Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression.

Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Potential aboveground biomass in drought-prone forest used for rangeland pastoralism.

The restoration of cleared dry forest represents an important opportunity to sequester atmospheric carbon. In order to account for this potential, the influences of climate, soils, and disturbance need to be deciphered. A data set spanning a region defined the aboveground biomass of mulga (Acacia aneura) dry forest and was analyzed in relation to climate and soil variables using a Bayesian model averaging procedure. Mean annual rainfall had an overwhelmingly strong positive effect, with mean maximum temperature (negative) and soil depth (positive) also important. The data were collected after a recent drought, and the amount of recent tree mortality was weakly positively related to a measure of three-year rainfall deficit, and maximum temperature (positive), soil depth (negative), and coarse sand (negative). A grazing index represented by the distance of sites to watering points was not incorporated by the models. Stark management contrasts, including grazing exclosures, can represent a substantial part of the variance in the model predicting biomass, but the impact of management was unpredictable and was insignificant in the regional data set. There was no evidence of density-dependent effects on tree mortality. Climate change scenarios represented by the coincidence of historical extreme rainfall deficit with extreme temperature suggest mortality of 30.1% of aboveground biomass, compared to 21.6% after the recent (2003-2007) drought. Projections for recovery of forest using a mapping base of cleared areas revealed that the greatest opportunities for restoration of aboveground biomass are in the higher-rainfall areas, where biomass accumulation will be greatest and droughts are less intense. These areas are probably the most productive for rangeland pastoralism, and the trade-off between pastoral production and carbon sequestration will be determined by market forces and carbon-trading rules.

WAY-318068: a novel, potent and selective noradrenaline re-uptake inhibitor with activity in rodent models of pain and depression.

BACKGROUND AND PURPOSE: Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity. EXPERIMENTAL APPROACH: In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one). KEY RESULTS: WAY-318068 is a potent and effective inhibitor of the NET with a K(i) of 8.7 nM in a binding assay, and an IC(50) of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits. CONCLUSIONS AND IMPLICATIONS: Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.

Vegetation responses to the first 20 years of cattle grazing in an Australian desert.

Existing theoretical frameworks suggest three predictions relevant to grazing effects in Australian aridlands: grazing has a negative but moderate effect on plant species richness; a separate "state" resulting from degradation caused by extreme grazing will be evident; some plant species will have a strong association with grazing relief refuges that have only ever been subject to light grazing. These predictions were examined in the dune swales of an Australian desert, with data on herbaceous species collected along transects up to 14 km from artificial water points between four and 33 years old. A cumulative grazing index was constructed utilizing both the spatial occupation patterns of cattle and the length of exposure. Despite restricting sampling to a narrow habitat, silt/clay content and soil pH influence floristic patterns independent of grazing. The analysis of quadrat data in relation to grazing revealed almost no patterns in plant cover, species richness (at two different scales), or abundance across plant life-form groups. Five species had an increasing response, and seven a decreasing response, while the only species restricted to areas of extremely low grazing pressure was sufficiently rare that it could have occurred there by chance. The dominant annual grass, the most common shrub, and a perennial tussock-forming sedge all decrease with high levels of grazing. Most species exhibit an ephemeral life strategy in response to unreliable rainfall, and this boom and bust strategy effectively doubles as an adaptation to grazing. After 20 years of exposure to managed grazing with domestic stock in Australian dune swales, patterns in species richness have not emerged in response to grazing pressure, the ecosystem has not been transformed to another degradation "state," and there is no evidence that grazing relief refuges provide havens for species highly sensitive to grazing.

Focus groups with smokers to develop a smoke-free home campaign.

OBJECTIVE: To identify key messages and strategies suggested to be effective in influencing attitudinal and behavioral change in homes in which smoking is allowed to occur. METHODS: Four focus-group interviews were conducted with 35 daily smokers and analyzed for common themes. RESULTS: The themes related to messages that focus on the health of children, respect smokers, are accurate and supported by research and statistics, provide information and assistance on quitting smoking, and use a harm-reduction approach to smoke-free homes. CONCLUSION: The results of this research suggest that a smoke-free home campaign should include messages that address a variety of issues that are of concern and sensitive to smokers.

High-risk sexual behaviours and genital infections during pregnancy.

