Disrupted habenula function in major depression.

The habenula is a small, evolutionarily conserved brain structure that plays a central role in aversive processing and is hypothesised to be hyperactive in depression, contributing to the generation of symptoms such as anhedonia. However, habenula responses during aversive processing have yet to be reported in individuals with major depressive disorder (MDD). Unmedicated and currently depressed MDD patients (N=25, aged 18-52 years) and healthy volunteers (N=25, aged 19-52 years) completed a passive (Pavlovian) conditioning task with appetitive (monetary gain) and aversive (monetary loss and electric shock) outcomes during high-resolution functional magnetic resonance imaging; data were analysed using computational modelling. Arterial spin labelling was used to index resting-state perfusion and high-resolution anatomical images were used to assess habenula volume. In healthy volunteers, habenula activation increased as conditioned stimuli (CSs) became more strongly associated with electric shocks. This pattern was significantly different in MDD subjects, for whom habenula activation decreased significantly with increasing association between CSs and electric shocks. Individual differences in habenula volume were negatively associated with symptoms of anhedonia across both groups. MDD subjects exhibited abnormal negative task-related (phasic) habenula responses during primary aversive conditioning. The direction of this effect is opposite to that predicted by contemporary theoretical accounts of depression based on findings in animal models. We speculate that the negative habenula responses we observed may result in the loss of the capacity to actively avoid negative cues in MDD, which could lead to excessive negative focus.

Measurements in wound healing with observations on the effects of topical agents on full thickness dermal incised wounds.

INTRODUCTION: A multitude of topical wound treatments are used today. Although it is well established that the micro-environment of healing wounds can be altered to improve healing, it is difficult to measure the subtle differences in outcome where therapies are compared. METHOD: We compared wound healing properties between four different topical agents in surgically incised wounds in a pig model. The four topical agents, 5% Povidone-Iodine cream, 1% Silver-Sulphadiazine, 2% Mupirocin, and 1% Silver-Sulphadiazine plus 1mg/100g recombinant-human epithelial growth factor (EGF) were randomly assigned to four test animals each. Test agents were compared to each other and to untreated controls. We investigated existing and new methodologies of measurement of wound healing: clinical and histological visual scoring systems, immuno-histochemistry, and computerized image analysis of the wounds on days 3, 7, and 28. RESULTS: All agents were found to have improved healing rates with better cellular architecture. Healing was faster, histological appearance resembled normal architecture sooner, clinical appearance improved, mitotic activity was stimulated and more collagen was deposited in comparison to the wounds with no agents. EGF-treated wounds showed an increased rate of epithelisation, but the rate of healing did not correlate well with evaluation of cosmetic outcome. CONCLUSION: Topical agents improve all aspects of wound healing. The addition of a human recombinant EGF to Silver-Sulphadiazine increases epithelial growth and amounts of collagen in the regenerating wounds at day 7.

Dental caries management at a rural district hospital in northern Rwanda: a neglected disease.

SETTING: While some studies have reported the prevalence of dental caries in sub-Saharan Africa, little is known about care-seeking behavior or how dental caries are managed, particularly at rural district hospitals. OBJECTIVE: To describe the management of patients seeking care for dental caries at Butaro District Hospital (BDH) in rural Rwanda. DESIGN: This cross-sectional descriptive study was conducted in BDH, in northern Rwanda. A sample of 287 patient encounters for dental caries between January and December 2013 was randomly selected and stratified by age group (⩽5 years, 6-21 years and >21 years). We estimated the treatment received with 95% confidence intervals in each age group, and differences between age groups were assessed using Fisher's exact test. RESULTS: Nearly all patients (97.6%) underwent tooth extraction, and this did not vary significantly by age group (P = 0.558). In addition to dental caries, most patients also had chronic pulpitis (74.9%). CONCLUSION: Caries prevention and care should be prioritized through a developed community program on oral health. We recommend introducing advanced training, equipment and materials for dental caries management other than tooth extraction, and increasing the number of qualified dentists.

