'Positive' inter-ictal clinical signs of functional neurological disorders are found in patients with functional dissociative seizures.

BACKGROUND AND PURPOSE: Prior studies highlighted the high diagnostic specificity (ranging from 92% to 100%) of clinical signs observed in functional neurological disorders (FNDs). However, these signs are rarely looked for by epileptologists when trying to distinguish between functional dissociative seizure (FDS) and epileptic seizure. The aim of this study was to determine the prevalence of inter-ictal clinical signs of FND in a cohort of patients with probable FDS. The secondary objective was to compare the prevalence of inter-ictal FND clinical signs in FDS patients with age- and gender-matched epileptic patients without FDS. METHODS: Patients diagnosed with FDS seen at two tertiary care centres and epileptic outpatients were included in the study. Each patient underwent a physical examination, searching for inter-ictal clinical signs of FND. RESULTS: In the FDS group, 79% of patients presented at least one sign of FND, compared to 16.6% of patients with epilepsy (p < 0.001). Moreover, 66.6% of FDS patients presented three or more FND signs, whereas only 4.1% of epileptic patients did (p < 0.001). The median number of FND clinical signs in the FDS group was four (SD 1.7; 5.5). Using the threshold of three signs or more, the specificity of detecting three or more FND signs was 83.3%, with a sensitivity of 79.2%. CONCLUSION: Inter-ictal clinical signs of FND are present in patients with FDS and should be looked for during neurological examination.

From Software to Hardware: A Case Series of Functional Neurological Symptoms and Cerebrovascular Disease.

OBJECTIVE: Neuroimaging studies have identified alterations in both brain structure and functional connectivity in patients with functional neurological disorder (FND). For many patients, FND emerges from physical precipitating events. Nevertheless, there are a limited number of case series in the literature that describe the clinical presentation and neuroimaging correlates of FND following cerebrovascular disease. METHODS: The authors collected data from two clinics in the United Kingdom on 14 cases of acute, improving, or delayed functional neurological symptoms following cerebrovascular events. RESULTS: Most patients had functional neurological symptoms that were localized to cerebrovascular lesions, and the lesions mapped onto regions known to be part of functional networks disrupted in FND, including the thalamus, anterior cingulate gyrus, insula, and temporoparietal junction. CONCLUSIONS: The findings demonstrate that structural lesions can lead to FND symptoms, possibly explained through changes in relevant mechanistic functional networks.

The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum.

BACKGROUND: The ultra-rare autosomal recessive genetic disorder, You-Hoover-Fong Syndrome (YHFS), is caused by defects in the TELO2 gene and is characterized by intellectual disability, developmental delay, and ocular impairments. This study aims to contribute to a better understanding of YHFS by reviewing previous cases and introducing a novel variant in a new case. METHODS: Whole exome sequencing (WES) was conducted on the proband to identify genetic variants, and Sanger sequencing was used to confirm variants within the family. This article presents a comprehensive collection of reported cases of YHFS, incorporating both molecular and clinical data, through an extensive literature search and analysis of English-language studies published until June 2023. RESULTS: Using WES, a novel homozygous missense variant, c.1799A > G (p. Tyr600Cys), was identified in the TELO2 gene in a 4-year-old Iranian male patient. Novel clinical features, including choanal atresia and clubfoot, were also identified. A comprehensive literature review identified 27 patients with YHFS, with 20 variants in the TELO2 gene. Missense pathogenic variants were the most common type of pathogenic variant, and the most common features were microcephaly and intellectual impairment. CONCLUSION: This study presents the first case of pathogenic variants in TELO2 gene in Iran, expands the genotypic and phenotypic spectrum of YHFS and contributes to the growing body of literature pertaining to YHFS. Furthermore, our findings highlight the importance of genetic testing for non-consanguineous carrier screening, as compound heterozygosity may be a significant factor in the development of YHFS. Further research is needed to clarify the molecular mechanisms underlying YHFS pathogenesis.

TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature.

