A metagenomic-based study of two sites from the Barbadian reef system.

We study the microbiome of sea water collected from two locations of the Barbadian coral reefs. The two sites differ in several environmental and ecological variables including their endogenous benthic community and their proximity to urban development and runoffs from inland watersheds. The composition of the microbial communities was estimated using whole genome DNA shotgun sequencing with adjuvant measurements of chemical and environmental qualities. Although both sites exhibit a similar degree of richness, the less urbanized site (Maycocks reef at Hangman's Bay) has a strong concentration of phototrophs whereas the more urbanized location (Bellairs reef at Folkstone) is enriched for copiotrophs, macroalgal symbionts and marine-related disease-bearing organisms from taxa scattered across the tree of life. Our results are concordant with previous profiles of warm ocean surface waters, suggesting our approach captures the state of each coral reef site, setting the stage for longitudinal studies of marine microbiome dynamics in Barbados. Supplementary Information: The online version contains supplementary material available at 10.1007/s00338-022-02330-y.

Opinions and clinical practices related to diagnosing and managing functional (psychogenic) movement disorders: changes in the last decade.

BACKGROUND AND PURPOSE: There is large variability in the diagnostic approach and clinical management in functional movement disorders (FMD). This study aimed to examine whether opinions and clinical practices related to FMD have changed over the past decade. METHODS: Adapted from a 2008 version, we repeated the survey to members of the International Parkinson and Movement Disorder Society (MDS). RESULTS: In all, 864/7689 responses (denominator includes non-neurologists) were received from 92 countries. Respondents were more often male (55%), younger than 45 (65%) and from academic practices (85%). Although the likelihood of ordering neurological investigations prior to delivering a diagnosis of FMD was nearly as high as in 2008 (47% vs. 51%), the percentage of respondents communicating the diagnosis without requesting additional tests increased (27% vs. 19%; P = 0.003), with most envisioning their role as providing a diagnosis and coordinating management (57% vs. 40%; P < 0.001). Compared to patients with other disorders, 64% of respondents were more concerned about missing a diagnosis of another neurological disorder. Avoiding iatrogenic harm (58%) and educating patients about the diagnosis (53%) were again rated as the most effective therapeutic options. Frequent treatment barriers included lack of physician knowledge and training (32%), lack of treatment guidelines (39%), limited availability of referral services (48%) and cultural beliefs about psychological illnesses (50%). The preferred term for communication favored 'functional' over 'psychogenic' (P < 0.001). CONCLUSIONS: Attitudes and management of FMDs have changed over the past decade. Important gaps remain in access to treatment and in the education of neurologists about the inclusionary approach to FMD diagnosis.

Detecting gene signature activation in breast cancer in an absolute, single-patient manner.

BACKGROUND: The ability to reliably identify the state (activated, repressed, or latent) of any molecular process in the tumor of a patient from an individual whole-genome gene expression profile obtained from microarray or RNA sequencing (RNA-seq) promises important clinical utility. Unfortunately, all previous bioinformatics tools are only applicable in large and diverse panels of patients, or are limited to a single specific pathway/process (e.g. proliferation). METHODS: Using a panel of 4510 whole-genome gene expression profiles from 10 different studies we built and selected models predicting the activation status of a compendium of 1733 different biological processes. Using a second independent validation dataset of 742 patients we validated the final list of 1773 models to be included in a de novo tool entitled absolute inference of patient signatures (AIPS). We also evaluated the prognostic significance of the 1773 individual models to predict outcome in all and in specific breast cancer subtypes. RESULTS: We described the development of the de novo tool entitled AIPS that can identify the activation status of a panel of 1733 different biological processes from an individual breast cancer microarray or RNA-seq profile without recourse to a broad cohort of patients. We demonstrated that AIPS is stable compared to previous tools, as the inferred pathway state is not affected by the composition of a dataset. We also showed that pathway states inferred by AIPS are in agreement with previous tools but use far fewer genes. We determined that several AIPS-defined pathways are prognostic across and within molecularly and clinically define subtypes (two-sided log-rank test false discovery rate (FDR) <5%). Interestingly, 74.5% (1291/1733) of the models are able to distinguish patients with luminal A cancer from those with luminal B cancer (Fisher's exact test FDR <5%). CONCLUSION: AIPS represents the first tool that would allow an individual breast cancer patient to obtain a thorough knowledge of the molecular processes active in their tumor from only one individual gene expression (N-of-1) profile.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Lack of efficacy of levetiracetam in oromandibular and cranial dystonia.