Contexte : Si certaines études rapportent des taux de prévalence des caries dentaires en Afrique sub-saharienne, on sait peu de choses sur le comportement en termes de recherche de soins ni de prise en charge des caries, surtout dans les hôpitaux de district ruraux.Objectif : Décrire la prise en charge des patients sollicitant des soins pour caries dentaires à l'Hôpital de District de Butaro (BDH) en zone rurale du Rwanda.Schéma : Cette étude descriptive transversale a été réalisée au BDH, au nord du Rwanda. Un échantillon de 287 consultations de patients pour caries dentaires entre janvier et décembre 2013 a été sélectionné de façon aléatoire et stratifié sur l'âge (⩽5 ans, 6­21 ans et >21 ans). Nous avons estimé le traitement reçu avec des intervalles de confiance de 95% dans chaque tranche d'âge et les différences entre les groupes d'âge ont été évaluées grâce au test exact de Fisher.Résultats : Presque tous les patients (97,6%) ont eu une extraction de la dent cariée et cela n'a pas varié de façon significative en fonction du groupe d'âge (P = 0,558). En plus des caries, la majorité des patients avait également une pulpite chronique (74,9%).Conclusion : La prévention des caries et les soins conservateurs devraient être une priorité grâce à un programme de santé orale communautaire. Nous recommandons l'introduction d'une formation avancée, d'équipement et de matériels de prise en charge des caries dentaires autres que l'extraction des dents et l'augmentation du nombre de dentistes qualifiés.

Marco de referencia: Algunos estudios han notificado la prevalencia de caries dental en África subsahariana, pero se conoce poco sobre el comportamiento de búsqueda de atención o el tratamiento de la caries dental, sobre todo en los hospitales distritales de las zonas rurales.Objetivo: Describir el tratamiento de los pacientes que buscan atención por caries dental en el Hospital Distrital de Butaro, en una zona rural de Rwanda.Métodos: El presente estudio transversal se llevó a cabo en el Hospital Distrital de Butaro en el norte de Rwanda. Se escogió una muestra aleatoria de 287 citas de pacientes que acudían por caries dental de enero a diciembre del 2013 y se estratificó por grupos de edad (⩽5 años, 6 a 21 años y >21 años). Se evaluaron las proporciones del tipo de tratamiento recibido con un intervalo de confianza del 95% en cada grupo etario y las diferencias entre los grupos se analizaron con una prueba exacta de Fisher.Resultados: En casi todos los pacientes se practicó la extracción (97,6%) y no se observaron diferencias significativas en los grupos de edad (P = 0,558). Además de la caries, la mayoría de pacientes presentaba pulpitis crónica (74,9%).Conclusión: Es preciso priorizar la prevención y el tratamiento de la caries mediante un programa comunitario de salud bucodental. Se recomienda introducir una capacitación avanzada, suministrar equipos y materiales de tratamiento de la caries dental diferente de la extracción y aumentar la cantidad de odontólogos calificados.

Higher order analytical solutions of water table fluctuations in coastal aquifers.

The groundwater response of coastal aquifers to tidal forcing is described by Laplace's equation coupled with the nonlinear phreatic-free surface boundary condition. Here we describe fluctuations in the water table using two small parameters, extending previous work by proposing an ansatz to compute higher order, semi-analytical solutions. The new solutions are compared with known lower order solutions. The relative difference between the linear solution and higher order solutions can reach up to 30% of the linear solution for shallow beaches. The new solutions exhibit a reduction in the over height of the groundwater fluctuations compared with the lower order solutions. In addition, the super elevation of the water table, both near shore and as the aquifer tends landward, is examined with the inclusion of higher order terms.

Choosing to make an effort: the role of striatum in signaling physical effort of a chosen action.

