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Tau is a microtubule-associated protein that stabilizes the neuronal cytoskeleton. In the family of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE), abnormal tau aggregation destabilizes microtubule structure, contributing to a cascade of cellular processes leading to neuronal cell death. The gut microbiome has increasingly become a target of neurodegenerative disease research since gut microbiome imbalances have been linked to protein aggregation and inflammation through a bidirectional axis linking the gut and brain. Accordingly, the present study examined tau-mediated changes to gut microbiome composition and immune activation in a Drosophila melanogaster model of human mutant tauopathy. Fecal deposit quantification and gastric emptying time courses suggested an abnormal food distribution and reduced gut motility in tau transgenic flies compared to controls. Tau transgenic flies also showed an increase in gut bacteria colony forming units (CFUs) from diluted fly homogenate, indicating an increased bacterial load. Finally, we showed that tau transgenic flies have a trend towards elevated systemic levels of antimicrobial peptides targeting gram-negative bacteria using qPCR, suggesting an enhanced innate immune response to bacterial insult. These data demonstrate qualifiable and quantifiable gut microbial and innate immune responses to tauopathy. Furthermore, these results provide a framework for future studies targeting the gut microbiome as a modifier of neurodegenerative disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rydbom, Kohl, Hyde and Lohr.)

Background: Mutations in LRRK2 are the most common cause of familial Parkinson's disease and typically cause disease in the context of abnormal aggregation and deposition of α-synuclein within affected brain tissue., Methods: We combine genetic analysis of Lrrk-associated toxicity in a penetrant Drosophila model of wild type human α-synuclein neurotoxicity with biochemical analyses and modeling of LRRK2 toxicity in human neurons and transgenic mouse models., Results: We demonstrate that Lrrk and α-synuclein interact to promote neuronal degeneration through convergent effects on the actin cytoskeleton and downstream dysregulation of mitochondrial dynamics and function. We find specifically that monomers and dimers of Lrrk efficiently sever actin and promote normal actin dynamics in vivo. Oligomerization of Lrrk, which is promoted by dominant Parkinson's disease-causing mutations, reduces actin severing activity in vitro and promotes excess stabilization of F-actin in vivo. Importantly, a clinically protective Lrrk mutant reduces oligomerization and α-synuclein neurotoxicity., Conclusions: Our findings provide a specific mechanistic link between two key molecules in the pathogenesis of Parkinson's disease, α-synuclein and LRRK2, and suggest potential new approaches for therapy development.

Vesicular trafficking defects, particularly those in the autophagolysosomal system, have been strongly implicated in the pathogenesis of Parkinson's disease and related α-synucleinopathies. However, mechanisms mediating dysfunction of membrane trafficking remain incompletely understood. Using a Drosophila model of α-synuclein neurotoxicity with widespread and robust pathology, we find that human α-synuclein expression impairs autophagic flux in aging adult neurons. Genetic destabilization of the actin cytoskeleton rescues F-actin accumulation, promotes autophagosome clearance, normalizes the autophagolysosomal system, and rescues neurotoxicity in α-synuclein transgenic animals through an Arp2/3 dependent mechanism. Similarly, mitophagosomes accumulate in human α-synuclein-expressing neurons, and reversal of excessive actin stabilization promotes both clearance of these abnormal mitochondria-containing organelles and rescue of mitochondrial dysfunction. These results suggest that Arp2/3 dependent actin cytoskeleton stabilization mediates autophagic and mitophagic dysfunction and implicate failure of autophagosome maturation as a pathological mechanism in Parkinson's disease and related α-synucleinopathies., Competing Interests: The authors have declared that no competing interests exist.

Mitochondrial and metabolic dysfunction are often implicated in neurological disease, but effective mechanism-based therapies remain elusive. We performed a genome-scale forward genetic screen in a Drosophila model of tauopathy, a class of neurodegenerative disorders characterized by the accumulation of the protein tau, and identified manipulation of the B-vitamin biotin as a potential therapeutic approach in tauopathy. We show that tau transgenic flies have an innate biotin deficiency due to tau-mediated relaxation of chromatin and consequent aberrant expression of multiple biotin-related genes, disrupting both carboxylase and mitochondrial function. Biotin depletion alone causes mitochondrial pathology and neurodegeneration in both flies and human neurons, implicating mitochondrial dysfunction as a mechanism in biotin deficiency. Finally, carboxylase biotin levels are reduced in mammalian tauopathies, including brains of human Alzheimer's disease patients. These results provide insight into pathogenic mechanisms of human biotin deficiency, the resulting effects on neuronal health, and a potential therapeutic pathway in the treatment of tau-mediated neurotoxicity., Competing Interests: The authors declare no competing interest.

