Aging and urinary control: Alterations in the brain–bladder axis

Age-associated alterations in bladder control affect millions of older adults, with a heavy burden added to families both economically and in quality of life. Therapeutic options are limited with poor efficacy in older adults, lending to a growing need to address the gaps in our current understanding of urinary tract aging. This review summarizes the current knowledge of age-associated alterations in the structure and function of the brain–bladder axis and identifies important gaps in the field that have yet to be addressed. Urinary aging is associated with decreased tissue responsiveness, decreased control over the voiding reflex, signaling dysfunction along the brain–bladder axis, and structural changes within the bladder wall. Studies are needed to improve our understanding of how age affects the brain–bladder axis and identify genetic targets that correlate with functional outcomes.     

Serotonin depletion produces long lasting increase in striatal glutamatergic transmission

The ability of serotonin (5-HT) to influence striatal glutamatergic transmission was examined by determining changes over time in glutamate extracellular levels, transporter expression and synaptosomal uptake in rats with lesion of serotonergic neurones. By 8 days after intraraphe injections of 5,7-dihydroxytryptamine, producing 80% decreases in striatal tissue 5-HT levels, no changes were observed in the glutamatergic transmission. When 5-HT depletion was almost complete (21 days post-lesion), high affinity glutamate uptake in striatal synaptosomal preparations was significantly increased (156% of control), although no changes in striatal GLT1, GLAST and EAAC1 mRNAs, and GLT1 protein were detected by in situ hybridization and immunohistochemistry. Meanwhile, the serotonin lesion produced large increases in basal extracellular levels of glutamate and glutamine (364% and 259%, respectively) determined in awake rats by in vivo microdialysis, whereas no change was observed in dopamine levels as compared with control rats. High potassium depolarization as well as L-trans-pyrrolidine-2,4-dicarboxylate, also induced larger increases in extracellular levels of glutamate in lesioned rats than in controls. Finally, similar changes in glutamate transmission were observed by 3 months post-lesion. These results suggest that 5-HT has a long lasting and tonic inhibitory influence on the striatal glutamatergic input, without affecting the basal dopaminergic transmission.     

Arbovirus surveillance using FTATM cards in modified CO2‐baited encephalitis virus surveillance traps in the Northern Territory,Australia

In 2016, modified CO₂‐baited encephalitis virus surveillance (EVS) traps were evaluated for flavivirus surveillance in the Northern Territory, Australia. The traps were fitted with honey‐soaked nucleic acid preservation cards (FTA^TM) for mosquitoes to expectorate virus while feeding on the cards. Cards were tested for the presence of selected arboviruses, with two cards testing positive for Kunjin virus and Alfuy, while sentinel chickens tested in parallel also showed Kunjin virus activity at the same time. The results from the cards and vector mosquito feeding rates indicate that CO₂‐baited EVS traps coupled with honey‐baited FTA^TM cards are an effective tool for broad‐scale arbovirus surveillance.     

Malaria control and elimination in sri lanka: documenting progress and success factors in a conflict setting

Background

Sri Lanka has a long history of malaria control, and over the past decade has had dramatic declines in cases amid a national conflict. A case study of Sri Lanka''s malaria programme was conducted to characterize the programme and explain recent progress.

Methods

The case study employed qualitative and quantitative methods. Data were collected from published and grey literature, district-level and national records, and thirty-three key informant interviews. Expenditures in two districts for two years – 2004 and 2009 – were compiled.

Findings

Malaria incidence in Sri Lanka has declined by 99.9% since 1999. During this time, there were increases in the proportion of malaria infections due to Plasmodium vivax, and the proportion of infections occurring in adult males. Indoor residual spraying and distribution of long-lasting insecticide-treated nets have likely contributed to the low transmission. Entomological surveillance was maintained. A strong passive case detection system captures infections and active case detection was introduced. When comparing conflict and non-conflict districts, vector control and surveillance measures were maintained in conflict areas, often with higher coverage reported in conflict districts. One of two districts in the study reported a 48% decline in malaria programme expenditure per person at risk from 2004 to 2009. The other district had stable malaria spending.

Conclusions/Significance

Malaria is now at low levels in Sri Lanka – 124 indigenous cases were found in 2011. The majority of infections occur in adult males and are due to P. vivax. Evidence-driven policy and an ability to adapt to new circumstances contributed to this decline. Malaria interventions were maintained in the conflict districts despite an ongoing war. Sri Lanka has set a goal of eliminating malaria by the end of 2014. Early identification and treatment of infections, especially imported ones, together with effective surveillance and response, will be critical to achieving this goal.     

Defects in Mitochondrial ATP Synthesis in Dystrophin-Deficient Mdx Skeletal Muscles May Be Caused by Complex I Insufficiency

Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca²⁺ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca²⁺ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca²⁺ environment. Using isolated mitochondria from the diaphragm and tibialis anterior of 12 week-old dystrophin-deficient mdx and healthy control mice (C57BL10/ScSn) we have demonstrated severely depressed Complex I-mediated mitochondrial ATP production rate in mdx mitochondria that occurs irrespective of the macronutrient-derivative substrate combination fed into the Kreb’s cycle, and, which is partially, but significantly, ameliorated by inhibition of Complex I with rotenone and stimulation of Complex II-mediated ATP-production with succinate. There was no difference in the MAPR response of mdx mitochondria to increasing extramitochondrial Ca²⁺ load in comparison to controls, and 400 nM extramitochondrial Ca²⁺ was generally shown to be inhibitory to MAPR in both groups. Our data suggests that DMD pathology is exacerbated by a Complex I deficiency, which may contribute in part to the severe reductions in ATP production previously observed in dystrophic skeletal muscle.     

