Review: Astrocytes in Alzheimer's disease and other age-associated dementias: a supporting player with a central role.

Astrocytes have essential roles in the central nervous system and are also implicated in the pathogenesis of neurodegenerative disease. Forming non-overlapping domains, astrocytes are highly complex cells. Immunohistochemistry to a variety of proteins can be used to study astrocytes in tissue, labelling different cellular components and sub-populations, including glial fibrillary acidic protein, ALDH1L1, CD44, NDRG2 and amino acid transporters, but none of these labels the entire astrocyte population. Increasing heterogeneity is recognized in the astrocyte population, a complexity that is relevant both to their normal function and pathogenic roles. They are involved in neuronal support, as active components of the tripartite synapse and in cell interactions within the neurovascular unit (NVU), where they are essential for blood-brain barrier maintenance and neurovascular coupling. Astrocytes change with age, and their responses may modulate the cellular effects of neurodegenerative pathologies, which alone do not explain all of the variance in statistical models of neurodegenerative dementias. Astrocytes respond to both the neurofibrillary tangles and plaques of Alzheimer's disease, to hyperphosphorylated tau and Aß, eliciting an effect which may be neuroprotective or deleterious. Not only astrocyte hypertrophy, in the form of gliosis, occurs, but also astrocyte injury and atrophy. Loss of normal astrocyte functions may contribute to reduced support for neurones and dysfunction of the NVU. Understanding how astrocytes contribute to dementia requires an understanding of the underlying heterogeneity of astrocyte populations, and the complexity of their responses to pathology. Enhancing the supportive and neuroprotective components of the astrocyte response has potential translational applications in therapeutic approaches to dementia.

Electrocardiographic detection of hypertensive left atrial enlargement in the presence of obesity: re-calibration against cardiac magnetic resonance.

Left atrial enlargement (LAE) has adverse prognostic implications in hypertension. We sought to determine the accuracy of five electrocardiogram (ECG) criteria for LAE in hypertension relative to cardiac magnetic resonance (CMR) gold standard and investigate the effect of concomitant obesity. One hundred and thirty consecutive patients (age: 51.4±15.1 years, 47% male, 51% obese, systolic blood pressure (BP): 171±29 mm Hg, diastolic BP: 97±15 mm Hg) referred for CMR (1.5 T) from a tertiary hypertension clinic were included. Patients with concomitant cardiac pathology were excluded. ECGs were assessed blindly for the following: (1) P-wave >110 ms, (2) P-mitrale, (3) P-wave axis <30°, (4) area of negative P-terminal force in V1 >40 ms.mm and (5) positive P-terminal force in augmented vector left (aVL) >0.5 mm. Left atrial volume ≥55 ml m-2, measured blindly by CMR, was defined as LAE. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy and area under the receiver operator curve were calculated. The prevalence of LAE by CMR was 26%. All the individual ECG LAE criteria were more specific than sensitive, with specificities ranging from 70% (P-axis <30o) to 99% (P-mitrale). Obesity attenuated the specificity of most of the individual ECG LAE criteria. Obesity correlated with significant lower specificity (48% vs 65%, P<0.05) and a trend towards lower sensitivity (59 vs 43%, P=0.119) when ≥1 ECG LAE criteria were present. Individual ECG criteria of LAE in hypertension are specific, but not sensitive, at identifying LAE. The ECG should not be used to excluded LAE in hypertension, particularly in obese subjects.

Cationic disulfide-functionalized worm gels.

