Informing mental health policies and services in the EMR: cost-effective deployment of human resources to deliver integrated community-based care.

For EMR countries to deliver the expectations of the Global Mental Health Action Plan 2013-2020 & the ongoing move towards universal health coverage, all health & social care providers need to innovate and transform their services to provide evidence-based health care that is accessible, cost-effective & with the best patient outcomes. For the primary and community workforce, this includes general medical practitioners, practice & community nurses, community social workers, housing officers, lay health workers, nongovernmental organizations & civil society, including community spiritual leaders/healers. This paper brings together the current best evidence to support transformation & discusses key approaches to achieve this, including skill mix and/or task shifting and integrated care. The important factors that need to be in place to support skill mix/task shifting and good integrated care are outlined with reference to EMR countries.

Informing mental health policies and services in the EMR:cost-effective deployment of human resources to deliver integrated community-based care

For EMR countries to deliver the expectations of the Global Mental Health Action Plan 2013-2020 and the ongoing move towards universal health coverage, all health and social care providers need to innovate and transform their services to provide evidence-based health care that is accessible, cost-effective and with the best patient outcomes. For the primary and community workforce, this includes general medical practitioners, practice and community nurses, community social workers, housing officers, lay health workers, nongovernmental organizations and civil society, including community spiritual leaders/healers. This paper brings together the current best evidence to support transformation and discusses key approaches to achieve this, including skill mix and/or task shifting and integrated care. The important factors that need to be in place to support skill mix/task shifting and good integrated care are outlined with reference to EMR countries

Pour que les pays de la Région de la Méditerranée orientale puissent répondre aux attentes créées par le Plan d'action mondial sur la santé mentale 2013-2020 et pour faciliter le mouvement continu vers la couverture sanitaire universelle, tous les acteurs de la prestation de soins socio-sanitaires doivent faire preuve d'innovation et transformer leurs services afin de fournir des soins de santé fondés sur des bases factuelles qui soient accessibles, d'un bon rapport coût-efficacité et procurent les meilleurs résultats pour les patients. Pour ce qui est des personnels aux niveaux primaires et communautaires, ceci concerne les médecins généralistes, les infirmières praticiennes, les infirmières communautaires, les travailleurs sociaux communautaires, les responsables des logements sociaux,les travailleurs de la santé non professionnels, les membres des organisations non gouvernementales et de la société civile, y compris les leaders et les guérisseurs spirituels communautaires.Le présent article rassemble les meilleures bases factuelles actuellement disponibles à l'appui de cette transformation et examine les approches principales à cet égard, y compris l'éventail des compétences et/ou la délégation des tâches et les soins intégrés.Les facteurs importants qui doivent être en place à l'appui de l'éventail des compétences/la délégation des tâches et de bons soins intégrés sont présentés dans le contexte des pays de la Région de la Méditerranée orientale

Designing Endocrine Disruption Out of the Next Generation of Chemicals.

A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via different endocrinological mechanisms through the protocol using published literature. Each was identified as endocrine active by one or more tiers. We believe that this voluntary testing protocol will be a dynamic tool to facilitate efficient and early identification of potentially problematic chemicals, while ultimately reducing the risks to public health.

Gap junctions and memory: an investigation using a single trial discrimination avoidance task for the neonate chick.

Gap junctions are important to how the brain functions but are relatively under-investigated with respect to their contribution towards behaviour. In the present study a single trial discrimination avoidance task was used to investigate the effect of the gap junction inhibitor 18-alpha-glycyrrhetinic acid (alphaGA) on retention. Past studies within our research group have implied a potential role for gap junctions during the short-term memory (STM) stage which decays by 15 min post-training. A retention function study comparing 10 microM alphaGA and vehicle given immediately post-training demonstrated a significant main effect for drug with retention loss at all times of test (10-180 min post-training). Given that the most common gap junction in the brain is that forming the astrocytic network it is reasonable to conclude that alphaGA was acting upon these. To confirm this finding and interpretation two additional investigations were undertaken using endothelin-1 (ET-1) and ET-1+tolbutamide. Importantly, a retention function study using 10nM ET-1 replicated the retention loss observed for alphaGA. In order to confirm that ET-1 was acting on astrocytic gap junctions the amnestic action of ET-1 was effectively challenged with increasing concentrations of tolbutamide. The present findings suggest that astrocytic gap junctions are important for memory processing.

Inhibition of mGluR1 and IP3Rs impairs long-term memory formation in young chicks.