The possibility that we will have to invest effort influences our future choice behavior. Indeed deciding whether an action is actually worth taking is a key element in the expression of human apathy or inertia. There is a well developed literature on brain activity related to the anticipation of effort, but how effort affects actual choice is less well understood. Furthermore, prior work is largely restricted to mental as opposed to physical effort or has confounded temporal with effortful costs. Here we investigated choice behavior and brain activity, using functional magnetic resonance imaging, in a study where healthy participants are required to make decisions between effortful gripping, where the factors of force (high and low) and reward (high and low) were varied, and a choice of merely holding a grip device for minimal monetary reward. Behaviorally, we show that force level influences the likelihood of choosing an effortful grip. We observed greater activity in the putamen when participants opt to grip an option with low effort compared with when they opt to grip an option with high effort. The results suggest that, over and above a nonspecific role in movement anticipation and salience, the putamen plays a crucial role in computations for choice that involves effort costs.

Pain relativity in motor control.

Motivational theories of pain highlight its role in people's choices of actions that avoid bodily damage. By contrast, little is known regarding how pain influences action implementation. To explore this less-understood area, we conducted a study in which participants had to rapidly point to a target area to win money while avoiding an overlapping penalty area that would cause pain in their contralateral hand. We found that pain intensity and target-penalty proximity repelled participants' movement away from pain and that motor execution was influenced not by absolute pain magnitudes but by relative pain differences. Our results indicate that the magnitude and probability of pain have a precise role in guiding motor control and that representations of pain that guide action are, at least in part, relative rather than absolute. Additionally, our study shows that the implicit monetary valuation of pain, like many explicit valuations (e.g., patients' use of rating scales in medical contexts), is unstable, a finding that has implications for pain treatment in clinical contexts.

Primary antibody deficiency and diagnostic delay.

AIMS: To assess the occurrence of diagnostic delay in primary antibody deficiency in the period 1989-2002, since a similar study in 1989, and to assess the impact of UK national guidelines communicated in 1995. METHODS: A retrospective case note review was performed of 89 consecutive patients with antibody deficiency referred to a regional referral centre for clinical immunology in north west England and north Wales. The delay in diagnosis and the estimated resulting morbidity in terms of infections were assessed. RESULTS: Fifty six of the 89 patients experienced delay in diagnosis. The overall median delay was 2 years (mean, 4.4), resulting in substantial morbidity (equivalent to two major infections and one minor infection). This shows a moderate improvement since the previous study in 1989 and since the introduction of UK national guidelines in 1995. Respiratory infections are the most frequent presenting infections, and respiratory physicians the most common source of referral. CONCLUSIONS: There is still considerable delay in the diagnosis of primary antibody deficiency, but the data suggest an improvement in practice since the previous study in 1989 and the distribution of national guidelines in 1995.

American psychology and schools: a critique.

No one denies that the Boulder Conference on Clinical Psychology marked a turning point on American psychology. This paper by one of the three or four living participants lists the conference as one in which psychology was at a choice point, went in one and only one direction, without examining the possible consequences or the possibility of going in more than 1 direction. A second theme is that the APA has to be faulted for a lack of searching self-scrutiny of its past. Organizations, like individuals, resist such self-scrutiny.

The obligations of the moral-scientific stance.

One of the most important contributions of community psychology is to have community interventions that have intended outcomes and to describe the intervention in ways that are sufficiently complete and replicable. However, the descriptions we have are too incomplete. A suggestion is made for how the field should take steps to remedy the weaknesses.

Modulation of inhaled antigen-induced IgE tolerance by ongoing Th2 responses in the lung.

The normal response to inhaled Ag is the absence of Ag-specific IgE and cytokine production to later Ag challenges. Although the mechanism of this aerosol-induced IgE tolerance is not completely understood, it may prevent sensitization to inhaled Ags, which could otherwise lead to allergy and asthma. We examined the consequences of ongoing Th1 and Th2 responses in the lungs of mice during OVA inhalation to mimic conditions that may subvert tolerance and lead to sensitization. We found that concurrent, secondary Th2 lung responses to keyhole limpet hemocyanin or primary responses to Nippostrongylus larvae or Asperigillus fumagatus extract prevented establishment of IgE tolerance to aerosolized OVA. Intranasal rIL-4 given before OVA aerosolization also prevented establishment of tolerance, whereas concurrent Th1 responses to influenza virus or Mycobacterium bovis bacillus Calmette-Guérin had no effect. However, once established, aerosol tolerance to OVA could not be completely broken by OVA rechallenge concurrent with a secondary Th2 response to keyhole limpet hemocyanin or A. fumagatus extract, or by intranasal rIL-4. These data suggest that the immune status of the lung of an individual may profoundly influence the initial response to inhaled Ag, and that aerosol-induced IgE tolerance may not be appropriately established in individuals undergoing concurrent, Th2-mediated responses to Ags or pathogens.

Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3).

We have generated rat monoclonal antibodies specific for the mouse eotaxin receptor, C-C chemokine receptor 3 (CCR3). Several anti-CCR3 mAbs proved to be useful for in vivo depletion of CCR3-expressing cells and immunofluorescent staining. In vivo CCR3 mAbs of the IgG2b isotype substantially depleted blood eosinophil levels in Nippostrongyus brasiliensis-infected mice. Repeated anti-CCR3 mAb treatment in these mice significantly reduced tissue eosinophilia in the lung tissue and bronchoalveolar lavage fluid. Flow cytometry revealed that mCCR3 was expressed on eosinophils but not on stem cells, dendritic cells, or cells from the thymus, lymph node, or spleen of normal mice. Unlike human Th2 cells, mouse Th2 cells did not express detectable levels of CCR3 nor did they give a measurable response to eotaxin. None of the mAbs were antagonists or agonists of CCR3 calcium mobilization. To our knowledge, the antibodies described here are the first mAbs reported to be specific for mouse eosinophils and to be readily applicable for the detection, isolation, and in vivo depletion of eosinophils.

The effects of dietary iron overload on fumonisin B1-induced cancer promotion in the rat liver.

The present study was performed to determine whether excess hepatic iron modulates the cancer-initiating and promoting properties of FB1. Thirty-eight male F344 rats were divided into four dietary treatment groups: (i) control diet (AIN, n = 8); (ii) FB1 250 mg/kg diet (FB1, n = 10); (iii) 1-2% carbonyl iron (CI, n = 10); or (iv) FB1 plus iron loading (FB1/CI, n = 10) for 5 weeks (2 x 2 factorial design). Hepatic iron concentrations in iron-loaded animals at 5 weeks were 444 +/- 56 (CI) and 479 +/- 80 micromol/g dry weight (FB1/CI) (mean +/- SEM). All the FB1-fed rats, in the presence or absence of CI, developed a toxic hepatitis with a 4-fold rise in serum alanine transaminase (ALT) levels. FB1 appeared to augment iron-induced hepatic lipid peroxidation, as measured by the generation of thiobarbituric acid reacting substances (TBARS) in liver homogenates (P < 0.0001). Morphometric analysis showed that FB1 caused a significantly greater mean +/- SEM number of 'enzyme-altered' foci and nodules per cm2 (5.34 +/- 1.42 vs. 1.50 +/- 0.52, P < 0.05), as well as a greater area (%) of liver occupied by foci and nodules (0.33 +/- 0.12% vs. 0.05 +/- 0.03%, P < 0.001), compared with FB1/CI. The addition of FB1 to dietary iron loading caused a shift in distribution of iron from hepatocytes to Kupffer cells, probably due to phagocytosis of necrotic iron-loaded hepatocytes. In conclusion, (i) FB1 appears to cause toxicity in the liver independently from effects on lipid peroxidation; (ii) FB1 has a potentiating effect on iron-induced lipid peroxidation; and (iii) dietary iron loading appears to protect against the cancer promoting properties of FB1, possibly due to a stimulatory effect of iron on hepatocyte regeneration.

A modified method of continuous venous anastomosis in microsurgery.

