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.

In vivo suppression of delayed hypersensitivity: prolongation of desensitization in guinea pigs.

Administering moderate (milligram) amounts of antigen to a guinea pig immunized with thatntigen leads to a transient loss of all delayed hypersensitivity (DH) responses in that animal. In this study, we demonstrate that this "desentization" can be prolonged for 10 days by repeated injection of antigen. At this time, tolerance to the desensitizing antigen develops in both the humoral and cellular systems of the immune response and DH responsiveness to other antigens returns. Repeated cycles of sensitization and desensitization produce repeated episodes of generalized anergy. Neither cells nor serum from desensitized animals could be shown to exert a suppressor effect when transferred to immunized animals and the cells responded normally to antigen and mitogen in tissue culture. The best generalized depression of DH was seen in those animals producing the best DH before desensitization. The inability of antigen to react with tolerant cells to produce desensitization suggests that this phenomenon is an active rather than a passive one and may represent an exaggeration of a normal regulatory mechanism for DH triggered by a regimen of antigen administration that activates suppressor cells to produce a systemic effect.

Regulation of delayed hypersensitivity. Failure to transfer delayed hypersensitivity to desensitized guinea pigs.

Two potential mechanisms for terminating delayed hypersensitivity (DH) reactions have been examined in desensitized guinea pigs. Lack of macrophage responsiveness to lymphokines was sought as an explanation for the reduced ability of these animals to express delayed hypersensitivity. Skin-reactive factor was injected into the skin of desensitized guinea pigs and a control group of similarly immunized animals. The resulting inflammatory reactions were similar in size and intensity in both groups indicating normal macrophage responsiveness in the desensitized state. Passive cellular transfer of DH responses to desensitized animals was markedly less successful than transfer to normal animals. However, cells from desensitized guinea pigs did transfer DH responsiveness to normal animals. These data support the concept of a humoral suppressant of cellular immunity, perhaps acting as a feedback inhibitor, produced when guinea pigs are desensitized.

The effect of anti-mu suppression of gammaM and gammaG on the production of gammaE.

Newbonr mice were treated from the day of birth with either bovine gamma globulin or anti-mu chain sera. The latter was administered using a protocol known to produce suppression of gammaM, gammaG, and gammaA production. Subsequent immunization with ovalbumin (OA) in alum was attempted to see if suppression of gammaM, gammaG, and gammaA classes of antibody would also be accompanied by suppression of gammaE-producing capacity. gammaG and gammaM antibody to OA and mercaptoethanol-resistant (gammaG) antibody to OA were measured by passive hemagglutination; gammaG and gammaE anti-OA antibodies were measured by passive cutaneous anaphylaxis. Anti-mu suppression was achieved with significant reduction in gammaM and gammaG antibodies. gammaE antibodies were not affected, suggesting an ontogenetic development for gammaE-bearing lymphocytes independent of the previously described gammaM to gammaG to gammaA ontogenetic sequence.

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.

Overwhelming sepsis in the adult variant of Wiskott-Aldrich syndrome.

Two brothers with a variant form of Wiskott-Aldrich syndrome suffered episodes of severe bacterial infection commencing in their fourth decade of life. One man died of overwhelming pneumococcal infection. This study emphasizes (1) the importance of recognizing the variant form of Wiskott-Aldrich syndrome in male adults with thrombocytopenia and (2) the treatment of these patients with prophylactic antibiotics.

Transplantation of thymic tissue into patients with AIDS. An attempt to reconstitute the immune system.

Thymic epithelial fragments were transplanted into 15 patients in an advanced stage of the acquired immunodeficiency syndrome (AIDS). One patient was given interleukin 2 in addition to thymic tissue. We demonstrated the following: Thymic epithelial fragments cultured before transplantation to remove T cells survived for months after transplantation in eight of 15 patients and seemed to be responsible for a partial, selective, but transient repopulation of the circulating T-cell pool. The absolute number of T8 cells, but not T4 cells, increased three to four weeks after the procedure in eight of the 15 subjects. This increase in T8 cells was associated with clinical improvement in some cases and increased T-cell responsiveness in vitro. Thymic tissue transplantation as a single therapeutic maneuver is unlikely to reconstitute the immune system of patients with AIDS, but the potential of the approach, used in combination with agents that block replication of human T-cell lymphotropic virus type III, deserves further study.

Progressive immune failure in dyskeratosis congenita. Report of an adult in whom Pneumocystis carinii and fatal disseminated candidiasis developed.

Community-acquired Pneumocystis carinii pneumonia developed in a young adult patient with dyskeratosis congenita. His hospitalization ended fatally with disseminated candidiasis. Evaluation during the admission showed evidence of cellular immune dysfunction as indicated by skin test anergy and absent lymphocyte proliferation in an in vitro mixed lymphocyte culture. Treatment with transfer factor failed to reverse the cutaneous anergy or affect the clinical course. Dyskeratosis congenita is a rare multisystem disorder with prominent dermatologic manifestations; bone marrow failure or malignant neoplasm are common fatal outcomes. Immune system abnormalities are not classically considered a part of the disease complex. Serial evaluation of our patient's condition over several years suggests that depressed immune function, especially of the cellular limb, may evolve as a feature of clinical importance in these patients.

