Non-motor symptom burden is strongly correlated to motor complications in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: The objective of this study was to analyze the relationship between motor complications and non-motor symptom (NMS) burden in a population of patients with Parkinson's disease (PD) and also in a subgroup of patients with early PD. METHODS: Patients with PD from the COPPADIS cohort were included in this cross-sectional study. NMS burden was defined according to the Non-Motor Symptoms Scale (NMSS) total score. Unified Parkinson's Disease Rating Scale (UPDRS) part IV was used to establish motor complication types and their severity. Patients with ≤5 years of symptoms from onset were included as patients with early PD. RESULTS: Of 690 patients with PD (62.6 ± 8.9 years old, 60.1% males), 33.9% and 18.1% presented motor fluctuations and dyskinesia, respectively. The NMS total score was higher in patients with motor fluctuations (59.2 ± 43.1 vs. 38.3 ± 33.1; P < 0.0001) and dyskinesia (63.5 ± 40.7 vs. 41.4 ± 36.3; P < 0.0001). In a multiple linear regression model and after adjustment for age, sex, disease duration, Hoehn & Yahr stage, UPDRS-III score and levodopa equivalent daily dose, UPDRS-IV score was significantly related to a higher NMSS total score (ß = 0.27; 95% confidence intervals, 2.81-5.61; P < 0.0001), as it was in a logistic regression model on dichotomous NMSS total score (≤40, mild or moderate vs. >40, severe or very severe) (odds ratio, 1.31; 95% confidence intervals, 1.17-1.47; P < 0.0001). In the subgroup of patients with early PD (n = 396; mean disease duration 2.7 ± 1.5 years), motor fluctuations were frequent (18.1%) and similar results were obtained. CONCLUSIONS: Motor complications were frequent and were associated with a greater NMS burden in patients with PD even during the first 5 years of disease duration.

High ultrasensitive serum C-reactive protein may be related to freezing of gait in Parkinson's disease patients.

C-reactive protein (CRP) is a biomarker of systemic inflammation that has been linked to accelerated decline in walking speed in older adults. The aim of the present study was to compare the CRP levels of PD patients with vs patients without freezing of gait (FOG). Patients and controls participating in the COPPADIS-2015 study that performed blood extraction for determining molecular serum biomarkers were included. Patients with FOG were identified as those with a score of 1 or greater on item-3 of the Freezing of Gait Questionnaire (FOG-Q). Immunoassay was used for determining ultrasensitive CRP (US-CRP) level (mg/dL). In the PD group (n = 225; 61.8 ± 9.5 years old, 61.8% males), 32% of the patients presented FOG but none in the control group (n = 65; 60.3 ± 6.1 years old, 56.9% males) (p < 0.0001). Differences in US-CRP level were significant in patients with FOG vs patients without FOG and vs controls (0.31 ± 0.52 vs 0.16 ± 0.21 vs 0.21 ± 0.22; p = 0.04). Significant differences were also observed between patients with vs without FOG (p = 0.001) but not between patients and controls (p = 0.163). US-CRP level was related to FOG (OR = 4.369; 95% CI 1.105-17.275; p = 0.036) along with H&Y (OR = 2.974; 95% CI 1.113-7.943; p = 0.030) and non-motor symptoms burden (NMSS total score; OR = 1.017; 95% CI 1.005-1.029; p = 0.006) after adjusting for age, gender, disease duration, equivalent daily levodopa dose, number of non-antiparkinsonian drugs per day, motor fluctuations, cognition, motor phenotype, and chronic use of anti-inflammatory drugs. The present study suggests that serum US-CRP level is related to FOG in PD patients. Inflammation could be linked to FOG development.

Epigenetics and periodontics: A systematic review.