You-Hoover-Fong syndrome (YHFS) is an autosomal recessive condition caused by pathogenic variants in the TELO2 gene. Affected individuals were reported to have global developmental delay, intellectual disability, microcephaly, dysmorphic facial features, ocular involvement including cortical visual impairment, strabismus, cataract and rotatory nystagmus, movement disorder, hypertonia and spasticity, balance disturbance and ataxia, and abnormal sleep pattern. Other features reported include poor growth, cleft palate, cardiac malformations, epilepsy, scoliosis, and hearing loss. To date, 12 individuals with YHFS have been reported in the literature. Here we describe 14 new individuals with YHFS from 10 families. Their clinical presentation provides additional support of the phenotype recognized previously and delineates the clinical spectrum associated with YHFS syndrome. In addition, we present a review of the literature including follow-up data on four previously reported individuals with YHFS.

Contamination-Free Milling of Ketoprofen Nanoparticles Using Mannitol Medium and Hoover Automatic Muller: Optimization of Effective Design of Experiment.

Wear-resistant polymers and ceramics-based media have been used to pulverize the bulk powder of poorly water-soluble drugs to nanoscale size in conventional milling; however, contamination of such media is still an issue in the context of drug formulation manufacturing. In the present study, we developed a novel method for pulverizing the particles of a poorly water-soluble drug, ketoprofen, to nanoscale size by mixing mannitol and polypropylene glycol as a safe pulverizing medium. The ketoprofen nanoparticles were prepared using a Hoover automatic muller, equipment that traditionally has been used for the mixing of paint and ink. This process represents a novel application of this machine for the on-demand preparation of nanoparticulate formulations for use in the clinical setting. The optimal composition of the drug formulation was determined by designing an experiment consisting of the central composite design and responsive surface method. We obtained a design space that yielded ketoprofen nanoparticles with targeted particle size, poly-dispersity index, and drug release properties. We validated the manufacturing conditions by preparing ketoprofen nanoparticles in four compositions. Thus, the present study provided useful information regarding not only simple and effective contamination-free milling but also the experimental conditions need to produce nanoparticles of a poorly water-soluble drug.

Para-Hamiltonian form for General Autonomous ODE Systems: Introductory Results.

We propose a new tool to deal with autonomous ODE systems for which the solution to the Hamiltonian inverse problem is not available in the usual, classical sense. Our approach allows a class of formally conserved quantities to be constructed for dynamical systems showing dissipative behavior and other, more general, phenomena. The only ingredients of this new framework are Hamiltonian geometric mechanics (to sustain certain desirable properties) and the direct reformulation of the notion of the derivative along the phase curve. This seemingly odd and inconsistent marriage of apparently remote ideas leads to the existence of the generator of motion for every autonomous ODE system. Having constructed the generator, we obtained the Lie invariance of the symplectic form ω for free. Various examples are presented, ranging from mathematics, classical mechanics, and thermodynamics, to chemical kinetics and population dynamics in biology. Applications of these ideas to geometric integration techniques of numerical analysis are suggested.

Conserving the linear momentum in stochastic dynamics: Dissipative particle dynamics as a general strategy to achieve local thermostatization in molecular dynamics simulations.

Stochastic dynamics is a widely employed strategy to achieve local thermostatization in molecular dynamics simulation studies; however, it suffers from an inherent violation of momentum conservation. Although this short-coming has little impact on structural and short-time dynamic properties, it can be shown that dynamics in the long-time limit such as diffusion is strongly dependent on the respective thermostat setting. Application of the methodically similar dissipative particle dynamics (DPD) provides a simple, effective strategy to ensure the advantages of local, stochastic thermostatization while at the same time the linear momentum of the system remains conserved. In this work, the key parameters to employ the DPD thermostats in the framework of periodic boundary conditions are investigated, in particular the dependence of the system properties on the size of the DPD-region as well as the treatment of forces near the cutoff. Structural and dynamical data for light and heavy water as well as a Lennard-Jones fluid have been compared to simulations executed via stochastic dynamics as well as via use of the widely employed Nose-Hoover chain and Berendsen thermostats. It is demonstrated that a small size of the DPD region is sufficient to achieve local thermalization, while at the same time artifacts in the self-diffusion characteristic for stochastic dynamics are eliminated. © 2016 Wiley Periodicals, Inc.

On the use of mass scaling for stable and efficient simulated tempering with molecular dynamics.

