Alpha-melanocyte-stimulating hormone suppresses antigen-induced lymphocyte proliferation in humans independently of melanocortin 1 receptor gene status

Studies in mice indicate that alpha-melanocyte-stimulating hormone (alphaMSH) is immunosuppressive, but it is not known whether alphaMSH suppresses human immune responses to exogenous Ags. Human PBMCs, including monocytes, express the melanocortin 1 receptor (MC1R), and it is thought that the ability of alphaMSH to alter monocyte-costimulatory molecule expression and IL-10 release is mediated by this receptor. However, the MC1R gene is polymorphic, and certain MC1R variants compromise receptor signaling via cAMP, resulting in red hair and fair skin. Here, we have investigated whether alphaMSH can suppress Ag-induced lymphocyte proliferation in humans and whether these effects are dependent on MC1R genotype. alphaMSH suppressed streptokinase-streptodornase-induced lymphocyte proliferation, with maximal inhibition at 10(-13)-10(-11) M alphaMSH. Anti-IL-10 Abs failed to prevent suppression by alphaMSH, indicating that it was not due to MC1R-mediated IL-10 release by monocytes. Despite variability in the degree of suppression between subjects, similar degrees of alphaMSH-induced immunosuppression were seen in individuals with wild-type, heterozygous variant, and homozygous/compound heterozygous variant MC1R alleles. RT-PCR of streptokinase-streptodornase-stimulated PBMCs for all five melanocortin receptors demonstrated MC1R expression by monocytes/macrophages, MC1R and MC3R expression by B lymphocytes, but no melanocortin receptor expression by T lymphocytes. In addition, alphaMSH did not significantly inhibit anti-CD3 Ab-induced lymphocyte proliferation, whereas alphaMSH and related analogs (SHU9119 and MTII) inhibited Ag-induced lymphocyte proliferation in monocyte-depleted and B lymphocyte-depleted assays. These findings demonstrate that alphaMSH, acting probably via MC1R on monocytes and B lymphocytes, and possibly also via MC3R on B lymphocytes, has immunosuppressive effects in humans but that suppression of Ag-induced lymphocyte proliferation by alphaMSH is independent of MC1R gene status.     

Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus

Adult dentate neurogenesis is important for certain types of hippocampal-dependent learning and also appears to be important for the maintenance of normal mood and the behavioural effects of antidepressants. Neuropeptide Y (NPY), a peptide neurotransmitter released by interneurons in the dentate gyrus, has important effects on mood, anxiety-related behaviour and learning and memory. We report that adult NPY receptor knock-out mice have significantly reduced cell proliferation and significantly fewer immature doublecortin-positive neurons in the dentate gyrus. We also show that the neuroproliferative effect of NPY is dentate specific, is Y1-receptor mediated and involves extracellular signal-regulated kinase (ERK)1/2 activation. NPY did not exhibit any effect on cell survival in vitro but constitutive loss of the Y1 receptor in vivo resulted in greater survival of newly generated neurons and an unchanged total number of dentate granule cells. These results show that NPY stimulates neuronal precursor proliferation in the dentate gyrus and suggest that NPY-releasing interneurons may modulate dentate neurogenesis.     

Model studies of cholesterol and ascorbate oxidation by copper complexes: relevance to Alzheimer's disease beta-amyloid metallochemistry

The neurotoxicity of the amyloid-beta peptide (Abeta) is causally linked to Alzheimer's disease (AD) and may be related to the redox chemistry associated with its interactions with copper ions and cholesterol in brain tissue. We have used density functional theory (DFT) calculations to study the mechanism controlling the Abeta/Cu catalyzed oxidation reactions of cholesterol and ascorbate using a model system. The computed results based on a binuclear Cu complex predict that oxidation of cholesterol (yielding 4-cholesten-3-one as a specific product) proceeds at a slow rate when catalyzed by a Abeta/Cu(II)|His-|Cu(II)/Abeta) aggregate. The computed results also suggest that monomeric Abeta/Cu(II) is not able to oxidize cholesterol. DFT also predicted that Abeta will cross-link via covalent dityrosine formation during the oxidation of ascorbate but not during the oxidation of cholesterol. Experimental data were consistent with these predictions.     