The recent development of polymerization-induced self-assembly (PISA) has facilitated the rational synthesis of a range of diblock copolymer worms, which hitherto could only be prepared via traditional post-polymerization processing in dilute solution. Herein we explore a new synthetic route to aqueous dispersions of cationic disulfide-functionalized worm gels. This is achieved via the PISA synthesis of poly[(glycerol monomethacrylate-stat-glycidyl methacrylate)]-block-poly(2-hydroxypropyl methacrylate) (P(GMA-stat-GlyMA)-PHPMA) block copolymer worms via reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of HPMA. A water-soluble reagent, cystamine, is then reacted with the pendent epoxy groups located within the P(GMA-stat-GlyMA) stabilizer chains to introduce disulfide functionality, while simultaneously conferring cationic character via formation of secondary amine groups. Moreover, systematic variation of the cystamine/epoxy molar ratio enables either chemically cross-linked worm gels or physical (linear) primary amine-functionalized disulfide-based worm gels to be obtained. These new worm gels were characterized using gel permeation chromatography, 1H NMR spectroscopy, transmission electron microscopy, dynamic light scattering, aqueous electrophoresis and rheology. In principle, such hydrogels may offer enhanced mucoadhesive properties.

A Robust Cross-Linking Strategy for Block Copolymer Worms Prepared via Polymerization-Induced Self-Assembly.

A poly(glycerol monomethacrylate) (PGMA) chain transfer agent is chain-extended by reversible addition-fragmentation chain transfer (RAFT) statistical copolymerization of 2-hydroxypropyl methacrylate (HPMA) with glycidyl methacrylate (GlyMA) in concentrated aqueous solution via polymerization-induced self-assembly (PISA). A series of five free-standing worm gels is prepared by fixing the overall degree of polymerization of the core-forming block at 144 while varying its GlyMA content from 0 to 20 mol %. 1H NMR kinetics indicated that GlyMA is consumed much faster than HPMA, producing a GlyMA-rich sequence close to the PGMA stabilizer block. Temperature-dependent oscillatory rheological studies indicate that increasing the GlyMA content leads to progressively less thermoresponsive worm gels, with no degelation on cooling being observed for worms containing 20 mol % GlyMA. The epoxy groups in the GlyMA residues can be ring-opened using 3-aminopropyltriethoxysilane (APTES) in order to prepare core cross-linked worms via hydrolysis-condensation with the siloxane groups and/or hydroxyl groups on the HPMA residues. Perhaps surprisingly, 1H NMR analysis indicates that the epoxy-amine reaction and the intermolecular cross-linking occur on similar time scales. Cross-linking leads to stiffer worm gels that do not undergo degelation upon cooling. Dynamic light scattering studies and TEM analyses conducted on linear worms exposed to either methanol (a good solvent for both blocks) or anionic surfactant result in immediate worm dissociation. In contrast, cross-linked worms remain intact under such conditions, provided that the worm cores comprise at least 10 mol % GlyMA.

Quantifying sympathetic neuro-haemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control.

KEY POINTS: We have developed a simple analytical method for quantifying the transduction of sympathetic activity into vascular tone. This method demonstrates that as women age, the transfer of sympathetic nerve activity into vascular tone is increased, so that for a given level of sympathetic activity there is more vasoconstriction. In men, this measure decreases with age. Test-re-test analysis demonstrated that the new method is a reliable estimate of sympathetic transduction. We conclude that increased sympathetic vascular coupling contributes to the age-related increase in blood pressure that occurs in women only. This measure is a reliable estimate of sympathetic transduction in populations with high sympathetic nerve activity. Thus, it will provide information regarding whether treatment targeting the sympathetic nervous system, which interrupts the transfer of sympathetic nerve activity into vascular tone, will be effective in reducing blood pressure in hypertensive patients. This may provide insight into which populations will respond to certain types of anti-hypertensive medication. ABSTRACT: Sex and age differences in the sympathetic control of resting blood pressure (BP) may be due to differences in the transduction of sympathetic nerve activity (SNA) into vascular tone. Current methods for dynamically quantifying transduction focus on the relationship between SNA and vasoconstriction during a pressor stimulus, which increases BP and may be contra-indicated in patients. We describe a simple analytical method for quantifying transduction under resting conditions. We performed linear regression analysis of binned muscle SNA burst areas against diastolic BP (DBP). We assessed whether the slope of this relationship reflects the transduction of SNA into DBP. To evaluate this, we investigated whether this measure captures differences in transduction in different populations. Specifically, we (1) quantified transduction in young men (YM), young women (YW), older men (OM) and postmenopausal women (PMW); and (2) measured changes in transduction during ß-blockade using propranolol in YW, YM and PMW. YM had a greater transduction vs. OM (0.10 ± 0.01 mmHg (% s)(-1) , n = 23 vs. 0.06 ± 0.01 mmHg (% s)(-1) , n = 18; P = 0.003). Transduction was lowest in YW (0.02 ± 0.01 mmHg (% s)(-1) , n = 23) and increased during ß-blockade (0.11 ± 0.01 mmHg (% s)(-1) ; P < 0.001). Transduction in PMW (0.07 ± 0.01 mmHg (% s)(-1) , n = 23) was greater compared to YW (P = 0.001), and was not altered during ß-blockade (0.06 ± 0.01 mmHg (% s)(-1) ; P = 0.98). Importantly, transduction increased in women with age, but decreased in men. Transduction in women intersected that in men at 55 ± 1.5 years. This measure of transduction captures age- and sex-differences in the sympathetic regulation of DBP and may be valuable in quantifying transduction in disease. In particular, this measure may help target treatment strategies in specific hypertensive subpopulations.

