Sherifa A. Hamed

Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations.

Aminoglycosides have previously been shown to suppress nonsense mutations, allowing translation of full‐length proteins in vitro and in animal models. In the mdx mouse, where muscular dystrophy is due to a nonsense mutation in the dystrophin gene, gentamicin suppressed truncation of the protein and ameliorated the phenotype. A subset of patients with Duchenne and Becker muscular dystrophy similarly possess a nonsense mutation, causing premature termination of dystrophin translation. Four such patients, with various stop codon sequences, were treated once daily with intravenous gentamicin at 7.5 mg/kg/day for 2 weeks. No ototoxicity or nephrotoxicity was detected. Full‐length dystrophin was not detected in pre‐ and post‐treatment muscle biopsies.

Vascular Risk Factors, Endothelial Function, and Carotid Thickness in Patients with Migraine: Relationship to Atherosclerosis

Recent studies indicated that migraine is associated with specific vascular risk profile. However, the functional and structural vascular abnormalities in migraine are rarely addressed. We evaluated the vascular risk factors, endothelial function, and carotid artery (CA)-intima-media thickness (IMT), segregators of preclinical atherosclerosis, in migraineurs. This preliminary study included 63 adults with headache (migraine with aura [n=14], migraine without aura [n=24], transformed migraine [n=6], and tension headache [n=19]) and 35 matched healthy subjects. The following vascular risks were assessed: body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressures (DBP), serum levels of C-reactive protein, fasting glucose, fasting insulin, total cholesterol, and triglycerides. Plasma endothelin (ET)-1, a vasoactive peptide produced by vascular smooth muscle cells and marker for endothelial injury and atherosclerosis, was measured. Endothelial-dependent vasoreactivity was assessed using brachial artery flow-mediated dilatation (FMD) in response to hyperemia. CA-IMT, structural marker of early atherosclerosis, was measured. Compared with control subjects, SBP, DBP, glucose, insulin, ET-1, and CA-IMT were elevated with migraine. FMD% was inversely correlated with SBP (P < .001), DBP (P < .01), glucose (P < .001), and insulin levels (P < .01). CA-IMT was correlated with BMI (P < .05), SBP (P < .01), total cholesterol (P < .01), triglycerides (P < .001), glucose (P < .001), insulin (P < .01), and FMD% (P < .05). In multivariate analysis, ET-1 was correlated with duration of illness, SBP, DBP, glucose, insulin, IMT, and FMD%. We conclude that endothelial injury, impaired endothelial vasoreactivity, and increased CA-IMT occur with migraine and are associated with vascular risk factors that strongly suggest that migraine could be a risk for atherosclerosis.

VASCULAR RISKS AND COMPLICATIONS IN DIABETES MELLITUS: THE ROLE OF HELICOBACTER PYLORI INFECTION

Patients with diabetes mellitus (DM) are at risk for Helicobacter pylori infection. This infection has been linked to atherosclerosis and its vascular complications. The aim of this study was to evaluate the: (1) prevalence of H pylori infection in patients with DM; (2) association between diabetic vascular complications and H pylori infection; and (3) influence of H pylori infection on atherosclerosis and inflammatory biomarkers. In this study, we evaluated 80 patients with DM for atherosclerosis; cardiac, cerebral, and peripheral vascular diseases; retinopathy; neuropathy; and nephropathy. We estimated the blood levels of glucose, glycosylated hemoglobin, complete blood cell count, erythrocytic sedimentation rate, lipid profile, tumor necrosis factor-alpha, interleukin (IL)-6, and anti-H pylori IgG antibodies. H pylori infection was detected in 85% of patients versus 76.7% for control subjects. Carotid artery intima-media thickness was significant in H pylori-infected patients. IL-6 and tumor necrosis factor-alpha were significantly associated with H pylori infection. In multivariate analysis, blood glucose, triglycerides, erythrocytic sedimentation rate, IL-6, and tumor necrosis factor-alpha increased the odds for atherothrombotic cause of cerebral ischemia in H pylori infection. We concluded that H pylori infection is common in DM and seems to be linked to the presence of atherosclerosis and ischemic cerebrovascular stroke. This effect could be mediated by increasing cytokine levels.

States of serum leptin and insulin in children with epilepsy: Risk predictors of weight gain

