timing of genu recurvatum (GR) might be caused by different underlying factors and that equinus leads to GR especially during early stance. The purpose of this study was to investigate the reduction of GR after surgical correction of equinus in children with bilateral spastic cerebral palsy and whether the children with early and late type GR show differences in reduction of knee hyperextension after a surgery. In 24 limbs (mean age 10.3 years, GMFCS I-III) showing equinus and GR the kinematics of the knee and ankle as well as the kinetics of the knee were evaluated before and one year (mean follow up period: 12.8 months) after surgical correction of equinus. The study was approved by the local ethical committee. Limbs with early type GR showed a reduction by 11.1° (p < 0.001) and those with late type GR by 6.0° (p < 0.049) in GR after surgery. Before surgery limbs with early type GR showed increased external extending moments, which decreased significantly after surgery. In contrast limbs with late GR did not show a significant reduction of those moments. The findings of this study underline the influence of equinus on early GR as an underlying factor. As equinus is attributed to early knee hyperextension and proximal factors are more important as underlying factors in late type GR, a classification into early and late onset GR is useful to identify underlying factors and to choose adequate treatment.     

Affective and inflammatory responses among orchestra musicians in performance situation

A number of studies have shown that mental challenge under controlled experimental conditions is associated with elevations in inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). However, relatively little work has been done on the effects of ‘naturalistic’ stressors on acute changes in inflammatory markers. The present study examined whether perceived arousal, valence and dominance in musicians are associated with pro-inflammatory and oxidative responses to a concert situation. Blood and salivary samples obtained from 48 members of a symphony orchestra on the day of rehearsal (i.e. control situation) and on the following day of premiere concert (i.e. test situation) were used to determine changes in salivary cortisol, pro-inflammatory markers (plasma myeloperoxidase, serum CRP, plasma IL-6), oxidative stress markers (paraoxonase1 activity and malondialdehyde), and homocysteine, a risk factor for vascular disease. Results of regression analyses showed a significant trend to increased myeloperoxidase (MPO) response in individuals with low valence score. Both affective states, valence and arousal, were identified as significant predictors of cortisol response during concert. In addition, control levels of plasma malondialdehyde were positively correlated with differences in IL-6 levels between premiere and rehearsal (r = .38, p = .012), pointing to higher oxidative stress in individuals with pronounced IL-6 response. Our results indicate that stress of public performance leads to increased concentrations of plasma MPO (20%), IL-6 (27%) and salivary cortisol (44%) in musicians. The decreasing effect of pleasantness on the MPO response was highly pronounced in non-smokers (r = −.60, p < .001), suggesting a significant role of emotional valence in stress-induced secretion of MPO. Additional studies are needed to assess the generalizability of these findings to other ’naturalistic’ stress situations.     

Effect of added dead space on sleep disordered breathing at high altitude

ObjectiveSleep disordered breathing with central apnea or hypopnea frequently occurs at high altitude and is thought to be caused by a decrease in blood CO₂ level. The aim of this study was to assess the effects of added respiratory dead space on sleep disordered breathing.MethodsFull polysomnographies were performed on 12 unacclimatized swiss mountaineers (11 males, 1 female, mean age 39 ± 12 y.o.) in Leh, Ladakh (3500 m). In random order, half of the night was spent with a 500 ml increase in dead space through a custom designed full face mask and the other half without it.ResultsBaseline data revealed two clearly distinct groups: one with severe sleep disordered breathing (n = 5, AHI > 30) and the other with moderate to no disordered breathing (n = 7, AHI < 30). DS markedly improved breathing in the first group (baseline vs DS): apnea hypopnea index (AHI) 70.3 ± 25.8 vs 29.4 ± 6.9 (p = 0.013), oxygen desaturation index (ODI): 72.9 ± 24.1/h vs 42.5 ± 14.4 (p = 0.031), whereas it had no significant effect in the second group or in the total population. Respiratory events were almost exclusively central apnea or hypopnea. Microarousal index, sleep efficiency, and sleep architecture remained unchanged with DS. A minor increase in mean PtcCO₂ (n = 3) was observed with DS.ConclusionA 500 ml increase in dead space through a fitted mask may improve nocturnal breathing in mountaineers with severe altitude-induced sleep disordered breathing.     

Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: Does adherence to CPAP treatment improve glycemic control?