BACKGROUND: Despite decades of research, our knowledge of several important aspects of periodontal pathogenesis remains incomplete. Epigenetics allows to perform dynamic analysis of different variations in gene expression, providing this great advantage to the static measurement provided by genetic markers. The aim of this systematic review is to analyze the possible relationships between different epigenetic mechanisms and periodontal diseases, and to assess their potential use as biomarkers of periodontitis. MATERIAL AND METHODS: A systematic search was conducted in six databases using MeSH and non-MeSH terms. The review fulfilled PRISMA criteria (Preferred Reporting Items for Systematic reviews and Meta-analysis). RESULTS: 36 studies met the inclusion criteria. Due to the heterogeneity of the articles, it was not possible to conduct quantitative analysis. Regarding qualitative synthesis, however, it was found that epigenetic mechanisms may be used as biological markers of periodontal disease, as their dynamism and molecular stability makes them a valuable diagnostic tool. CONCLUSIONS: Epigenetic markers alter gene expression, producing either silencing or over-expression of molecular transcription that respond to the demands of the cellular surroundings. Gingival crevicular fluid collection is a non-invasive and simple procedure, which makes it an ideal diagnostic medium for detection of both oral and systemic issues. Although further research is needed, this seems to be a promising field of research in the years to come.

Multiplexed direct-frequency-comb Vernier spectroscopy of carbon dioxide 2ν1 + ν3 ro-vibrational combination band.

We investigated a set of nineteen 12C16O2 transitions of the 2ν1 + ν3 ro-vibrational band in the spectral region from 5064 to 5126 cm-1 at different pressures, using frequency-comb Vernier spectroscopy. Our spectrometer enabled the systematic acquisition of molecular absorption profiles with high precision. Spectroscopic parameters, namely, transition frequency, linestrength, and self-pressure broadening coefficient, have been accurately determined by using a global fit procedure. These data are in agreement with theoretical values contained in HITRAN2016 database [I. E. Gordon et al., J. Quant. Spectrosc. Radiat. Transfer 203, 3-69 (2017)] at the same precision level. A moderate improvement of the line intensity determinations, by a factor 1.5 in the best case [P(10) transition at 5091.6 cm-1], should be noticed, projecting direct-comb-Vernier-spectroscopy as an adequate tool for spectral intensity calibration.

miR-1226 detection in GCF as potential biomarker of chronic periodontitis: A pilot study.

BACKGROUND: The study and identification of new biomarkers for periodontal disease, such as microRNAs (miRNAs), may give us more information about the location and severity of the disease and will serve as a basis for treatment planning and disease-monitoring. miRNAs are a group of small RNAs which are involved in gene regulation by binding to their messenger RNA target (mRNA). In this pilot study, the procedure for purifying miRNAs from gingival crevicular fluid (GCF) was, for the first time, described. In addition, the concentration of miRNAs in GCF was analyzed and compared between patients with moderate or severe chronic periodontitis (CP) and healthy controls. MATERIAL AND METHODS: GCF samples were collected from single-rooted teeth of patients with moderate or severe CP (n=9) and of healthy individuals (n=9). miRNAs were isolated from GCF using miRNeasy Serum/Plasma kit (Qiagen, CA. USA). Reverse transcription polymerase chain reaction (qRT-PCR) was used to determine the expression of a series of miRNAs candidates that are related to bone metabolism. The significance of differences in miRNA levels between both groups was determined using Mann-Whitney U test. RESULTS: The results from this pilot study indicate that miRNAs can be isolated from GCF. Six different miRNAs were analyzed (miR-671, miR-122, miR-1306, miR-27a, miR-223, miR-1226), but only miR-1226 showed statically significant differences between the CP group and healthy controls (p<0.05). This miRNA was downregulated in patients with CP. CONCLUSIONS: Within the limitations of the present study, it may be concluded that miR-1226 can be a promising biomarker for periodontal disease, adding relevant information to common clinical parameters used for diagnosis and prognosis of periodontitis.

Ultimate Limit in the Spectral Resolution of Extreme Ultraviolet Frequency Combs.

