Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido

Malnutrition Has No Effect on the Timing of Human Tooth Formation

The effect of nutrition on the timing of human tooth formation is poorly understood. Delays and advancements in dental maturation have all been reported as well as no effect. We investigated the effect of severe malnutrition on the timing of human tooth formation in a large representative sample of North Sudanese children. The sample (1102 males, 1013 females) consisted of stratified randomly selected healthy individuals in Khartoum, Sudan, aged 2-22 years using a cross-sectional design following the STROBE statement. Nutritional status was defined using WHO criteria of height and weight. Body mass index Z-scores and height for age Z-scores of ≤-2 (cut-off) were used to identify the malnourished group (N = 474) while the normal was defined by Z-scores of ≥0 (N = 799). Clinical and radiographic examination of individuals, with known ages of birth was performed including height and weight measurements. Mandibular left permanent teeth were assessed using eight crown and seven root established tooth formation stages. Mean age at entry and mean age within tooth stages were calculated for each available tooth stage in each group and compared using a t-test. Results show the mean age at entry and mean age within tooth stages were not significantly different between groups affected by severe malnutrition and normal children (p>0.05). This remarkable finding was evident across the span of dental development. We demonstrate that there is little measurable effect of sustained malnutrition on the average timing of tooth formation. This noteworthy finding supports the notion that teeth have substantial biological stability and are insulated from extreme nutritional conditions compared to other maturing body systems

Hepatic involvement in Wegener's granulomatosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report the case of a 58-year-old Caucasian Greek man who presented with dry cough, fever, bilateral alveolar infiltrates and acute hepatitis.</p> <p>Case presentation</p> <p>After a lung biopsy, the patient was diagnosed with Wegener's granulomatosis. The diagnosis was supported by the presence of anti-proteinase-3 anti-neutrophil cytoplasmic antibodies. A liver biopsy demonstrated the presence of mild non-specific lobular hepatitis and periodic acid-Schiff positive Lafora-like inclusions in a large number of his liver cells. The patient was treated with prednisone and cyclophosphamide, which was followed by subsequent remissions of chest X-ray findings and liver function studies.</p> <p>Conclusion</p> <p>What makes this case worth reporting is the coexistence of liver inflammation with a biochemical profile of severe anicteric non-viral, non-drug induced hepatitis coinciding with the diagnosis of Wegener's granulomatosis. Our paper may be the first report of hepatic involvement in a patient diagnosed with Wegener's granulomatosis. The aetiological link between the two diseases is supported by the reversion of hepatitis after the immunosuppression of Wegener's granulomatosis. We favor the hypothesis that hepatic vasculitis may be the cause of acute hepatocellular necrosis.</p

A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn

Background: Lamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents. Results: We initially demonstrated contacts between dendritic spines of vertical cells that had been recorded in spinal cord slices and axonal boutons containing the vesicular glutamate transporter 1 (VGLUT1), which is expressed by myelinated low-threshold mechanoreceptive afferents. To confirm that the VGLUT1 boutons included primary afferents, we then examined vertical cells recorded in rats that had received injections of cholera toxin B subunit (CTb) into the sciatic nerve. We found that over half of the VGLUT1 boutons contacting the vertical cells were CTb-immunoreactive, indicating that they were of primary afferent origin. Conclusions: These results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia

Assessment of severity and frequency of self-reported hypoglycemia on quality of life in patients with type 2 diabetes treated with oral antihyperglycemic agents: A survey study