Calcium (Ca(2+)) is involved in a myriad of cellular functions in the brain including synaptic plasticity. However, the role of intracellular Ca(2+) stores in memory processing remains poorly defined. The current study explored a role for glutamate-dependent intracellular Ca(2+) release in memory processing via blockade of metabotropic glutamate receptor subtype 1 (mGluR1) and inositol (1,4,5)-trisphosphate receptors (IP(3)Rs). Using a single-trial discrimination avoidance task developed for the young chick, administration of the specific and potent mGluR1 antagonist JNJ16259685 (500nM, immediately post-training, ic), or the IP(3)R antagonist Xestospongin C (5microM, immediately post-training, ic), impaired retention from 90min post-training. These findings are consistent with mGluR1 activating IP(3)Rs to release intracellular Ca(2+) required for long-term memory formation and have been interpreted within an LTP2 model. The consequences of different patterns of retention loss following ryanodine receptor (RyR) and IP(3)R inhibition are discussed.

D-Lactate inhibition of memory in a single trial discrimination avoidance task in the young chick.

L-Lactate is a metabolite possibly able to meet some neuronal energy demands. However, a clear role for L-lactate in behaviour remains elusive. Administration of the inactive isomer D-lactate (1.75 mM; ic), immediately post-training, resulted in a persistent retention loss from 40 min post-training when used in conjuction with a single trial discrimination avoidance task designed for the young chick. Furthermore, 1mM noradrenaline (ic) administered 20 min post-training overcame the retention loss induced by D-lactate. Although not directly demonstrated in the current study, it is plausible that D-lactate inhibited memory processing by competing with L-lactate for uptake into neurons. The time of onset of the retention loss induced by D-lactate is in accord with findings where the action of noradrenaline is inhibited. The successful challenge of D-lactate inhibition by a high concentration of noradrenaline may suggest a relationship by some unidentified mechanism.

Phosphodiesterase type 5 inhibition coupled to strong reinforcement results in two periods of transient retention loss in the young chick.

Previous behavioural studies which have administered phosphodiesterase type-5 (PDE5) inhibitors have consistently demonstrated improved retention. However, when young chicks were trained on a strongly reinforced passive avoidance task 100microM zaprinast caused two periods of transient retention loss. This is opposed to past findings and may suggest an effect on retrieval. It is hypothesised that the level of reinforcement is central to this phenomenon. The molecular corollary of this may be the need to maintain cGMP homeostasis such that strong reinforcement+zaprinast may impair retention through the production of excessive levels of cGMP. This was demonstrated by two challenge studies whereby increasing concentrations of 8-Br-cGMP were administered in the presence of the guanylate cyclase inhibitor ODQ (100microM; ic) resulting in an inverted "U-shaped" retention curve. These findings suggest a more complex role for PDE5 and cGMP in memory processing than previously described and question the role of PDE5 inhibitors as nootropes under all circumstances.

Evidence for the role of endogenous carbon monoxide in memory processing.

For a decade and a half, nitric oxide (NO) has been implicated in memory processing across a wide variety of tasks and species. Comparatively, endogenously produced carbon monoxide (CO) has lagged behind as a target for research into the pharmacological processes underlying memory formation. This is surprising given that CO is formed in memory-associated brain regions, is structurally similar to NO, and along with NO can activate guanylate cyclase, which is an enzyme well characterized in memory processing. Nevertheless, a limited number of electrophysiological investigations have concluded that endogenous CO is involved in long-term potentiation. Although not evidence for a role in memory per se, these studies did point to the possible importance of CO in memory processing. In addition, there is now evidence to suggest that endogenous CO is important in avoidance learning and possible for other tasks. This review therefore seeks to promote endogenous CO as a potentially important target for memory research.

Fecundity, 17beta-estradiol concentrations and expression of vitellogenin and estrogen receptor genes throughout the ovarian cycle in female Eastern mosquitofish from three lakes in Florida.