Simulated tempering (ST) is a generalized-ensemble algorithm that employs trajectories exploring a range of temperatures to effectively sample rugged energy landscapes. When implemented using the molecular dynamics method, ST can require the use of short time steps for ensuring the stability of trajectories at high temperatures. To address this shortcoming, a mass-scaling ST (MSST) method is presented in which the particle mass is scaled in proportion to the temperature. Mass scaling in the MSST method leads to velocity distributions that are independent of temperature and eliminates the need for velocity scaling after the accepted temperature updates that are required in conventional ST simulations. The homogeneity in time scales with changing temperature improves the stability of simulations and allows for the use of longer time steps at high temperatures. As a result, the MSST is found to be more efficient than the standard ST method, particularly for cases in which a large temperature range is employed. © 2016 Wiley Periodicals, Inc.

Weak gluteus maximus and weak iliopsoas with normal gluteus maximus: Two complementary new signs to diagnose lower limb functional weakness.

BACKGROUND AND PURPOSE: The diagnosis of functional neurological disorder should be actively made based on the neurological signs. We described two new complementary signs to diagnose functional weakness of the lower limb, "weak gluteus maximus (weak GM)" and "weak Iliopsoas with normal gluteus maximus (weak iliopsoas with normal GM)," and tested their validity. METHODS: The tests comprised Medical Research Council (MRC) examinations of the iliopsoas and GM in the supine position. We retrospectively enrolled patients with functional weakness (FW) or structural weakness (SW) who presented with weakness of either iliopsoas or GM, or both. Weak GM means that the MRC score of GM is 4 or less. Its complementary sign, weak ilopsoas with normal GM, means that the MRC score of ilopsoas is 4 or less, whereas that of GM is 5. RESULTS: Thirty-one patients with FW and 72 patients with SW were enrolled. The weak GM sign was positive in all 31 patients with FW and in 11 patients with SW, that is, 100% sensitivity and 85% specificity. Therefore, the complementary sign, weak iliopsoas with normal GM, was 100% specific for SW. DISCUSSION: Although 100% should be discounted considering limitations of this study, these signs will likely be helpful in differentiating between FW and SW in the general neurology setting. Downward pressing of the lower limb to the bed in the supine position is interpreted by the patient as an active movement exerted with an effort and might be preferentially impaired in FW.

Interrelationships and properties of parasite aggregation measures: a user's guide.

Aggregation of macroparasites among hosts is nearly universal among parasite-host associations. Researchers testing hypotheses on origins of parasite aggregation and its importance to parasite and host population ecology have used different measures of aggregation that are not necessarily measuring the same thing, potentially clouding our understanding of underlying epidemiological processes. We highlight these differences in meanings by exploring properties and interrelationships of six common measures of parasite aggregation, and provide a "user's guide" to inform researchers' decisions regarding their application. We compared the mathematical expressions of the different measures of aggregation, and ran two series of simulations and analyses. The first simulations tested the effect of random removals of parasites on aggregation levels under different conditions, while the second explored interrelationships between the measures, as well as between other individual parasitological sample measures (i.e. mean abundance, prevalence) and aggregation. Results of simulations and analyses showed that the six measures of aggregation could be separated readily into three groups: the variance-to-mean ratio (VMR) together with mean crowding, patchiness with k of the negative binomial, and Poulin's D with Hoover's index. These three pairs of measures showed differing responses to random parasite removals and differing relations with mean abundance and/or prevalence, highlighting that metrics capture different variation in other sample measures and different attributes of aggregation. We used results of our simulations and analyses, and a literature review, to list the properties, advantages, and disadvantages of each aggregation metric. We provide a comprehensive exploration of what is assessed by each metric, as a guide to metric choice. We implore researchers to provide enough information such that aggregation measures from each group are reported or can be readily calculated. Such steps are needed to allow large-scale analyses of variation in degrees of aggregation within and among parasite-host associations, to uncover epidemiological processes shaping parasite distributions.

Association of Hoover's Sign with Maximal Expiratory-to-Inspiratory Pressure Ratio in Patients with COPD.

