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Background: We investigated whether chronotype is associated with glycemic control, antidiabetic treatment, and risk of developing complications in patients with type 2 diabetes (T2DM). Methods: The diabetologists filled out an online questionnaire on the Google Form platform to collect the following parameters of subjects with T2DM: body mass index (BMI), fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), diabetes history, antidiabetic treatment, diabetic complications, and chronotype categories. Results: We enrolled 106 subjects with T2DM (M/F: 58/48; age: 63.3 ± 10.4 years; BMI: 28.8 ± 4.9 kg/m2). Thirty-five point eight% of the subjects showed a morning chronotype (MC), 47.2% an intermediate chronotype (IC), and 17% an evening chronotype (EC). EC subjects reported significantly higher HbA1c (p < 0.001) and FPG (p = 0.004) values, and higher prevalence of cardiovascular complications (CVC) (p = 0.028) and of subjects taking basal (p < 0.001) and rapid insulin (p = 0.01) compared to MC subjects. EC subjects reported significantly higher HbA1c (p < 0.001) and FPG (p = 0.015) than IC subjects. An inverse association was found between chronotype score, HbA1c (r = −0.459; p < 0.001), and FPG (r = −0.269; p = 0.05), remaining significant also after adjustment for BMI, age, and disease duration. Conclusions: EC is associated with higher prevalence of CVC and poorer glycemic control independently of BMI and disease duration in subjects with T2DM.

Background and Purpose— Sublethal injury induces tolerance to a subsequent lethal insult, a phenomenon termed preconditioning (PC). PC occurs within hours (early tolerance) or days (delayed tolerance) after the inducing stimulus. In the brain, delayed tolerance has been studied extensively, but very little is known about early tolerance. We investigated whether the proinflammatory agent lipopolysaccharide (LPS), a well-established inducer of delayed tolerance, can also induce early tolerance and, if so, whether nitric oxide (NO) is involved in its mechanisms. Methods— In C57BL/6 mice, LPS was administered and N -methyl- d -aspartate (NMDA) was microinjected into the neocortex 30 minutes to 24 hours later. Lesion volume was assessed 24 hours after NMDA administration in thionine-stained sections. Results— LPS reduced NMDA lesions when administered 1 hour (−25±1%; P P P >0.05). The protection at 1 hour was independent of protein synthesis and was blocked by inhibition of neuronal NO synthase or soluble guanylyl cyclase. Furthermore, early protection was not observed in neuronal or endothelial NO synthase–null mice, but it was present in inducible NO synthase–null mice. Conclusions— The data demonstrate that LPS induces both early and late tolerance. At variance with delayed tolerance, which depends on inducible NO synthase and peroxynitrite, early tolerance is mediated by endothelial and neuronal NO through production of cGMP. The findings suggest that LPS can trigger signaling between endothelial cells and neurons, leading to NO production and cGMP-dependent neuroprotection.

We sought to determine whether reactive oxygen species (ROS) derived from cyclooxygenase-2 (COX-2) are involved in ischemic brain injury. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in C57BL/6 mice. The time course of neocortical ROS production was assessed in vivo using hydroethidine as a marker. The same brain sections were used for infarct volume measurements. Transient middle cerebral artery occlusion led to a biphasic increase in ROS production with peaks 2 and 72 h after reperfusion. The COX-2 inhibitor NS398 (10 mg/kg) attenuated the production of COX-2-derived prostaglandin E2 and reduced brain injury, but did not affect ROS production at 2 and 72 h. Similarly, ROS production was not reduced in COX-2-null mice. In contrast, ROS production and brain injury were reduced in mice lacking the nox2 subunit of the superoxide-producing enzyme nicotinamide adenine dinucleotide phosphate (reduced form) oxidase. The data suggest that COX-2 is not a major source of oxygen radicals after cerebral ischemia and raise the possibility that other COX-2 reaction products, including prostanoids or nonoxygen-based radicals, mediate the COX-2-dependent component of the injury.

Background and aims Berberine (BBR) is an isoquinoline derivative alkaloid isolated from Rhizoma Coptidis traditionally used as anti diarrheic and, more recently, as hypolipidemic and insulin sensitizer agent. Thus, BBR could represent a potential therapeutic option for patients with polycystic ovary syndrome (PCOS). The aim of this study was to evaluate the clinical, metabolic and hormonal effects of BBR in PCOS women. Methods Fifty oligoamenorrheic PCOS obese women and 50 age and Body Mass Index (BMI) matched healthy controls were enrolled. PCOS women received BBR treatment (500 mg, 2 times daily) for 6 months. Clinical and biochemical parameters were assessed before and after the treatment period. Results Total testosterone (p Conclusions BBR improves clinical, metabolic and reproductive features in PCOS women. Its mechanism of actions need to be elucidated in further studies.

