RNA- and ATAC-sequencing Reveals a Unique CD83+ Microglial Population Focally Depleted in Parkinson's Disease.

All brain areas affected in Parkinson's disease (PD) show an abundance of microglia with an activated morphology together with increased expression of pro-inflammatory cytokines, suggesting that neuroinflammation may contribute to the neurodegenerative process in this common and incurable disorder. We applied a single nucleus RNA- and ATAC-sequencing approach using the 10x Genomics Chromium platform to postmortem PD samples to investigate microglial heterogeneity in PD. We created a multiomic dataset using substantia nigra (SN) tissues from 19 PD donors and 14 non-PD controls (NPCs), as well as three other brain regions from the PD donors which are differentially affected in this disease: the ventral tegmental area (VTA), substantia inominata (SI), and hypothalamus (HypoTs). We identified thirteen microglial subpopulations within these tissues as well as a perivascular macrophage and a monocyte population, of which we characterized the transcriptional and chromatin repertoires. Using this data, we investigated whether these microglial subpopulations have any association with PD and whether they have regional specificity. We uncovered several changes in microglial subpopulations in PD, which appear to parallel the magnitude of neurodegeneration across these four selected brain regions. Specifically, we identified that inflammatory microglia in PD are more prevalent in the SN and differentially express PD-associated markers. Our analysis revealed the depletion of a CD83 and HIF1A- expressing microglial subpopulation, specifically in the SN in PD, that has a unique chromatin signature compared to other microglial subpopulations. Interestingly, this microglial subpopulation has regional specificity to the brainstem in non-disease tissues. Furthermore, it is highly enriched for transcripts of proteins involved in antigen presentation and heat-shock proteins, and its depletion in the PD SN may have implications for neuronal vulnerability in disease.

Neutralization of the anthrax toxin by antibody-mediated stapling of its membrane-penetrating loop.

Anthrax infection is associated with severe illness and high mortality. Protective antigen (PA) is the central component of the anthrax toxin, which is one of two major virulence factors of Bacillus anthracis, the causative agent of anthrax disease. Upon endocytosis, PA opens a pore in the membranes of endosomes, through which the cytotoxic enzymes of the toxin are extruded. The PA pore is formed by a cooperative conformational change in which the membrane-penetrating loops of PA associate, forming a hydrophobic rim that pierces the membrane. Due to its crucial role in anthrax progression, PA is an important target for monoclonal antibody-based therapy. cAb29 is a highly effective neutralizing antibody against PA. Here, the cryo-EM structure of PA in complex with the Fab portion of cAb29 was determined. It was found that cAb29 neutralizes the toxin by clamping the membrane-penetrating loop of PA to the static surface-exposed loop of the D3 domain of the same subunit, thereby preventing pore formation. These results provide the structural basis for the antibody-based neutralization of PA and bring into focus the membrane-penetrating loop of PA as a target for the development of better anti-anthrax vaccines.

Alpha galactosidase A activity in Parkinson's disease.

Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 µmol/l/h versus 3.12 µmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 µmol/l/h versus 3.10 µmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 µmol/l/h versus 3.10 µmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31-0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

Glucocerebrosidase mutations in a Serbian Parkinson's disease population.

BACKGROUND AND PURPOSE: To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinson's disease (PD) population. METHODS: Glucocerebrosidase exons 8-11 harbouring the most common mutations were sequenced in 360 patients with PD and 348 controls from Serbia. Haplotype analysis was performed for the N370S mutation and compared with German and Ashkenazi Jewish carriers. RESULTS: Glucocerebrosidase mutations were significantly more frequent in patients with PD (21/360; 5.8%) vs. controls (5/348; 1.4%; OR = 4.25; CI, 1.58-11.40; P = 0.0041). Two patients with PD carried homozygous or compound heterozygous mutations in GBA. The N370S mutation accounted for about half of the mutated alleles in patients (10/23) but was absent amongst controls. Three novel variants were detected including two non-synonymous variants (D380V, N392S) in the patient group and one synonymous change (V459V) in a control. Carriers of the D409H mutation were also sequenced for H255Q, and all were found to carry the [D409H; H255Q] double-mutant allele. Genotyping suggested a common haplotype for all N370S carriers. CONCLUSION: Glucocerebrosidase mutations represent a PD risk factor in the Serbian population.

Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study.

OBJECTIVE: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). METHODS: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. RESULTS: Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale-III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). CONCLUSION: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.

The relation between depression and parkin genotype: the CORE-PD study.