A subset of people exposed to a traumatic event develops post-traumatic stress disorder (PTSD), which is associated with dysregulated fear behavior. Genetic variation in SLC18A2, the gene that encodes vesicular monoamine transporter 2 (VMAT2), has been reported to affect risk for the development of PTSD in humans. Here, we use transgenic mice that express either 5% (VMAT2-LO mice) or 200% (VMAT2-HI mice) of wild-type levels of VMAT2 protein. We report that VMAT2-LO mice have reduced VMAT2 protein in the hippocampus and amygdala, impaired monoaminergic vesicular storage capacity in both the striatum and frontal cortex, decreased monoamine metabolite abundance and a greatly reduced capacity to release dopamine upon stimulation. Furthermore, VMAT2-LO mice showed exaggerated cued and contextual fear expression, altered fear habituation, inability to discriminate threat from safety cues, altered startle response compared with wild-type mice and an anxiogenic-like phenotype, but displayed no deficits in social function. By contrast, VMAT2-HI mice exhibited increased VMAT2 protein throughout the brain, higher vesicular storage capacity and greater dopamine release upon stimulation compared with wild-type controls. Behaviorally, VMAT2-HI mice were similar to wild-type mice in most assays, with some evidence of a reduced anxiety-like responses. Together, these data show that presynaptic monoamine function mediates PTSD-like outcomes in our mouse model, and suggest a causal link between reduced VMAT2 expression and fear behavior, consistent with the correlational relationship between VMAT2 genotype and PTSD risk in humans. Targeting this system is a potential strategy for the development of pharmacotherapies for disorders like PTSD., (© 2020 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

We report a case of calcium pyrophosphate deposition disease (CPPD) with an unusual presentation of severe chondrocalcinosis with atypical large burden deposited in the metacarpophalangeal joints as well as more typical deposition in wrists and knees as demonstrated on plain radiographs. A 77-year-old African-American woman 1-year status post parathyroidectomy for hyperparathyroidism initially presented to the rheumatology clinic to treat suspected rheumatoid arthritis given her pattern of joint involvement but was found to have CPPD. The patient's history is notable for end-stage renal disease which complicates medical management. This case illustrates radiographic findings of CPPD and explores the challenges of treating CPPD in the setting of comorbid conditions., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Vesicular monoamine transporter 2 (VMAT2, SLC18A2) is a transmembrane transporter protein that packages dopamine, serotonin, norepinephrine, and histamine into vesicles in preparation for neurotransmitter release from the presynaptic neuron. VMAT2 function and related vesicle dynamics have been linked to susceptibility to oxidative stress, exogenous toxicants, and Parkinson's disease. To address a recent depletion of commonly used antibodies to VMAT2, we generated and characterized a novel rabbit polyclonal antibody generated against a 19 amino acid epitope corresponding to an antigenic sequence within the C-terminal tail of mouse VMAT2. We used genetic models of altered VMAT2 expression to demonstrate that the antibody specifically recognizes VMAT2 and localizes to synaptic vesicles. Furthermore, immunohistochemical labeling using this VMAT2 antibody produces immunoreactivity that is consistent with expected VMAT2 regional distribution. We show the distribution of VMAT2 in monoaminergic brain regions of mouse brain, notably the midbrain, striatum, olfactory tubercle, dopaminergic paraventricular nuclei, tuberomammillary nucleus, raphe nucleus, and locus coeruleus. Normal neurotransmitter vesicle dynamics are critical for proper health and functioning of the nervous system, and this well-characterized VMAT2 antibody will be a useful tool in studying neurodegenerative and neuropsychiatric conditions characterized by vesicular dysfunction., (Copyright © 2016. Published by Elsevier B.V.)

Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to l-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted α-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.

Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) are regulators of dopamine homeostasis in the presynaptic neuron. DAT transports dopamine from the extracellular space into the cytosol of the presynaptic terminal. VMAT2 then packages this cytosolic dopamine into vesicular compartments for subsequent release upon neurotransmission. Thus, DAT and VMAT2 act in concert to move the transmitter efficiently throughout the neuron. Accumulation of dopamine in the neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of dopamine is critical for neuron function and risk of disease. For decades, studies have examined the effects of reduced transporter function in mice (e.g. DAT-KO, VMAT2-KO, VMAT2-deficient). However, we have only recently been able to assess the effects of elevated transporter expression using BAC transgenic methods (DAT-tg, VMAT2-HI mice). Complemented with in vitro work and neurochemical techniques to assess dopamine compartmentalization, a new focus on the importance of transporter proteins as both models of human disease and potential drug targets has emerged. Here, we review the importance of DAT and VMAT2 function in the delicate balance of neuronal dopamine., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.

Drugs of abuse induce sensitization, which is defined as enhanced response to additional drug following a period of withdrawal. Sensitization occurs in both humans and animal models of drug reinforcement and contributes substantially to the addictive nature of drugs of abuse, because it is thought to represent enhanced motivational wanting for drug. The ventral pallidum, a key member of the reward pathway, contributes to behaviors associated with reward, such as sensitization. Dopamine inputs to the ventral pallidum have not been directly characterized. Here we provide anatomical, neurochemical, and behavioral evidence demonstrating that dopamine terminals in the ventral pallidum contribute to reward in mice. We report subregional differences in dopamine release, measured by ex vivo fast-scan cyclic voltammetry: rostral ventral pallidum exhibits increased dopamine release and uptake compared with caudal ventral pallidum, which is correlated with tissue expression of dopaminergic proteins. We then subjected mice to a methamphetamine-sensitization protocol to investigate the contribution of dopaminergic projections to the region in reward related behavior. Methamphetamine-sensitized animals displayed a 508% and 307% increase in baseline dopamine release in the rostral and caudal ventral pallidum, respectively. Augmented dopamine release in the rostral ventral pallidum was significantly correlated with sensitized locomotor activity. Moreover, this presynaptic dopaminergic plasticity occurred only in the ventral pallidum and not in the ventral or dorsal striatum, suggesting that dopamine release in the ventral pallidum may be integrally important to drug-induced sensitization.

The vesicular monoamine transporter 2 (VMAT2) packages neurotransmitters for release during neurotransmission and sequesters toxicants into vesicles to prevent neuronal damage. In mice, low VMAT2 levels causes catecholaminergic cell loss and behaviors resembling Parkinson's disease, while high levels of VMAT2 increase dopamine release and protect against dopaminergic toxicants. However, comparisons across these VMAT2 mouse genotypes were impossible due to the differing genetic background strains of the animals. Following back-crossing to a C57BL/6 line, we confirmed that mice with approximately 95% lower VMAT2 levels compared with wild-type (VMAT2-LO) display significantly reduced vesicular uptake, progressive dopaminergic terminal loss with aging, and exacerbated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Conversely, VMAT2-overexpressing mice (VMAT2-HI) are protected from the loss of striatal terminals following MPTP treatment. We also provide evidence that enhanced vesicular filling in the VMAT2-HI mice modifies the handling of newly synthesized dopamine, indicated by changes in indirect measures of extracellular dopamine clearance. These results confirm the role of VMAT2 in the protection of vulnerable nigrostriatal dopamine neurons and may also provide new insight into the side effects of L-DOPA treatments in Parkinson's disease., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We previously demonstrated that mice with reduced expression of the vesicular monoamine transporter 2 (VMAT2 LO) undergo age-related degeneration of the catecholamine-producing neurons of the substantia nigra pars compacta and locus ceruleus and exhibit motor disturbances and depressive-like behavior. In this work, we investigated the effects of reduced vesicular transport on the function and viability of serotonin neurons in these mice. Adult (4-6 months of age), VMAT2 LO mice exhibit dramatically reduced (90%) serotonin release capacity, as measured by fast scan cyclic voltammetry. We observed changes in serotonin receptor responsivity in in vivo pharmacological assays. Aged (months) VMAT2 LO mice exhibited abolished 5-HT1A autoreceptor sensitivity, as determined by 8-OH-DPAT (0.1 mg/kg) induction of hypothermia. When challenged with the 5HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (1 mg/kg), VMAT2 LO mice exhibited a marked increase (50%) in head twitch responses. We observed sparing of serotonergic terminals in aged mice (18-24 months) throughout the forebrain by SERT immunohistochemistry and [(3)H]-paroxetine binding in striatal homogenates of aged VMAT2 LO mice. In contrast to their loss of catecholamine neurons of the substantia nigra and locus ceruleus, aged VMAT2 LO mice do not exhibit a change in the number of serotonergic (TPH2+) neurons within the dorsal raphe, as measured by unbiased stereology at 26-30 months. Collectively, these data indicate that reduced vesicular monoamine transport significantly disrupts serotonergic signaling, but does not drive degeneration of serotonin neurons., (Copyright © 2015. Published by Elsevier Inc.)