OBJECTIVE To test the hypothesis that the risk of persistent glucose impairment after gestational diabetes mellitus (GDM) is increased in patients with polycystic ovary syndrome (PCOS). RESEARCH DESIGN AND METHODS The prospective case-control study included 42 pregnant patients with PCOS and GDM and 84 pregnant control patients with GDM but without clinical and biochemical hyperandrogenism, polycystic ovaries, and oligo-anovulation. The case and control subjects were matched one to two for age and BMI. The glycemic profiles were studied in all subjects 6 weeks, 12 weeks, and 18 months after delivery. The incidence and the relative risk (RR) were calculated for overall persistence of an abnormal glycemic pattern and for each specific alteration, i.e., impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus (DM). RESULTS At 18 months after delivery, the incidences of IFG, IGT, and IFG-IGT were significantly (P < 0.05) higher in the cases than in the controls. At the 18-month follow-up, the RR for the composite outcome of glucose metabolism impairment in PCOS women was 3.45 (95% CI 1.82–6.58). CONCLUSIONS Patients with PCOS are at increased risk for a persistent impaired glucose metabolism after GDM.

Cyclooxygenases (COX) are prostanoid synthesizing enzymes constitutively expressed in the brain that contribute to excitotoxic neuronal cell death. While the neurotoxic role of COX-2 is well established and has been linked to prostaglandin E(2) synthesis, the role of COX-1 is not clearly understood. In a model of N-Methyl-D-aspartic acid (NMDA) induced excitotoxicity in the mouse cerebral cortex we found a distinctive temporal profile of COX-1 and COX-2 activation where COX-1, located in microglia, is responsible for the early phase of prostaglandin E(2) synthesis (10 minutes after NMDA), while both COX-1 and COX-2 contribute to the second phase (3-24 hours after NMDA). Microglial COX-1 is strongly activated by ATP but not excitatory neurotransmitters or the Toll-like receptor 4 ligand bacterial lipopolysaccharide. ATP induced microglial COX-1 dependent prostaglandin E(2) synthesis is dependent on P2X7 receptors, extracellular Ca(2+) and cytoplasmic phospholipase A2. NMDA receptor activation induces ATP release from cultured neurons leading to microglial P2X7 receptor activation and COX-1 dependent prostaglandin E(2) synthesis in mixed microglial-neuronal cultures. Pharmacological inhibition of COX-1 has no effect on the cortical lesion produced by NMDA, but counteracts the neuroprotection exerted by inhibition of COX-2 or observed in mice lacking the prostaglandin E(2) receptor type 1. Similarly, the neuroprotection exerted by the prostaglandin E(2) receptor type 2 agonist butaprost is not observed after COX-1 inhibition. P2X7 receptors contribute to NMDA induced prostaglandin E(2) production in vivo and blockage of P2X7 receptors reverses the neuroprotection offered by COX-2 inhibition. These findings suggest that purinergic signaling in microglia triggered by neuronal ATP modulates excitotoxic cortical lesion by regulating COX-1 dependent prostanoid production and unveil a previously unrecognized protective role of microglial COX-1 in excitotoxic brain injury.

Polycystic ovary syndrome (PCOS) is considered a sex-specific form of the metabolic syndrome (MetS). Visceral obesity is one of the main diagnostic criteria for the MetS. Patients with MetS have a significantly higher risk for cardiovascular disease (CVD). PCOS is the most common endocrine-metabolic disease of reproductive-age women and PCOS patients are predisposed to an androgen adiposity phenotype, characterized by a prevalent fat accumulation in the abdominal area, and by insulin resistance. PCOS women are exposed to a cluster of metabolic abnormalities and cardiovascular risk factors from a young age, and therefore PCOS patients might represent a high-risk group for developing early-onset CVD. Early signs of CVD have been reported in PCOS patients and correlated to the amount of visceral fat. Visceral fat might represent a new prognostic and therapeutic target to define the cardiovascular risk profile and prevent CVD in PCOS patients.

Summary Objective The aim of the present study was to determine if the favourable cardiopulmonary and metabolic benefits induced by exercise training (ET) programme are maintained after its cessation. Patients Thirty-two young overweight polycystic ovary syndrome (PCOS) women matched for age and body mass index (BMI) with other 32 PCOS patients was enrolled. The first group [PCOS-T (trained)] underwent 24-week ET programme, whereas the second [PCOS-DT (detrained)] underwent 12-week ET programme followed by 12-week detraining period. Methods At baseline, after 12- and 24-week follow-up, all PCOS women were studied for their hormonal (ovarian and adrenal androgens), metabolic (glucose and insulin) and lipid profile, and underwent cardiopulmonary exercise test. Results After the initial 12-week ET programme, both PCOS-T and PCOS-DT groups, without differences between groups, showed a similar significant (P

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, has been implicated in the neurotoxicity resulting from hypoxia-ischemia, and its inhibition has therapeutic potential for ischemic stroke. However, COX-2 inhibitors increase the risk of cardiovascular complications. We therefore sought to identify the downstream effectors of COX-2 neurotoxicity, and found that prostaglandin E(2) EP1 receptors are essential for the neurotoxicity mediated by COX-2-derived prostaglandin E(2). EP1 receptors disrupt Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange, a key mechanism by which neurons cope with excess Ca(2+) accumulation after an excitotoxic insult. Thus, EP1 receptors contribute to neurotoxicity by augmenting the Ca(2+) dysregulation underlying excitotoxic neuronal death. Pharmacological inhibition or gene inactivation of EP1 receptors ameliorates brain injury induced by excitotoxicity, oxygen glucose deprivation and middle cerebral artery (MCA) occlusion. An EP1 receptor inhibitor reduces brain injury when administered 6 hours after MCA occlusion, suggesting that EP1 receptor inhibition may be a viable therapeutic option in ischemic stroke.