This article describes the sexual behaviours of some pregnant women that contribute to vaginal and cervical infections, and describes their lack of awareness about the dangers associated with sexually transmitted infections during pregnancy. It presents a subanalysis of data from a principal epidemiological study of the association between preterm delivery and genital hygiene habits and sexual behaviour during pregnancy. One-hundred and nine postpartum women were questioned about high-risk sexual behaviours during their pregnancies, their partner's sexually transmitted disease status and their knowledge about the effect of sexually transmitted infections on their pregnancy. Global concerns about the prevalence, diagnosis and treatment of cervical and vaginal infection from sexually transmitted diseases are discussed. The dangers associated with high-risk sexual behaviours during pregnancy, and recommendations for clinicians, are included.

A preliminary study to determine the effect of an infusion of cryopreserved autologous lymphocytes on immunocompetence and viral load in HIV-infected patients.

Therapeutic measures aimed at boosting the immunity of HIV-infected patients are a critical component of strategies for effective therapy of HIV and AIDS. To improve immunocompetence in patients with progressive disease, autologous lymphocytes that were collected and cryopreserved earlier in the course of HIV-infection were reinfused. None of the 12 patients receiving cell infusions experienced any adverse effects. Improvements in immunologic parameters (CD4+ counts, CD8+ counts, or both; HIV-specific cytotoxic T-lymphocyte (CTL) activity; or viral load) were seen in seven patients. Restoration of the CD4+ count to the level recorded at the time of cell harvest was achieved in two patients with less advanced disease. Plasma HIV RNA was reduced by >0.5 logs in two of the four patients tested. These preliminary results suggest that cellular immunotherapy using cryopreserved autologous lymphocytes has the potential to improve some measures of immunity in patients with HIV/AIDS and warrants further investigation.

Schizophrenia in people with intellectual disability: the role of pregnancy and birth complications.

The literature suggests that mental illness is more common in people with intellectual disability than in the general population. Having reviewed the literature, Turner (1989) [Psychological Medicine 19, 301-14] suggested that about 3% of people with intellectual disability also have schizophrenia. As pregnancy and birth complications (PBCs) occur more commonly in people with intellectual disability than in the general population and are also implicated in the aetiology of schizophrenia, it is possible that these conditions share a common aetiology. This study reports on the occurrence of PBCs in those people with intellectual disability who develop schizophrenia. Fifty people with intellectual disability and schizophrenia were matched for age, sex, degree of intellectual disability and presence of epilepsy with a control group who did not suffer from schizophrenia or a schizophreniform psychosis. The obstetric history was obtained and events rated on a scale specifically designed for this study. This PBCs scale consists of six sub-scales covering areas of general maternal health, pregnancy, delivery, medication in labour, total medication score and neonatal score, as well as an overall total score. The study found that people with intellectual disability who develop schizophrenia have significantly higher rates of PBCs than controls. All of the sub-scales on the PBCs scale were significantly higher in people with schizophrenia, with the exception of the medication scales. Only five out of the 50 people with schizophrenia had not had a major obstetric complication, compared to 13 subjects from the control group. A number of abnormalities were specifically higher in people who later developed schizophrenia. These included: abnormally long or short labour; maternal episiotomy; maternal preeclamptic toxaemia; induction of labour; dysmaturity; maternal smoking in pregnancy; and a delay in neonatal crying. The results suggest that PBCs are important in the aetiology of schizophrenia in people with intellectual disability.

Suppression of HIV replication in vitro by CD8+ T-cells from HIV-infected and HIV-seronegative individuals.

The inhibitory effect of CD8+ T-cells from HIV-infected or HIV-seronegative individuals on HIV replication in the naturally-infected CD4+ T-cells in vitro was examined. Not only autologous CD8+ T-cells from HIV-infected individuals but also allogeneic CD8+ T-cells from HIV-seronegative individuals prevented or delayed HIV replication, even in transwell cocultures using a semi-permeable 0.45 micron filter. The level of the inhibitory effect of allogeneic CD8+ T-cells from the HIV-seronegative individuals on the HIV replication was varied among CD4+ T-cells obtained from HIV-infected individuals used. The results suggested that CD8+ T-cells from HIV-seronegative individuals as well as HIV-infected individuals could produce some cytokine(s) which suppress HIV replication in vitro. The sensitivity to the cytokine(s) might be variable among HIV strains, depending on differences in the nucleotide sequence of different HIV-1 strains. Further studies of control of HIV replication by CD8+ anti-HIV cytokine(s) should provide new strategies for the therapy of HIV infection.