Mycobacterium marinum infection has been historically associated with exposure to aquariums, swimming pools, fish, or other marine fauna. We present a case of M marinum left wrist tenosynovitis and elbow bursitis associated with a puncture injury and exposure to coal mine water in Illinois.

Objective: The American College of Rheumatology (ACR) Adult Rheumatology In-Training Examination (ITE) is a feedback tool designed to identify strengths and weaknesses in the content knowledge of individual fellows-in-training and the training program curricula. We determined whether scores on the ACR ITE, as well as scores on other major standardized medical examinations and competency-based ratings, could be used to predict performance on the American Board of Internal Medicine (ABIM) Rheumatology Certification Examination., Methods: Between 2008 and 2012, 629 second-year fellows took the ACR ITE. Bivariate correlation analyses of assessment scores and multiple linear regression analyses were used to determine whether ABIM Rheumatology Certification Examination scores could be predicted on the basis of ACR ITE scores, United States Medical Licensing Examination scores, ABIM Internal Medicine Certification Examination scores, fellowship directors' ratings of overall clinical competency, and demographic variables. Logistic regression was used to evaluate whether these assessments were predictive of a passing outcome on the Rheumatology Certification Examination., Results: In the initial linear model, the strongest predictors of the Rheumatology Certification Examination score were the second-year fellows' ACR ITE scores (β = 0.438) and ABIM Internal Medicine Certification Examination scores (β = 0.273). Using a stepwise model, the strongest predictors of higher scores on the Rheumatology Certification Examination were second-year fellows' ACR ITE scores (β = 0.449) and ABIM Internal Medicine Certification Examination scores (β = 0.276). Based on the findings of logistic regression analysis, ACR ITE performance was predictive of a pass/fail outcome on the Rheumatology Certification Examination (odds ratio 1.016 [95% confidence interval 1.011-1.021])., Conclusion: The predictive value of the ACR ITE score with regard to predicting performance on the Rheumatology Certification Examination supports use of the Adult Rheumatology ITE as a valid feedback tool during fellowship training., (© 2015, American College of Rheumatology.)

Preferential dysfunction/degeneration of midbrain substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons contributes to the main movement symptoms manifested in Parkinson's disease (PD). Although the Leucine-rich repeat kinase 2 (LRRK2) G2019S missense mutation (LRRK2 G2019S) is the most common causative genetic factor linked to PD, the effects of LRRK2 G2019S on the function and survival of SNpc DA neurons are poorly understood. Using a binary gene expression system, we generated transgenic mice expressing either wild-type human LRRK2 (WT mice) or the LRRK2 G2019S mutation (G2019S mice) selectively in the midbrain DA neurons. Here we show that overexpression of LRRK2 G2019S did not induce overt motor abnormalities or substantial SNpc DA neuron loss. However, the LRRK2 G2019S mutation impaired dopamine homeostasis and release in aged mice. This reduction in dopamine content/release coincided with the degeneration of DA axon terminals and decreased expression of DA neuron-enriched genes tyrosine hydroxylase (TH), vesicular monoamine transporter 2, dopamine transporter and aldehyde dehydrogenase 1. These factors are responsible for dopamine synthesis, transport and degradation, and their expression is regulated by transcription factor paired-like homeodomain 3 (PITX3). Levels of Pitx3 mRNA and protein were similarly decreased in the SNpc DA neurons of aged G2019S mice. Together, these findings suggest that PITX3-dependent transcription regulation could be one of the many potential mechanisms by which LRRK2 G2019S acts in SNpc DA neurons, resulting in downregulation of its downstream target genes critical for dopamine homeostasis and release., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The psychostimulant methamphetamine (METH) is highly addictive and neurotoxic to dopamine terminals. METH toxicity has been suggested to be due to the release and accumulation of dopamine in the cytosol of these terminals. The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is a critical mediator of dopamine handling. Mice overexpressing VMAT2 (VMAT2-HI) have an increased vesicular capacity to store dopamine, thus augmenting striatal dopamine levels and dopamine release in the striatum. Based on the altered compartmentalization of intracellular dopamine in the VMAT2-HI mice, we assessed whether enhanced vesicular function was capable of reducing METH-induced damage to the striatal dopamine system. While wildtype mice show significant losses in striatal levels of the dopamine transporter (65% loss) and tyrosine hydroxylase (46% loss) following a 4 × 10 mg/kg METH dosing regimen, VMAT2-HI mice were protected from this damage. VMAT2-HI mice were also spared from the inflammatory response that follows METH treatment, showing an increase in astroglial markers that was approximately one-third of that of wildtype animals (117% vs 36% increase in GFAP, wildtype vs VMAT2-HI). Further analysis also showed that elevated VMAT2 level does not alter the ability of METH to increase core body temperature, a mechanism integral to the toxicity of the drug. Finally, the VMAT2-HI mice showed no difference from wildtype littermates on both METH-induced conditioned place preference and in METH-induced locomotor activity (1 mg/kg METH). These results demonstrate that elevated VMAT2 protects against METH toxicity without enhancing the rewarding effects of the drug. Since the VMAT2-HI mice are protected from METH despite higher basal dopamine levels, this study suggests that METH toxicity depends more on the proper compartmentalization of synaptic dopamine than on the absolute amount of dopamine in the brain.