The continuous suture technique for end-to-end vascular anastomosis is cautioned against because of the risk of vessel constriction. A modified method of continuous suture for end-to-end venous microanastomosis is presented in which vessel constriction does not occur. This technique was compared with the conventional interrupted suture technique in the rat femoral vein, with each rat serving as its own control. Forty-eight Long-Evans rats were used. The mean time taken to complete the anastomosis was 9.8 minutes (range, 8-14 minutes) for the modified continuous technique and 17.7 minutes (range, 14-24 minutes) for the conventional interrupted technique (p < 0.05, independent t-test). In addition, the veins were examined under the microscope for patency and the milk test was performed on each anastomosis 30 minutes postanastomosis, and 1 week and 1 month postoperatively. Two groups of rats were sacrificed, one at 1 week and one at 1 month, and the two different anastomoses were compared using vessel morphometry in 40 rats and corrosion casts in 8 rats. All veins were patent postoperatively, as well as at 1 week and 1 month postoperatively. Vessel morphometry confirmed a similar luminal surface area in all veins examined at 1 week and 1 month. A two-way analysis of variance of vessel morphometry indicated no significant interaction between the methods used and the postoperative time (p = 0.60). The modified continuous technique is twice as quick as the conventional interrupted technique for end-to-end microvenous anastomosis and does not lead to vessel constriction.

Aerosol-induced immunoglobulin (Ig)-E unresponsiveness to ovalbumin does not require CD8+ or T cell receptor (TCR)-gamma/delta+ T cells or interferon (IFN)-gamma in a murine model of allergen sensitization.

Mice exposed for 20 min daily to aerosolized ovalbumin (OVA) for 10 d at concentrations from 1 to 0.01% OVA made greatly reduced immunoglobulin (Ig)-E responses to subsequent immunogenic OVA challenges, given either intraperitoneally or by aerosol. This IgE-specific unresponsiveness lasted for at least four months. However, these aerosol-treated mice were primed for larger OVA-specific IgG1 and IgG2a responses. The specific reduction in IgE responses was not due to preferential induction of a T helper (Th)-1 response as aerosol OVA- primed mice made greatly reduced Th2 and no detectable Th1 response after rechallenge in vitro. Consistent with this, the increase in circulating eosinophils observed in control Th2-primed mice was absent in aerosol OVA-treated animals. Interferon (IFN)-gamma was not required for this unresponsiveness, as IFN-gamma knockout mice and anti-IFN-gamma antibody-treated wild-type mice had greatly reduced levels of IgE similar to wild-type controls. CD8+ T cells played a relatively small role as IgE responses were reduced to about the same extent in beta2 microglobulin-deficient, or in anti-CD8-treated wild-type mice as in normal mice after aerosol OVA treatment. Similarly, T cell receptor (TCR)-gamma/delta T cells were not required for maximal inhibition of the IgE response. These results demonstrate that exposure to inhaled protein antigens can induce a state of unresponsiveness of CD4+ T cells that results in a prolonged loss of IgE and eosinophil responses to subsequent challenges. This T cell unresponsiveness was shown not to require CD8+ or TCR-gamma/delta+ T cells or IFN-gamma.

Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis.

We have used interleukin-10 (IL-10) gene knockout mice (IL-10-/-) to examine the role of endogenous IL-10 in allergic lung responses to Aspergillus fumigatus Ag. In vitro restimulated lung cells from sensitized IL-10-/- mice produced exaggerated amounts of IL-4, IL-5, and interferon-gamma (IFN-gamma) compared with wild-type (WT) lung cells. In vivo, the significance of IL-10 in regulating responses to repeated A. fumigatus inhalation was strikingly revealed in IL-10-/- outbred mice that had a 50-60% mortality rate, while mortality was rare in similarly treated WT mice. Furthermore, IL-10-/- outbred mice exhibited exaggerated airway inflammation and heightened levels of IL-5 and IFN-gamma in bronchoalveolar lavage (BAL) fluids. In contrast, the magnitude of the allergic lung response was similar in intranasally (i.n.) sensitized IL-10-/- and wild-type mice from a different strain (C57BL/6). Using a different route of priming (intraperitoneal) followed by one i.n. challenge we found that IL-10-/- C57BL/6 mice had heightened eosinophilic airway inflammation, BAL-IL-5 levels, and numbers of alphabetaT cells in the lung tissues compared with WT mice. We conclude that IL-10 can suppress inflammatory Th2-like lung responses as well as Th1-like responses given the constraints of genetic background and route of priming.