Previous studies of Eastern mosquitofish in contaminated Lake Apopka, Florida, have documented reduced sperm count and sexual behaviour in males but increased fecundity and liver weight in females, compared to nearby reference lakes. Liver weight can be an indicator of vitellogenin (Vtg) synthesis in fish, such as the mosquitofish. It was therefore hypothesized that estrogenic organochlorine pesticides, present at elevated concentrations in animals from Lake Apopka, could cause the reproductive disorders in males, as well as increase female fecundity. We initiated a test of this hypothesis by examining the relationship between 17beta-estradiol (E2) tissue concentrations, hepatic estrogen receptor alpha (ERalpha) and Vtg A, B and C gene expression and fecundity in sexually mature female Eastern mosquitofish from Lake Apopka and two reference lakes, Lake Woodruff and Lake Orange. We observed that female Eastern mosquitofish from one site in contaminated Lake Apopka produced fewer but bigger embryos than females from the other Lake Apopka site and two reference sites. However, female E2 concentrations and hepatic ERalpha and Vtg A, B and C gene expression showed no overall differences among the four sites, and it is therefore unlikely that the differences in fecundity were caused by estrogenic EDCs. In addition, we observed no induction of any of the three Vtg genes in male Eastern mosquitofish at the two Lake Apopka sites. Based on the well-documented high sensitivity of Vtg induction as a biomarker of xenoestrogen exposure, the evidence from the present study does not support the hypothesis that estrogenic EDCs are affecting reproduction in Eastern mosquitofish living in Lake Apopka. Our experimental design tested specifically for effects mediated via the ER, and e.g. antiandrogenic DDT metabolites might still be of importance for mosquitofish reproduction in Lake Apopka.

New perspectives on the mechanisms through which nitric oxide may affect learning and memory processes.

Nitric oxide (NO) has been well established as a molecule necessary for memory consolidation. Interestingly, the majority of research has focused on only a single mechanism through which NO acts, namely the up-regulation of guanylate cyclase (GC). However, since NO and NO-derived reactive nitrogen species are capable of interacting with a broad array of enzymes, ion channels and receptors, a singular focus on GC appears short-sighted. Although NO inhibits the action of a number of molecules there are four, in addition to GC, which are up-regulated by the direct presence of NO, or NO-derived radicals, and implicated in memory processing. They are: cyclic nucleotide-gated channels; large conductance calcium-activated potassium channels; ryanodine receptor calcium release (RyR) channels; and the enzyme mono(ADP-ribosyl) transferase. This review presents evidence that not only are these four molecules worthy of investigation as GC-independent mechanisms through which NO may act, but that behavioural evidence already exists suggesting a relationship between NO and the RyR channel.

HIV-1 protein gp120 rapidly impairs memory in chicks by interrupting the glutamate-glutamine cycle.

Learning and memory impairments are frequently observed in patients suffering from AIDS Dementia Complex (ADC). These effects have been linked to the presence of gp120, an HIV viral coat glycoprotein. The present study investigated the possibility that gp120 prevents the uptake of extracellular glutamate by astrocytes, leading to an interruption of the glutamate-glutamine cycle and a subsequent impairment of memory. Ten microliters of 10nM gp120 was bilaterally injected into the region of the intermediate medial mesopallium of day-old chicks at various times before, or after, training using a single-trial passive avoidance task. Gp120 was found to significantly impair memory retention when injected 10-40 min after training. Memory impairments were evident within 5 min of gp120 administration and remained evident 24h later. Further, the amnestic effect of gp120 could be overcome with glutamine or with precursors of glutamate synthesis, but only weakly by glutamate. These results support the conclusion that the amnestic effect of gp120 is due to an impaired uptake of glutamate by astrocytes and a subsequent interruption of glutamine supply to neurones. The data indicate that the glutamate-glutamine cycle may be a useful therapeutic target in the treatment of ADC.

Pharmaco-behavioural evidence indicating a complex role for ryanodine receptor calcium release channels in memory processing for a passive avoidance task.

Calcium signalling is an important process underlying neuronal function and consequently behaviour. The release of calcium from intracellular stores via the ryanodine receptor calcium release (RyR) channel has been implicated in both synaptic plasticity and to a limited extent in memory processing. While past investigations have suggested a role for RyR channels in long-term memory, the present study suggests their action is more complex. Using a single trial passive avoidance task developed for the day-old chick, it is proposed that RyR channels are necessary both prior to the expression of long-term memory and also in retrieval processes. Specifically, 5 mM dantrolene (a specific RyR channel blocker) resulted in a persistent retention loss from 40 min post-training while 10 nM dantrolene produced a transient retention loss centred at 40 min post-training. We speculate that in the context of memory formation, RyR channels may be activated by nitric oxide and in the context of memory retrieval may lead to the activation of large conductance calcium-activated potassium BK(Ca) channels which, when blocked by 50 nM iberiotoxin, also demonstrated a transient retention loss centred at 40 min post-training.

Inhibition of endogenous carbon monoxide production induces transient retention losses in the day-old chick when trained using a single trial passive avoidance learning task.