We observed two families with a dominantly inher- ited complex neurological syndrome with onset in adult- hood. Family F included 9 affected in four generations. One patient showed prominent anticipation of onset age. Onset was with cerebellar signs followed by dementia, psychiatric symptoms, seizures, and extrapyramidal features. Family M included 14 affected individuals in five generations. Presenting symptoms were either psychiatric and cognitive impairment or a cerebellar syndrome. Extrapyramidal fea- tures, dysphagia, incontinence, seizures, and myoclonus may occur. In both families magnetic resonance imaging showed marked atrophy of the brain and cerebellum. Molecular analyses demonstrated an expanded CAG/CAA repeat in the in the TATA box-binding protein (TBP) gene (SCA17). There is a wide genetic heterogeneity within autosomal dom- inant spinocerebellar ataxias (SCAs), and 19 different loci have been identified. An expanded trinucleotide cytosine- adenine-guanine (CAG) repeat has been shown in most of the cloned genes (1). An expanded CAG repeat has been described in the TATA box-binding protein (TBP) gene (2), a general transcription initiation factor, in four Japanese pedi- grees (SCA17). We describe the phenotype of two Italian families with this mutation. The first kindred (Family F) originated from Campania and included 9 patients in four generations. The clinical fea- tures of the four personally examined patients are shown in Table 1. The patients in III generations had disease onset in the 3rd to 4th decade, whereas in the only patient in the IV gener- ation the disease began at 3 years. The mean age at death was 54 years in 7 deceased patients. Cerebellar signs, such as gait ataxia, dysarthria, and dysmetria, were the first symptoms in all patients. Dementia was early and severe; psychiatric symp- toms, such as mood depression, insomnia, and delusions, were frequent. Increased tendon reflexes, abnormal involuntary movements, seizures, and hypoacusia may occur. Incontinence and dysphagia were late features. Magnetic resonance imaging (MRI) showed atrophy of the cerebrum and cerebellum in all patients. Peripheral nerve conduction studies demonstrated a mild sensorimotor axonal neuropathy. The clinical picture of patient 4 was peculiar, with ataxia and dysarthria presenting at the age of 3 years, fast progres- sion with loss of independent gait and sphincter control, dys- phagia, spasticity, growth delay, grand mal seizures, and death at the age of 15 years. The second pedigree (Family M) originated from Calabria and included 14 patients in five generations. The clinical features of the 7 personally examined patients are shown in Table 1. The age at onset was usually in the 3rd-4th decade. No differences in age at onset were found between generations. The mean age at death was 56 years in 7 deceased patients. Psychiatric features, such as depression, personality changes, aggressiveness, negligence of personal hygiene, delusional thoughts, hallucinations, and alcoholism, were present in the majority of patients at onset. Cognitive impairment was an early feature. Ataxia, dysarthria, rigidity, and dystonia developed successively. Perioral dyskinesia, brisk tendon reflexes, and seizures may occur and late stages were characterized by anarthria, dysphagia, and inconti- nence. In some cases the disease began with a cerebellar syn- drome followed by dementia and other neurological features. MRI showed marked atrophy of the brain and cerebellum. Genomic DNA was prepared from peripheral blood

A form of autosomal recessive spastic ataxia (ARSACS) has been described in the Charlevoix and Saguenay regions of Quebec. So far a frameshift and a nonsense mutation have been identified in the SACS gene. The authors report a new mutation (1859insC), leading to a frameshift with a premature termination of the gene product sacsin, in two sisters from consanguineous parents. The phenotype is similar to previously described patients with ARSACS.

Background:Gerstmann-Sträussler-Scheinker disease is an autosomal dominant prion disease. The clinical features include ataxia, dementia, spastic paraparesis and extrapyramidal signs.Methods:We report a new large Italian family affected by Gerstmann-Sträussler-Scheinker disease.Results:The four generation pedigree includes 11 patients. The mean age at onset ± SD was 41.4 ± 16.2 years. Mean disease duration to death in four patients was 5.5 ± 1.7 years. Two clinical patterns were evident: cognitive impairment with scarce neurological features or ataxia followed by cognitive impairment. Molecular analysis showed P102L mutation in PRNP gene.Conclusion:Three Italian families have been reported to date. The variable phenotype has already been reported, and does not appear related to the codon 129 polymorphism.