We present the results of direct interferometric measurements on the pulse-to-pulse phase jitter of a metrological, fiber-based, infrared (IR) frequency comb. We show that the short-time evolution of such phase fluctuations, which cannot be actively controlled by any feedback system, imposes a stringent limit on the tooth linewidth of extreme ultraviolet (XUV) combs produced by high-order harmonic conversion, thus explaining the difference of 9 orders of magnitude between the coherence times of state-of-the-art IR and XUV frequency combs.

Clinical and neuroimaging characteristics of 14 patients with prionopathy: a descriptive study.

INTRODUCTION: Prionopathy is the cause of 62% of the rapidly progressive dementias (RPD) in which a definitive diagnosis is reached. The variability of symptoms and signs exhibited by the patients, as well as its different presentation, sometimes makes an early diagnosis difficult. METHODS: Patients withdiagnosis of definite or probable prionopathy during the period 1999-2012 at our hospital were retrospectively reviewed.The clinical features and the results of the complementary tests (14-3-3 protein, EEG, MRI, FDG-PET, and genetic analysis) were evaluated in order to identify some factors that may enable an earlier diagnosis to be made. RESULTS: A total of 14 patients are described: 6 with definite sporadic Creutzfeldt-Jakob (sCJD) disease, 3 with probable sCJD, 4 with fatal familial insomnia, and 1 with the new variant. The median age at diagnosis was 54 years old. The mean survival was 9.5 months. Mood disorder was the most common feature, followed by instability and cognitive impairment. 14-3-3 protein content in the cerebrospinal fluid was positive in 7 of 11 patients, and the EEG showed typical signs in 2 of 12 patients. Neuroimaging (FDG-PET, MRI) studies suggested the diagnosis in 13 of the 14 patients included. CONCLUSIONS: Most patients presenting with RPD suffer from a prion disease. In our series the most useful complementary tests were MRI and FDG-PET, being positive in 13 of the 14 patients studied.

Automated analysis of FDG PET as a tool for single-subject probabilistic prediction and detection of Alzheimer's disease dementia.

PURPOSE: To introduce, evaluate and validate a voxel-based analysis method of ¹8F-FDG PET imaging for determining the probability of Alzheimer's disease (AD) in a particular individual. METHODS: The subject groups for model derivation comprised 80 healthy subjects (HS), 36 patients with mild cognitive impairment (MCI) who converted to AD dementia within 18 months, 85 non-converter MCI patients who did not convert within 24 months, and 67 AD dementia patients with baseline FDG PET scan were recruited from the AD Neuroimaging Initiative (ADNI) database. Additionally, baseline FDG PET scans from 20 HS, 27 MCI and 21 AD dementia patients from our institutional cohort were included for model validation. The analysis technique was designed on the basis of the AD-related hypometabolic convergence index adapted for our laboratory-specific context (AD-PET index), and combined in a multivariable model with age and gender for AD dementia detection (AD score). A logistic regression analysis of different cortical PET indexes and clinical variables was applied to search for relevant predictive factors to include in the multivariable model for the prediction of MCI conversion to AD dementia (AD-Conv score). The resultant scores were stratified into sixtiles for probabilistic diagnosis. RESULTS: The area under the receiver operating characteristic curve (AUC) for the AD score detecting AD dementia in the ADNI database was 0.879, and the observed probability of AD dementia in the six defined groups ranged from 8% to 100% in a monotonic trend. For predicting MCI conversion to AD dementia, only the posterior cingulate index, Mini-Mental State Examination (MMSE) score and apolipoprotein E4 genotype (ApoE4) exhibited significant independent effects in the univariable and multivariable models. When only the latter two clinical variables were included in the model, the AUC was 0.742 (95% CI 0.646 - 0.838), but this increased to 0.804 (95% CI 0.714 - 0.894, bootstrap p=0.027) with the addition of the posterior cingulate index (AD-Conv score). Baseline clinical diagnosis of MCI showed 29.7% of converters after 18 months. The observed probability of conversion in relation to baseline AD-Conv score was 75% in the high probability group (sixtile 6), 34% in the medium probability group (merged sixtiles 4 and 5), 20% in the low probability group (sixtile 3) and 7.5% in the very low probability group (merged sixtiles 1 and 2). In the validation population, the AD score reached an AUC of 0.948 (95% CI 0.625 - 0.969) and the AD-Conv score reached 0.968 (95% CI 0.908 - 1.000), with AD patients and MCI converters included in the highest probability categories. CONCLUSION: Posterior cingulate hypometabolism, when combined in a multivariable model with age and gender as well as MMSE score and ApoE4 data, improved the determination of the likelihood of patients with MCI converting to AD dementia compared with clinical variables alone. The probabilistic model described here provides a new tool that may aid in the clinical diagnosis of AD and MCI conversion.

Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease.

Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.

Update on genetics of essential tremor.

Despite the research, few advances in the etiopathogenesis on essential tremor (ET) have been made to date. The high frequency of positive family history of ET and the observed high concordance rates in monozygotic compared with dizygotic twins support a major role of genetic factors in the development of ET. In addition, a possible role of environmental factors has been suggested in the etiology of ET (at least in non-familial forms). Although several gene variants in the LINGO1 gene may increase the risk of ET, to date no causative mutated genes have been identified. In this review, we summarize the studies performed on families with tremor, twin studies, linkage studies, case-control association studies, and exome sequencing in familial ET.

Transcriptional and post-transcriptional control of odorant receptor choice in ants.

Insects and mammals have independently evolved odorant receptor genes that are arranged in large genomic tandem arrays. In mammals, each olfactory sensory neuron chooses to express a single receptor in a stochastic process that includes substantial chromatin rearrangements. Here, we show that ants, which have the largest odorant receptor repertoires among insects, employ a different mechanism to regulate gene expression from tandem arrays. Using single-nucleus RNA sequencing, we found that ant olfactory sensory neurons choose different transcription start sites along an array but then produce mRNA from many downstream genes. This can result in transcripts from dozens of receptors being present in a single nucleus. Such rampant receptor co-expression at first seems difficult to reconcile with the narrow tuning of the ant olfactory system. However, RNA fluorescence in situ hybridization showed that only mRNA from the most upstream transcribed odorant receptor seems to reach the cytoplasm where it can be translated into protein, whereas mRNA from downstream receptors gets sequestered in the nucleus. This implies that, despite the extensive co-expression of odorant receptor genes, each olfactory sensory neuron ultimately only produces one or very few functional receptors. Evolution has thus found different molecular solutions in insects and mammals to the convergent challenge of selecting small subsets of receptors from large odorant receptor repertoires.

Complications related to the prehabilitation with preoperative pneumoperitoneum in loss of domain hernias: our experience in 180 consecutive cases.

OBJECTIVE: Progressive pneumoperitoneum (PPP) is useful tool in the preparation of patients with loss of domain hernias (LODH). The purpose of this observational retrospective study was to report our experience in the management of complications associated with the PPP procedure after treating 180 patients with LODH and to report preventive measures to avoid them. METHODS: Of the 971 patients with a ventral incisional hernia operated on between June 2012 and July 2022, 180 consecutive patients with LODH were retrospectively analysed. Diameters of abdominal cavity, and volumes of incisional hernia and abdominal cavity were calculated from CT scan, based on the modified index of Tanaka. Complications related to the PPP procedure (catheter placement and following insufflations of air) were recorded by Clavien-Dindo classification. RESULTS: Complications associated to PPP were 26.6%. No complications occurred during the administration of botulinum toxin (BT). Eighteen patients (10% of 180 patients) developed subcutaneous emphysema during the last days of the insufflations; there were 2 accidental perforations of the small bowel and four punctures with liver and splenic hematomas, detected during catheter placement; a laparotomy, however, was not needed because it was solved with conservative treatment. We diagnosed it as a peritoneum-cutaneous fistula due to the cutaneous atrophy secondary to chronic eventration. CONCLUSION: PPP is a safe technique well tolerated by patients, although at the cost of some specific complications. Hernia surgeons must understand these complications to prevent them and to inform the LODH patient about their existence.

