30-Year Trends in Stroke Rates and Outcome in Auckland,New Zealand (1981-2012): A Multi-Ethnic Population-Based Series of Studies

Background

Insufficient data exist on population-based trends in morbidity and mortality to determine the success of prevention strategies and improvements in health care delivery in stroke. The aim of this study was to determine trends in incidence and outcome (1-year mortality, 28-day case-fatality) in relation to management and risk factors for stroke in the multi-ethnic population of Auckland, New Zealand (NZ) over 30-years.

Methods

Four stroke incidence population-based register studies were undertaken in adult residents (aged ≥15 years) of Auckland NZ in 1981–1982, 1991–1992, 2002–2003 and 2011–2012. All used standard World Health Organization (WHO) diagnostic criteria and multiple overlapping sources of case-ascertainment for hospitalised and non-hospitalised, fatal and non-fatal, new stroke events. Ethnicity was consistently self-identified into four major groups. Crude and age-adjusted (WHO world population standard) annual incidence and mortality with corresponding 95% confidence intervals (CI) were calculated per 100,000 people, assuming a Poisson distribution.

Results

5400 new stroke patients were registered in four 12 month recruitment phases over the 30-year study period; 79% were NZ/European, 6% Māori, 8% Pacific people, and 7% were of Asian or other origin. Overall stroke incidence and 1-year mortality decreased by 23% (95% CI 5%-31%) and 62% (95% CI 36%-86%), respectively, from 1981 to 2012. Whilst stroke incidence and mortality declined across all groups in NZ from 1991, Māori and Pacific groups had the slowest rate of decline and continue to experience stroke at a significantly younger age (mean ages 60 and 62 years, respectively) compared with NZ/Europeans (mean age 75 years). There was also a decline in 28-day stroke case fatality (overall by 14%, 95% CI 11%-17%) across all ethnic groups from 1981 to 2012. However, there were significant increases in the frequencies of pre-morbid hypertension, myocardial infarction, and diabetes mellitus, but a reduction in frequency of current smoking among stroke patients.

Conclusions

In this unique temporal series of studies spanning 30 years, stroke incidence, early case-fatality and 1-year mortality have declined, but ethnic disparities in risk and outcome for stroke persisted suggesting that primary stroke prevention remains crucial to reducing the burden of this disease.     

Testosterone and sexual experience alter levels of plasma membrane binding sites for progesterone in the male rat brain.

Physiological levels of progesterone act in conjunction with androgens to facilitate copulatory behavior in male rats, mice, and lizards. Radiolabeled progesterone conjugated to bovine serum albumin measured specific binding sites in membrane fractions from male rats that were gonadectomized and testosterone treated, or remained gonadally intact, to determine the role of gonadal steroids on mPR binding. To determine whether behavioral experience could alter binding levels, males either remained sexually na?ve or became sexually experienced. In sexually na?ve males, the highest levels of specific binding occurred in the dorsal portions of the medial preoptic area, with only moderate levels of binding in ventral portions of the medial preoptic area and the dorsal and ventral medial hypothalamus. However, conjugated progesterone binding in these brain regions did not change as a function of testosterone or behavioral manipulations. In contrast, the amygdala responded to behavioral experience with significantly (4-fold) increased binding in gonadectomized, T-treated males with sexual experience. These data indicate that the neuronal plasticity for membrane-associated progesterone binding is regionally specific, being regulated by sexual experience following the reinstatement of testosterone levels, thus suggesting a functional role for plasma membrane activity of progesterone in male rat reproduction.     

Abnormal Glycosphingolipid Mannosylation Triggers Salicylic Acid–Mediated Responses in Arabidopsis

The Arabidopsis thaliana protein GOLGI-LOCALIZED NUCLEOTIDE SUGAR TRANSPORTER (GONST1) has been previously identified as a GDP-d-mannose transporter. It has been hypothesized that GONST1 provides precursors for the synthesis of cell wall polysaccharides, such as glucomannan. Here, we show that in vitro GONST1 can transport all four plant GDP-sugars. However, gonst1 mutants have no reduction in glucomannan quantity and show no detectable alterations in other cell wall polysaccharides. By contrast, we show that a class of glycosylated sphingolipids (glycosylinositol phosphoceramides [GIPCs]) contains Man and that this mannosylation is affected in gonst1. GONST1 therefore is a Golgi GDP-sugar transporter that specifically supplies GDP-Man to the Golgi lumen for GIPC synthesis. gonst1 plants have a dwarfed phenotype and a constitutive hypersensitive response with elevated salicylic acid levels. This suggests an unexpected role for GIPC sugar decorations in sphingolipid function and plant defense signaling. Additionally, we discuss these data in the context of substrate channeling within the Golgi.     