The effect of obesity on electrocardiographic detection of hypertensive left ventricular hypertrophy: recalibration against cardiac magnetic resonance.

Electrocardiograph (ECG) criteria for left ventricular hypertrophy (LVH) are a widely used clinical tool. We recalibrated six ECG criteria for LVH against gold-standard cardiac magnetic resonance (CMR) and assessed the impact of obesity. One hundred and fifty consecutive tertiary hypertension clinic referrals for CMR (1.5 T) were reviewed. Patients with cardiac pathology potentially confounding hypertensive LVH were excluded (n=22). The final sample size was 128 (age: 51.0±15.2 years, 48% male). LVH was defined by CMR. From a 12-lead ECG, Sokolow-Lyon voltage and product, Cornell voltage and product, Gubner-Ungerleidger voltage and Romhilt-Estes score were evaluated, blinded to the CMR. ECG diagnostic performance was calculated. LVH by CMR was present in 37% and obesity in 51%. Obesity significantly reduced ECG sensitivity, because of significant attenuation in mean ECG values for Cornell voltage (22.2±5.7 vs 26.4±9.4 mm, P<0.05), Cornell product (2540±942 vs 3023±1185 mm • ms, P<0.05) and for Gubner-Ungerleider voltage (18.2±7.1 vs 23.3±1.2 mm, P<0.05). Obesity also significantly reduced ECG specificity, because of significantly higher prevalence of LV remodeling (no LVH but increased mass-to-volume ratio) in obese subjects without LVH (36% vs 16%, P<0.05), which correlated with higher mean ECG LVH criteria values. Obesity-specific partition values were generated at fixed 95% specificity; Cornell voltage had highest sensitivity in non-obese (56%) and Sokolow-Lyon product in obese patients (24%). Obesity significantly lowers ECG sensitivity at detecting LVH, by attenuating ECG LVH values, and lowers ECG specificity through changes associated with LV remodeling. Our obesity-specific ECG partition values could improve the diagnostic performance in obese patients with hypertension.

Candida pelliculosa meningitis as an opportunistic infection in HIV: the first reported case.

We describe the first reported case of Candida pelliculosa meningitis in HIV infection. This case highlights the risk of uncommon opportunistic infections in association with the immunocompromised and the importance of autopsy as a diagnostic tool in HIV infection. We discuss the epidemiology, diagnosis and management of C. pelliculosa, a non-albicans species which is rarely associated with disease, and review current literature.

A venture capital view of challenges, opportunities, and innovation in biomedical research.

Small biotech companies have been an important source of innovation, pipelines, and new products for the pharmaceutical industry, and are primarily financed by venture capital (VC). The significant changes happening within the VC industry have broad implications for these small companies. This includes a shift to financing later-stage programs with increasing interest in orphan or specialty indications. Nontraditional sources of capital and innovative risk-sharing structures can enable early-stage companies.

Acute presentations of HIV are still missed in low prevalence areas.