Epidemiological studies indicate exposures to the herbicide paraquat (PQ) and fungicide maneb (MB) are associated with increased risk of Parkinson's disease (PD). Oxidative stress appears to be a premier mechanism that underlies damage to the nigrostriatal dopamine system in PD and pesticide exposure. Enhanced oxidative stress leads to lipid peroxidation and production of reactive aldehydes; therefore, we conducted proteomic analyses to identify carbonylated proteins in the striatum and cortex of pesticide-treated mice in order to elucidate possible mechanisms of toxicity. Male C57BL/6J mice were treated biweekly for 6 weeks with saline, PQ (10 mg/kg), MB (30 mg/kg), or the combination of PQ and MB (PQMB). Treatments resulted in significant behavioral alterations in all treated mice and depleted striatal dopamine in PQMB mice. Distinct differences in 4-hydroxynonenal-modified proteins were observed in the striatum and cortex. Proteomic analyses identified carbonylated proteins and peptides from the cortex and striatum, and pathway analyses revealed significant enrichment in a variety of KEGG pathways. Further analysis showed enrichment in proteins of the actin cytoskeleton in treated samples, but not in saline controls. These data indicate that treatment-related effects on cytoskeletal proteins could alter proper synaptic function, thereby resulting in impaired neuronal function and even neurodegeneration.

Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease.

Giant cell arteritis (GCA) is an autoimmune disorder characterized by the inflammation of medium to large vessels. Although classic descriptions have centered on features such as vision loss, headaches, fevers, and jaw claudication, there is increasing recognition of more atypical manifestations. We report a case of GCA in a 77-year-old male patient initially presenting with depressed mood and headache. His psychiatric symptoms promptly responded to treatment with corticosteroids without the use of antidepressants. This case adds to the literature that GCA may initially present with affective or psychotic symptoms and highlights the need for clinicians to consider GCA in the differential diagnosis for new-onset psychiatric disorders in the elderly.

Flourine-18 fluoro-2-deoxy-glucose ((18)F-FDG) positron emission tomography combined with computed tomography (PET/CT) is a useful test for the management of malignant conditions. Inflammatory and infectious processes, however, can cause increased uptake on PET scanning, often causing diagnostic dilemmas. This knowledge is important to the rheumatologist not only because of the inflammatory conditions we treat but also because certain rheumatic diseases impose an increased risk of malignancy either due to the disease itself or as a consequence of medications used to treat the rheumatic diseases. There is an increasing body of evidence investigating the role of PET scans in inflammatory conditions. This paper describes a patient with rheumatoid arthritis who developed pulmonary nodules that showed increased uptake on PET/CT scan and reviews the use of PET scanning in the diagnosis and management of rheumatoid arthritis.