OBJECTIVE: To determine the efficacy of levetiracetam in oromandibular or cranial dystonia. METHODS: We recruited seven subjects with oromandibular or cranial dystonia. Five completed the study, median age was 71 years (range 42-79 years), median disease duration was 12 years (range 2-30 years). Participants were randomized to receive levetiracetam or placebo and were then crossed over. They titrated up to a total daily dose of 4000 mg or the maximum tolerated dose over 3 weeks and maintained that dose for another 3 weeks. The primary endpoint was the percent change of the eyes, mouth, speech, and swallowing Burke-Fahn-Marsden (BFM) subscores from baseline to weeks 6 and 14. Additional endpoints included the BFM subscore at weeks 3 and 11, and the global dystonia severity (GDS) subscore at weeks 3, 6, 11, and 14, as well as all adverse side effects. RESULTS: The mean percent increase in the BFM subscore (placebo: 31.25%, levetiracetam: 12.16%) was not significantly different between the two arms according to the Friedman analysis. The Wilcoxon signed-rank test showed that these percent changes were not significant, indicating that there was no statistical clinical worsening in either arm. The mean percent change of the BFM subscore at weeks 3 and 11 and the mean percent change of the GDS subscore at weeks 3, 6, 11, and 14 were not significantly different between the two arms, and the Wilcoxon signed-rank test did not show statistical significance. CONCLUSION: Levetiracetam does not appear to be efficacious in patients with oromandibular or cranial dystonia.

Limb-kinetic apraxia affects activities of daily living in Parkinson's disease: a multi-center study.

BACKGROUND AND PURPOSE: Impaired dexterity (fine hand movements) is often present in Parkinson's disease (PD), even at early to moderate disease stages. It has a detrimental impact on activities of daily living (ADL) such as buttoning, contributing to reduced quality of life. Limb-kinetic apraxia, a loss of the ability to make precise, independent but coordinated finger and hand movements, may contribute to impaired dexterity even more than bradykinesia per se. However, the impact of limb-kinetic apraxia on ADL remains controversial. Our aim was to identify the strongest predictor of buttoning and unbuttoning in PD. It was hypothesized that coin rotation (a surrogate of limb-kinetic apraxia) represents the most important determinant. METHODS: Sixty-four right-handed, early to moderate PD patients were recruited from three movement disorder centers (Hoehn andYahr stages 1-3). Buttoning, unbuttoning and coin rotation (right and left hand) represented the target tasks. Motor impairment was assessed according to the Unified Parkinson's Disease Rating Scale. RESULTS: Multiple linear regression analysis showed that coin rotation with the right hand was the only significant predictor of buttoning (P < 0.001) and unbuttoning (P = 0.002). Notably, measures of bradykinesia or overall motor impairment did not represent significant predictors. CONCLUSIONS: Constituting the novel key finding, limb-kinetic apraxia seems to be particularly relevant for ADL requiring dexterity skills in PD, even at early to moderate disease stages. Our results prompt research into the pathophysiological background and therapeutic options to treat limb-kinetic apraxia. The simple coin rotation test provides valuable information about ADL-related dexterity skills.

Progressive supranuclear palsy (PSP): Richardson syndrome and other PSP variants.

Phenotypic heterogeneity of progressive supranuclear palsy (PSP) has been increasingly reported in the literature and can be the source of incorrect clinical diagnosis particularly in the early stages of the disease when the classically associated symptoms of early falls and supranuclear gaze palsy may not be apparent. In addition to Richardson syndrome (RS), several atypical clinical phenotypes have been described. Advances in genetic, neuroimaging, and biochemical/molecular technologies contribute to the identification of these clinical subtypes in the context of typical PSP pathological findings. Our goal is to review the phenomenology reported in the literature that is associated with confirmed histopathological changes consistent with a PSP diagnosis and to highlight the clinical spectrum of PSP. A systematic review of the literature in PubMed through July 2015 using MeSH terms and key words related to PSP was conducted. Articles describing PSP classifications, diagnostic criteria, and case reports were reviewed and summarized. Additional PSP phenotypes not seen in recent clinicopathological studies are included. These include primary lateral sclerosis, pallido-nigro-luysian degeneration, axonal dystrophy, and multiple system atrophy in the spectrum of atypical PSP variants beyond the traditionally classified PSP subtypes. This review is intended to help with the diagnostic challenges of atypical PSP variants. We believe that large multicenter clinicopathological studies will help expand our understanding of etiology and specific mechanisms of neurodegeneration and will aid in the appropriate interpretation of outcomes when conducting clinical and basic science research.

Subthalamic oscillatory activity in parkinsonian patients with off-period dystonia.

