Volumetric effects of motor cortex injury on recovery of ipsilesional dexterous movements

Damage to the motor cortex of one hemisphere has classically been associated with contralateral upper limb paresis, but recent patient studies have identified deficits in both upper limbs. In non-human primates, we tested the hypothesis that the severity of ipsilesional upper limb motor impairment in the early post-injury phase depends on the volume of gray and white matter damage of the motor areas of the frontal lobe. We also postulated that substantial recovery would accompany minimal task practice and that ipsilesional limb recovery would be correlated with recovery of the contralesional limb. Gross (reaching) and fine hand motor functions were assessed for 3–12 months post-injury using two motor tests. Volumes of white and gray matter lesions were assessed using quantitative histology. Early changes in post-lesion motor performance were inversely correlated with white matter lesion volume indicating that larger lesions produced greater decreases in ipsilesional hand movement control. All monkeys showed improvements in ipsilesional hand motor skill during the post-lesion period, with reaching skill improvements being positively correlated with total lesion volume indicating that larger lesions were associated with greater ipsilesional motor skill recovery. We suggest that reduced trans-callosal inhibition from the lesioned hemisphere may play a role in the observed skill improvements. Our findings show that significant ipsilesional hand motor recovery is likely to accompany injury limited to frontal motor areas. In humans, more pronounced ipsilesional motor deficits that invariably develop after stroke may, in part, be a consequence of more extensive subcortical white and gray matter damage.     

Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes

OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA). DESIGN AND METHODS: This was a cross-sectional study comprising a total of 881 patients, aged < or = 70 years, diagnosed with type 2 diabetes after the age of 40 years, and consecutively recruited in five clinics located in different geographic areas of Italy (Milan, Florence, Rome, Naples and Catania). Their mean disease duration was 8.1 (6.9; s.d.) years. GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta. Anthropometric and clinical data were collected and compared amongst patients with or without autoantibodies. RESULTS: Sixty-three (7.1%) patients had one or more autoantibodies, 58 (6.6%) had GADA, 22 (2.5%) had IA-2A, six (0.7%) had IA-2betaA and 19 (2.15%) had two or more autoantibodies. IA-2A or IA-2betaA, in the absence of GADA, were found in only five patients. Autoantibody-positive patients were more often female (63.5 vs 36.5%; P < 0.009), had higher glycated haemoglobin (Hb A1c) (P < 0.001), lower body mass index (BMI; P < 0.0005) and waist/hip ratio (WHR; P < 0.01); female gender being the main contributor to BMI and WHR. We did not observe any differences in age at diagnosis or duration of disease with respect to the presence or absence of islet autoantibodies. The proportion of patients on insulin therapy was higher in patients with two or more antibodies, compared with those with one antibody only, and no antibodies (P for trend < 0.001), and among patients with GADA, in those with higher antibody titre (73.9% in those with > 10 units vs 42.0% in those with < or = 10 units; P < 0.007). CONCLUSIONS: Patients with adult onset diabetes characterized by autoimmunity to beta-cells showed a clinical phenotype with anthropometric features that differed from those classically observed in patients with type 2 diabetes. The number and titre of autoantibodies, which reflect the severity of autoimmunity and beta-cell impairment, amplified this difference. The usefulness of autoantibody screening in adult-onset diabetes is further emphasized by these findings.     

Increased nitric oxide production in eating disorders

Animal studies showed that nitric oxide (NO)/cyclic-GMP (cGMP) pathway is involved in the modulation of eating behavior. To address its role in eating disorders (ED), plasma nitrite and cGMP levels were studied in 50 ED patients (25 with Anorexia Nervosa, AN; 25 with Bulimia Nervosa, BN) and 20 sex- and age-matched controls (C). Nitrites (nmol/mg protein, mean+/-S.E.M.: any ED 1.01+/-0.29; AN 1.15+/-0.47; BN 0.88+/-0.36; C 0.25+/-0.07; p<0.01) and cGMP (nmol/ml plasma, mean+/-S.E.M.: any ED 2.58+/-0.60; AN 2.81+/-1.10; BN 2.41+/-0.70; C 0.11+/-0.05; p<0.01) were significantly higher in ED patients than in C. Nitrite and cGMP levels inversely correlated with BMI in AN patients (nitrites: r=-0.62 p<0.01; cGMP r=-0.45 p<0.05) but not in BN patients (nitrites: r=-0.15 p=0.49; cGMP: r=-0.05 p=0.13) or in control subjects (nitrites: r=0.11 p=0.98; cGMP r=0.37 p=0.32). Significant correlations were also present in bulimic patients between nitrite levels, frequency of binges and several psychopathological dimensions, as assessed through the EDE. This is the first evidence of an alteration of the NO pathway in ED patients. Further studies are needed to ascertain whether an increase in NO levels plays a possible role in the pathogenesis of ED.     