<p>Abstract</p> <p>Background</p> <p>Some oral antihyperglycemic agents may increase risk of hypoglycemia and thereby reduce patient quality of life. Our objective was to assess the impact of the severity and frequency of self-reported hypoglycemia on health-related quality of life (HRQoL) among patients with type 2 diabetes treated with oral antihyperglycemic agents.</p> <p>Findings</p> <p>A follow-up survey was conducted in participants with self-reported type 2 diabetes treated with oral antihyperglycemic agents from the US National Health and Wellness Survey 2007. Data were collected on the severity and frequency of hypoglycemic episodes in the 6 months prior to the survey, with severity defined as mild (no interruption of activities), moderate (some interruption of activities), severe (needed assistance of others), or very severe (needed medical attention). HRQoL was assessed using the EuroQol-5D Questionnaire (EQ-5D) US weighted summary score (utility) and Worry subscale of the Hypoglycemia Fear Survey (HFS). Of the participants who completed the survey (N = 1,984), mean age was 58 years, 57% were male, 72% reported an HbA_1c<7.0%, and 50% reported treatment with a sulfonylurea-containing regimen. Hypoglycemic episodes were reported by 63% of patients (46% mild, 37% moderate, 13% severe and 4% very severe). For patients reporting hypoglycemia, mean utility score was significantly lower (0.78 versus 0.86, p < 0.0001) and mean HFS score was significantly higher (17.5 versus 6.2, p < 0.0001) compared to patients not reporting hypoglycemia. Differences in mean scores between those with and without hypoglycemia increased with the level of severity (mild, moderate, severe, very severe) for utility (0.03, 0.09, 0.18, 0.23) and HFS (6.1, 13.9, 20.1, 25.6), respectively. After adjusting for age, gender, weight gain, HbA_1c, microvascular complications, and selected cardiovascular conditions, the utility decrement was 0.045 (by level of severity: 0.009, 0.055, 0.131, 0.208), and the HFS increase was 9.6 (by severity: 5.3, 12.4, 17.6, 23.2). HRQoL further decreased with greater frequency of hypoglycemic episodes.</p> <p>Conclusions</p> <p>Self-reported hypoglycemia is independently associated with lower HRQoL, and the magnitude of this reduction increases with both severity and frequency of episodes in patients with type 2 diabetes treated with oral antihyperglycemic agents.</p

Perspectives on supporting fathers affected by postnatal depression and a history of violence

Intimate partner violence in the perinatal period is a significant problem that remains underscreened, underdiagnosed and undertreated. The establishment of evidence-based guidelines to enable health visitors to identify couples experiencing violence and offer appropriate support has been hampered by the complex interplay between maternal and paternal mental health problems and violence. This study explored the experiences of UK fathers who voluntarily engaged with services designed to eliminate their ideation to violence. The findings indicate that the tendency to violence is increased by stresses associated with the transition to parenthood. Men felt pressured by concerns for their partner's mental health, changes in the relationship, sleep disturbances and the burden of infant care they assumed when the mother was unable to cope. Health visitors are ideally placed to assess for factors linked to the emergence of violence and put in place interventions to minimise occurrence

Progastrin Represses the Alternative Activation of Human Macrophages and Modulates Their Influence on Colon Cancer Epithelial Cells

Macrophage infiltration is a negative prognostic factor for most cancers but gastrointestinal tumors seem to be an exception. The effect of macrophages on cancer progression depends on their phenotype, which may vary between M1 (pro-inflammatory, defensive) to M2 (tolerogenic, pro-tumoral). Gastrointestinal cancers often become an ectopic source of gastrins and macrophages present receptors for these peptides. The aim of the present study is to analyze whether gastrins can affect the pattern of macrophage infiltration in colorectal tumors. We have evaluated the relationship between gastrin expression and the pattern of macrophage infiltration in samples from colorectal cancer and the influence of these peptides on the phenotype of macrophages differentiated from human peripheral monocytes in vitro. The total number of macrophages (CD68+ cells) was similar in tumoral and normal surrounding tissue, but the number of M2 macrophages (CD206+ cells) was significantly higher in the tumor. However, the number of these tumor-associated M2 macrophages correlated negatively with the immunoreactivity for gastrin peptides in tumor epithelial cells. Macrophages differentiated from human peripheral monocytes in the presence of progastrin showed lower levels of M2-markers (CD206, IL10) with normal amounts of M1-markers (CD86, IL12). Progastrin induced similar effects in mature macrophages treated with IL4 to obtain a M2-phenotype or with LPS plus IFNγ to generate M1-macrophages. Macrophages differentiated in the presence of progastrin presented a reduced expression of Wnt ligands and decreased the number and increased cell death of co-cultured colorectal cancer epithelial cells. Our results suggest that progastrin inhibits the acquisition of a M2-phenotype in human macrophages. This effect exerted on tumor associated macrophages may modulate cancer progression and should be taken into account when analyzing the therapeutic value of gastrin immunoneutralization