Fetal and neonatal exposure to AZT and low-protein diet affects glucose homeostasis: a model with implications for AIDS prevention

Zidovudine (AZT) lowers the perinatal transmission of HIV but can impair mitochondrial function by depleting mitochondrial DNA (mtDNA). AZT therapy and perinatal nutritional deprivation affect the body fat distribution, which influences glucose tolerance. We sought to model intrauterine exposure to AZT in humans to determine whether it interacts with low-protein diet (LPD) to impact on birth weight and glucose homeostasis in the offspring. Pregnant dams and their offspring were given AZT, an LPD, or AZT and an LPD (LPD + AZT). AZT reduced mtDNA copy number in liver and birth weight in the offspring and increased their fasting glucose and insulin (P = 0.021, 0.03, 0.001, and 0.011 respectively) at 6-8 wk of age. LPD decreased litter size and birth weight (P = 0.01 and 0.012). In the LPD + AZT group, birth weight and litter size were reduced compared with untreated controls, and fasting blood glucose and insulin were raised. There was a significant interaction between LPD and AZT on fasting insulin levels (P = 0.025). Islet size was not significantly affected, but the mean beta-cell area/islet was reduced in the LPD + AZT group compared with controls (P < 0.05). Early exposure to AZT interacts with LPD to impair fetal development in this model. This combination appeared to impair the supply of insulin and, hence, glucose homeostasis, perhaps as a result of impaired mitochondrial function. Although it is not certain that this can be extrapolated to humans, maternal nutritional deprivation combined with AIDS therapy could influence both birth weight and onset of diabetes.     

Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 1: eradication of Helicobacter in the cachexia of idiopathic parkinsonism

BACKGROUND: Neuronal damage in idiopathic parkinsonism may be in response to ubiquitous occult infection. Since peptic ulceration is prodromal, Helicobacter is a prime candidate. AIM: To consider the candidature of Helicobacter in parkinsonism with cachexia. METHODS: We explore the relationship between being underweight and inflammatory products in 124 subjects with idiopathic parkinsonism and 195 controls, and present the first case-series evidence of efficacy of Helicobacter eradication, in parkinsonism advanced to the stage of cachexia. RESULTS: Association of a low body mass index with circulating interleukin-6 was specific to parkinsonism (p = .002), unlike that with antibodies against Helicobacter vacuolating-toxin and cytotoxicity-associated gene product (p < .04). Marked reversibility in both cachexia and disability of idiopathic parkinsonism followed Helicobacter heilmannii eradication in one case, Helicobacter pylori eradication in another, follow-up being > or = 3.5 years. The latter presented with postprandial bloating, and persistent nausea: following eradication, radioisotope gastric-emptying returned towards normal, and upper abdominal symptoms regressed. Reversibility of their cachexia/disability contrasts with the outcome of anti-Helicobacter therapy where eradication repeatedly failed (one case), and in non-Helicobacter gastritis (three cases). Anti-parkinsonian medication remained constant. Intestinal absorption and barrier function were normal in all. CONCLUSION: Categorization, according to presence or absence of Helicobacter infection, was a useful therapeutic tool in late idiopathic parkinsonism.     

Physiological stress responses of two species of coral trout (Plectropomus leopardus and Plectropomus maculatus)

The physiological responses of two species of coral trout (Plectropomus maculatus and Plectropomus leopardus) to capture, shallow water and low salinity stressors were investigated. The responses of P. maculatus and P. leopardus to capture stress were characterised by rapid and transient increases in glucose, haemoglobin, haematocrit and lactate, as well as an equally dramatic but delayed increase in cortisol levels that persisted for at least 72 h. The magnitude and duration of the response to capture stress was very similar in both species. In contrast, the levels of cortisol, glucose, lactate, haemoglobin and haematocrit were generally elevated sooner and to higher levels in P. maculatus than in P. leopardus after exposure to shallow water stress. Coral trout exposed to reduced salinity showed minimal changes in cortisol, glucose, lactate, haemoglobin and haematocrit, but such changes were not characteristic of a non-specific response to stress. Thus, the physiological stress responses of coral trouts are species-specific and dependent on the nature of the stressor. This observation probably reflects different cortical processes in the brains of P. maculatus and P. leopardus-a result that may be related to the differential variability of the respective environments in which the two species habit.     

Ubiquitylation of RAG-2 by Skp2-SCF links destruction of the V(D)J recombinase to the cell cycle

The periodic destruction of RAG-2 at the G1-to-S transition couples V(D)J recombination to the G0 and G1 cell cycle phases and coordinates RAG-mediated DNA cleavage with DNA repair by nonhomologous end joining. To define the mechanism by which this occurs, we reproduced cell cycle-dependent regulation of the V(D)J recombinase in a cell-free system. The ubiquitin-proteasomal pathway carries out destruction of RAG-2 in lysates of S phase cells and during S phase in vivo. Remarkably, the Skp2-SCF ubiquitin ligase, which plays a central role in cell cycle regulation through the destruction of p27, mediates ubiquitylation of RAG-2 in vitro and degradation of RAG-2 in vivo. The regulation of antigen receptor gene assembly by Skp2-SCF provides an unexpected and direct mechanistic link between DNA recombination and the cell cycle.     