Correlation between HDL cholesterol levels and beta-cell function in subjects with various degree of glucose tolerance

Some reports showed direct effects of high density lipoprotein cholesterol (HDL-C) on beta-cells survival and insulin secretion, suggesting an its role on glucose metabolism. We queried, whether subjects screened for type 2 diabetes (DM2) could display some impairment of beta-cell performance related to their HDL-C levels. A total of 1,087 clinical outpatients at risk of DM2 with no history of diabetes were studied. All participants were assessed for anthropometry, fasting lipid profile, and 2hOGTT with blood samples for plasma glucose and insulin determinations. Matsuda index of insulin sensitivity, early (insulinogenic index × Matsuda) and total (insulin secretion-sensitivity index-2 [ISSI-2]) indices of beta-cell function OGTT derived were applied. Linear regression analyzed the association between HDL-C levels and indices of beta-cell activity in subjects with normal glucose tolerance (NGT), impaired fasting glycemia (IFG), and impaired glucose tolerance (IGT). After adjustment for triglyceride levels, waist circumference, blood pressure and age, in total NGT subjects the HDL-C levels were not significantly associated with IGI × Matsuda (β = 0.039, P = 0.10) and ISSI-2 index (β = 0.069, P = 0.18), while in NGT with low HDL-C and IFG subjects the IGI × Matsuda (β = 0.052, P = 0.019) and ISSI-2 indices (β = 0.061, P = 0.023) were significantly associated with HDL-C levels. This significant linear correlation has been also observed in IGT patients for both indices (β = 0.264, P = 0.0001 and β = 0.191, P = 0.002, respectively). In conclusion, in subjects with impaired glucose regulation, HDL-C levels are associated with indices of beta-cell dysfunction; thus, more attention, it should be deserve to HDL-C concentrations in IFG/IGT patients due their potential conversion to DM2.     

Selective long‐term reorganization of the corticospinal projection from the supplementary motor cortex following recovery from lateral motor cortex injury

Brain injury affecting the frontal motor cortex or its descending axons often causes contralateral upper extremity paresis. Although recovery is variable, the underlying mechanisms supporting favorable motor recovery remain unclear. Because the medial wall of the cerebral hemisphere is often spared following brain injury and recent functional neuroimaging studies in patients indicate a potential role for this brain region in the recovery process, we investigated the long‐term effects of isolated lateral frontal motor cortical injury on the corticospinal projection (CSP) from intact, ipsilesional supplementary motor cortex (M2). After injury to the arm region of the primary motor (M1) and lateral premotor (LPMC) cortices, upper extremity recovery is accompanied by terminal axon plasticity in the contralateral CSP but not the ipsilateral CSP from M2. Furthermore, significant contralateral plasticity occurs only in lamina VII and dorsally within lamina IX. Thus, selective intraspinal sprouting transpires in regions containing interneurons, flexor‐related motor neurons, and motor neurons supplying intrinsic hand muscles, which all play important roles in mediating reaching and digit movements. After recovery, subsequent injury of M2 leads to reemergence of hand motor deficits. Considering the importance of the CSP in humans and the common occurrence of lateral frontal cortex injury, these findings suggest that spared supplementary motor cortex may serve as an important therapeutic target that should be considered when designing acute and long‐term postinjury patient intervention strategies aimed to enhance the motor recovery process following lateral cortical trauma. J. Comp. Neurol. 518:586–621, 2010. © 2009 Wiley‐Liss, Inc.