BACKGROUND AND OBJECTIVES Weight gain is an adverse metabolic effect in some children with epilepsy. The studies done to detect the effect of antiepileptic drugs and weight homeostatic hormones, insulin and leptin, were limited and controversial. MATERIALS AND METHODS We evaluated the serum leptin and insulin as predictors of weight gain in children receiving long-term treatment with valproate (VPA), carbamazepine (CBZ), lamotrigine (LTG). This study included 90 patients (treated: 70; untreated: 20). Serum lipid profile, insulin and leptin were measured. RESULTS BMI, serum leptin and insulin were significantly elevated in VPA compared with controls, untreated patients and those treated with CBZ, LTG and combined therapy with LTG. Girls on VPA had higher BMI and leptin levels than boys. With VPA, serum insulin was correlated with BMI (r=0.625, p<0.01), leptin (r=0.823, p<0.001), treatment duration (r=0.775, p<0.01) and VPA dose (r=0.975, p<0.0001). Serum leptin was correlated with age (r=0.980, p<0.0001), BMI (r=0.704, p<0.01), serum insulin (r=0.823, p<0.001), LDL-c (r=0.630, p<0.01), HDL-c (r=-0.880, p<0.001), treatment duration (r=0.770, p<0.01) and VPA dose (r=0.970, p<0.001). BMI is correlated with serum insulin, leptin, LDL-c (r=0.835, p<0.001) and HDL-c (r=-0.955, p<0.0001). CONCLUSION Hyperinsulinemia and hyperleptinemia are common with VPA and marked among epileptic children who gained weight suggesting states of insulin and leptin resistances. These alterations were not demonstrated with CBZ or LTG. The relationship between VPA, leptin and weight seems to be gender specific. Serum leptin may serve as a sensitive parameter for weight gain and reduction with intervention programs during follow-up of girls with epilepsy.

Leptin and insulin homeostasis in epilepsy: Relation to weight adverse conditions

During managing patients with epilepsy, there is a great risk of weight changes, particularly weight gain with some antiepileptic medications. Weight gain is not only a cosmetic problem that leads to non-compliance to medications but also increases the risk for atherosclerosis and its related complications. The mechanisms underlying weight gain in epilepsy are multiple and controversial and have been attributed to the effect of epilepsy and more commonly the effect of antiepileptic medications on the central and peripheral mechanisms regulating weight homeostasis including the two main homeostatic hormones, leptin, a protein product of obesity gene secreted by adipocytes and insulin, a protein product of pancreatic beta-cells. Increased blood levels of leptin and insulin due to leptin and insulin resistance is observed in patients with epilepsy. Leptin forms an important link between weight gain, insulin resistance, epilepsy and atherosclerosis. The knowledge of the novel roles of leptin in patients with epilepsy will help identification of early markers for the related adverse weight changes, thus allowing proper characterization of suitable antiepileptic medication as initial step during management and follow up of patients.

Serum thyroid hormone balance and lipid profile in patients with epilepsy

PURPOSE Patients with epilepsy may exhibit changes in thyroid hormone balance, lipids and lipoproteins concentrations. The suggestion that lipid abnormalities are associated with subclinical thyroid dysfunction remains controversial. The aim of this study was to analyze whether thyroid dysfunction encountered in patients with epilepsy would also be associated with abnormal lipid profile. METHODS Eighty-eight patients with epilepsy and 30 control subjects were included in the study. A fasting blood sample for thyroid hormones, lipid profile and GGT determination was obtained. RESULTS The serum levels of FT3 was elevated in 10.2% of patients, FT4 was low in 28.4%, TSH was high in 4.6% and low in 2.3%. 13.6% of patients had high TC, 17.1% had high LDL-c, 60.2% had marked reduction of HDL-c levels (P<0.0001) and only 2.3% had high TG levels. Abnormalities were predominated in CBZ-treated patients. 27.3% patients with abnormal hormones had abnormal lipid profile. Significant association was identified between the serum TC, LDL-c, TG, GGT and EIAEDs and between the duration of illness and TG (r=-0.411; P=0.017), and FT4 (r=-0.412; P=0.018). HDL was higher in women than men (r=0.416; P<0.002). However, changes in HDL-c levels associated neither with duration of illness, type or serum levels of AEDs nor with age or degree of control on AEDs. CONCLUSIONS Our results support that (1) altered lipid metabolism might be associated but not solely influenced by thyroid hormones and (2) enzyme induction is not the main or only reason for altered thyroid function or HDL-c among patients with epilepsy. Hypothalamic/pituitary dysregulation by precisely mechanism caused by epilepsy itself or AEDs seems possible and (3) it is important to recognize that patients with epilepsy are at great risk for atherosclerosis, hence monitoring and correction of the culprit risks are mandatory.

Cognitive impairment after cerebrovascular stroke: Relationship to vascular risk factors.