BACKGROUND: Mutations in parkin are a known genetic risk factor for early onset Parkinson's disease (EOPD) but their role in non-motor manifestations is not well established. Genetic factors for depression are similarly not well characterized. We investigate the role of parkin mutations in depression among those with EOPD and their relatives. METHODS: We collected psychiatric information using the Patient Health Questionnaire and Beck Depression Inventory II on 328 genotyped individuals including 88 probands with early onset PD (41 with parkin mutations, 47 without) and 240 first and second-degree relatives without PD. RESULTS: Genotype was not associated with depression risk among probands. Among unaffected relatives of EOPD cases, only compound heterozygotes (n = 4), and not heterozygotes, had significantly increased risk of depressed mood (OR = 14.1; 95% CI 1.2-163.4), moderate to severe depression (OR = 17.8; 95% CI 1.0-332.0), depression (score ≥ 15) on the Beck Depression Inventory II (BDI-II) (OR = 51.9; 95% CI 4.1-657.4), and BDI-II total depression score (ß = 8.4; 95% CI 2.4-11.3) compared to those without parkin mutations. CONCLUSIONS: Relatives of EOPD cases with compound heterozygous mutations and without diagnosed PD may have a higher risk of depression compared to relatives without parkin mutations. These findings support evidence of a genetic contribution to depression and may extend the phenotypic spectrum of parkin mutations to include non-motor manifestations that precede the development of PD.

Clinical vignettes in Parkinson's disease: a collection of unusual medication-induced hallucinations, delusions, and compulsive behaviours.

Hallucinations, delusions, and compulsive behaviors are frequent iatrogenic complications of the treatment of motor dysfunction in Parkinson's disease (PD). Although these have been studied, and the phenomenology described, there are few detailed descriptions of the various psychiatric problems our treated PD patients live with that allow physicians who do not have a great deal of experience with PD patients to appreciate the extent of their altered lives. This report is a compilation of vignettes describing these behavioral problems that the treating neurologist or psychiatrist attributed to the medications used for treating PD.

Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study.

BACKGROUND: While Parkinson disease (PD) is consistently associated with impaired olfaction, one study reported better olfaction among Parkin mutation carriers than noncarriers. Whether olfaction differs between Parkin mutation heterozygotes and carriers of 2 Parkin mutations (compound heterozygotes) is unknown. OBJECTIVE: To assess the relationship between Parkin genotype and olfaction in PD probands and their unaffected relatives. METHODS: We administered the University of Pennsylvania Smell Identification Test (UPSIT) to 44 probands in the Consortium on Risk for Early-Onset Parkinson Disease study with PD onset ≤50 years (10 Parkin mutation heterozygotes, 9 compound heterozygotes, 25 noncarriers) and 80 of their family members (18 heterozygotes, 2 compound heterozygotes, 60 noncarriers). In the probands, linear regression was used to assess the association between UPSIT score (outcome) and Parkin genotype (predictor), adjusting for covariates. Among family members without PD, we compared UPSIT performance in heterozygotes vs noncarriers using generalized estimating equations, adjusting for family membership, age, gender, and smoking. RESULTS: Among probands with PD, compound heterozygotes had higher UPSIT scores (31.9) than heterozygotes (20.1) or noncarriers (19.9) (p < 0.001). These differences persisted after adjustment for age, gender, disease duration, and smoking. Among relatives without PD, UPSIT performance was similar in heterozygotes (32.5) vs noncarriers (32.4), and better than in heterozygotes with PD (p = 0.001). CONCLUSION: Olfaction is significantly reduced among Parkin mutation heterozygotes with PD but not among their heterozygous relatives without PD. Compound heterozygotes with PD have olfaction within the normal range. Further research is required to assess whether these findings reflect different neuropathology in Parkin mutation heterozygotes and compound heterozygotes.

Salud para su Corazón: a community-based Latino cardiovascular disease prevention and outreach model.

Cardiovascular disease (CVD) is the leading cause of death for Latinos living in the United States. This population is generally unaware of important lifestyle or behavioral changes that can prevent CVD. The National Heart, Lung, and Blood Institute (NHLBI) designed and implemented Salud para su Corazón (Health for Your Heart), a culturally appropriate, community-based, theory-driven intervention model. NHLBI's goals were: (1) to design an intervention model appropriate to Latino populations; (2) to pilot test the model in a specific community with the objectives of increasing awareness about heart disease, raising knowledge about CVD prevention, and promoting heart-healthy lifestyles; and (3) to disseminate the model and the materials developed to other communities with similar needs. An agency-community partnership, under the leadership of the Community Alliance for Heart Health, guided all stages of the community intervention project. The multimedia bilingual community intervention included television telenovela format public service announcements (PSAs), radio programs, brochures, recipe booklets, charlas, a promotores training manual, and motivational videos. An evaluation survey assessed the impact of the intervention. A pre-post intervention survey was conducted with more than 300 participants, and results showed that the respondents were substantially more aware of risk factors for CVD, and had greatly increased their knowledge of ways to prevent heart disease. Dissemination efforts have resulted in numerous requests by health organizations, universities, and health maintenance organizations (HMOs) for educational materials and communication strategies produced by Salud para su Corazón. In addition, Univision, the largest Spanish-language broadcast television network, is airing the initiative's PSAs. Also, training seminars for promotores are being conducted in different regions of the United States, and several locations are planning to replicate this study.