OBJECTIVES: To evaluate missed opportunities and delays in the diagnosis of HIV in a low prevalence setting over a 24 year period. METHODS: Patients with acute presentations of HIV were included in a retrospective note based review. Data were compared from acute presentations in 1985-2001 (88/241 new patients) with 2005-2007 (99/136 new patients). The number of recorded clinical and laboratory clues to infection and subsequent time delays to diagnosis of HIV were evaluated. RESULTS: The findings reflect the shifting demographics of HIV in the UK over the past two decades, exemplified by an eightfold increase in tuberculosis at presentation. Despite recording clinical stigmata of HIV (clues) in the notes, the number of missed clues increased, and many clinicians failed to request HIV testing. The median delay between presentation and diagnosis reduced from 5 to 1 day (p<0.001), and mortality dropped from 14% to 4% among patients presenting with acute symptoms. However, there was still a delay of more than 30 days before diagnosis for almost one in five patients. CONCLUSIONS: Despite some improvement and better awareness, there are still significant delays before hospital doctors consider the diagnosis of HIV for patients in low prevalence areas, even among some patient groups with high risk. Hospitals should consider moving to opt-out routine HIV testing of all medical admissions.

Proteomic identification and profiling of canine lymphoma patients.

This study employed proteomic and bioinformatic approaches to identify serum biomarkers in canine lymphoma patients. Chilled serum samples derived from non-lymphoma (n = 92) and lymphoma (n = 87) patients were shipped from first opinion veterinary practices, subjected to ion exchange chromatography and analysed by surface-enhanced laser desorption ionization mass spectrometry. Nineteen serum protein peaks were identified between the two groups as being significantly different (P < 0.05) based upon their normalized ion intensities. Two biomarkers were identified that were capable of differentiating lymphoma and non-lymphoma patients. Analysis of the test data provided a positive predictive value (PPV) of 82%. A clinical follow-up study was carried out on 96 canine patients suspected of having lymphoma. Evaluation of this data gave a specificity value of 91%, sensitivity of 75%, PPV of 80% and negative predictive value of 88%. In conclusion, the expression pattern of two serum biomarkers has enabled serum samples to be classified into either lymphoma or non-lymphoma categories.

Autopsies in HIV: still identifying missed diagnoses.

This study reviews the deaths and autopsies carried out over 23 years, 1983-2005, in a British Infection Unit in HIV patients. Of 115 HIV patients known to have died, we obtained data on 93%. Of this 80% were male, median age 38 (25-68) years; 83% were Caucasian; 12% Black African. Major risk factors were men who have sex with men, 52%; heterosexual in Africa, 17%; and injecting drug use, 8%. The commonest diagnosis pre- and post-autopsy diagnosis was pneumonia. Changes in diagnoses in the 38% who underwent autopsy were high (we requested autopsy in 50%). Primary diagnosis changed in 70%, and 36% of all opportunistic infections were missed. This included six of nine cytomegalovirus, all tuberculosis and 75% of Kaposi's sarcoma. Lymphoma was overdiagnosed. Thus, despite excellent resources, the majority of primary diagnoses were wrong, suggesting inadequacy of current diagnostics. To improve these and improve both epidemiological data and future management autopsy should be considered for all deaths.

