Case 9 : From Theory to Action: Implementing an Internationally Developed Mental Health and Substance Abuse Program in Indigenous Communities in the Americas

Intergenerational trauma compounded throughout centuries by the effects of colonialism have left indigenous peoples within the Americas in grave despair. Indigenous communities are subject to a variety of human rights violations and social neglect, which contribute to reduced physical and mental health. The United Nations Permanent Forum on Indigenous Issues has identified these insufficiencies in acknowledging higher rates of poor mental health, substance abuse, and elevated rates of suicide, when compared to non-indigenous peoples. The World Health Organization has developed the Mental Health Gap Action Program Intervention Guide (mhGAP IG) to assess, monitor, and manage, neurological, and mental health conditions, including suicide, in non-specialized health contexts. This case provides an example of how one fictitious indigenous community located off the coast of Central America is seeking to use the mhGAP IG due to the recent suicide clusters within a six month period. The case seeks to highlight how international agencies collaborate in developing interventions for the populations they serve, specifically, between the Pan American Health Organization and the Americas. The protagonist, Juan Santos, is left to question how he will implement the mhGAP in his community with limited resources to encompass cultural considerations and appropriate community engagement to lower suicide rates, mental health, and substance abuse

{beta}3GnT2 Maintains Adenylyl Cyclase-3 Signaling and Axon Guidance Molecule Expression in the Olfactory Epithelium

In the olfactory epithelium (OE), odorant receptor stimulation generates cAMP signals that function in both odor detection and the regulation of axon guidance molecule expression. The enzyme that synthesizes cAMP, adenylyl cyclase 3 (AC3), is coexpressed in olfactory sensory neurons (OSNs) with poly-N-acetyllactosamine (PLN) oligosaccharides determined by the glycosyltransferase beta3GnT2. The loss of either enzyme results in similar defects in olfactory bulb (OB) innervation and OSN survival, suggesting that glycosylation may be important for AC3 function. We show here that AC3 is extensively modified with N-linked PLN, which is essential for AC3 activity and localization. On Western blots, AC3 from the wild-type OE migrates diffusely as a heavily glycosylated 200 kDa band that interacts with the PLN-binding lectin LEA. AC3 from the beta3GnT2(-/-) OE loses these PLN modifications, migrating instead as a 140 kDa glycoprotein. Furthermore, basal and forskolin-stimulated cAMP production is reduced 80-90% in the beta3GnT2(-/-) OE. Although AC3 traffics normally to null OSN cilia, it is absent from axon projections that aberrantly target the OB. The cAMP-dependent guidance receptor neuropilin-1 is also lost from beta3GnT2(-/-) OSNs and axons, while semaphorin-3A ligand expression is upregulated. In addition, kirrel2, a mosaically expressed adhesion molecule that functions in axon sorting, is absent from beta3GnT2(-/-) OB projections. These results demonstrate that PLN glycans are essential in OSNs for proper AC3 localization and function. We propose that the loss of cAMP-dependent guidance cues is also a critical factor in the severe axon guidance defects observed in beta3GnT2(-/-) mice

Olfactory discrimination largely persists in mice with defects in odorant receptor expression and axon guidance

<p>Abstract</p> <p>Background</p> <p>The defining feature of the main olfactory system in mice is that each olfactory sensory neuron expresses only one of more than a thousand different odorant receptor genes. Axons expressing the same odorant receptor converge onto a small number of targets in the olfactory bulb such that each glomerulus is made up of axon terminals expressing just one odorant receptor. It is thought that this precision in axon targeting is required to maintain highly refined odor discrimination. We previously showed that β3GnT2^−/− mice have severe developmental and axon guidance defects. The phenotype of these mice is similar to adenylyl cyclase 3 (AC3) knockout mice largely due to the significant down-regulation of AC3 activity in β3GnT2^−/− neurons.</p> <p>Results</p> <p>Microarray analysis reveals that nearly one quarter of all odorant receptor genes are down regulated in β3GnT2^−/− mice compared to controls. Analysis of OR expression by quantitative PCR and <it>in situ</it> hybridization demonstrates that the number of neurons expressing some odorant receptors, such as mOR256-17, is increased by nearly 60% whereas for others such as mOR28 the number of neurons is decreased by more than 75% in β3GnT2^−/− olfactory epithelia. Analysis of axon trajectories confirms that many axons track to inappropriate targets in β3GnT2^−/− mice, and some glomeruli are populated by axons expressing more than one odorant receptor. Results show that mutant mice perform nearly as well as control mice in an odor discrimination task. In addition, <it>in situ</it> hybridization studies indicate that the expression of several activity dependent genes is unaffected in β3GnT2^−/− olfactory neurons.</p> <p>Conclusions</p> <p>Results presented here show that many odorant receptors are under-expressed in β3GnT2^−/− mice and further demonstrate that additional axon subsets grow into inappropriate targets or minimally innervate glomeruli in the olfactory bulb. Odor evoked gene expression is unchanged and β3GnT2^−/− mice exhibit a relatively small deficit in their ability to discriminate divergent odors. Results suggest that despite the fact that β3GnT2^−/− mice have decreased AC3 activity, decreased expression of many ORs, and display many axon growth and guidance errors, odor-evoked activity in cilia of mutant olfactory neurons remains largely intact.</p

Identification of Chiari Type I Malformation subtypes using whole genome expression profiles and cranial base morphometrics.