Clinical utility of a personalized and long-term monitoring device for Parkinson's disease in a real clinical practice setting: An expert opinion survey on STAT-ON™.

BACKGROUND: STAT-ON™ is an objective tool that registers ON-OFF fluctuations making possible to know the state of the patient at every moment of the day in normal life. Our aim was to analyze the opinion of different Parkinson's disease experts about the STAT-ON™ tool after using the device in a real clinical practice setting (RCPS). METHODS: STAT-ON™ was provided by the Company Sense4Care to Spanish neurologists for using it in a RCPS. Each neurologist had the device for at least three months and could use it in PD patients at his/her own discretion. In February 2020, a survey with 30 questions was sent to all participants. RESULTS: Two thirds of neurologists (53.8% females; mean age 44.9±9 years old) worked in a Movement Disorders Unit, the average experience in PD was 16±6.9 years, and 40.7% of them had previously used other devices. A total of 119 evaluations were performed in 114 patients (range 2-9 by neurologist; mean 4.5±2.3). STAT-ON™ was considered "quite" to "very useful" by 74% of the neurologists with an overall opinion of 6.9±1.7 (0, worst; 10, best). STAT-ON™ was considered better than diaries by 70.3% of neurologists and a useful tool for the identification of patients with advanced PD by 81.5%. Proper identification of freezing of gait episodes and falls were frequent limitations reported. CONCLUSION: STAT-ON™ could be a useful device for using in PD patients in clinical practice.

Frequency metrology of helium around 1083 nm and determination of the nuclear charge radius.

We measure the absolute frequency of seven out of the nine allowed transitions between the 2 (3)S and 2 (3)P hyperfine manifolds in a metastable (3)He beam by using an optical frequency comb synthesizer-assisted spectrometer. The relative uncertainty of our measurements ranges from 1×10(-11) to 5×10(-12), which is, to our knowledge, the most precise result for any optical ^{3}He transition to date. The resulting 2 (3)P-2 (3)S centroid frequency is 276,702,827,204.8(2.4) kHz. Comparing this value with the known result for the (4)He centroid and performing ab initio QED calculations of the (4)He-(3)He isotope shift, we extract the difference of the squared nuclear charge radii δr(2) of (3)He and (4)He. Our result for δr(2)=1.074(3) fm(2) disagrees by about 4σ with the recent determination [R. van Rooij et al., Science 333, 196 (2011)].

Should the pharmaceutical industry be involved in continuing medical education?

INTRODUCTION: In July 2020, a draft bill was introduced in Spain's Congress which proposed that continuing medical education be funded exclusively by the Spanish government, barring involvement from private entities. AIMS: This work aims to gather physicians' and pharmacists' opinions on this draft bill, learn what they think about the funding of continuing medical education and possible conflicts of interest. METHODS: This work is a descriptive cross-sectional study conducted via voluntary anonymous surveys aimed at physicians and hospital pharmacists. RESULTS: Four hundred thirty-five surveys were analyzed, 59.8% of which were from women. Of the respondents, 87.6% were specialist physicians and 77.2% were part of a specialist department. A total of 55.2% did not agree with the draft bill while 92.4% agreed that the government and private institutes should subsidize training for their workers. Furthermore, 52.4% disagreed that each professional should pay for his or her own training while 14% agreed they should. A total of 19.8% have felt uncomfortable when a course or conference has been paid for by another entity and 74.5% believe that the involvement of private entities in funding does not influence prescribing. CONCLUSIONS: The majority of those surveyed did not agree with a draft bill aimed at prohibiting the pharmaceutical industry from funding continuing medical education. Nearly all agreed that the government and private institutions should fund training for their workers. In general, those surveyed did not find conflicts of interest in their relationship with the industry.