Global Population Genomics of Two Subspecies of Cryptosporidium hominis during 500 Years of Evolution

Cryptosporidiosis is a major global health problem and a primary cause of diarrhea, particularly in young children in low- and middle-income countries (LMICs). The zoonotic Cryptosporidium parvum and anthroponotic Cryptosporidium hominis cause most human infections. Here, we present a comprehensive whole-genome study of C. hominis, comprising 114 isolates from 16 countries within five continents. We detect two lineages with distinct biology and demography, which diverged circa 500 years ago. We consider these lineages two subspecies and propose the names C. hominis hominis and C. hominis aquapotentis (gp60 subtype IbA10G2). In our study, C. h. hominis is almost exclusively represented by isolates from LMICs in Africa and Asia and appears to have undergone recent population contraction. In contrast, C. h. aquapotentis was found in high-income countries, mainly in Europe, North America, and Oceania, and appears to be expanding. Notably, C. h. aquapotentis is associated with high rates of direct human-to-human transmission, which may explain its success in countries with well-developed environmental sanitation infrastructure. Intriguingly, we detected genomic regions of introgression following secondary contact between the subspecies. This resulted in high diversity and divergence in genomic islands of putative virulence genes, including muc5 (CHUDEA2_430) and a hypothetical protein (CHUDEA6_5270). This diversity is maintained by balancing selection, suggesting a co-evolutionary arms race with the host. Finally, we find that recent gene flow from C. h. aquapotentis to C. h. hominis, likely associated with increased human migration, maybe driving the evolution of more virulent C. hominis variants.     

The bacterial virulence factor NleA undergoes host-mediated O-linked glycosylation

Enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) are gastrointestinal pathogens responsible for severe diarrheal illness. EHEC and EPEC form “attaching and effacing” lesions during colonization and, upon adherence, inject proteins directly into host intestinal cells via the type III secretion system (T3SS). Injected bacterial proteins have a variety of functions but generally alter host cell biology to favor survival and/or replication of the pathogen. Non-LEE-encoded effector A (NleA) is a T3SS-injected effector of EHEC, EPEC, and the related mouse pathogen Citrobacter rodentium. Studies in mouse models indicate that NleA has an important role in bacterial virulence. However, the mechanism by which NleA contributes to disease remains unknown. We have determined that the following translocation into host cells, a serine and threonine-rich region of NleA is modified by host-mediated mucin-type O-linked glycosylation. Surprisingly, this region was not present in several clinical EHEC isolates. When expressed in C. rodentium, a non-modifiable variant of NleA was indistinguishable from wildtype NleA in an acute mortality model but conferred a modest increase in persistence over the course of infection in mixed infections in C57BL/6J mice. This is the first known example of a bacterial effector being modified by host-mediated O-linked glycosylation. Our data also suggests that this modification may confer a selective disadvantage to the bacteria during in vivo infection.     

Environmental effects on the covariation among pace‐of‐life traits

Pace‐of‐life syndromes (POLSs) are suites of life‐history, physiological and behavioural traits that arise due to trade‐offs between allocation to current and future reproduction. Traits generally show covariation that can arise from genetic and environmental influences on phenotypes and constrain the independent evolution of traits, resulting in fitness consequences and impacts on population dynamics. The notion that correlations among traits may vary among populations along environmental gradients suggests an important role for the environment in shaping and maintaining POLSs. However, no synthesis has been attempted of the myriad ways in which environmental factors should influence POLSs. Here, we formulate a series of hypotheses targeting the critical interfaces of the environment and life‐history ‐ behaviour associations across different organisms. We discuss the hypotheses in light of findings from a systematic review of studies that measured changes in the association between behaviour and life‐history traits as a function of environmental conditions. The review revealed that POLSs are often shaped by environmental variation, where harshness of the environment in early life has the most consistent effects on POLS. However, only partial or no effects of environmental variation were found in a number of studies, which may result from the highly variable study systems, traits and environments studied. We highlight promising directions arising from the available studies and identify knowledge gaps that, if unaddressed, will impede progress in the field.     

