The role of neurotransmitters in the development of Parkinson's disease-related psychosis.

Psychotic symptoms are common, disabling non-motor features of Parkinson's disease (PD). Despite noted heterogeneity in clinical features, natural history and therapy response, current dogma posits that psychosis generally progresses in a stereotypic manner through a cascade of events that begins with minor hallucinations and evolves to severe hallucinations and delusions. Further, the occurrence of psychotic symptoms is believed to indicate a poor prognosis. Here we propose a classification scheme that outlines the pathogenesis of psychosis as it relates to dysfunction of several neurotransmitter systems. We hypothesize that several subtypes exist, and that PD psychosis is not consistently indicative of a progressive cascade and poor prognosis. The literature was reviewed from 1990 to 2017. An overview of the features of PD psychosis is followed by a review of data indicating the existence of neurotransmitter-related subtypes of psychosis. We found that ample evidence exists to demonstrate the presence of multiple subtypes of PD psychosis, which are traced to dysfunction of the following neurotransmitter systems: dopamine, serotonin and acetylcholine. Dysfunction of each of these systems is recognizable through their clinical features and correlates, and the varied long-term prognoses. Identifying which neurotransmitter system is dysfunctional may help to develop targeted therapies. PD psychosis has various subtypes that differ in clinical features, underlying pathology and pathophysiology, treatment response and prognosis. A novel classification scheme is presented that describes the clinical subtypes with different outcomes, which could lead to the development of targeted therapies. Future research should focus on testing the viability of this classification.

Reconfigurable directional lasing modes in cavities with generalized PT symmetry.

We introduce a new family of generalized PT-symmetric cavities that involve gyrotropic elements and support reconfigurable unidirectional lasing modes. We derive conditions for which these modes exist and investigate a simple electronic circuit that experimentally demonstrates their feasibility in the radio-frequency domain.

A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease.

Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson's disease (PD), and currently, the disease-modifying potential of the nicotine patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C, which encodes a synaptic-vesicle protein in PD-vulnerable substantia nigra (P=1 × 10(-7) for gene-smoking interaction on PD risk), and CG14691, which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2 × 10(-11) for nicotine-paraquat interaction on gene expression). SV2C is biologically plausible because nicotine enhances the release of dopamine through synaptic vesicles, and PD is caused by the depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5 × 10(-10)). Taken together, cross-validating evidence from humans and Drosophila suggests SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.

Incident hypertension in older women and men with or at risk for HIV infection.

OBJECTIVES: Antiretroviral (ARV) therapy has prolonged the life expectancy of HIV-infected persons, increasing their risk of age-associated diseases, including atherosclerosis (AS). Decreased risk of AS has been associated with the prevention and control of hypertension (HTN). We conducted a cohort study of perimenopausal women and older men with or at risk of HIV infection to identify risk factors for incident HTN. METHODS: Standardized interviews, physical examinations, and laboratory examinations were scheduled at 6-month intervals. Interview data included demographics, medical, family, sexual behaviour and drug use histories, and physical activity. RESULTS: There were 330 women and 329 men eligible for inclusion in the study; 27% and 35% of participants developed HTN during a median follow-up period of 1080 and 1071 days, respectively. In gender-stratified analysis, adjusting for traditional HTN risk factors (age, race, body mass index, smoking, diabetes, family history of HTN, alcohol dependence, physical activity and high cholesterol), HIV infection was not associated with incident HTN in women [hazard ratio (HR) 1.31; 95% confidence interval (CI) 0.56, 3.06] or men (HR 1.67; 95% CI 0.75, 3.74). Among HIV-infected women, although exposure to ARVs was not significantly associated with incident HTN (HR 0.72; 95% CI 0.26, 1.99), CD4 T-cell count was positively associated with incident HTN (HR 1.15 per 100 cells/µL; 95% CI 1.03, 1.28). Among physically active HIV-infected men, exposure to ARVs was negatively associated with incident HTN (HR 0.15; 95% CI 0.03, 0.78). CONCLUSIONS: HIV infection was not associated with incident HTN in older men or women. This study provides additional evidence supporting a causal relationship between immune function and incident HTN, which warrants further study.

Observation of asymmetric transport in structures with active nonlinearities.