OBJECTIVES: The study was aimed to explore oscillatory activity in the subthalamic nucleus (STN) in Parkinson's disease (PD) with off-period dystonia, a type of levodopa-induced dyskinesias (LID). METHODS: Eighteen patients with PD who underwent STN DBS were studied. Nine patients had dyskinesia defined as the LID group and nine patients who did not present any sign of dyskinesia were defined as the control group. Microelectrode recordings in the STN together with electromyogram (EMG) were recorded. Spectral and coherence analyses were performed to study the neuronal oscillations in relation to limb muscles. RESULTS: Two hundred and fifteen neurons were identified. There were 39 neurons with tremor-frequency band (4-7 Hz) oscillation, 57 neurons with ß-frequency band (12-30 Hz, ß-FB) oscillation and 100 neurons without oscillation, and 19 neurons with very low-frequency band oscillation at a mean peak power of 1.2 ± 0.5 Hz (LFB). These LFB oscillatory neurons (n = 15) were frequently significantly coherent with EMG of off-period dystonia. Notably, 89% (n = 17) neurons with LFB oscillation were found in the patients in the off-dystonia group. The age at onset of PD, duration of PD, and levodopa equivalent dose daily consumption were statistically different between two groups (P < 0.05). CONCLUSIONS: Subthalamic LFB oscillatory neurons seem to play an important role in the genesis of off-period dystonia in advanced PD. Clinical and demographic analyses confirmed that the earlier age at onset of PD, longer duration of PD, and levodopa exposure are important risk factors in the development of the type of LID.

Restless legs syndrome and pregnancy: prevalence, possible pathophysiological mechanisms and treatment.

Restless legs syndrome (RLS) is a common sleep disorder that may be associated with pregnancy. Studies have found that the prevalence of RLS among pregnant women ranged from 10 to 34%. Typically, there is complete remission of symptoms soon after parturition; however, in some patients, they may continue postpartum. RLS has been shown to be associated with a number of complications in pregnancy including preeclampsia and increased incidence of Cesarean sections. Although multiple hypotheses have been proposed to explain this association, each individual hypothesis cannot completely explain the whole pathogenesis. Present understanding suggests that a strong family history, low serum iron and ferritin level, and high estrogen level during pregnancy might play important roles. Vitamin D deficiency and calcium metabolism may also play a role. Medical treatment of RLS during pregnancy is difficult and challenging considering the risks to mother and fetus. However, in some cases, the disease may be severe enough to require treatment.

A multifactorial conceptual model of peripheral neuromusculoskeletal predisposing factors in task-specific focal hand dystonia in musicians: etiologic and therapeutic implications.

A model is presented showing how peripheral factors may cause a process of movement adaptation that leads to task-specific focal hand dystonia in musicians (FHDM). To acquire a playing technique, the hand must find effective and physiologically sustainable movements within a complex set of functional demands and anatomic, ergonomic, and physiological constraints. In doing so, individually discriminating constraints may become effective, such as limited anatomic independence of finger muscles/tendons, limited joint ranges of motion, or (subclinical) neuromusculoskeletal defects. These factors may, depending on the instrument-specific playing requirements, compromise or exclude functional playing movements. The controller (i.e., the brain) then needs to develop alternative motions to execute the task, which is called compensation. We hypothesize that, if this compensation process does not converge to physiologically sustainable muscle activation patterns that satisfy all constraints, compensation could increase indefinitely under the pressure of practice. Dystonic symptoms would become manifest when overcompensation occurs, resulting in motor patterns that fail in proper task execution. The model presented in this paper only concerns the compensatory processes preceding such overcompensations and does not aim to explain the nature of the dystonic motions themselves. While the model considers normal learning processes in the development of compensations, neurological predispositions could facilitate developing overcompensations or further abnormal motor programs. The model predicts that if peripheral factors are involved, FHDM symptoms would be preceded by long-term gradual changes in playing movements, which could be validated by prospective studies. Furthermore, the model implies that treatment success might be enhanced by addressing the conflict between peripheral factors and playing tasks before decompensating/retraining the affected movements.

Temporal macrodynamics and microdynamics of the postoperative impedance at the tissue-electrode interface in deep brain stimulation patients.