Background and AimObstructive Sleep Apnea Hypopnea Syndrome (OSAHS) is associated with glucose dysmetabolism and insulin resistance, therefore the amelioration of breathing disturbances during sleep can allegedly modify the levels of markers of glucose regulation and insulin resistance, such as glycated hemoglobin, fasting glucose, insulin and HOMA_IR. The aim of this study was to explore the association between these parameters and sleep characteristics in non-diabetic OSAHS patients, as well as the effect of 6 months CPAP therapy on these markers, according to adherence to CPAP treatment.MethodsEuglycemic patients (n = 56; mean age ± SD: 46.07 ± 10.67 years) with newly diagnosed OSAHS were included. Glycated hemoglobin, fasting glucose, insulin levels and HOMA_IR were estimated at baseline and 6 months after CPAP application. According to CPAP adherence, patients were classified as follows: group 1 (mean CPAP use ? 4 h/night), group 2 (mean CPAP use < 4 h/night) and group 3 (refused CPAP treatment), and comparisons of levels of the examined parameters were performed.ResultsAt baseline, average SpO₂ during sleep was negatively correlated with insulin levels and HOMA_IR while minimum SpO₂ during sleep was also negatively correlated with insulin levels. After 6 months, only group 1 patients demonstrated a significant decrease in glycated hemoglobin (p = 0.004) accompanied by a decrease in hs-CRP levels (p = 0.002). No other statistically significant change was observed.ConclusionsNighttime hypoxia can affect fasting insulin levels in non-diabetic OSAHS patients. Good adherence to long-term CPAP treatment can significantly reduce HbA_1C levels, but has no effect on markers of insulin resistance.     

Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: A preliminary report

22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common genetic disorder and is characterized by an elevated risk for immune dysfunction, up to 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1β, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r = 0.851, p = 0.004; r = 0.580, p = 0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r = 0.795, p = 0.033; r = 0.774, p = 0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive association between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry.     

Nitrite or sildenafil, but not BAY 41-2272, blunt acute pulmonary embolism-induced increases in circulating matrix metalloproteinase-9 and oxidative stress

IntroductionInhibition of matrix metalloproteinases (MMPs) improves the hemodynamics during acute pulmonary embolism (APE) and oxidative stress upregulates MMPs. We compared the effects of different NO-cGMP pathway activators on APE-induced increases in MMPs.Materials and MethodsHemodynamic and biochemical evaluations were performed in non-embolized dogs treated with saline (N = 5), and in microspheres embolized dogs receiving saline (n = 9), or nitrite (6.75 µmol/kg i.v. over 15 min followed by 0.28 µmol/kg/min; n = 5), or sildenafil (0.25 mg/kg; n = 5), or BAY 41-2272 (0.03, 0.1, 0.3, and 1 mg/kg/h; n = 5). Plasma thiobarbituric acid reactive substances (TBARS) concentrations were determined. Zymograms of plasma samples were performed, and in vitro antioxidant effects or inhibition of MMPs by these drugs were examined.ResultsAPE increased mean pulmonary artery pressure by ~ 25 mmHg. Nitrite, BAY 41-2272, or sildenafil reversed this increase by ~ 40% (P < 0.05). Similar effects were seen on the pulmonary vascular resistance. While both nitrite and sildenafil produced no systemic effects, the highest dose of BAY 41-2272 produced systemic hypotension (P < 0.05). While nitrite and sildenafil blunted the increases in plasma pro-MMP-9 levels and TBARS (all P < 0.05), BAY 41-2272 produced no such effects. Nitrite and sildenafil produced in vitro antioxidant effects and inhibited MMPs only at high concentrations. BAY 41-2272 produced no such effects.ConclusionsActivation of the NO-cGMP pathway with nitrite or sildenafil, but not with BAY 41-2272, attenuates APE-induced oxidative stress and increased MMP-9 levels. These findings are consistent with the idea that NO-cGMP pathway activators with antioxidant effects prevent the release of MMP-9 during APE.     

Severity of depressive symptomatology and functional impairment in children and adolescents with temporal lobe epilepsy

ObjectiveDepression is a frequent psychiatric disorder in children with temporal lobe epilepsy (TLE). However, severity of depressive symptoms (DS) is frequently neglected in these patients. This study aimed to determine severity of DS and global functioning by using quantitative measures and to establish their correlation with patients’ demographics and clinical variables.Methods31 children (mean age of 11.8 ± 2.3 years) with TLE were assessed with K-SADS-PL for axis I DSM-IV diagnosis. Severity of DS was measured by Children Depression Rating Scale-Revised – CDRS-R. Global functional impairment was evaluated with Child Global Assessment Scale-CGAS.Results25 patients (56% boys; 12 ± 2.3 years) had current DS, moderate or severe in 84% according to CDRS-R T-Score. Severity of DS was not correlated with age (p = 0.377), gender (p = 0.132), seizure control (p = 0.936), age of onset (p = 0.731), duration of epilepsy (p = 0.602) and the presence of hippocampal sclerosis (p = 0.614). Patients had moderate to major functional impairment measured by CGAS (48.7 ± 8.8), being adolescents more impaired than children (p = 0.03). Impairment of global functioning was not associated with epilepsy variables (p > 0.05).ConclusionChildren with TLE had moderate to severe DS early in the course of their disease with a relevant impact on their global functional activities, especially considering adolescents. Epilepsy severity seems not to be correlated to the severity of DS, contradicting the idea of a cause–consequence relationship. More systematic research is needed to better understand the association of depressive disorders in children and adolescents with TLE.