[Health communication as a curriculum at United States universities]. / La comunicación para la salud como disciplina en las universidades estadounidenses.

This article analyzes the state of development of communications related to health in universities of the United States of America. This specialty is essential for people's well-being, and it involves interpersonal, organizational, and mass communications. In the United States, communications for health promotion is an area of applied communications with social relevance and generally performed in interdisciplinary settings. A number of universities in the United States offer communications master's degree programs with an emphasis on health. However, so far, the only program with a formal graduate degree in health and communications is one jointly offered by the Emerson University Department of Communications and the Tufts School of Medicine. Developing and including this specialization in the schools of communications in Latin America is crucial to improving the quality of life of the peoples of the continent.

The impact of the Wellness Guide/Guía on Hispanic women's well-being-related knowledge, efficacy beliefs, and behaviors: the mediating role of acculturation.

This study examined how acculturation mediated the impact of the California Wellness Guide/La Guía del Bienestar on Hispanic women's knowledge, efficacy beliefs, and behaviors. Knowledge gaps were found between acculturated and less acculturated women. Acculturated mothers had more confidence in their abilities to acquire wellness-related information both before and after Guide/Guía distribution and also had more assistance-seeking efficacy. Guide/Guía recipients were more knowledgeable, had greater confidence in their knowledge and their abilities to acquire information, and possessed better information acquisition strategies than nonrecipients. The publication also enhanced low-acculturated recipients' assistance-seeking self-efficacy. High-acculturated and low-acculturated recipients of the Guide/Guía were equally likely to have retained and used their copies, to anticipate using the publication in the future, and to have made a change in behavior as a result of the guide. Finally, the Guide/Guía did not increase the knowledge gap between high- and low-acculturated guide recipients.

Child care practices of mexican-american working mothers: a pilot study.

There is scarce information on child care strategies among Hispanics in the United States. The purpose of this pilot study was to identify and understand child care practices in a sample of forty-five Mexican-American working mothers living in northern California by means of conducting six focus groups. Results included data on child care selection, problems, and preferences. Results also expose myths based on ethnic stereotyping that have obscured the understanding of this issue. Suggestions for further research are discussed as well as child care policy considerations.

Designing prenatal care messages for low-income Mexican women.

Communication theories and research data were used to design cross-cultural health education messages. A University of California Los Angeles-Universidad Autonoma in Tijuana, Mexico, research team used the methods of ethnographic and survey research to study behaviors, attitudes, and knowledge concerning prenatal care of a sample of pregnant low-income women living in Tijuana. This audience provided information that served as a framework for a series of messages to increase awareness and change prenatal care behaviors. The message design process was guided by persuasion theories that included Petty and Caccioppo's elaboration likelihood model, McGuire's persuasion matrix, and Bandura's social learning theory. The results from the research showed that poor women in Tijuana tend to delay or not seek prenatal care. They were not aware of symptoms that could warn of pregnancy complications. Their responses also revealed pregnant women's culturally specific beliefs and behaviors regarding pregnancy. After examination of these and other results from the study, prenatal care messages about four topics were identified as the most relevant to communicate to this audience: health services use, the mother's weight gain, nutrition and anemia, and symptoms of high-risk complications during pregnancy. A poster, a calendar, a brochure, and two radio songs were produced and pretested in focus groups with low-income women in Tijuana. Each medium included one or more messages addressing informational, attitudinal, or behavioral needs, or all three, of the target population.

Perceptions about Prenatal Care Among Health Providers and Mexican-American Community Women: An Exploratory Study.

Latino women in California have less access to health care, particularly prenatal care, than any other ethnic group. This exploratory study identified perceptions about prenatal care needs, barriers to utilization of health services and common health behaviors during pregnancy among a sample of Mexican American women and a sample of prenatal care providers. The research used a combination of written questionnaires and focus-group discussions to gather data from a sample of sixty Mexican American community women, and a written questionnaire only to get information from a sample of forty providers. Results showed that providers perceived Mexican American women as doing better than non-Latino women regarding a series of health behaviors during pregnancy and as doing worse regarding another set of prenatal care behaviors. Results also showed that Mexican American pregnant teenagers are at particularly high risk regarding prenatal care due to a combination of structural and cultural factors. Acculturation was found to be an important factor affecting prenatal care beliefs and behaviors among this population. This relationship deserves further study. The influence of acculturation also needs to be considered in the design of prenatal care communication strategies with Mexican American women.

Profile of latino health and implications for health education.