OBJECTIVE: To study the temporal dynamics of tissue impedance after deep brain stimulation (DBS). BACKGROUND: DBS therapy commonly employs a constant voltage approach, and current delivery to the tissue is a function of electrode-tissue impedance. It is presumed that impedance fluctuates early postimplantation, with implications for variations in current delivery and therapeutic efficacy. We hypothesised that the largest variation will be recorded early after surgery, followed by stabilisation. METHODS: Review of impedance checks of implanted DBS systems at standard parameters during the first five months postimplantation. All measurement time points were binned into 1-week periods, and we used repeated measures analysis of variance with Tukey pairwise multiple comparisons correction. The analysis was repeated after normalising impedance values for each subject to that patient's baseline value. RESULTS: There was an initial (non-significant) drop in impedance at week 1, followed by significant increase at week 3 (p=0.0002). There were no further significant differences in impedance values at subsequent time points. Analysis of normalised data showed a significant difference between the initial measurement in postoperative week 1 (normalised value 1) and week 3 (normalised value 1.73, p<0.0001), with no further difference among the subsequent weekly points during the 5-month follow-up. No significant hourly variations were found at any time points. CONCLUSIONS: We found major changes in impedance within the first month postimplantation, with no further variation. This is an important confirmation in patients of this temporal dynamics of the impedance of implanted DBS hardware, with potential therapeutic implications.

Relationship and factor structure in multisystem neurodegeneration in Parkinson's disease.

OBJECTIVES: Parkinson's disease (PD) is a multisystem neurodegenerative disease. We aimed to identify the relationship and factor structure among its different features. MATERIALS & METHODS: Motor, olfactory and cognitive function, and cardiac sympathetic denervation were evaluated in 125 patients with PD using the Unified Parkinson's Disease Rating Scale (UPDRS) part III score, odor stick identification test for the Japanese (OSIT-J), Mini-Mental State Examination (MMSE), and [(123) I] meta-iodobenzylguanidine (MIBG) cardiac scintigraphy (heart-to-mediastinum (H/M) ratio). Pearson's correlation and multiple regression analysis were used to evaluate the association among the four measures with age, gender, and disease duration as the covariates. Exploratory factor analysis was used to identify the underlying factor structure among the measures and covariates. RESULTS: Pearson's correlation and multiple regression analysis showed correlations between OSIT-J score and MIBG H/M ratio, OSIT-J and MMSE scores, UPDRS part III score and MIBG H/M ratio, UPDRS part III score and disease duration, and MMSE score and age. Factor analysis identified three factors: (i) age and MMSE score; (ii) MIBG H/M ratio and OSIT-J score; and (iii) UPDRS part III score and disease duration. CONCLUSIONS: Our results suggest that aging, PD-related pathogenesis, and disease duration underlie the multisystem neurodegeneration present in PD. Moreover, age and disease duration are the major risk factors for cognitive impairment and motor symptoms, respectively. Olfactory impairment and cardiac sympathetic denervation are strongly associated in PD.

Antibody colocalization microarray: a scalable technology for multiplex protein analysis in complex samples.

DNA microarrays were rapidly scaled up from 256 to 6.5 million targets, and although antibody microarrays were proposed earlier, sensitive multiplex sandwich assays have only been scaled up to a few tens of targets. Cross-reactivity, arising because detection antibodies are mixed, is a known weakness of multiplex sandwich assays that is mitigated by lengthy optimization. Here, we introduce (1) vulnerability as a metric for assays. The vulnerability of multiplex sandwich assays to cross-reactivity increases quadratically with the number of targets, and together with experimental results, substantiates that scaling up of multiplex sandwich assays is unfeasible. We propose (2) a novel concept for multiplexing without mixing named antibody colocalization microarray (ACM). In ACMs, both capture and detection antibodies are physically colocalized by spotting to the same two-dimensional coordinate. Following spotting of the capture antibodies, the chip is removed from the arrayer, incubated with the sample, placed back onto the arrayer and then spotted with the detection antibodies. ACMs with up to 50 targets were produced, along with a binding curve for each protein. The ACM was validated by comparing it to ELISA and to a small-scale, conventional multiplex sandwich assay (MSA). Using ACMs, proteins in the serum of breast cancer patients and healthy controls were quantified, and six candidate biomarkers identified. Our results indicate that ACMs are sensitive, robust, and scalable.

Pilot study of topical acetyl hexapeptide-8 in the treatment for blepharospasm in patients receiving botulinum toxin therapy.

BACKGROUND AND PURPOSE: Injectable botulinum neurotoxin (BoNT) is the principal effective treatment for blepharospasm (BSP). This trial explores the safety and efficacy of topical acetyl hexapeptide-8 (AH8), a competitive SNAP25 inhibitor, as a potential new therapy in BSP. METHODS: Double-blind, placebo-controlled, randomized trial of daily topical application of AH8 in 24 patients with BSP. The primary outcome was time to return to baseline Jankovic Blepharospasm Rating Scale (JBRS) after a BoNT injection simultaneously with the initiation of AH8. Patients displaying a strictly regular pattern of response to 3-monthly injections of BoNT were included. RESULTS: There were no significant adverse events. There was a trend for longer time until return to baseline JBRS after injection in the active group compared to placebo (3.7 months vs. 3.0 months), and for better scores in the active group. One-third (4/12) of the patients in the active group had a considerable extension of symptom control after BoNT (range: 3.3-7.1 months). CONCLUSIONS: Topical AH8 is safe and promising for extending the duration of action of BoNT therapy for BSP.