A mechanism for asymmetric transport which is based on parity-time-symmetric nonlinearities is presented. We show that in contrast to the case of conservative nonlinearities, an increase of the complementary conductance strength leads to a simultaneous increase of asymmetry and transmittance intensity. We experimentally demonstrate the phenomenon using a pair of coupled Van der Pol oscillators as a reference system, each with complementary anharmonic gain and loss conductances, connected to transmission lines. An equivalent optical setup is also proposed.

Cardiac defects and renal failure in mice with targeted mutations in Pkd2.

PKD2, mutations in which cause autosomal dominant polycystic kidney disease (ADPKD), encodes an integral membrane glycoprotein with similarity to calcium channel subunits. We induced two mutations in the mouse homologue Pkd2 (ref.4): an unstable allele (WS25; hereafter denoted Pkd2WS25) that can undergo homologous-recombination-based somatic rearrangement to form a null allele; and a true null mutation (WS183; hereafter denoted Pkd2-). We examined these mutations to understand the function of polycystin-2, the protein product of Pkd2, and to provide evidence that kidney and liver cyst formation associated with Pkd2 deficiency occurs by a two-hit mechanism. Pkd2-/- mice die in utero between embryonic day (E) 13.5 and parturition. They have structural defects in cardiac septation and cyst formation in maturing nephrons and pancreatic ducts. Pancreatic ductal cysts also occur in adult Pkd2WS25/- mice, suggesting that this clinical manifestation of ADPKD also occurs by a two-hit mechanism. As in human ADPKD, formation of kidney cysts in adult Pkd2WS25/- mice is associated with renal failure and early death (median survival, 65 weeks versus 94 weeks for controls). Adult Pkd2+/- mice have intermediate survival in the absence of cystic disease or renal failure, providing the first indication of a deleterious effect of haploinsufficiency at Pkd2on long-term survival. Our studies advance our understanding of the function of polycystin-2 in development and our mouse models recapitulate the complex human ADPKD phenotype.

GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes.

GLUT4, the insulin-responsive glucose transporter, plays an important role in postprandial glucose disposal. Altered GLUT4 activity is suggested to be one of the factors responsible for decreased glucose uptake in muscle and adipose tissue in obesity and diabetes. To assess the effect of GLUT4 expression on whole-body glucose homeostasis, we disrupted the murine GLUT4 gene by homologous recombination. Male mice heterozygous for the mutation (GLUT4 +/-) exhibited a decrease in GLUT4 expression in adipose tissue and skeletal muscle. This decrease in GLUT4 expression did not result in obesity but led to increased serum glucose and insulin, reduced muscle glucose uptake, hypertension, and diabetic histopathologies in the heart and liver similar to those of humans with non-insulin-dependent diabetes mellitus (NIDDM). The male GLUT4 +/- mice represent a good model for studying the development of NIDDM without the complications associated with obesity.

Early postoperative dressing removal in hand surgery: Novel concepts for individualized surgical dressing management.

Postoperative dressing protocols after clean surgery without implant vary widely. The purpose of this study was to elucidate whether early postoperative dressing removal is a valid option, as compared to untouched dressing or twice-weekly dressing change approach. A prospective randomized study was conducted on patients who underwent carpal tunnel release (CTR) or trigger finger release (TFR) between January and November 2020. Patients were randomly distributed into 3 groups: surgical dressing untouched until first follow up (SDU); surgical dressing changed twice a week in a health maintenance organization (HMO); and surgical dressing removed at first postoperative day (SDR). Data collected included patient characteristics, pre-and post-operative functional (QuickDASH) and autonomy (Instrumental Activities of Daily Living performance (IADL)) scores, Vancouver scar scale (VSS) and potential complications. Eighty-four patients were included: 28 (33.3%), 29 (34.5%) and 27 (32.1%) in the SDU, HMO and SDR groups, respectively. Deterioration in mean IADL score at 2-week follow-up was statistically significant in the HMO group (mean delta 3.35, p = 0.008). Quick DASH score improved significantly between preoperative and 2-week follow-up values only in the SDU group (mean delta 9.12, p = 0.012). Other parameters, including wound complications, did not differ significantly between groups. Early removal of postoperative dressing and immediate wound exposure was a safe option after CTR and TFR. An untouched bulky dressing correlated with early functional improvement. Finally, iterative dressing change in HMO showed no benefit and led to significant deterioration in early postoperative autonomy. IRB APPROVAL: 0548-18-TLV. LEVEL OF EVIDENCE: I.