High infection rates of Triatoma dimidiata are associated with low levels of Trypanosoma cruzi seroprevalence in Pedro Carbo, Ecuador. Use of a tc24 gene-based PCR approach

In control programs for vectorial transmission of Chagas' disease, conventional microscopic procedures are generally performed to determine baseline levels of infectivity of vectors. Reported here are data using Polymerase Chain Reaction in the detection of Trypanosoma cruzi in Triatoma dimidiata, one of the principal vectors of Chagas' disease in Ecuador. The microscopy and PCR techniques showed a high percentage of vector infection in Pedro Carbo, province of Guayas (Ecuador), with 44.16% and 46.13% positive insects, respectively. This contrasted with the very low Chagas seropositivity recorded (0.5%). Since T. dimidiata was the only vector of the Chagas' disease found in Pedro Carbo and looking at the vector behavior, our data suggest that despite the high T. dimidiata infection, the low Chagas seropositivity detected is closely associated with the epidemiological and ecological context of T. dimidiata in Pedro Carbo.     

Renal tubular acidosis: developments in our understanding of the molecular basis

Renal tubular acidosis is a metabolic acidosis due to impaired acid excretion by the kidney. Hyperchloraemic acidosis with a normal anion gap and normal (or near normal) glomerular filtration rate, and in the absence of diarrhoea, defines this disorder. However, systemic acidosis is not always evident and renal tubular acidosis can present with hypokalaemia, medullary nephrocalcinosis and recurrent calcium phosphate stone disease, as well as growth retardation and rickets in children, or short stature and osteomalacia in adults. Renal dysfunction in renal tubular acidosis is not always confined to acid excretion and can be part of a more generalised renal tubule defect, as in the renal Fanconi syndrome. Isolated renal tubular acidosis is more usually acquired, due to drugs, autoimmune disease, post-obstructive uropathy or any cause of medullary nephrocalcinosis. Less commonly, it is inherited and may be associated with deafness, osteopetrosis or ocular abnormalities. The clinical classification of renal tubular acidosis has been correlated with our current physiological model of how the nephron excretes acid, and this has facilitated genetic studies that have identified mutations in several genes encoding acid and base ion transporters. In vitro functional studies of these mutant proteins in cell expression systems have helped to elucidate the molecular mechanisms underlying renal tubular acidosis, which ultimately may lead to new therapeutic options in what is still treatment only by giving an oral alkali.     

Consequences of the Elimination of Old Leaves upon Spring Phenological Events and the New Leaves Nutrient Concentration in a Wintergreen Woody Species in the Southern Hemisphere

Previous studies analyzed the importance of old leaves conservancy for wintergreen species plant growth only after early spring old leaves elimination. However, carbon and nutrient resources for growth could have already been translocated from old leaves to shoots during autumn. In this work, the effect of old leaves absence on the leaf mass per area (LMA, g m⁻²) and nutrient concentration of new spring leaves, shoot growth, and flowering was studied in Aristotelia chilensis, an Andean Patagonic woody wintergreen species of Argentina. Plants were studied after autumn defoliation (AD) or late winter defoliation (WD) and results were compared to those of undamaged control plants (CO). The new leaves LMA and mineral nutrient (N, P, K, and Mg) concentration values did not decrease in AD or WD compared to CO plants. Conversely, CO plants showed higher flowering intensity and shoot lengthening compared to AD or WD plants. There were not remarkable differences regarding the defoliation time, though non-flowering shoots grew in a lesser degree than the flowering shoots in WD plants. It was concluded that A. chilensis old leaves cohort is an important source to shoot growth and flowering but their absence does not affect the new leaves structure or nutritional status from early spring in either AD or in WD plants. New leaves formation probably is guaranteed by resources (carbon and nutrients) previously stored in stems or even in the buds containing the preformed leaves since March, by the end of summer. Provided the availability of complete resources for the new leaf flush independently of the old leaves A. chilensis would restore the carbon balance as soon as possible to resume the growth of heterotrophic tissues at normal rates. Endogenous response to counterbalance the old leaves absence on non-flowering shoots was more effective when there was greater lag time between defoliation and shoot growth resume. Flowering and non-flowering shoots compete for the available resources when A. chilensis have not yet expanded leaves and shoots supporting reproductive structures were stronger sinks compared to non-flowering shoots in WD plants.