Latinos are the fastest growing population in the United States. Yet in spite of their growing numbers, the health needs of Latinos are not met, they lack adequate access to health care and lack appropriate health education interventions. This article discusses key factors to be considered in dealing effectively with the health education needs of Latinos. These factors include demographic characteristics of this population; acculturation and its relationship to health practices; major health issues among Latinos and beliefs and practices which influence Latino health. Communication strategies most widely used by Latinos and most credible sources of health information are discussed. Recommendations for effective communication strategies to reach Latinos with culturally appropriate health messages are presented.

Ethnic differences in knowledge of AIDS transmission and attitudes towards gays and people with AIDS.

Epidemiological studies have shown disproportionately elevated risk rates of AIDS among Hispanics and blacks, particularly among the heterosexual population. Intense preventive education has resulted in dramatic infection reduction among the gay population. Yet these educational efforts aimed at the gay population failed to reach many of the minority population at risk. This study looked at some structural and cultural factors that might be preventing beneficial effects generated from existing educational programs designed to prevent AIDS. The same variables were compared among whites and Hispanics. The research showed that while all groups had a high level of knowledge regarding AIDS transmission, Hispanics had many misconceptions about the way AIDS is transmitted. In this study, Hispanics were not more intolerant toward homosexuals than whites; nor were they more intolerant towards people with AIDS. Thus AIDS education campaigns directed towards Hispanics need to be designed to address specific misconceptions regarding AIDs transmission. Homophobia does not appear to be an insurmountable barrier preventing Hispanics from dealing with this topic.

Non-availability of the IUD and contraceptive choice.

The Copper 7 and Lippes Loop IUD are no longer distributed in the United States, and the cost of the Progestasert precludes usage in many family planning clinics. The impact of the loss of this widely used contraceptive method was assessed in a pilot study at the UCLA Family Planning Clinic. The clients who would have selected an IUD at the time of their clinic visit between March and December of 1986 instead chose oral contraceptive pills (55%) or barrier methods (45%) but their level of dissatisfaction with the methods they received was significantly greater than that of all other contraceptors, and this led to their subsequent selection of another method which, in the majority (66%), was of lower efficacy than the IUD. There were two unplanned conceptions amongst twenty women who would have chosen an IUD, both due to non-compliance with oral contraceptive pills; and at the time of survey in March 1987, no clients had opted for sterilization. Women who no longer have their choice of the IUD represent a high risk for contraceptive dissatisfaction and failure, but have not made precipitous decisions to undergo permanent sterilization.

PIP: The Copper 7 and Lippes Loop IUD are no longer distributed in the US, and the cost of the Progestasert precludes usage in many family planning clinics. The impact of the loss of this widely used contraceptive method was assessed in a pilot study at the UCLA Family Planning Clinic. The clients who would have selected an IUD at the time of their clinic visit between March and December of 1986 instead chose oral contraceptive pills (55%) or barrier methods (45%) but their level of dissatisfaction with the methods they received was significantly greater than that of all other contraceptors, and this led to their subsequent selection of another method which, in the majority (66%), was of lower efficacy than the IUD. There were 2 unplanned conceptions amongst 20 women who would have chosen an IUD, both due to non-compliance with oral contraceptive pills; and at the time of survey in March 1987, no clients had opted for sterilization. Women who no longer have their choice of the IUD represent a high risk for contraceptive dissatisfaction and failure, but have not made precipitous decisions to undergo permanent sterilization.

Patterns of mass media use among Hispanic smokers: implications for community interventions.

A relatively large percentage of Hispanics in the United States smoke. Yet a large proportion of Hispanics are light smokers, smoking ten or fewer cigarettes per day. Previous research has shown that most light smokers quit smoking on their own and that health education and an environment conducive to non-smoking can have a significant impact in reducing smoking rates. Given the current smoking patterns of Hispanics, culturally appropriate media-based community intervention to promote smoking cessation can have a significant impact. This study identified patterns of media use and language preference among a sample of 263 Hispanic smokers from the San Francisco Bay Area. Based on this study, recommendations to reach Hispanic smokers with a series of communication strategies are suggested.

Psycho-social factors and the technologies of work.

This paper examines the probable association between use of complex technologies in the work setting and psycho-social factors believed to impact upon human health. The analysis is set within two long-standing philosophical perspectives on technology, one which holds that technology controls human choice and action, and the other which sees technology as a useful tool for extending human capabilities. Research evidence linking technologies of work to health are reviewed. On the basis of this literature, the authors conclude that, in general, among blue collar and clerical workers, technology is often a controlling element, to the detriment of health; but among professionals and managers, technology can be an aid to work and may therefore facilitate positive health. Strategies are offered toward the prevention and detection of, and intervention into work environments which, through the use of high technology, may pose a threat to health.