Cerebrospinal fluid biomarkers in Parkinson's disease with freezing of gait: an exploratory analysis.

We explore the association between three Alzheimer's disease-related and ten inflammation-related CSF markers and freezing of gait (FOG) in patients with Parkinson's disease (PD). The study population includes PD patients with FOG (PD-FOG, N = 12), without FOG (PD-NoFOG, N = 19), and healthy controls (HC, N = 12). Age and PD duration are not significantly different between groups. After adjusting for covariates and multiple comparisons, the anti-inflammatory marker, fractalkine, is significantly decreased in the PD groups compared to HC (P = 0.002), and further decreased in PD-FOG compared to PD-NoFOG (P = 0.007). The Alzheimer's disease-related protein, Aß42, is increased in PD-FOG compared to PD-NoFOG and HC (P = 0.001). Group differences obtained in individual biomarker analyses are confirmed with multivariate discriminant partial least squares regression (P < 0.001). High levels of Aß42 in PD-FOG patients supports an increase over time from early to advanced state. Low levels of fractalkine might suggest anti-inflammatory effect. These findings warrant replication.

Antibody-mediated autoimmune myocarditis depends on genetically determined target organ sensitivity.

Injury to cardiac myocytes often leads to the production of anti-myosin antibodies. While these antibodies are a marker of myocardial injury, their contribution to pathogenesis in diseases such as autoimmune myocarditis or rheumatic fever is much less clear. We demonstrate in this report that monoclonal anti-myosin antibodies can mediate myocarditis in a susceptible mouse strain. Additionally, we show disease susceptibility depends on the presence of myosin or a myosin-like molecule in cardiac extracellular matrix. This study demonstrates that susceptibility to autoimmune heart disease depends not only on the activation of self-reactive lymphocytes but also on genetically determined target organ sensitivity to autoantibodies.

End-capillary loops in the heart: an explanation for discrete myocardial infarctions without border zones.

Separate perfusions of canine coronary arteries with colored silicone-rubber compound reveal that in the region where two microcirculations abut, capillaries derived from individual large vessels are discrete, with no interconnections. Terminal homologous capillaries from loops rather than anastomosing with heterologous capillaries. This anatomic arrangement may account for discrete myocardial infarctions without ischemic border zones.

Cardiac alpha-myosin heavy chains differ in their induction of myocarditis. Identification of pathogenic epitopes.

BALB/c mice develop autoimmune myocarditis after immunization with mouse cardiac myosin, whereas C57B/6 mice do not. To define the immunogenicity and pathogenicity of cardiac myosin in BALB/c mice, we immunized mice with different forms of cardiac myosin. These studies demonstrate the discordance of immunogenicity and pathogenicity of myosin heavy chains. The cardiac alpha-myosin heavy chains of BALB/c and C57B/6 mice differ by two residues that are near the junction of the head and rod in the S2 fragment of myosin. Myosin preparations from both strains are immunogenic in susceptible BALB/c as well as in nonsusceptible C57B/6 mice; however, BALB/c myosin induces a greater incidence of disease. To further delineate epitopes of myosin heavy chain responsible for immunogenicity and disease, mice were immunized with fragments of genetically engineered rat alpha cardiac myosin. Epitopes in the region of difference between BALB/c and C57B/6 (residues 735-1032) induce disease in both susceptible and nonsusceptible mice. The data presented here demonstrate that pathogenic epitopes of both mouse and rat myosin residue in the polymorphic region of the S2 subunit. In addition, these studies suggest that polymorphisms in the autoantigen may be part of the genetic basis for autoimmune myocarditis.

Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy.

Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertrophic cardiomyopathy (FHC). Patients with cTnT mutations generally exhibit mild or no ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. To understand the functional basis of these phenotypes, we created transgenic mouse lines expressing 30%, 67%, and 92% of their total cTnT as a missense (R92Q) allele analogous to one found in FHC. Similar to a mouse FHC model expressing a truncated cTnT protein, the left ventricles of all R92Q lines are smaller than those of wild-type. In striking contrast to truncation mice, however, the R92Q hearts demonstrate significant induction of atrial natriuretic factor and beta-myosin heavy chain transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocytes from R92Q mice have increased basal sarcomeric activation, impaired relaxation, and shorter sarcomere lengths. Isolated working heart data are consistent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with FHC. These mice represent the first disease model to exhibit hypercontractility, as well as a unique model system for exploring the cellular pathogenesis of FHC. The distinct phenotypes of mice with different TnT alleles suggest that the clinical heterogeneity of FHC is at least partially due to allele-specific mechanisms.

A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.

Mutations in multiple cardiac sarcomeric proteins including myosin heavy chain (MyHC) and cardiac troponin T (cTnT) cause a dominant genetic heart disease, familial hypertrophic cardiomyopathy (FHC). Patients with mutations in these two genes have quite distinct clinical characteristics. Those with MyHC mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with cTnT mutations generally exhibit mild or no hypertrophy, but a high frequency of sudden death at an early age. To understand the basis for these distinctions and to study the pathogenesis of the disease, we have created transgenic mice expressing a truncated mouse cTnT allele analogous to one found in FHC patients. Mice expressing truncated cTnT at low (< 5%) levels develop cardiomyopathy and their hearts are significantly smaller (18-27%) than wild type. These animals also exhibit significant diastolic dysfunction and milder systolic dysfunction. Animals that express higher levels of transgene protein die within 24 h of birth. Transgenic mouse hearts demonstrate myocellular disarray and have a reduced number of cardiac myocytes that are smaller in size. These studies suggest that multiple cellular mechanisms result in the human disease, which is generally characterized by mild hypertrophy, but, also, frequent sudden death.

Improving postpartum glucose monitoring in women with gestational diabetes.

OBJECTIVE: To improve 6-week postpartum visit attendance, glucose test ordering and test completion among postpartum patients with a history of gestational diabetes (GDM). METHODS: Pre- and post-intervention GDM women at Mount Sinai Hospital were studied via chart review. Interventions included advanced order sets for glucose monitoring at the 35-week pregnancy visit, educational modules, and nutritionist phone calls reminding patients to attend postpartum visits fasting. RESULTS: One hundred and seven pre-intervention and 42 post-intervention women were studied. Percentages of orders placed for postpartum testing was higher post-intervention vs. pre-intervention (57% vs. 42%, p = 0.03). There were higher test completion rates post-intervention vs. pre-intervention (36% vs. 17%, p = 0.01). Postpartum visit attendance rates did not vary between the groups (73% vs. 69% p = 0.60). Six percent of patients pre-intervention fasted for postpartum visits vs. 60% post-intervention. CONCLUSION: There was no observed increase in women attending their 6-week postpartum visits, yet rates of completed orders for postpartum testing, women attending visits fasting, and postpartum test completions were higher post-intervention. More research may identify the barriers to attendance at 6-week postpartum visits.

LRRK2 levels in immune cells are increased in Parkinson's disease.

Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson's disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative regulatory function of nuclear factor of activated T cells implicates leucine-rich repeat kinase 2 in the development of the inflammatory environment characteristic of Parkinson's disease. The aim of this study was to determine the expression pattern of leucine-rich repeat kinase 2 in immune cell subsets and correlate it with the immunophenotype of cells from Parkinson's disease and healthy subjects. For immunophenotyping, blood cells from 40 Parkinson's disease patients and 32 age and environment matched-healthy control subjects were analyzed by flow cytometry. Multiplexed immunoassays were used to measure cytokine output of stimulated cells. Leucine-rich repeat kinase 2 expression was increased in B cells (p = 0.0095), T cells (p = 0.029), and CD16+ monocytes (p = 0.01) of Parkinson's disease patients compared to healthy controls. Leucine-rich repeat kinase 2 induction was also increased in monocytes and dividing T cells in Parkinson's disease patients compared to healthy controls. In addition, Parkinson's disease patient monocytes secreted more inflammatory cytokines compared to healthy control, and cytokine expression positively correlated with leucine-rich repeat kinase 2 expression in T cells from Parkinson's disease but not healthy controls. Finally, the regulatory surface protein that limits T-cell activation signals, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), was decreased in Parkinson's disease compared to HC in T cells (p = 0.029). In sum, these findings suggest that leucine-rich repeat kinase 2 has a regulatory role in immune cells and Parkinson's disease. Functionally, the positive correlations between leucine-rich repeat kinase 2 expression levels in T-cell subsets, cytokine expression and secretion, and T-cell activation states suggest that targeting leucine-rich repeat kinase 2 with therapeutic interventions could have direct effects on immune cell function.