Thermal sensitivity of heart rate and insensitivity of blood pressure in the Antarctic nototheniid fish <Emphasis Type="Italic">Pagothenia borchgrevinki</Emphasis>

The Antarctic notothenioids are among the most stenothermal of fishes, well adapted to their stable, cold and icy environment. The current study set out to investigate the thermal sensitivity/insensitivity of heart rate and ventral aortic blood pressure of the Antarctic nototheniid fish Pagothenia borchgrevinki over a range of temperatures. The heart rate increased rapidly from –1 to 6°C (Q₁₀=2.0–3.3), but was relatively insensitive to temperature above the ~6°C lethal limit of the species (Q₁₀=1.2). The increase in heart rate from –1 to 6°C was the result of a 45% increase in excitatory adrenergic tone, masking a 37% increase in inhibitory cholinergic tone. Ventral aortic pressure was regulated well above the lethal limit, up to at least 10°C. With the return of the fish to environmental temperatures, the heart rate rapidly decreased back to control levels, while ventral aortic pressure increased and remained elevated for over an hour following a 6°C exposure.     

Phospholipids trigger Cryptococcus neoformans capsular enlargement during interactions with amoebae and macrophages

A remarkable aspect of the interaction of Cryptococcus neoformans with mammalian hosts is a consistent increase in capsule volume. Given that many aspects of the interaction of C. neoformans with macrophages are also observed with amoebae, we hypothesized that the capsule enlargement phenomenon also had a protozoan parallel. Incubation of C. neoformans with Acanthamoeba castellanii resulted in C. neoformans capsular enlargement. The phenomenon required contact between fungal and protozoan cells but did not require amoeba viability. Analysis of amoebae extracts showed that the likely stimuli for capsule enlargement were protozoan polar lipids. Extracts from macrophages and mammalian serum also triggered cryptococcal capsular enlargement. C. neoformans capsule enlargement required expression of fungal phospholipase B, but not phospholipase C. Purified phospholipids, in particular, phosphatidylcholine, and derived molecules triggered capsular enlargement with the subsequent formation of giant cells. These results implicate phospholipids as a trigger for both C. neoformans capsule enlargement in vivo and exopolysaccharide production. The observation that the incubation of C. neoformans with phospholipids led to the formation of giant cells provides the means to generate these enigmatic cells in vitro. Protozoan- or mammalian-derived polar lipids could represent a danger signal for C. neoformans that triggers capsular enlargement as a non-specific defense mechanism against potential predatory cells. Hence, phospholipids are the first host-derived molecules identified to trigger capsular enlargement. The parallels apparent in the capsular response of C. neoformans to both amoebae and macrophages provide additional support for the notion that certain aspects of cryptococcal virulence emerged as a consequence of environmental interactions with other microorganisms such as protists.     

Interspecies chimeric conditions affect the developmental rate of human pluripotent stem cells

Human pluripotent stem cells hold significant promise for regenerative medicine. However, long differentiation protocols and immature characteristics of stem cell-derived cell types remain challenges to the development of many therapeutic applications. In contrast to the slow differentiation of human stem cells in vitro that mirrors a nine-month gestation period, mouse stem cells develop according to a much faster three-week gestation timeline. Here, we tested if co-differentiation with mouse pluripotent stem cells could accelerate the differentiation speed of human embryonic stem cells. Following a six-week RNA-sequencing time course of neural differentiation, we identified 929 human genes that were upregulated earlier and 535 genes that exhibited earlier peaked expression profiles in chimeric cell cultures than in human cell cultures alone. Genes with accelerated upregulation were significantly enriched in Gene Ontology terms associated with neurogenesis, neuron differentiation and maturation, and synapse signaling. Moreover, chimeric mixed samples correlated with in utero human embryonic samples earlier than human cells alone, and acceleration was dose-dependent on human-mouse co-culture ratios. The altered gene expression patterns and developmental rates described in this report have implications for accelerating human stem cell differentiation and the use of interspecies chimeric embryos in developing human organs for transplantation.     

Lack of Viral Escape and Defective In Vivo Activation of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes in Rapidly Progressive Infection

Human immunodeficiency virus type 1 (HIV-1)-specific immune responses over the course of rapidly progressive infection are not well defined. Detailed longitudinal analyses of neutralizing antibodies, lymphocyte proliferation, in vivo-activated and memory cytotoxic T-lymphocyte (CTL) responses, and viral sequence variation were performed on a patient who presented with acute HIV-1 infection, developed an AIDS-defining illness 13 months later, and died 45 months after presentation. Neutralizing-antibody responses remained weak throughout, and no HIV-1-specific lymphocyte proliferative responses were seen even early in the disease course. Strong in vivo-activated CTL directed against Env and Pol epitopes were present at the time of the initial drop in viremia but were quickly lost. Memory CTL against Env and Pol epitopes were detected throughout the course of infection; however, these CTL were not activated in vivo. Despite an initially narrow CTL response, new epitopes were not targeted as the disease progressed. Viral sequencing showed the emergence of variants within the two targeted CTL epitopes; however, viral variants within the immunodominant Env epitope were well recognized by CTL, and there was no evidence of viral escape from immune system detection within this epitope. These data demonstrate a narrowly directed, static CTL response in a patient with rapidly progressive disease. We also show that disease progression can occur in the presence of persistent memory CTL recognition of autologous epitopes and in the absence of detectable escape from CTL responses, consistent with an in vivo defect in activation of CTL.