The retrotrapezoid nucleus (RTN) is thought to regulate breathing in response to changes in blood carbon dioxide (CO(2)), and to make a vital contribution to respiratory drive, especially during sleep. However, cells in the female RTN fail to upregulate c-fos in response to low level CO(2) exposure, while cells in the male RTN have a robust upregulation of c-fos in response to low level CO(2) exposure. In this study, we examined the possibility that the female RTN has a higher threshold for c-fos upregulation in response to CO(2). Following exposure of Fos-Tau-LacZ (FTL) transgenic mice to 10% CO(2), c-fos was upregulated in just as many cells in the female as in the male RTN. In addition, the male RTN responded equivalently to 5% and 10% CO(2), consistent with a lack of a dose response to CO(2) in the male RTN. Cells in the nearby facial nucleus upregulated c-fos in the same number of cells regardless of sex or gas exposure, confirming that the sex difference in the RTN is unique to that nucleus. We propose that the male and female RTN upregulate c-fos differently in response to CO(2) due to differences in the transcriptional regulation by estrogens of genes that encode proteins related to neuronal excitability or specifically related to central chemoreception, such as potassium channels. These findings could have clinical relevance to sleep related breathing disorders that disproportionately affect males, including the sudden infant death syndrome and sleep apnea., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Relapsing polychondritis (RP) is a disease characterized by inflammation and the destruction of cartilage. The detection of antibodies to native type II collagen (CII) in the sera of some patients with relapsing polychondritis suggests that autoimmunity to this cartilage specific protein plays a role in the pathogenesis of the disease. RP is so rare that controlled therapeutic trials have not been carried out. We describe herein a child with RP who had amelioration of symptoms and a deviation in the cellular immune response to CII after being treated with daily oral CII as a toleragen.

Objective: To investigate the efficacy of oral type II collagen (CII) in the treatment of rheumatoid arthritis (RA), when added to existing therapy., Methods: Patients with active RA (n = 190) were randomized into a 6-month, double-blind, placebo-controlled trial. Patients continued to take their current arthritis medications. Patients received either placebo or bovine CII, 0.1 mg/day for 1 month, then 0.5 mg/day for 5 months., Results: There were no significant differences between the baseline characteristics of either group. The primary response parameter was the American College of Rheumatology (ACR) preliminary definition of improvement in RA (ACR 20). There was no statistically significant difference in the ACR 20 after 6 months (20.0% of placebo patients; 16.84% of bovine CII patients). There were significant differences in several clinical variables after treatment, all favoring the placebo group., Conclusion: Oral solubilized bovine CII, added to existing therapy, did not improve disease activity in patients with RA.

The syndrome of pseudothrombophlebitis is a well-known complication of popliteal cysts. We report the case of a patient with a neuropathic arthropathy of the shoulder in whom pseudothrombophlebitis of the upper extremity subsequently developed. To our knowledge, this is the first such case that has been reported.

Three months after splenic infarct, a 50-year-old woman underwent arteriography for persistent low-grade fever and abdominal complaints. After 5 months of corticosteroid therapy for "polyarteritis nodosa," another arteriogram confirmed embolic disease; transesophageal echocardiography (TEE) showed a pedunculated mobile thrombus in the aortic arch. We suggest this represents "pseudovasculitis" from an aortic thrombus.

In the animal model of tyrosinemia II only corneas from tyrosine(tyr)-fed rats produce chemoattractants in organ culture. To study the role of neutrophils (PMNs) in production of these chemoattractants, leukocytes (WBCs) were depleted using i.p. cyclophosphamide (CP). Saline (SAL)-treated rats maintained 18,375 +/- 894 WBC/mm3 (mean +/- SEM) with 4168 +/- 424 PMNs. Rats receiving CP (150 mg/kg day 0, 75 mg/kg day 4) has 1565 +/- 170 WBC (565 +/- 129 PMN) on day 3, and 398 +/- 68 WBC (19 +/- 5 PMN) on day 8. Rats ate a low-protein +/- 5% tyr diet on days 4-8. Only SAL-treated tyr-fed rats developed plaque-like gray epithelial lesions; histopathology showed corneal epithelial necrosis, stromal edema, and epithelial and stromal PMN infiltration. Control and CP-treated tyr-fed rat corneas showed no inflammation. On day 8 corneas were cultured in RPMI 1640 + 5% heat-inactivated fetal bovine serum. After 3 days, supernatants were assayed for chemotactic activity (leading front method); data were expressed as the percentage of peritoneal PMN migration relative to 5% zymosan-activated rat serum. The mean total migration toward 75% supernatant from SAL-treated, tyr-fed rat corneas was 79%, whereas migration toward corneal supernatants from controls and CP-treated tyr-fed rats ranged from 42-48%. Corneal extracts were assayed for proteolytic activity. WBC depletion prevented the increase in cathepsin B- and D-like activities present in tyr-fed corneas, suggesting that PMNs were a major source of these enzymes. The data suggest that WBC depletion reduces both corneal inflammation in vivo and the production of chemotactic activity by tyr-fed corneas in culture.