BACKGROUND: Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population. METHODS: A collection of forty-four pediatric CMI patients were ascertained to identify disease subtypes using whole genome expression profiles generated from patient blood and dura mater tissue samples, and radiological data consisting of posterior fossa (PF) morphometrics. Sparse k-means clustering and an extension to accommodate multiple data sources were used to cluster patients into more homogeneous groups using biological and radiological data both individually and collectively. RESULTS: All clustering analyses resulted in the significant identification of patient classes, with the pure biological classes derived from patient blood and dura mater samples demonstrating the strongest evidence. Those patient classes were further characterized by identifying enriched biological pathways, as well as correlated cranial base morphological and clinical traits. CONCLUSIONS: Our results implicate several strong biological candidates warranting further investigation from the dura expression analysis and also identified a blood gene expression profile corresponding to a global down-regulation in protein synthesis

Evaluation of Extended Interval Dosing Aminoglycosides in the Morbidly Obese Population

Aminoglycoside dosing has been studied in the obese population, typically recommending an adjusted weight utilizing a 40% dosing weight correction factor (IBW + 0.4 × (TBW–IBW)). These studies included limited numbers of morbidly obese patients and were not done in the era of extended interval aminoglycoside dosing. Here, we report a retrospective evaluation of morbidly obese patients receiving gentamicin or tobramycin at our hospital. The objective of this study was to evaluate the accuracy of the commonly recommended adjusted weight for weight-based dosing. There were 31 morbidly obese patients who received gentamicin or tobramycin 5–7 mg/kg every 24 hours using a 40% dosing weight correction factor. Our institution utilizes 16-hour postdose concentrations to monitor extended interval aminoglycosides. Twenty-two of the 31 patients (71%) achieved an appropriate serum drug concentration. Four patients (13%) were found to be supratherapeutic and 5 patients (16%) subtherapeutic. The only variable that correlated with supratherapeutic levels was older age (P=0.0378). Our study helps to validate the current dosing weight correction factor (40%) in the morbidly obese population. We recommend caution when dosing aminoglycosides in morbidly obese patients who are of older age

Chemical characteristics of air from differing source regions during the Pacific Exploratory Mission‐Tropics A (PEM‐Tropics A)

Ten‐day backward trajectories are used to determine the origins of air parcels arriving at airborne DC‐8 chemical measurement sites during NASA\u27s Pacific Exploratory Mission‐Tropics A (PEM‐T) that was conducted during August‐October 1996. Those sites at which the air had a common geographical origin and transport history are grouped together, and statistical measures of chemical characteristics are computed. Temporal changes in potential temperature are used to determine whether trajectories experience a significant convective influence during the 10‐day period. Those trajectories that do not experience a significant convective influence are divided into four geographical categories depending on their origins and paths. Air parcels originating over Africa and South America are characterized by enhanced mixing ratios of O3, CO, HNO3, and PAN. The backward trajectories travel at high altitudes (∼10–11 km), covering long distances due to strong upper‐tropospheric westerly winds. The observed enhancement of combustion‐related species is attributed to biomass burning from distant sources to the west, extending even to South America. The relatively large value of Be‐7 probably is due either to less efficient removal of aerosols from upper tropospheric air or to small stratospheric contributions. Aged marine parcels are found to have relatively small concentrations of burning‐related species. Although these trajectories arrive at a wide range of aircraft altitudes, they do not pass over a land mass during the preceding 10‐day period. Air passing over Australia but no other land mass exhibits a combustion signature; however, photochemical product species such as O3 and PAN are less enhanced than in the long‐range transport category. These trajectories travel shorter distances and are at lower altitudes (∼5–8 km) than those reaching Africa and/or South America. The combustion influence on these parcels is attributed to biomass burning emissions injected over Australia. That burning is less widespread than in Africa and South America. Finally, trajectories originating over Southeast Asia appear to receive a weak combustion influence. However, compared to Africa and South America, Southeast Asia has a relatively small incidence of biomass burning. There is little combustion input from Australia due to the high transport altitudes compared to the lower heights of the convection. The Southeast Asian parcels exhibit the greatest NOx to ∑NOi ratio of any category, perhaps due to lightning. Parcels experiencing a significant convective influence also are examined. Most of these parcels pass through widespread, persistent convection along either the South Pacific Convergence Zone or Intertropical Convergence Zone approximately 5 days prior to arriving at the aircraft locations. Thus the category mostly represents marine convection. Mixing ratios of peroxides and acids in the convective category are found to be smaller than in parcels not experiencing convection. Small mixing ratios of Be‐7 and Pb‐210 suggest particle removal by precipitation