Clinical electrophysiology of axonal polyneuropathies.

Axonal neuropathies encompass a wide range of acquired and inherited disorders with electrophysiologic characteristics that arise from the unique neurophysiology of the axon. Accurate interpretation of nerve conduction studies and electromyography requires an in-depth understanding of the pathophysiology of the axon. Here we review the unique neurophysiologic properties of the axon and how they relate to clinical electrodiagnostic features. We review the length-dependent Wallerian or "dying-back" processes as well as the emerging body of literature from acquired axonal neuropathies that highlights the importance of axonal disease at the nodes of Ranvier. Neurophysiologic features of individual inherited and acquired axonal diseases, including primary nerve disease as well as systemic immune mediated, metabolic, and toxic diseases involving the peripheral nerve, are reviewed. This comprehensive review of electrodiagnostic findings coupled with the current understanding of pathophysiology will aid the clinician in the evaluation of axonal polyneuropathies.

Fine grained compositional analysis of Port Everglades Inlet microbiome using high throughput DNA sequencing.

BACKGROUND: Similar to natural rivers, manmade inlets connect inland runoff to the ocean. Port Everglades Inlet (PEI) is a busy cargo and cruise ship port in South Florida, which can act as a source of pollution to surrounding beaches and offshore coral reefs. Understanding the composition and fluctuations of bacterioplankton communities ("microbiomes") in major port inlets is important due to potential impacts on surrounding environments. We hypothesize seasonal microbial fluctuations, which were profiled by high throughput 16S rRNA amplicon sequencing and analysis. METHODS & RESULTS: Surface water samples were collected every week for one year. A total of four samples per month, two from each sampling location, were used for statistical analysis creating a high sampling frequency and finer sampling scale than previous inlet microbiome studies. We observed significant differences in community alpha diversity between months and seasons. Analysis of composition of microbiomes (ANCOM) tests were run in QIIME 2 at genus level taxonomic classification to determine which genera were differentially abundant between seasons and months. Beta diversity results yielded significant differences in PEI community composition in regard to month, season, water temperature, and salinity. Analysis of potentially pathogenic genera showed presence of Staphylococcus and Streptococcus. However, statistical analysis indicated that these organisms were not present in significantly high abundances throughout the year or between seasons. DISCUSSION: Significant differences in alpha diversity were observed when comparing microbial communities with respect to time. This observation stems from the high community evenness and low community richness in August. This indicates that only a few organisms dominated the community during this month. August had lower than average rainfall levels for a wet season, which may have contributed to less runoff, and fewer bacterial groups introduced into the port surface waters. Bacterioplankton beta diversity differed significantly by month, season, water temperature, and salinity. The 2013-2014 dry season (October-April), was warmer and wetter than historical averages. This may have driven significant differences in beta diversity. Increased nitrogen and phosphorous concentrations were observed in these dry season months, possibly creating favorable bacterial growth conditions. Potentially pathogenic genera were present in the PEI. However their relatively low, non-significant abundance levels highlight their relatively low risk for public health concerns. This study represents the first to sample a large port at this sampling scale and sequencing depth. These data can help establish the inlet microbial community baseline and supplement the vital monitoring of local marine and recreational environments, all the more poignant in context of local reef disease outbreaks and worldwide coral reef collapse in wake of a harsh 2014-16 El Niño event.

Rapidly Progressive Quadriplegia and Encephalopathy.

A woman aged 77 years was transferred to our neurocritical care unit for evaluation and treatment of rapidly progressive motor weakness and encephalopathy. Examination revealed an ability to follow simple commands only and abnormal movements, including myoclonus, tongue and orofacial dyskinesias, and opsoclonus. Imaging study findings were initially unremarkable, but when repeated, they demonstrated enhancement of the cauda equina nerve roots, trigeminal nerve, and pachymeninges. Cerebrospinal fluid examination revealed mildly elevated white blood cell count and protein levels. Serial electrodiagnostic testing demonstrated a rapidly progressive diffuse sensory motor axonopathy, and electroencephalogram findings progressed from generalized slowing to bilateral periodic lateralized epileptiform discharges. Critical details of her recent history prompted a diagnostic biopsy. Over time, the patient became completely unresponsive with no further abnormal movements and ultimately died. The differential diagnosis, pathological findings, and diagnosis are discussed with a brief review of a well-known yet rare diagnosis.