Sarcoid.

Patients with sarcoidosis were separated into those treated or not treated with prednisone. Skin test reactivity of both groups was clearly diminished but a significant decrease in T-cells was seen only in the steroid-treated group and this was not sufficient to explain the profound energy. Lymphocyte stimulation studies generally revealed elevated baseline incorporation of [3H]thymidine and reduced stimulation. Factors were present in the plasmsa of 1/4 to 1/3 of the patients which suppressed normal lymphocyte stimulation. When cells from 3 sarcoid patients were precultured in vitro, recovery towards normal occurred with a drop of the elevated baseline and rise in peak response.

Thirty years of supplying the missing link. History of gamma globulin therapy for immunodeficient states.

Man has been injecting himself with gamma globulin for almost 100 years. As a result, both the benefits and the hazards of such therapy have been convincingly demonstrated. For 30 years physicians have realized that one group of patients must receive regular injections of this material to avoid death from overwhelming bacterial infections. The health of subjects with congenital or acquired hypogammaglobulinemia is directly related to the successful administration of adequate amounts of immunoglobulin G (IgG). Three phases are easily recognizable when examining the history of how physicians have accomplished such replacement therapy. Initially, therapy was limited to frequent and painful intramuscular injections of concentrated immune serum globulin. In some patients, the administration of monthly infusions of fresh plasma from "buddies" supplied a better approach. Now, the elusive goal of having a concentrated form of gamma globulin suitable for intravenous administration has been reached. Such preparations are revolutionizing the treatment of human immune deficiencies and expanding the therapeutic potential of gamma globulin itself.

Clinical and immunologic response to antigen-specific transfer factor in drug-resistant infection with Mycobacterium xenopi.

The administration of transfer factor obtained from three donors who had recovered from clinical infections with Mycobacterium xenopi to a patient who had a destructive pulmonary infection with this organism, was associated with the reversal of an unfavorable clinical course. Cavitary tuberculosis associated with resistance to all combinations of antituberculosis drugs was probably related to a concurrent depression of cell-mediated immunity of unknown origin. Antigen specific but not nonspecific transfer factor caused a rapid and prolonged improvement in both the pulmonary disease and the immunologic deficiency. Cross-reactivity between the antigenic determinants of M. xenopi and Mycobacterium tuberculosis made it possible to use transfer factor obtained from donors responsive to purified protein derivative of tuberculin. This study clearly demonstrates the additional benefits to be gained from using transfer factor that is antigen-specific in the treatment of infectious diseases.

Cellular immune findings in Lyme disease. Correlation with serum IgM and disease activity.

Cellular immune findings were studied in 48 patients with various stages of Lyme disease. At each stage, some patients, particularly those with neuritis or carditis, had elevated serum IgM levels and lymphopenia. During early disease, mononuclear cells tended to respond normally to phytohemagglutinin, and spontaneous suppressor cell activity was greater than normal. Later, during active neuritis, carditis, or arthritis, the trend was toward heightened phytohemagglutinin responsiveness and less suppression than normal. By multiple regression analysis, serum IgM levels correlated directly with disease activity (p = 0.025) and inversely with the number of T cells (p = 0.02); during acute disease only, elevated IgM levels correlated with increased phytohemagglutinin responsiveness (p = 0.004) and decreased suppressor cell activity (p = 0.03). Decreased suppression, observed later in the disease, may permit damage to host tissues because of either autoimmune phenomena or a heightened response to the Lyme spirochete.

Intraventricular gamma-globulin for the management of enterovirus encephalitis.

Although bacterial infections predominate in patients with hypogammaglobulinemia, patients who do not produce normal amounts of immunoglobulin also have an increased incidence of viral infections. This is particularly true of infections with enteroviruses. Echovirus encephalitis has been a major problem for patients with hypogammaglobulinemia. Neurologic damage, frequently resulting in death, has been common in such patients. Because there is an obligatory extracellular phase in the cell to cell spread of enteroviruses, therapy with immunoglobulin has been attempted. In certain patients intravenous and intrathecal gammaglobulin has temporarily halted progression of the disease, but no patients have been cured by this approach. In this report we detail treatment of three children with X-linked hypogammaglobulinemia who had encephalitis caused by echovirus infections. Despite doses of intravenous immunoglobulin that maintained the patients' IgG levels within the normal range, their condition deteriorated in all cases. Treatment with intraventricular immunoglobulin was then tried. In all three cases cerebrospinal fluid protein levels and cell counts returned to normal after this treatment and the echoviruses can no longer be isolated from the cerebrospinal fluid. Follow-up time has ranged from 18 months to 4 years. Ommaya reservoirs were placed into the lateral ventricle of each patient and concentrated (6%) immunoglobulin (Sandoglobulin) was injected into the reservoir on a daily basis. On Days 1 through 7 of the regimen patients were given 120, 300, 450, 510, 540 and 600 mg of IgG, respectively. Patients then received 300 mg daily for periods ranging from 1 week to 1 month. Cultures of cerebrospinal fluid removed from the reservoir were repeatedly analyzed to determine the need for further treatment. Clinically the patients improved markedly.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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.

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.

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'.

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.