Castration and antisteroid treatment impari vocal learning in male zebra finches

Both song behavior and its neural substrate are hormone sensitive: Castrated adult male zebra finches need replacement of gonadal steroids in order to restore normal levels of song production, and sexsteroids are necessary to establish male-typical neural song-controlcircuits during early development. This pattern of results suggests that hormones may be required for normal development of learned songbehavior, but evidence that steroids are necessary for normal neuraland behavioral development during song learning has been lacking. Weaddressed this question by attempting to eliminate the effects of gonadal steroids in juvenile male zebra finches between the time of initial song production and adulthood. Males were castrated at 20 daysof age and received systemic implants of either an antiandrogen (flutamide). an antiestrogen (tamoxifen), or both drugs. The songs of both flutamide-and tamoxifen-treated birds were extremely disrupted relative to normal controls in terms of the stereotypy and acoustic quality of individual note production, as well as stereotypy of the temporal structure of the song phrase. We did not discern any differences in the pattern of behavioral disruption between birds that were treated with either flutamide, tamoxifen, or a combination of both drugs. Flutamide treatment resulted in a reduced size of two forebrain nuclei that are known to play some role unique to early phases of song learning [lateral magnocellular nucleus of the anterior neostriatum (IMAN) and area X (X)], but did not affect the size of two song-control nuclei that are necessary for normal song productionin adult birds [caudal nucleus of the ventral hyperstriatum (HVc) and robust nucleus of the archistriatum (RA)]. In contrast, treatment with tamoxifen did not result in any changes in the size of song-control nuclei relative to normal controls, and it blocked the effects of flutamide on the neural song-control system in birds that were treated with both drugs. Castration and antisteroid treatment exerted no deleterious effects on the quality of song behavior in adult birds, indicating that gonadal hormones are necessary for the development of normal song behavior during a sensitive period. © 1992 John Wiley & Sons, Inc.     

Changes in soil phosphorus fractions in a calcareous paddy soil under intensive rice cropping

We conducted a 4-year field experiment on a calcareous paddy soil in Zhejiang province of China to measure the changes in chemically extracted soil P fractions in an irrigated double-cropping rice system. Treatments included four fertilizer combinations (unfertilized control, NK, NP, and NPK) as main-plots and two rice cultivar types (inbred vs. hybrid rice) as sub-plots. Total plant P uptake and grain yield of rice declined in all treatments over time. Severe P-deficiency and significant rice yield losses began in treatments without P application after the second rice crop. Compared to inbred rice, hybrid rice increased grain yield (+18%), N uptake (+11%) and K uptake (+27%) but there was no significant difference in total plant P uptake. Recovery efficiencies of fertilizer-P averaged 31–32% in both cultivars. In treatments without P application, the P mass balance was negative (−6 to −8 kg P ha⁻¹ crop⁻¹) and phosphorus was drawn down in all inorganic P fractions, including resin, alkali- (NaHCO₃-Pi and NaOH-Pi) and acid-soluble P fractions (dilute HCl-P, concentrated HCl-P, residual-P). Only small amounts were removed from organic P fractions, 1–3 mg P kg⁻¹ year⁻¹ from NaHCO₃-Po and none from NaOH-Po. In treatments with fertilizer-P addition, the P mass balance was positive (+8 to 10 kg P ha⁻¹ crop⁻¹), soil P declined at a slower rate in inorganic P fractions and it increased (+51%) in the residual-P fraction. Hybrid rice generally caused greater depletion of inorganic soil P fractions than inbred rice, but there was no difference among cultivars in their effect on NaHCO₃-Po and NaOH-Po. Positive correlations (r = 0.63–0.81, P < 0.001) were observed between all inorganic P fractions (except residual-P) and total P uptake by rice. Our results suggest that rice plants draw P from a continuum of chemically extracted fractions that are assumed to have widely differing plant P availability. Regular P additions are required to maintain the effective soil P supply and differences between inbred and hybrid rice should be taken into account in P management strategies.     

Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction

Suppression of inflammation is critical for effective therapy of many infectious diseases. However, the high rates of mortality caused by sepsis attest to the need to better understand the basis of the inflammatory sequelae of sepsis and to develop new options for its treatment. In mice, inflammatory responses to host danger-associated molecular patterns (DAMPs), but not to microbial pathogen-associated molecular patterns (PAMPs), are repressed by the interaction [corrected] of CD24 and SiglecG (SIGLEC10 in human). Here we use an intestinal perforation model of sepsis to show that microbial sialidases target the sialic acid-based recognition of CD24 by SiglecG/10 to exacerbate inflammation. Sialidase inhibitors protect mice against sepsis by a mechanism involving both CD24 and Siglecg, whereas mutation of either gene exacerbates sepsis. Analysis of sialidase-deficient bacterial mutants confirms the key contribution of disrupting sialic acid-based pattern recognition to microbial virulence and supports the clinical potential of sialidase inhibition for dampening inflammation caused by infection.     

The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9-39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7-36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.