Background: Cognitive decline after cerebrovascular stroke has adverse outcome consequences. Since some vascular causes can be prevented and treated, the identification of stroke-related cognitive impairment is a challenge. Patients with cognitive impairment and vascular diseases exhibit higher homocysteine (Hcy) concentrations. Whether Hcy is an independent risk factor for cognitive impairment after stoke is still in question. The objectives of this study were to determine: 1) the relative frequency of first-ever post-stroke dementia (PSD) (three months after onset) in a consecutive sample of our population, 2) the risk factors associated with PSD, and 3) the relationship between Hcy levels and PSD. Methods: Eighty-one inpatients with first-ever stroke were prospectively evaluated with a neuropsychological battery and event-related evoked potentials (P300) at onset and then after three months. A wide range of demographic, clinical, radiological and laboratory variables were examined. PSD was diagnosed if the clinical presentation fulfilled DSM-IV criteria of vascular dementia, the patient scored ≤21 on Mini Mental State Examination (MMSE) and ≤67 points on Cognitive Abilities Screening Instruments (CASI). Results: PSD was diagnosed in 21%. PSD was significantly associated with increasing age, low levels of education, large sized and lacunar infarctions, severity of stroke, prolonged P300 latency, smoking, hypertension, and elevated Hcy levels. High Hcy levels increased the odds ratio of PSD after adjustment of significantly relevant variables including age, smoking, size of infarction, and carotid stenosis. Conclusions: Cognitive decline is common after stroke. The results of this study indicate that PSD may result from stroke and its related risk factors including possible direct association with high Hcy levels. Better knowledge of the risk factors for PSD should increase the effectiveness of preventive strategies in patients with this condition.

The sexual and reproductive health in men with generalized epilepsy: a multidisciplinary evaluation

This study was specifically aimed to evaluate the sexual and reproductive health in a group of men with generalized epilepsy. In total, 44 men with generalized epilepsy were included in this study, their ages between 18 and 48 years (29.2±9.9) and duration of illness between 2 and 35 years (11.2±7.4); 34 patients were treated with conventional antiepileptic drugs (AEDs). Sexological and psychological interviews together with serum total testosterone, E2, FSH, LH and prolactin were determined. Hyposexuality was diagnosed in 61.4%. Erectile dysfunction (ED) and premature ejaculation represented 70.4 and 66.7%, respectively. Variables such as hyposexuality, seizure duration and its poor control on AEDs were significantly associated with depressive symptoms. Compared to the normal control group, all patients reported elevated E2 levels (P<0.001), 10 had FSH (n=4) and LH (n=6) levels exceeding that of the normal range for controls and two had hyperprolactinemia. Although the patients’ mean value of total testosterone remained within the normal range, but it was significantly lower in hyposexual men compared to nonhyposexual (P<0.002), only two epileptic patients had markedly reduced level of total testosterone beyond normal control levels. This study strongly supports that: (1) The risk of hyposexuality and reproductive disturbances is high in epileptic patients with GTC convulsions despite the AEDs utilized. The risk for SD is further increased by poor seizure control and the frequently accompanied depressive manifestations. (2) It is possible that elevated E2 could increase the risk of SD by reducing active testosterone through negative feedback and the reduction of active testosterone could increase seizure intractability to antiepileptic medications.

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

High-throughput next-generation sequencing can identify disease-causing mutations in extremely heterogeneous disorders. Kara et al . investigate a series of 97 index cases with complex hereditary spastic paraplegia (HSP). They identify SPG11 defects in 30 families, as well as mutations in other HSP genes and genes associated with disorders including Parkinson’s disease.

The effects of glucocorticoid therapy on the inflammatory and Dendritic cells in muscular dystrophies

Various clinical trials have documented the therapeutic benefit of glucocorticoids (GCs) in enhancing muscle strength and slowing disease progression of Duchenne and Becker muscular dystrophies (DMD/BMD). We hypothesized that GCs may have relevance to the differential anti‐inflammatory effect on mononuclear inflammatory cells (MICs) and Dendritic cells (DCs) infiltrating the dystrophic muscles. In this prospective study, two muscle biopsies were obtained (before and after 6‐month prednisone therapy) from 30 patients with dystrophies (DMD = 18; BMD = 6; and limb girdle muscular dystrophies (LGMD) = 6). MICs and DCs infiltrating the muscles were examined using mouse monoclonal antibodies and immunoperoxidase staining methods. Muscle strength was evaluated monthly by manual testing, motor ability and timed tests. Prednisone therapy was associated with: (i) functional improvement of overall motor disability, in upper limbs of DMD (P < 0.001) and BMD (P < 0.01) and lower limbs of DMD (P < 0.001) and BMD (P < 0.05); (ii) histological improvement such as fibre size variation (DMD, P < 0.01; BMD, P < 0.05), internalization of nuclei (DMD, P < 0.05), degeneration and necrosis (DMD and BMD, P < 0.01), regeneration (DMD, P < 0.001; BMD, P < 0.01) and endomysial connective tissue proliferation (DMD, P < 0.01; BMD, P < 0.05) and (iii) reduction of total MICs (P < 0.01) and DCs (P < 0.01). There was a positive correlation between the degree of improvement in overall motor disability and reduction of DCs numbers (In upper limbs; r = 0.638, P < 0.01 for DMD and r = 0.725, P < 0.01 for BMD, in Lower limbs; r = 0.547, P < 0.05 for DMD and r = 0.576, P < 0.05 for BMD). Such improvements and changes of MICs/DCs were absent in LGMD. In DMD/BMD, prednisone therapeutic effect was associated with reduced MICs and DCs numbers. Whether this therapeutic effect reflects targeting of the deleterious immune response produced by these cells mandates further investigations.