Long-term outcome of tenofovir disoproxil fumarate use against hepatitis B in an HIV-coinfected cohort.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is active against hepatitis B virus (HBV) and HIV. However, the long-term efficacy of tenofovir disoproxil fumarate (TDF) is not well known and the appearance of resistance is a major concern. We have studied the efficacy of TDF against HBV in patients treated at an Infectious Diseases Unit. METHODS: We carried out a retrospective observational study of the efficacy of TDF against HBV replication in a cohort of 52 HIV-coinfected patients who received TDF for at least 6 months. RESULTS: The median duration of follow-up of TDF treatment was 34 months. Forty-one patients (79%) were positive for HBV envelope antigen (HBeAg) and 35 had received previous lamivudine monotherapy for a median duration of 32 months. Virological breakthrough was observed in nine cases (17%). At the end of the follow-up period, HBV DNA levels were <1000 copies/mL in 42 patients (81%) and <200 copies/mL in 31 patients (60%). There were no significant differences between the lamivudine-naïve and lamivudine-experienced groups. In the lamivudine-experienced group, the duration of previous lamivudine monotherapy was associated with failure to achieve HBV DNA levels <200 copies/mL (P=0.036). Adding lamivudine or emtricitabine to TDF did not improve virological suppression. In 39 patients who achieved <200 HBV DNA copies/mL during TDF treatment, virological breakthrough was seen only in two patients (5%) after a median follow-up duration of 39.7 months. CONCLUSIONS: TDF was able to control HBV replication in most HIV-coinfected patients after a median follow-up duration of 34 months, regardless of previous lamivudine treatment. However, a sizeable proportion of patients developed virological breakthrough.

Failure to detect seasonal changes in the song system nuclei of the black-capped chickadee (Poecile atricapillus).

Most temperate songbird species sing seasonally, and the brain areas involved in producing song (the song system) vary in size alongside the changes in behavior. Black-capped chickadees (Poecile atricapillus) also sing seasonally, and we find that there are changes in the stereotypy and the length of the fee-bee song from the nonbreeding to the breeding season. Yet despite these changes, we fail to find any evidence of seasonal changes in the song system. The song system of males is larger than that of females, as is typical in songbirds, but the ratio between the sexes is small compared to other species. We suggest three hypotheses to explain our failure to find seasonal variation in the chickadee song system.

Clinical and diagnostic findings of an echovirus meningitis outbreak in the north west of England.

INTRODUCTION: An outbreak of echovirus meningitis occurred in the north west of England in 2001. This paper reviewed the clinical features and the role of different diagnostic methods. METHODS: This was a prospective study of adults admitted to a regional infectious disease unit with a probable diagnosis of meningitis, March to August 2001. RESULTS: Half the 40 cases were male; median age was 28 (range 16-51) years. Fifteen of 38 (39.5%) were smokers, and 20 of 24 (83.3%) had close contact with children. Median (range) duration of symptoms was 1.1 (0.25-7) days. Symptoms included headache (100%), photophobia (87.5%), and nausea (67.5%), and severity ranged from minimal signs to those consistent with a meningoencephalitis. The diagnosis was confirmed virologically in 29 of 40 (72%); echovirus 30 was isolated from six. Cerebrospinal fluid (CSF) enterovirus polymerase chain reaction (PCR) was positive in 26 of 32 (81%), and CSF virus culture in 3 of 16 (19%). Thirty one per cent of CSF samples had a neutrophil predominance, and 3 of 29 (10%) virologically confirmed cases had normal CSF microscopy and biochemistry. CONCLUSION: CSF microscopy may be normal or suggest bacterial meningitis in a substantial minority of cases of echovirus meningitis. CSF PCR for enterovirus seems to be more sensitive than virus culture of CSF, although PCR does not yield information on circulating virus type. Early and accurate diagnosis could reduce both use of parenteral antibiotics and length of hospital stay with both morbidity and cost implications. Close contact with children may be a risk factor, particularly if good hygiene measures are not practised.

Disruptive sexual selection for plumage coloration in a passerine bird.

The theory of sexual selection was developed to explain the evolution of highly exaggerated sexual ornaments. Now supported by vast empirical evidence, sexual selection is generally considered to favour individuals with the most extreme trait expression. Here we describe disruptive selection on a sexual ornament, plumage coloration, in yearling male lazuli buntings (Passerina amoena). In habitats with limited good-quality nesting cover, the dullest and the brightest yearlings were more successful in obtaining high-quality territories, pairing with females and siring offspring, than yearlings with intermediate plumage. This pattern reflects the way that territorial adult males vary levels of aggression to influence the structure of their social neighbourhood. Adult males showed less aggression towards dull yearlings than intermediate and bright ones, permitting the dull yearlings to settle on good territories nearby. Fitness comparisons based on paternity analyses showed that both the adults and dull yearlings benefited genetically from this arrangement, revealing a rare example of sexually selected male-male cooperation.