Corneal inflammation with subsequent scarring and blindness occurs in the inherited human metabolic disease tyrosinemia type II, yet putative inflammatory mediators in this disorder and in the avascular cornea in general are poorly defined. In a Tyr-fed rat model of tyrosinemia type II, intracellular crystals, presumably Tyr, are hypothesized to be responsible for the increased lysosomal activity observed in corneal epithelial lesions. Because polymorphonuclear leukocytes (PMNs) are seen only at the site of these lesions, we used this model to study humoral mediators released from Tyr-fed rat corneal organ cultures. Only Tyr-fed rats developed stromal edema and linear granular opacities in gray edematous corneal epithelium, compatible with a noninfectious keratitis. Electron micrographs confirmed epithelial edema and showed focal epithelial necrosis with PMN invasion of the stroma. Only Tyr-fed rat corneal culture supernatants contained chemotactic activity that was heat labile and moderately trypsin sensitive. Four peaks with varying amounts of chemotactic activity were found on Sephadex G-75 chromatography. Although the identity of these peaks of activity has not yet been established, we suggest that they may be responsible for the PMN infiltration observed in this model of corneal inflammation.

Wegener's granulomatosis rarely involves the pituitary, and is limited to the posterior gland. A young woman developed sinusitis, otitis media, asymptomatic pulmonary density, blindness, and anterior pituitary hormone deficiency over 7 years. Mucosal biopsies showed only chronic necrotizing inflammation without vasculitis. Since her clinical course suggested an atypical presentation of Wegener's granulomatosis, cyclophosphamide was finally added to corticosteroid therapy. All symptoms but monocular blindness and hypopituitarism remitted.

An institution-wide program for residents impaired by alcohol, other drugs, or emotional problems was established in 1983 at the Medical College of Wisconsin Affiliated Hospitals. The goal of the program was to help impaired house staff members to continue their training in a nonpunitive environment. An approach to reviewing allegations of impairment and a legal agreement between the hospital and the recovering resident were implemented. Because no residents were reported for impairment during its first two years, the program's emphasis was shifted from an investigative to an educational, assistive role. Major problems in carrying out the program have been the program's lack of authority to ensure cooperation by program directors and by impaired residents; a widespread unfamiliarity with intervention procedures despite efforts to inform residents, their spouses, faculty members, and administrators about the program; and misconceptions that the program is punitive. Further impediments are lack of a budget to provide educational activities, inadequate socializing between the faculty and the house staff that would enable faculty members to recognize early signs of impairment; and inadequate health insurance coverage for long-term treatment.

A patient with ankylosing spondylitis (AS) for 10 years suddenly developed localized midback pain after minimal activity. Although he sought immediate medical assistance, recognition of a septic spondylodiscitis was delayed 3 weeks. One day after admission, he developed fever and admitted to intravenous drug use. Staphylococcus aureus empyema and spondylodiscitis were subsequently diagnosed. Clinical differentiation of aseptic from septic spondylodiscitis cannot be ignored in patients with AS.

Phenothiazines depress Ca++-dependent neutrophil functions, perhaps by binding to calmodulin or perturbing membrane structure through hydrophobic interactions. We examined effects of chlorpromazine (CPZ) on the human polymorphonuclear neutrophil (PMN) chemotactic-oligopeptide receptor and PMN membrane fluidity. CPZ had a reversible, biphasic effect on PMN motility in the Boyden chamber (slight depression at 5 microM, enhancement at 10 microM, and dose-dependent inhibition at higher concentrations). Order of potency for inhibition of motility (trifluoperazine greater than CPZ greater than promethazine) was identical to that for both inhibition of superoxide (O-2) release and binding to calmodulin. CPZ nonspecifically altered the binding affinity of chemotactic fMet-Leu-[3H]Phe. As assessed with two spin-probes, PMN membrane fluidity was unaltered at CPZ concentrations that depressed PMN receptor-mediated chemotaxis and O-2 release. The data suggest that CPZ nonspecifically alters receptor affinity and depresses chemotaxis and O-2 release independently, without altering bulk membrane fluidity. We speculate that unidentified "post-receptor changes" at a common translocation step for functions tested account for the observed inhibition.