Challenge and response: HIV in Asia and the Pacific.

Inexorably, the epicentre of the global HIV pandemic is moving from Africa to Asia. Despite many years of much-publicised analysis of the African epidemic, most countries in Asia and many in the Pacific have not introduced the public health strategies known to minimise the spread of HIV. What must be done now, and how can the developed countries in the region, such as Australia, assist their neighbours?

PIP: In the Asia-Pacific region, almost 5000 people become infected with HIV every day. The leading mode of HIV transmission is heterosexual intercourse. Sharing of injecting equipment among drug users is also a major mode of HIV transmission. Myanmar is the epicenter of the HIV epidemic in Asia. The political tensions there interfere with attempts to curb the spread of HIV in-country and to neighboring countries. The lack of effective cross-border programs has resulted in an explosive situation in China's south Yunnan province, especially among drug abusers. In many countries in the region, the blood supply is unsafe. Thailand is the only country politically committed to curbing HIV transmission. Government-facilitated massive education programs and other interventions preceded a decline in the overall rate of sexually transmitted diseases (STDs) in Thailand. Key strategies in Thailand include detailed epidemiologic studies to determine the incidence and prevalence of HIV infection nationwide, promotion of safer sex practices in commercial sex establishments (e.g., 100% condom campaign), and official willingness to work with nongovernmental organizations. The government of India has not responded appropriately to the HIV/AIDS epidemic and the outcome has been disastrous. India will likely soon have more HIV-infected people than any other Asia-Pacific country. Preventive programs may spare western Pacific countries, where HIV incidence is low. Obstacles to tackling the HIV epidemic include poverty, poor facilities for the treatment of STDs, failure to address discrimination against those infected with HIV, and problems associated with the very low status of women. Many years of national development can be lost to the HIV epidemic. Australia has model HIV prevention and control policies and can help its Asia-Pacific neighbors fight HIV/AIDS. Health professionals in only Thailand, Australia, and New Zealand are prepared for the future AIDS caseload. Australia offers clinical programs for the region's health professionals. Greater political commitment is needed in the region to minimize the HIV/AIDS epidemic.

Immunoglobulins in autoimmunity: history and mechanisms of action.

The search for preparations of human gammaglobulin that could be administered safely intravenously was driven by the need to better manage immune deficiency states. However, when suitable formulations were developed, it was soon realised that large infusions of immunoglobulin could be used to manipulate the immune system. The production of autoantibodies was minimised or their effects neutralised; T cell effector and regulatory function could be manipulated and cytokine release modified. More than fifty human disease states, many until now lacking safe and effective therapies, can be improved by the administration of intravenous immunoglobulin. Better understanding of the mechanisms involved will not only improve therapy but will provide a better understanding of the immunopathogenic mechanisms responsible.

Intravenous immunoglobulin therapy for autoimmune diabetes mellitus.

OBJECTIVE: A variety of immune therapies have been used in an attempt to reduce the immune destruction of the insulin secreting beta cells which results in insulin dependent diabetes mellitus (IDDM). This study investigated the use of intravenous gammaglobulin therapy (IVIG) in children and adults with IDDM who participated in a two-year randomised controlled trial which also examined the effect of transfer factor in altering the natural course of IDDM. METHODS: Treatment was administered every two months for the duration of the study. IVIG was given in a dose of 2 g/ kg body weight in divided doses over two days. The other two groups received an intramuscular injection-the control group received normal saline and the transfer factor group received 1 i.u. of transfer factor. Remission rates, beta cell function and treatment side effects were assessed. RESULTS: Compared with the control group, IVIG therapy given every 2 months for 2 years, did not result in an increased number of complete remissions or differences in insulin dose, diabetes control or endogenous insulin secretion assessed as fasting and stimulated C-peptide responses to glucagon and a meal. IVIG therapy was associated with significant side effects. CONCLUSION: It is unlikely that IVIG therapy will be a viable option for immunotherapy in IDDM.