Syphilis in pregnant women and their children in the United Kingdom: results from national clinician reporting surveys 1994-7.

OBJECTIVE: To measure the incidence of syphilis detected in pregnancy and congenital syphilis in the United Kingdom. DESIGN: Surveys through consultants in genitourinary medicine and paediatricians with active surveillance. SETTING: United Kingdom, 1994-7. SUBJECTS: Women treated for syphilis in pregnancy, and children with early congenital syphilis born in the United Kingdom. RESULTS: Over 3 years 139 women were diagnosed with and treated for syphilis in pregnancy; 121 were detected through antenatal screening. Thirty one had confirmed or probable congenitally transmissible syphilis, putting their pregnancies at risk. These were minimum figures but are compatible with the 90 to 100 women newly diagnosed annually as having infectious or early latent syphilis. A universal screening policy would require 18 600 and 55 700 women (maximum numbers) to be screened, respectively, to detect one woman needing treatment and to prevent one case of congenital syphilis. Nine presumptive cases of children with congenital syphilis born in the United Kingdom were reported. Mothers requiring treatment for syphilis were found in almost every health region but were more prevalent in London and the south east. Being born abroad and belonging to an ethnic minority group were strong risk factors, but 14% (19 of 121) of cases treated and six of 31 definite or probably transmissible cases occurred in white women born in the United Kingdom. CONCLUSIONS: Congenitally transmissible syphilis continues to occur among pregnant women in the United Kingdom. Cases would be missed and stillbirths and congenitally infected babies would occur if antenatal screening was abandoned.

Reference laboratory surveillance of syphilis in England and Wales, 1994 to 1996.

Routine surveillance of syphilis of public health importance (infectious, congenital, and neurosyphilis) began in England and Wales in 1994, using reports from six PHLS laboratories that undertook serological and other reference work. One hundred and thirty-one cases were reported in the first two years, including 100 cases of infectious syphilis, with all regions reporting some infectious syphilis. Reports from PHLS laboratories represented one sixth of the number of cases seen in genitourinary clinics (KC60 data), but both systems produced comparable results. Laboratory reports provided more data on risk factors, which were not available elsewhere. This study documents the risk in England and Wales from infections originating in eastern Europe, where sexually transmitted infections including syphilis have reached epidemic proportions. Forty-five per cent of cases of infectious syphilis were reported to have been acquired in the United Kingdom (UK) and 59% of people with infectious syphilis were reported to have been born in the UK. Twenty per cent of the infectious cases were associated directly or indirectly with transmission in Russia or elsewhere in eastern Europe. The majority of infectious cases were from the white ethnic group. Eighty-five per cent of cases of infectious syphilis were reported to have been acquired heterosexually; 26% of male cases were reported to have been acquired homosexually. The PHLS laboratory reporting system is now well established, and could usefully be expanded to include other, non PHLS, laboratories that undertake reference work. It has the capacity to detect changes in the national epidemiology of syphilis, including imported infections.

Song transmission and auditory perception of distance in wood warblers (Parulinae)

The influence of breeding habitat on the evolution of song structure was examined in four wood warbler species of the sub-family Parulinae. The effects of song degradation on the ability of territorial paruline males to estimate distance by means of acoustic cues was also investigated. Song transmission characteristics of paruline breeding habitats were compared in southeastern Ontario, Canada; songs native to the habitat in which they were broadcast did not degrade less than foreign songs. The response of territorial paruline males to playback of 'near' (undegraded) and 'far' (degraded) conspecific songs broadcast from the same position within the territory at the same amplitude were then compared. Males responded to near songs as they would to a conspecific territorial intruder and with less intensity to far songs, suggesting that males may use cues from song degradation to estimate distance to vocal conspecifics. Our results from transmission and playback experiments are discussed with respect to the ranging hypothesis, which proposes that selection should favour males that structure songs to minimize their degradation, so that songs function to disrupt or intimidate rivals by providing unreliable distance cues.