Management of Charcot-Marie-Tooth disease: improving long-term care with a multidisciplinary approach.

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy and one of the most common inherited diseases in humans. The diagnosis of CMT is traditionally made by the neurologic specialist, yet the optimal management of CMT patients includes genetic counselors, physical and occupational therapists, physiatrists, orthotists, mental health providers, and community resources. Rapidly developing genetic discoveries and novel gene discovery techniques continue to add a growing number of genetic subtypes of CMT. The first large clinical natural history and therapeutic trials have added to our knowledge of each CMT subtype and revealed how CMT impacts patient quality of life. In this review, we discuss several important trends in CMT research factors that will require a collaborative multidisciplinary approach. These include the development of large multicenter patient registries, standardized clinical instruments to assess disease progression and disability, and increasing recognition and use of patient-reported outcome measures. These developments will continue to guide strategies in long-term multidisciplinary efforts to maintain quality of life and preserve functionality in CMT patients.

High numbers of Staphylococcus aureus at three bathing beaches in South Florida.

While the value of Staphylococcus aureus as an indicator for non-enteric diseases is unclear, understanding its prevalence in recreational beaches would prove useful, given its pathogenic potential. Staphylococcus aureus levels were evaluated in sand and seawater at three beaches during one year. To elucidate possible S. aureus sources or colonization trends, distribution in sand was analyzed at Hollywood Beach. Staphylococcus aureus levels fluctuated throughout the study with highest average densities detected in dry sand (3.46 × 105 CFU/g, Hobie Beach), particularly at beaches with high human density. Patchy distribution marked hotspots of human use and/or possible bacterial re-growth. Data from a brief epidemiological survey indicated a very slight association between beach usage and skin conditions; suggesting high S. aureus levels in sand may not necessarily constitute major health risks. Because the possibility of disease transmission exists, particularly to children and immuno-compromised beach-goers, periodic surveying of highly frequented beaches seems warranted.

Mutation screening of mitofusin 2 in Charcot-Marie-Tooth disease type 2.

Charcot-Marie-Tooth (CMT) disease is among the most common inherited neurological disorders. Mutations in the gene mitofusin 2 (MFN2) cause the axonal subtype CMT2A, which has also been shown to be associated with optic atrophy, clinical signs of first motor neuron involvement, and early onset stroke. Mutations in MFN2 account for up to 20-30% of all axonal CMT type 2 cases. To further investigate the prevalence of MFN2 mutations and to add to the genotypic spectrum, we sequenced all exons of MFN2 in a cohort of 39 CMT2 patients. We identified seven variants, four of which are novel. One previously described change was co-inherited with a PMP22 duplication, which itself causes the demyelinating form CMT1A. Another mutation was a novel in frame deletion, which is a rare occurrence in the genotypic spectrum of MFN2 characterized mainly by missense mutations. Our results confirm a MFN2 mutation rate of ~15-20% in CMT2.

Genetic control of human brain transcript expression in Alzheimer disease.

We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.

Prevalence and distribution of fecal indicator organisms in South Florida beach sand and preliminary assessment of health effects associated with beach sand exposure.

Fecal indicator levels in nearshore waters of South Florida are routinely monitored to assess microbial contamination at recreational beaches. However, samples of sand from the surf zone and upper beach are not monitored which is surprising since sand may accumulate and harbor fecal-derived organisms. This study examined the prevalence of fecal indicator organisms in tidally-affected beach sand and in upper beach sand and compared these counts to levels in the water. Since indicator organisms were statistically elevated in sand relative to water, the study also considered the potential health risks associated with beach use and exposure to sand. Fecal coliforms, Escherichia coli, enterococci, somatic coliphages, and F(+)-specific coliphages were enumerated from sand and water at three South Florida beaches (Ft. Lauderdale Beach, Hollywood Beach, and Hobie Beach) over a 2-year period. Bacteria were consistently more concentrated in 100g samples of beach sand (2-23 fold in wet sand and 30-460 fold in dry sand) compared to 100ml samples of water. Somatic coliphages were commonly recovered from both sand and water while F(+)-specific coliphages were less commonly detected. Seeding experiments revealed that a single specimen of gull feces significantly influenced enterococci levels in some 3.1m(2) of beach sand. Examination of beach sand on a micro-spatial scale demonstrated that the variation in enterococci density over short distances was considerable. Results of multiple linear regression analysis showed that the physical and chemical parameters monitored in this study could only minimally account for the variation observed in indicator densities. A pilot epidemiological study was conducted to examine whether the length of exposure to beach water and sand could be correlated with health risk. Logistic regression analysis results provided preliminary evidence that time spent in the wet sand and time spent in the water were associated with a dose-dependent increase in gastrointestinal illness.