Behavioural interventions required in South East Asia to minimize infections with HIV.

PIP: The World Health Organization expects the rate of new HIV infections to decline in all global regions before the year 2005, except in South East Asia. More than 3 million people become HIV infected each year in South East Asia. It is incorrect to discuss it as a whole since the cultures in the region are so different. For example, in Thailand, relatively relaxed attitudes toward sexuality make it relatively easy to openly discuss sexual matters, while in India men tend to disrespect women and discussion of sexual matters, even among middle class couples, is rare. So far, there have been few successful HIV/AIDS prevention programs in the region due to various obstacles. A lack of political commitment and a heavy-handed approach by governments are common. In many countries, it is impossible to introduce sex education in schools or HIV education in the workplace. In those cases where there is sex education, lack of frankness and a dearth of peer group discussion make the programs ineffectual. The cultural conservatism of the approach to HIV prevention is not matched by behavioral conservatism in many people. In Myanmar, there are more than 200,000 HIV-infected individuals, most of whom are injecting drug users. Commercial sex workers in Myanmar operate underground. HIV is spreading from Myanmar into Bangladesh and India in the north, into southern China (especially Yunnan Province) in the south, and Thailand, Laos, Vietnam, and Cambodia. In many South East Asian countries, governments hesitate to support nongovernmental organizations (NGOs) as well as to form partnerships with NGOs to plan and implement HIV prevention strategies. Testing blood and blood products for HIV infection continues to be sporadic throughout the region. Even in those cases where HIV testing of the blood supply is done, quality control is often absent. For example, in India, there are few adequate testing programs and paid donors, many of whom are HIV infected, supply 50% of all blood used. The effectiveness of programs and resources to diagnose and treat sexually transmitted diseases varies widely.^ieng

Transfer factor in the age of molecular biology: a review.

Current data suggests that the transferring of immunologically specific information by transfer factor molecules requires interaction with a cell that has been genetically programmed to be antigen reactive but at the time of interaction is unprimed. Contact with transfer factor molecules would allow a naive recipient, on a first encounter with antigen, to make a secondary rather than a primary immunological response. Transfer factor molecules for each and every antigenic determinant are thus necessary. Transfer factors made from animals or humans are capable of transferring antigen specificity across a species barrier. Even primitive species have cells from which one can make transfer factors. The molecules are, therefore, well conserved and it is reasonable to suggest that they are important for normal immunological functioning. Proposed mechanisms of action must explain the fact that transfer factors obtained from the cells of high responder animals are capable of transferring delayed hypersensitivity to low responder animals while the reverse is not true. Transfer factor molecules are likely to interact with the variable regions of the alpha and/or beta chain of T cell receptors to change their avidity and affinity for antigen in a way that otherwise would only occur after an encounter with antigen.

A falls and balance clinic for the elderly.

A Falls and Balance Clinic for the elderly has been developed with the aim of identifying those at risk of subsequent falls, and recommending intervention strategies to reduce this risk. The physical and functional status of 149 clients referred to the Clinic are reported. Neurological and musculoskeletal pathologies were identified as the cause of falls in the majority of clients. Measures of gait velocity and stride length, and ability to stand on one leg were markedly reduced compared with normative data for healthy elderly. A number of other measures of balance, strength, and function are also reported. The results of a questionnaire about home environment indicated that only 28% of those referred had been assessed in their own home in the previous year. Home environment was considered a potential risk in a further 28% of clients and a home visit was instituted in these cases. Other intervention strategies included referral for further investigations (36%), Day Hospital (33%), provision of a home program of balance or strengthening exercises (27%), and medication change (15%). Issues related to the establishment, operation and long term evaluation of the effectiveness of a specialist Falls and Balance Clinic for the elderly are discussed.

Multiple personality disorder following childbirth.

A case of multiple personality disorder is described as a coping mechanism protecting the patient from the abuse to which she was subjected throughout her life. The multiple personalities became more prominent following the birth of a severely handicapped child.

The rational use of the HIV antibody test.

The clinical skills of the medical profession can be used to identify unsuspected HIV infection in a cost-effective way. However, other strategies are needed to optimise the detection of HIV infection and achieve the benefits to patients and the community that result from detection.