Rhabdomyolysis induced by epsilon-aminocaproic acid.

OBJECTIVE: To report a case of rhabdomyolysis associated with epsilon-aminocaproic acid (epsilon-ACA). CASE SUMMARY: A 33-year-old female patient with chronic granulocytic leukemia was treated with epsilon-ACA for approximately 3.5 months for thrombocytopenic bleeding. The initial dosage was 4 g po q6h. One month after an increase in dosage to 5 g po 14h the patient developed severe lower extremity myalgia and marked weakness. Laboratory investigations revealed an elevated creatine kinase (CK), lactate dehydrogenase (LDH). aspartate aminotransferase (AST), and myoglobinemia. Epsilon-ACA was thought to be the causative agent and was discontinued. The patient received intravenous fluids to minimize renal damage due to myoglobin. Serum enzyme concentrations did not return to normal. The patient died of a central nervous system hemorrhage 1 week after the epsilon-ACA was discontinued. DISCUSSION: There were 31 cases of epsilon-ACA-induced myopathies published in the literature (MEDLINE) from 1972 to June 1995. Of these, 10 cases were reviewed. In all cases, patients received epsilon-ACA in doses ranging from 16 to 36 g/d for more than 28 days. Clinical findings varied from extreme muscle weakness to myopathic changes in electromyelograms. All patients recovered following discontinuation of epsilon-ACA. CONCLUSIONS: Long-term therapy with high-dose epsilon-ACA may produce muscle weakness or rhabdomyolysis. Patients who require long-term, high-dose epsilon-ACA therapy should be monitored for myoglobinuria and changes in serum CK, LDH, and AST, for myoglobinemia, for decreases in muscle strength, and/or for myalgia. Significant changes in these parameters compared with baseline values should suggest a need to discontinue epsilon-ACA therapy.

Second-hand smoke is an adjuvant for T helper-2 responses in a murine model of allergy.

Epidemiologic studies have suggested that "second-hand smoke" increases the incidence and severity of allergies and asthma. To address this, we developed a murine model that included generation of and exposure to environmental tobacco smoke (ETS) followed by aerosolized Ag challenge. We report herein that exposure of OVA-sensitized BALB/c mice to ETS elicits a rapid and prolonged exaggerated response with respect to IgE, IgG1, eosinophils, and Th2 cytokines (particularly IL-4 and IL-10). There was a significant increase (p = 0.0159) in the total cells of the bronchoalveolar lavage in OVA-sensitized mice exposed to ETS when compared with those in ambient air. This is the first experimental data to demonstrate that "second-hand smoke" up-regulates the allergic response to inhaled Ag. The results have important health implications for children and allergic individuals residing in households with smokers.

Particulate Aspergillus fumigatus antigens elicit a TH2 response in BALB/c mice.

BACKGROUND: In order to understand the immunoregulation in allergic aspergillosis, a murine model was developed by exposing animals to particulate and soluble antigens of Aspergillus fumigatus. METHODS: BALB/c mice were exposed to soluble Aspergillus antigen intranasally. Animals showing moderate levels of IgE were subsequently exposed to soluble antigen or antigen conjugated to polystyrene beads intranasally. The IgE and IgG1 in the sera and the eosinophils in the blood and lungs were studied. The spleen and lung mononuclear cells were stimulated with both concanavalin A and antigen and evaluated for production of interleukin (IL)-4, IL-5, IL-10, and interferon-gamma. RESULTS: Animals exposed to particulate antigens showed more elevated serum IgE levels and increased numbers of eosinophils in the blood and lungs than those exposed to soluble antigen. Lung cell cultures from animals exposed to particulate antigens when stimulated with Aspergillus produced IL-4 and IL-5, indicating a TH2 type of response. Animals exposed to soluble antigens showed a weaker TH2 response, as evidence by low IgE levels in sera, fewer eosinophils in the blood, and low levels of cytokine production from lung and spleen cells. CONCLUSION: The results indicate that the physical nature of the antigen may have a major role in determining the type of immune response of the host.