Rheumatic manifestations of substance abuse are uncommon but recognized complications. Repeated injections of drugs and adulterants represent repeated antigenic challenge. The population at greatest risk is that of young males, although females with eating disorders are more apt to develop myopathy, clubbing, or periostitis. Alcohol, the most common substance abused, is associated more often with myopathy. In IV drug abusers, hepatitis B viral infection, bacterial endocarditis, primary skeletal infections, and venous complications are most common in that order. However, the spectrum may evolve as the pattern of substance abuse changes. First, the frequency of cocaine dependence is rapidly approaching that of alcohol. Two regular cocaine users are reported as having Raynaud's phenomenon and abnormal serologies. Second, synthesis of lookalike drugs may produce new associations, such as parkinsonism after IV N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Third, the increased use of ipecac and purgatives in eating disorders is an important consideration in young women with otherwise unexplained myopathy or arthritis. Finally, patients with AIDS are presenting with autoimmune phenomena or a spectrum of unusual infections that change as the epidemic evolves. Increased recognition of these symptom complexes may lead to earlier, more accurate diagnoses and avoidance of unnecessary diagnostic evaluations and delays in treatment.

A model to study the immune system in Pseudomonas keratitis was developed using defined flora rats (WAG/RijMCW) that have not been exposed to Pseudomonas aeruginosa. One group of rats was made immunocompetent towards P. aeruginosa by intraperitoneal injection of phenol-killed P. aeruginosa while a second group remained naive to this organism. Corneas of both groups were scratched centrally with a 21-g needle, before inoculation with 2 X 10(8) P. aeruginosa organisms. Corneas of control animals were either only scratched or only inoculated with the bacterium. At 18 hr, the naive animals were killed. In naive rat corneas, light and electron microscopy showed bacteria throughout the cornea, polymorphonuclear leukocytes (PMNs) distributed from the limbus towards the center, and little stromal degradation. In contrast, massive corneal degradation was observed in the immunocompetent rats; PMNs were present, but no bacteria were observed free in the stroma. The total acid protease content was higher in the immunocompetent than in the naive rat corneas, a possible reason for the observed difference in corneal degradation. This difference was not due to increased numbers of PMNs since nearly equal numbers of PMNs were counted after enzymatic disaggregation of both types of corneas. Glycogen-induced peritoneal PMNs from both types of rats migrated equally well towards P. aeruginosa culture media and media of corneas incubated with this bacterium. The authors conclude that immune recognition is (1) involved in the corneal host response to P. aeruginosa and (2) required for efficient phagocytosis by PMNs but not their recruitment.

Leukocyte chemotaxis is initiated by the binding of chemotactic factors to specific, high-affinity receptors. Amphotericin B, a polyene antibiotic that binds to membrane cholesterol, inhibits human neutrophil (PMN) chemotaxis. We examined the effects of this drug on PMN functions mediated by the oligopeptide chemotactic factor receptor. The antibiotic irreversibly inhibited chemotaxis and depressed the binding of the radiolabeled chemoattractant, fMet-Leu-[3H]Phe, to its receptor without affecting the receptor's specificity. The drug lowered the binding affinity of the receptor by up to fivefold and slightly increased its number. Doses of amphotericin B that depressed receptor affinity and inhibited chemotaxis did not diminish lysosomal enzyme secretion or superoxide anion production. Nystatin, a less potent polyene antibiotic, also diminished chemotactic factor binding, but to a lesser degree than amphotericin B did. A chemically unrelated antifungal agent had no effect on either binding or chemotaxis. Thus, pharmacologic manipulation can alter the affinity of the chemotactic factor receptor on human PMN; this alteration is associated with a change in receptor function. The data suggest that receptor affinity regulates or at least reflects its functional state, and that the transduction mechanisms for various biologic responses mediated by the chemoattractant receptor are heterogeneous. By pharmacologic alterations of receptor affinity, one may be able to modulate specific biologic responses elicited by chemoattractant receptor-ligand interactions.