OBJECTIVE: It is unclear whether isolated cutaneous lupus erythematosus (CLE) affects cardiovascular risk. We estimated the cumulative incidence and mortality of cardiovascular diseases in a population-based CLE cohort and compared the risk with a matched non-CLE cohort. METHODS: All incident cases of CLE in Olmsted County, Minnesota, between 1965 and 2005 were followed until December 2013. The cumulative incidence of cerebrovascular accidents (CVAs [including stroke and transient ischemic attack]), ischemic heart disease (IHD [including coronary artery disease, myocardial infarction, and angina pectoris]), heart failure, and peripheral arterial disease (PAD) was derived and compared to an age-, sex-, and calendar year-matched non-CLE cohort using Cox models. RESULTS: There were 155 patients with CLE (mean ± SD age at diagnosis 48 ± 16 years, 65% female, mean ± SD BMI 26.3 ± 7.1 kg/m2 , 40% smokers, 9% with diabetes mellitus). During a median followup of 14.6 years, 41 CLE patients had cardiovascular events (15 patients with CVAs, 32 patients with IHD), with a 20-year cumulative incidence of 31.6%. As compared to non-CLE subjects, the risk of CVAs (smoking-adjusted hazard ratio [HR] 2.97 [95% confidence interval (95% CI) 1.13-7.78]) and PAD (HR 2.06 [95% CI 0.99-4.32]) was increased in patients with CLE, but the risk of IHD was not increased (HR 0.94 [95% CI 0.57-1.54]). There was no increase in cardiovascular mortality (HR 1.68 [95% CI 0.76-3.75]). The magnitude of risk for any cardiovascular outcome was not significantly influenced by the extent of cutaneous involvement. CONCLUSION: CLE may be associated with an increased risk of CVAs and PAD, but not IHD. Factors contributing to increased CVA risk in patients with CLE merit evaluation.

Introduction

Health-related quality of life (HRQOL) is decreased in patients with kidney stones at all stages of stone disease, even when asymptomatic. Stress is thought to contribute to HRQOL, although there has been minimal investigation into the effect of stress on stone-related quality of life (QOL). We used the Wisconsin Stone Quality of Life Questionnaire (WISQOL) to assess the relationship of stress to stone-related QOL in kidney stone patients.

Methods

As part of the WISQOL Research Consortium, patients were approached in outpatient clinics and completed the WISQOL and the Perceived Stress Scale 10-item questionnaire (PSS-10). Patients with stones at enrollment were divided into those with symptoms and those without, while patients with no current stones formed another group. Questionnaire scores from each group were compared statistically and correlations between the groups were calculated.

Results

Patients (n=704) were enrolled from six centers. The WISQOL successfully discriminated between patients with current stones and those without (p<0.0001), while the PSS-10 did not (p=0.0869). The PSS-10 revealed patients with symptomatic kidney stones experienced higher levels of general stress than asymptomatic subjects (p<0.0001). However, a Pearson correlation test comparing the responses from each instrument revealed no overall correlation between general stress and HRQOL (r=0.05).

Conclusions

Symptomatic kidney stones increase general stress, as these patients demonstrate higher PSS-10 scores. Despite this, no correlation exists between general stress and stone-related QOL in patients with stone disease regardless of their stone and symptom status. This implies the existence of other factors impacting QOL in these patients, which warrants further exploration.

Research on the relation between phytoestrogens and breast cancer risk has been limited in scope. Most epidemiologic studies have involved Asian women and have examined the effects of traditional soy foods (e.g., tofu), soy protein, or urinary excretion of phytoestrogens. The present study extends this research by examining the effects of a spectrum of phytoestrogenic compounds on breast cancer risk in non-Asian US women. African-American, Latina, and White women aged 35-79 years, who were diagnosed with breast cancer between 1995 and 1998, were compared with women selected from the general population via random digit dialing. Interviews were conducted with 1,326 cases and 1,657 controls. Usual intake of specific phytoestrogenic compounds was assessed via a food frequency questionnaire and a newly developed nutrient database. Phytoestrogen intake was not associated with breast cancer risk (odds ratio = 1.0, 95% confidence interval: 0.80, 1.3 for the highest vs. lowest quartile). Results were similar for pre- and postmenopausal women, for women in each ethnic group, and for all seven phytoestrogenic compounds studied. Phytoestrogens appear to have little effect on breast cancer risk at the levels commonly consumed by non-Asian US women: an average intake equivalent to less than one serving of tofu per week.

Hydrogen, the simplest element in the universe, has a surprisingly complex phase diagram. Because of applications to planetary science, inertial confinement fusion and fundamental physics, its high-pressure properties have been the subject of intense study over the past two decades. While sophisticated static experiments have probed hydrogen's structure at ever higher pressures, studies examining the higher-temperature regime using dynamic compression have mostly been limited to optical measurement techniques. Here we present spectrally resolved x-ray scattering measurements from plasmons in dynamically compressed deuterium. Combined with Compton scattering, and velocity interferometry to determine shock pressure and mass density, this allows us to extract ionization state as a function of compression. The onset of ionization occurs close in pressure to where density functional theory-molecular dynamics (DFT-MD) simulations show molecular dissociation, suggesting hydrogen transitions from a molecular and insulating fluid to a conducting state without passing through an intermediate atomic phase.

Objective

To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients.

Methods

Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 μL/hemisphere) at escalating doses: 9 × 10¹⁰ vg (n = 6); 3 × 10¹¹ vg (n = 6); and 9 × 10¹¹ vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [¹⁸ F]FDOPA-PET scanning preoperatively and 6 and 18 months postoperatively.

Results

Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [¹⁸ F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5-274% and 8-130%; median, 36% and 54%), respectively. Ki differences between baseline and 6- and 18-month follow-up were statistically significant (P < 0.0002).

Conclusion

Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor infusion was safe and well tolerated. Increased [¹⁸ F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. © 2019 International Parkinson and Movement Disorder Society.

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

Introduction

Urolithiasis causes a significant impact on health-related quality of life (HRQOL). Patients with kidney stones have high levels of stress and anxiety. Symptom resolution often requires treatment. Travel distance is a barrier to care but little is known about its effects on HRQOL. We hypothesize that increased distance to treatment site is associated with decreased HRQOL.

Methods

Patients with a history of stones were enrolled at 11 tertiary centers as part of the QOL Stone Consortium of North America. HRQOL data were obtained using the Wisconsin Stone Quality of Life questionnaire (WISQOL). We calculated distance between patient and treatment site using national ZIP codes. We used linear models to evaluate the effect of distance on HRQOL, while also considering demographics data, stones/symptom status, and distance.

Results

Of the 1676 enrolled patients, 52% were male, 86% non-Latino White, and the mean age was 53 years. Mean distance to treatment site was 63.3 km (range 0-3774), with 74% reporting current stones and 45% current symptoms. WISQOL score and distance were negatively correlated for patients reporting current stones and symptoms (p=0.0010). Linear modelling revealed decreased WISQOL scores for patients with symptoms as distance increased from treatment site (p=0.0001), with a 4.7-point decrease for every 100 km traveled.

Conclusions

Stone disease imposes significant burden on patients' HRQOL due to a variety of factors. Patients with active stone symptoms report worse HRQOL with increased distance to their treatment site. Possible etiologies include travel burden, increased disease burden, decreased healthcare use, and delays in care.

The human brain vasculature is of great medical importance: its dysfunction causes disability and death¹, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders^2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.