Optimizing human post-mortem brain tissue gene expression profiling in Parkinson's disease and other neurodegenerative disorders: from target "fishing" to translational breakthroughs.

Insights on the etiopathogenesis of common neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD) have been largely based on the discovery of gene mutations in genetically determined forms. Although these discoveries have been helpful in elucidating the basic molecular pathogenesis of familial forms, they represent a small fraction of cases, leaving the large majority classified as idiopathic. In the postgenomic era, brain tissue gene expression profiling has allowed relative quantitative assessment of thousands of genes simultaneously from one tissue sample, providing clues for novel candidate genes and processes implicated in neurodegenerative disorders. Some remain critical of "fishing expedition" science, but gene expression profiling is a discovery-based procedure well suited for the study of largely idiopathic and multifactorial diseases. However, the technology is still under development, and many methodological and biological aspects contribute to the heterogeneous results obtained from gene expression profiling. In this Review, we discuss the advantages and limitations of this technology in simple terms and identify the key variables that influence/limit gene expression profiling-derived translational breakthroughs in neurodegenerative diseases.

Multiregional gene expression profiling identifies MRPS6 as a possible candidate gene for Parkinson's disease.

Combining large-scale gene expression approaches and bioinformatics may provide insights into the molecular variability of biological processes underlying neurodegeneration. To identify novel candidate genes and mechanisms, we conducted a multiregional gene expression analysis in postmortem brain. Gene arrays were performed utilizing Affymetrix HG U133 Plus 2.0 gene chips. Brain specimens from 21 different brain regions were taken from Parkinson's disease (PD) (n = 22) and normal aged (n = 23) brain donors. The rationale for conducting a multiregional survey of gene expression changes was based on the assumption that if a gene is changed in more than one brain region, it may be a higher probability candidate gene compared to genes that are changed in a single region. Although no gene was significantly changed in all of the 21 brain regions surveyed, we identified 11 candidate genes whose pattern of expression was regulated in at least 18 out of 21 regions. The expression of a gene encoding the mitochondria ribosomal protein S6 (MRPS6) had the highest combined mean fold change and topped the list of regulated genes. The analysis revealed other genes related to apoptosis, cell signaling, and cell cycle that may be of importance to disease pathophysiology. High throughput gene expression is an emerging technology for molecular target discovery in neurological and psychiatric disorders. The top gene reported here is the nuclear encoded MRPS6, a building block of the human mitoribosome of the oxidative phosphorylation system (OXPHOS). Impairments in mitochondrial OXPHOS have been linked to the pathogenesis of PD.

Cortical and amygdalar Lewy body burden in Parkinson's disease patients with visual hallucinations.

Visual hallucinations (VH) are among the most common non-motor complications of Parkinson's disease (PD). A few studies on their etiopathogenesis have suggested involvement of cortical and amygdalar areas. In order to investigate the possible association between extranigral Lewy Body (LB) distribution across cortical and amygdalar regions and the presence of VH in PD brain donors, we conducted a clinico-pathological comparison of 10 PD patients with VH vs 10 closely matched PD patients without VH. The LB burden was significantly higher across the amygdala and the frontal, temporal and parietal cortical areas in patients with VH. Although our results suggest significant extranigral involvement, the precise etiopathologic mechanisms responsible for the development of VH need further clarification.

Cause, seasonality of death and co-morbidities in progressive supranuclear palsy (PSP).

The aim of this study was to investigate the causes and seasonality of death and co-morbid conditions among progressive supranuclear palsy (PSP) patients. 22 consecutive clinicopathologically confirmed PSP patients were compared with 22 gender and age-matched Parkinson's disease (PD) patients and 26 non-neurological controls. All subjects consented during life to donate their brains to the University of Miami Brain Endowment Bank. Respiratory-related deaths were significantly more frequent in PSP when compared to PD patients. Recurrent respiratory infections were also very frequent in PSP patients and were commonly associated with respiratory-related deaths. Deaths that occurred during winter and spring months accounted for about 70% of deaths among PSP patients. The most common co-morbid condition in PSP was hypertension, present in 50% of cases.