Alteration of brain functional network at rest and in response to YMCA physical stress test in concussed athletes: RsFMRI study.

There is still controversy in the literature whether a single episode of mild traumatic brain injury (mTBI) results in short- and/or long-term functional and structural deficits in the concussed brain. With the inability of traditional brain imaging techniques to properly assess the severity of brain damage induced by a concussive blow, there is hope that more advanced applications such as resting state functional magnetic resonance imaging (rsFMRI) will be more specific in accurately diagnosing mTBI. In this rsFMRI study, we examined 17 subjects 10±2 days post-sports-related mTBI and 17 age-matched normal volunteers (NVs) to investigate the possibility that the integrity of the resting state brain network is disrupted following a single concussive blow. We hypothesized that advanced brain imaging techniques may reveal subtle alterations of functional brain connections in asymptomatic mTBI subjects. There are several findings of interest. All mTBI subjects were asymptomatic based upon clinical evaluation and neuropsychological (NP) assessments prior to the MRI session. The mTBI subjects revealed a disrupted functional network both at rest and in response to the YMCA physical stress test. Specifically, interhemispheric connectivity was significantly reduced in the primary visual cortex, hippocampal and dorsolateral prefrontal cortex networks (p<0.05). The YMCA physical stress induced nonspecific and similar changes in brain network connectivity patterns in both the mTBI and NV groups. These major findings are discussed in relation to underlying mechanisms, clinical assessment of mTBI, and current debate regarding functional brain connectivity in a clinical population. Overall, our major findings clearly indicate that functional brain alterations in the acute phase of injury are overlooked when conventional clinical and neuropsychological examinations are used.

Optical complexities of living cytoplasm--implications for live cell imaging and photo-micromanipulation techniques.

The ability to manipulate the intracellular environment within living cells and to monitor the cytosolic chemical changes which occur during cell stimulation has lead to major advances in our understanding of how cells read and respond to their environment. Perhaps the most powerful suite of techniques for achieving these dual objectives is based on the use of light (photons). Because cells are 'transparent', light has been used to both interrogate and manipulate the chemistry inside living cells, exploiting technical advances in both the physical and biochemical sciences. However, cells are neither transparent nor homogeneous with respect to their optical properties. The interface between light and the living cell cytoplasm thus represent an important, yet largely ignored, interface. There has been no review of the optical properties of cytoplasm and little discussion about how the optical properties of living cytoplasm influence the outcome of such measurements and manipulations. In this short review, we discuss the importance of understanding the optical properties of cytoplasm for such techniques and how imperfections in experimental interpretation can arise.

Clinical features of patients with blepharospasm: a report of 240 patients.

BACKGROUND AND PURPOSE: To characterize patients with benign essential blepharospasm (BEB) by diagnosis, environmental risk factors, and family history. METHODS: Two hundred and forty patients with BEB were evaluated through a clinical examination and questionnaire. The questionnaire reviewed personal medical history, demographic factors, risk factors for the development of blepharospasm and family history of dystonia and other neurological conditions. RESULTS: Benign essential blepharospasm was more commonly found in women (2.8:1) and 93% of the patients were Caucasian. Fifty percent had pure BEB, 31% had BEB/Meige's syndrome, and 4% had BEB and eyelid opening apraxia (+/- Meige's syndrome). A minority of patients reported preceding photophobia (25%) or other eye conditions (22%). The majority were non-smokers, had no exposure to anti-emetic or antipsychotic agents, had a normal birth history, and had no history of head trauma. Seventy-two percent did report a stressful event immediately prior to the development of symptoms. Treatments reported included botulinum toxin (BoNT), oral medications, surgical procedures, and acupuncture. Thirty-two percent of patients reported a family history of focal dystonia, and BEB was the most commonly reported. CONCLUSION: This study confirms previous reports of usual age, sex, caffeine and tobacco use, and family history in patients with blepharospasm. New findings include a report on occupation, lower reports of preceding eye conditions and photophobia, and higher reported stressful events. Further, this study shows a change in treatment with an increase in BoNT use and decrease in surgical procedures.