Carbon monoxide (CO) is most often thought of as an exogenous toxin rather than as a possible endogenous nootrope. However, a limited number of studies have suggested that CO is necessary in memory processing for at least some tasks. While nitric oxide (NO) and CO are known activators of guanylyl cyclase (GC), only the effect of NO on GC has been extensively investigated as a mechanism underlying memory processing. The aim of the present study was to determine if inhibition of CO production would have an effect on memory processing. Using chicks trained on a single trial passive avoidance task, inhibition of CO production using zinc (II) deuteroporphyrin IX 2,4-bis ethylene glycol (ZnBG; 5 microM) resulted in two transient retention losses occurring at around 40 and 130 min post-training. The timing of these transient retention losses was similar to those observed following inhibition of GC, using the same species and task in a previous study. This supports the notion that CO is necessary in memory processing for this task and may act through a GC-dependent mechanism. As ZnBG also directly inhibits GC or nitric oxide synthase (NOS) at high concentrations, a second experiment was carried-out to confirm the specificity of ZnBG for heme oxygenase (HO) at the concentration used. The action of ZnBG was challenged with the HO agonist hemin (100 microM) and the transient deficits were abolished. This confirmed that the action of ZnBG on memory was through a CO-related mechanism rather than directly on GC or NOS. In this way the specificity of ZnBG (5 microM) for HO could be confirmed. The results support a role for endogenous CO in memory processing, possibly through activation of GC. In addition, the transient retention losses observed following administration of ZnBG suggest that CO may be necessary for memory retrieval and not formation as previously thought.

A scavenger of peroxynitrite prevents long-term memory formation using a single trial passive avoidance task for the day-old chick.

The important role of nitric oxide (NO) in memory processing has been recognised for some time. However, the mechanisms through which NO may act are only partially understood. One highly reactive radical brought about by the reaction of NO and superoxide ions is peroxynitrite. The current study investigated the effect of peroxynitrite scavenging on retention for a single trial passive avoidance task developed for the day-old chick. Administration of a range of concentrations of the peroxynitrite scavenger Trolox (0.1 microM-1.2 mM) yielded a bimodal retention curve. This dose-response curve had nadirs at 300 and 800 microM. A time of administration study was conducted for each optimal concentration of Trolox and in both studies, the effective range of administration times extended from at least 10 min before training to 20 min post-training. Finally, a retention function was conducted for each optimum concentration of Trolox and in both studies a persistent retention loss was observed from 40 min post-training until the conclusion of the experiment 24 h post-training. The findings suggest that physiological levels of peroxynitrite may be required for the consolidation of long-term memory in this model of memory formation. Interestingly, the effective times of administration and time of retention loss onset are consistent with previous studies which blocked NO synthesis. Therefore it may be suggested that NO acts to facilitate long-term memory formation through the production of peroxynitrite.

Monte Carlo simulation estimates of neutron doses to critical organs of a patient undergoing 18 MV x-ray LINAC-based radiotherapy.

Absorbed photoneutron dose to patients undergoing 18 MV x-ray therapy was studied using Monte Carlo simulations based on the MCNPX code. Two separate transport simulations were conducted, one for the photoneutron contribution and another for neutron capture gamma rays. The phantom model used was of a female patient receiving a four-field pelvic box treatment. Photoneutron doses were determinate to be higher for organs and tissues located inside the treatment field, especially those closest to the patient's skin. The maximum organ equivalent dose per x-ray treatment dose achieved within each treatment port was 719 microSv/Gy to the rectum (180 degrees field), 190 microSv/Gy to the intestine wall (0 degrees field), 51 microSv/Gy to the colon wall (90 degrees field), and 45 microSv/Gy to the skin (270 degrees field). The maximum neutron equivalent dose per x-ray treatment dose received by organs outside the treatment field was 65 microSv/Gy to the skin in the antero-posterior field. A mean value of 5 +/- 2 microSv/Gy was obtained for organs distant from the treatment field. Distant organ neutron equivalent doses are all of the same order of magnitude and constitute a good estimate of deep organ neutron equivalent doses. Using the risk assessment method of the ICRP-60 report, the greatest likelihood of fatal secondary cancer for a 70 Gy dose is estimated to be 0.02% for the pelvic postero-anterior field, the rectum being the organ representing the maximum contribution of 0.011%.

Neutron spectra and dosimetric features around an 18 mv linac accelerator.