Arthroscopic bone block metal-free fixation for anterior shoulder instability. Short-term functional and radiological outcomes. / Fijación artroscópica sin metal del bloque óseo en la inestabilidad anterior del hombro. Resultados funcionales y radiológicos a corto plazo.

INTRODUCTION: Anterior glenohumeral bone loss reconstruction reduces failure rates after soft tissue surgery in patients with large glenoid bone defects. Multiple bone block techniques have been described, most with metal hardware fixation. The objective of this study is to evaluate the safety, as well as the short-term functional and radiological results of an arthroscopic bone block metal-free fixation or bone block cerclage. MATERIAL AND METHODS: Retrospective study of patients with glenohumeral instability and>15% glenoid bone loss operated during 2019 with follow-up of at least 12 months. Radiography and computerized tomography studies were performed. Functional outcomes were evaluated before and after surgery with the Western Ontario Shoulder Instability Index and Rowe score. RESULTS: A total of 21 patients with a median age of 30.6 (SD 7.1) were included. All showed radiographic consolidation at 3 months follow-up. A percentage of 90.4 of bone grafts presented osteolysis at peripherical areas and 95.2% revealed consolidation in the areas with contact to the glenoid. The median glenoid estimated surface went from 79.3% before surgery to 98.4% at 12 months. Functional scores were statically significant (P<.001) for Western Ontario Shoulder Instability Index (35.6-86.9) and Rowe score (25.2 to 96.4). No serious complications were reported. CONCLUSION: The bone block cerclage is a safe, metal-free technique that achieves total consolidation of the bone graft and favorable functional and radiological outcomes at 12 months follow-up.

Air pollution and health prevention: A document of reflection.

Ambient air quality, pollution and its implication on health is a topic of enormous importance that is normally dealt with by major specialists in their particular areas of interest. In general, it is not discussed from multidisciplinary approaches or with a language that can reach everyone. For this reason, the Health Sciences Foundation, from its prevention area, has formulated a series of questions to people with very varied competences in the area of ambient air quality in order to obtain a global panorama of the problem and its elements of measurement and control. The answers have been produced by specialists in each subject and have been subjected to a general discussion that has allowed conclusions to be reached on each point. The subject was divided into three main blocks: external ambient air, internal ambient air, mainly in the workplace, and hospital ambient air and the consequences of its poor control. Along with the definitions of each area and the indicators of good and bad quality, some necessary solutions have been pointed out. We have tried to know the current legislation on this problem and the competences of the different administrations on it. Despite its enormous importance, ambient air quality and health is not usually a topic of frequent presence in the general media and we have asked about the causes of this. Finally, the paper addresses a series of reflections from the perspective of ethics and very particularly in the light of the events that the present pandemic raises. This work aims to provide objective data and opinions that will enable non-specialists in the field to gain a better understanding of this worrying reality.

Lack of association of LINGO1 rs9652490 and rs11856808 SNPs with familial essential tremor.

BACKGROUND: Essential tremor (ET) is a frequent movement disorder with a substantial family aggregation. A genome-wide association study has recently shown that LINGO1 gene variants are associated with increased risk of ET. METHODS: We intended to replicate these findings by genotyping rs9652490 and rs11856808 in a series of 226 familial ET subjects and 1117 healthy controls from referral movement disorder clinics in Spain. RESULTS: We were unable to replicate the association between LINGO1 variants and familial ET. CONCLUSIONS: Our results indicate that the LINGO1 variants analyzed are not a major risk factor for developing familial ET in our population, which suggests the existence of other unknown genetic risk factors responsible for familial ET in the Spanish population.