Over 100 years ago, Robert Koch introduced his ideas about how to prove a causal relationship between a microorganism and a disease. Koch's postulates created a scientific standard for causal evidence that established the credibility of microbes as pathogens and led to the development of modern microbiology. In more recent times, Koch's postulates have evolved to accommodate a broader understanding of the host-parasite relationship as well as experimental advances. Techniques such as in situ hybridization, PCR, and representational difference analysis reveal previously uncharacterized, fastidious or uncultivated, microbial pathogens that resist the application of Koch's original postulates, but they also provide new approaches for proving disease causation. In particular, the increasing reliance on sequence-based methods for microbial identification requires a reassessment of the original postulates and the rationale that guided Koch and later revisionists. Recent investigations of Whipple's disease, human ehrlichiosis, hepatitis C, hantavirus pulmonary syndrome, and Kaposi's sarcoma illustrate some of these issues. A set of molecular guidelines for establishing disease causation with sequence-based technology is proposed, and the importance of the scientific concordance of evidence in supporting causal associations is emphasized.

Whipple's disease of the central nervous system (CNS) may be associated with normal intestinal histology as a result of minimal or patchy involvement. The diagnosis is difficult and is frequently made post mortem. We studied 6 patients with clinically suspected CNS Whipple's disease; 2 had oculomasticatury myorhythmia (OMM) fitting criteria for a diagnosis of definite CNS Whipple's disease. One of the 2 had duodenal histology highly suggestive of Whipple's disease the other 5 patients had normal duodenal histology. DNA was extracted from paraffin-embedded duodenal tissues in all patients and frozen pontine tissue in 1. Two primer pairs (W3F-W4R, W3F-W2R) were used in separate polymerase chain reactions (PCRs) to amplify fragments of Tropberyma whippelii 16S rDNA from these tissue samples. PCR amplicons were detected only in the duodenal tissues from the 2 patients with OMM. The sequences of these amplicons were identical to the corresponding region of the previously published Tropheryma whippelii 16S rDNA sequence. PCR-based assays of intestinal or brain tissue may be of value for confirming, and possibly refuting, a clinical diagnosis of CNS Whipple's disease in a patient with any combination of dementia, supranuclear gaze palsy, hypothalamic manifestations, myoclonus, seizures, ataxia, or OMM, especially when tissue histology is unrevealing.

Background : PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. Objective : To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive‐enhancing medications. Methods : Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21‐24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive‐enhancing medications. The primary outcome measure was change in the PD‐adapted Scale for the Assessment of Positive Symptoms. Results : Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; –6.62 vs. –0.91; P = 0.002) versus the cognitively unimpaired (n = 135; –5.50 vs. –3.23; p = 0.046) group. The comparable change was –6.04 versus –2.18 ( P = 0.012) and –5.66 versus –3.15 ( P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive‐enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive‐enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. Conclusions : The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive‐enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

No abstract

No abstract

Parkinson's disease psychosis (PDP) is a clinical condition that affects patients diagnosed with Parkinson's disease (PD) and has a spectrum of neuropsychiatric symptoms distinct from the hallmark motor symptoms. Although prior studies have reported on the prevalence of PDP in select European nations, variations in study design complicate study-to-study comparisons. In this study, we surveyed 1,667 medical practitioners across France, Germany, Italy, Spain, and the UK (collectively, the EU-5) to estimate the prevalence of PDP or symptoms of psychosis among patients with PD. Analysis of the survey data suggest approximately 29% of the general PD population in the EU-5 exhibit signs of PDP. Among the PD population, country-specific rates of PDP are estimated at 30% in France, 27% in Germany, 34% in Italy, 30% in Spain and 21% in the UK. These rates appear in line with those reported in prior country-specific studies. Results from the subset of 437 neurologists who proceeded to take the full survey suggest the symptoms of PDP are disruptive to patients or their respective caregivers in approximately 53% of cases. These results provide a resource that enables cross-country comparison of PDP rates across these major European nations.

Over half of patients with Parkinson’s disease (PD) develop symptoms of psychosis during the course of their disease. Existing guidelines include recommendations for managing symptoms of psychosis in patients with PD. However, the extent to which such recommendations translate to clinical practice in major European nations is unclear. The current study describes trends in the clinical management of patients diagnosed with PD psychosis (PDP) based on survey responses and patient chart reviews from 437 neurologists across France, Germany, Italy, Spain, and the UK (collectively, the EU-5). Surveyed neurologists reported that PDP typically manifests four or more years after the diagnosis of PD, with the most commonly reported initial symptoms being moderately disruptive visual hallucinations, agitation, and illusions/false sense of presence. PD medications adjustment was the most common first-line intervention, applicable to an estimated 59–79% of patients for the initial management of PDP depending on country. Responses from surveyed neurologists suggest PD medications adjustment is a temporary solution for many patients with PDP and that there is considerable variability in subsequent lines of intervention. The current report provides a resource for understanding the patterns of care and treatment for PDP across these major European nations.

had > 2 opioid prescriptions, we identified beneficiaries with high-dose use (> 120 daily morphine milligram equivalents for ≥ 90 consecutive days) and multiple providers (≥ 4 prescribers and ≥ 4 pharmacies) each year; and concurrent benzodiazepine use (≥ 30 cumulative days) from 2013-2015 when Part D began coverage for benzodiazepines. We obtained adjusted annual rates of high-risk measures across 306 hospital referral regions (HRRs) using multivariable logistic regression and examined the association between these measures and overdose risk(claimbased) in the subsequent year using Cox proportional regression, adjusting for sociodemographic, health status, and access-to-care factors. ReSultS: Adjusted annual rates of high-dose use (~9%), having multiple providers(~5%), and concurrent benzodiazepine use (~34%) remained stable over five years. In 2015, the ratio of 75th-to-25th percentile rates of high-risk measures across HRRs were 1.80 for high-dose use, 1.87 for having multiple providers, and 1.33 for concurrent benzodiazepine use. The top 3 HRRs with the highest rate of: high-dose use were Sarasota, FL(17.2%), Sun City, AZ(17.2%) and Clearwater, FL(16.9%); multiple providers were Slidell, LA(14.0%), Muskegon, MI(12.5%), and Bryan, TX(12.0%); and concurrent benzodiazepine use were Dearborn, MI(58.0%), Miami, FL(55.4%), and Spartanburg, SC(55.1%). These measures were associated with subsequent overdose risk for high-dose (hazard ratio [HR]= 2.19, 95%CI= 1.86-2.57); multiple providers (HR= 1.58,; and concurrent benzodiazepine use (HR= 1.82, 95%CI= 1.58-2.10). ConCluSionS: High-risk opioid use measures were associated with overdose risk among disabled Medicare beneficiaries. Areas and individuals with prevalent high-risk opioid use may benefit from targeted interventions (e.g.,lock-in programs) to prevent overdose. MH4