Using the difference between responses to neutrons of TLD-600 and TLD-700, three experimental devices were constructed and arranged to measure thermal neutron fluences, neutron spectra, and neutron doses inside the treatment room of a radiotherapy 18 MV Linear electron accelerator (Linac). Thermal neutron fluences were measured with TLD-600/TLD-700 pairs arranged in both a bare and a cadmium (Cd) foil covered methacrylate box. Neutron spectra were measured in 26 energy bins by introducing pairs of TLD-600/TLD-700 in air and into the middle of five polyethylene spheres with diameters of 3, 5, 8, 10, and 12 inches. A PC version of the BUNKI code was used to unfold the six measurements in each sphere to obtain the 26 energy bins. Neutron and photon doses were measured by introducing pairs of TLD-600/TLD-700 into the middle of a single 25-cm-diameter paraffin sphere. The three required neutron calibrations were carried out at the Nuclear Technology Laboratory of the Polytechnique University of Madrid (UPM), using an 241Am-Be neutron source with an alpha activity of 111 GBq and a yield of 6.6 x 10(6) neutrons s(-1). Three devices were needed for the necessary calibrations: a BF3 counter for the thermal neutron fluence calibration, a LUDLUM 42-5 Bonner spectrometer with five 0.95 g cm(-3) polyethylene spheres with a LiI(Eu) 4 x 4 mm2 scintillation counter for the neutron spectrometer calibration and a NEMO 9140 remmeter for the paraffin remmeter calibration. The Monte Carlo code MCNP 4C has been used in two ways: to calculate the neutron kerma contribution to two TLDs (type 600 and 700) both in air and inside the paraffin sphere, and to determine the neutron spectra at those Linac room zones where the neutron spectra were measured. Thermal neutron fluences of 2.9 x 10(4) +/- 8.6 x 10(3) cm(-2) s(-1), measured around the Linac head plane, and 2.3 x 10(4) +/- 2.3 x 10(3) cm(-2) s(-1), measured at the patient couch plane, are in agreement with previous independent measurements from other authors. The calculated and measured neutron spectra obtained in the treatment room showed three distinct regions: a peak around 0.1 MeV, a flat epithermal region and a thermal region with values similar to those mentioned above. Patient dose equivalents of 0.5 mSv and 5 mSv from neutrons and photons, respectively, were obtained per treatment Gray.

Inhibition of monoADP-ribosylation prevents long-term memory consolidation of a single-trial passive avoidance task in the day-old chick.

The cytosolic posttranslational protein-modifying mechanism of monoADP-ribosylation has been implicated in long-term potentiation, a synaptic model of memory formation. The current study investigated the effect of inhibiting mono(ADP-ribosyl) transferase on memory for the passive avoidance task in day-old chicks (white Leghorn-black Australorp). Various doses of novobiocin or menadione sodium bisulfite were administered intracranially at different times before or after training. Control chicks were administered saline at matched times. Novobiocin (650 microM) or menadione sodium bisulfite (250 microM) administered between 5.0 min pretraining and 2.5 min posttraining was found to cause a persistent loss of retention from 120 min posttraining. These data provide the first demonstration that monoADP-ribosylation is required for the maintenance of long-term memory. Furthermore, the temporal characteristics of the memory loss caused by monoADP-ribosylation inhibition appears to exclude this mechanism as a downstream effect of the well-established nitric oxide activity previously shown to occur within 40 min of passive avoidance training.

Inhibition of guanylate cyclase and protein kinase G impairs retention for the passive avoidance task in the day-old chick.

Nitric oxide (NO) is a highly labile chemical messenger which has previously been implicated in memory processes in a variety of learning paradigms and species. However, there is only limited evidence to suggest which enzymes are acted upon by NO during the formation of memory. The present study investigates the role of guanylate cyclase (GC) and protein kinase G (PKG) in a form of passive avoidance learning known to be dependent on nitric oxide activity. It was determined that in vivo pharmacological inhibition of GC using either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one or 6-anilino-5,8-quinolinedione resulted in two transitory memory retention deficits centred around 40 and 120 min posttraining, respectively. In contrast, inhibition of PKG with N-[2-(methylamino)ehtyl]-5-isoquinoline-sulfornamide hydrochloride (H-8) resulted in a single temporary retention loss centered at 120 min posttraining. These temporary retention losses appear to be specific to memory since they were dose-dependent and could not be explained by nonspecific performance effects. Further, these results suggest that these agents inhibit memory retrieval rather than formation, since memory is subsequently available. The current findings indicate that guanylyl cyclase mediates two memory retrieval processes, the latter of which appears to be PKG-dependent. In contrast, since inhibition of NO results in a permanent retention loss, it is suggested that NO is required for memory formation through GC-independent processes.