Immunoglobulin isotype determines pathogenicity in antibody-mediated myocarditis in naïve mice.

Antimyosin reactivity is associated with cardiac damage in autoimmune myocarditis, an inflammatory heart disease characterized by a cellular infiltrate in the myocardium and myocyte necrosis. We are interested in the pathogenicity of antimyosin antibodies and their ability to cause autoimmune myocarditis. We have shown that antimyosin antibodies of the IgG isotype will induce disease in the DBA/2 mouse. In the present study, we show that IgM antimyosin antibodies do not induce myocarditis; however, these same antibodies become pathogenic when converted to the IgG isotype. Although IgM antibodies can penetrate the myocardium during cardiac inflammation, they are usually less able to leave the vascular compartment and penetrate cardiac tissue, thus accounting for their lack of pathogenicity. Thus, antimyosin B cells may be potentially pathogenic only after antigen activation and heavy chain class switching or under conditions that alter vascular permeability in the heart.

Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle.

Impaired skeletal muscle glucose utilization under insulin action is a major defect in the etiology of type 2 diabetes. This is underscored by a new mouse model of type 2 diabetes generated by genetic disruption of one allele of glucose transporter 4 (GLUT4+/-), the insulin-responsive glucose transporter in muscle and adipose tissue. Male GLUT4+/- mice exhibited decreased GLUT4 expression and glucose uptake in muscle that accompanied impaired whole-body glucose utilization, hyperinsulinemia, hyperglycemia, and heart histopathology. To determine whether development of the diabetic phenotype in GLUT4+/- mice can be forestalled by preventing the onset of impaired muscle GLUT4 expression and glucose utilization, standard genetic crossing was performed to introduce a fast-twitch muscle-specific GLUT4 transgene--the myosin light chain (MLC) promoter-driven transgene MLC-GLUT4--into GLUT4+/- mice (MLC-GLUT4+/- mice). GLUT4 expression and 2-deoxyglucose uptake levels were normalized in fast-twitch muscles of MLC-GLUT4+/- mice. In contrast to GLUT4+/- mice, MLC-GLUT4+/- mice exhibited normal whole-body glucose utilization. In addition, development of hyperinsulinemia and hyperglycemia observed in GLUT4+/- mice was prevented in MLC-GLUT4+/- mice. The occurrence of diabetic heart histopathology in MLC-GLUT4+/- mice was reduced to control levels. Based on these results, we propose that the onset of a diabetic phenotype in GLUT4+/- mice can be avoided by preventing decreases in muscle GLUT4 expression and glucose uptake.

Smooth muscle contraction bands in the media of coronary arteries: a postmortem marker of antemortem coronary spasm?

To date, no unequivocal morphologic markers have been described that would allow the diagnosis of coronary artery spasm to be made at autopsy. The coronary arteries of 63 adult patients without myocardial infarction were examined at autopsy, and the presence of medial smooth muscle contraction bands in these vessels was correlated with other vascular changes, myocardial pathologic changes and clinical history. These contraction bands have not been reported previously in human coronary arteries, but they were identified in experimental vascular spasm induced with catecholamines. It was found that 47 of the 63 cases were positive for contraction bands. As evidence of an antemortem process, there was a significant correlation between these changes and the presence of nonocclusive microthrombi, found in 25 cases. Contraction bands were also highly correlated with atherosclerotic plaque ruptures and mural plaque hemorrhages, which may be secondary to coronary spasm. In 78.7% of the cases positive for contraction bands, the cause of death was related to a diagnosis possibly associated with high catecholamine levels. On the basis of experimental evidence and the correlations identified in this study, coronary artery medial smooth muscle contraction bands may represent a postmortem marker of antemortem coronary spasm.