Purpose: In chronic obstructive pulmonary disease (COPD) some patients develop paradoxical inspiratory rib motion, which is termed Hoover's sign. Our objective was to determine whether Hoover's sign is associated with a difference in the maximal expiratory pressure (MEP), the maximal inspiratory pressure (MIP), the MEP/MIP ratio, and other features on pulmonary function tests (PFTs). Methods: This observational prospective single-center cohort study enrolled patients with an established diagnosis of COPD with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3 (severe) and 4 (very severe) based on PFTs. Respiratory pressure measurements were also collected. Patients were examined for the presence or absence of Hoover's sign on physical examination by 2 internal medicine resident physicians trained in examining for Hoover's sign by a pulmonologist. Results: A total of 71 patients were examined for the presence of Hoover's sign. Hoover's sign was present in 49.3% of patients. Observer agreement (k statistic) was 0.8 for Hoover's sign. Median MEP/MIP was significantly greater in patients with Hoover's sign than those without Hoover's sign (1.88 versus 1.16, p<0.001). Patients with Hoover's sign also had a significantly lower MIP (39.0 versus 58.0, p<0.001) and higher residual volume (RV) to total lung capacity (TLC) ratio indicating a higher degree of air trapping (65 versus 59.5, p<0.014). Conclusion: The presence of Hoover's sign in patients with COPD is associated with a higher MEP/MIP ratio. This suggests respiratory pressure measurements can predict diaphragm dysfunction in patients with GOLD stage 3 and 4 COPD. Patients with Hoover's sign were also found to have a lower MIP and more air trapping.

Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review.

We report here the clinical diagnosis and treatment and genetic mutations of an infant with You-Hoover-Fong syndrome (YHFS). The relevant literature review was conducted. A female infant aged 17 months was admitted to Nanhai Affiliated Maternity and Children's Hospital of Guangzhou University of Chinese Medicine due to "global development delay complicated with postnatal growth retardation for more than 1 year." The infant was diagnosed with YHFS due to the onset of extremely severe mental retardation, microcephaly, abnormal hearing, severe protein-energy malnutrition, congenital cataract, cleft palate (I°), congenital atrial septal defect, brain atrophy, hydrocephalus, and brain hypoplasia. The whole exon sequencing revealed two compound heterozygous mutations, including a likely pathogenic TELO2 variant, c.2245A > T (p.K749X) from her mother and an uncertain variant, c.2299C > T (p.R767C) from her father, validated by Sanger sequencing. After bilateral cataract surgery, the infant obtained better visual acuity and showed more responses and interactions with her parents. Diagnosis and treatment of this case prompt that these TELO2 variants have not been reported, deepening the understanding of the molecular and genetic mechanism of YHFS in clinical practice.

The Final Illness of Herbert Hoover.

Herbert Hoover, the archetypal self-made man, was the 31st president of the United States. His term in office was overwhelmed by the Great Depression and he was defeated by Franklin Delano Roosevelt in the 1932 November presidential election. His post-presidential years were spent writing and serving 4 subsequent presidents. Near the end of his life, he underwent a cholecystectomy for symptomatic gallstones and a colectomy for colon cancer. His health care was complicated by the development of cirrhosis and recurrent gastrointestinal bleeding. After his 90th birthday, he died in October 1964 from massive bleeding due to a Dieulafoy lesion of the gastric cardia. This manuscript will review the details of his health and the physicians who cared for Hoover during his final years.

Sarcotubular Myopathy Due to Novel TRIM32 Mutation in Association with Multiple Sclerosis.

Azerbaijani 28-year-old female showed weakness (MRC (Medical Research Council Scale for Muscle Strength) grade 4 in the proximal part of the upper and MRC grade 2-3 in the lower extremities), difficulty in stair lifting, positive symptom of Hoover's rising, «waddling gait¼, decline deep reflexes symmetrical, lack of surface reflexes, positive Babinsky's reflex on the right, urinary incontinence during sneezing, prolonged walking and exercise from puberty. Additional methods made it possible to identify minor violations of conduction of the left ventricle, electromyography signs of primary muscular disease with predominant involvement of the proximal muscles of the lower extremities, elevation of serum creatine kinase (746.81 U/l), active foci of demyelination in the left frontal lobe, intrathecal synthesis of oligoclonal IgG bands (type 2) in cerebrospinal fluid, atrophy and fatty degeneration of all muscles of the shins, homozygous Variant of Uncertain Significance (VUS) c.1855C > T (p.Pro619Ser) in TRIM32 gene and heterozygous VUS c.2300C > G (p.Thr767Arg) in KIF5A, c.2840G > A (p.Arg947Lys) in MYH2, c.1502G > C (p.Gly501Ala) in POMT1 genes. Comparison of the phenotypes of the mutations that have been identified with the clinical picture of the patient suggests that VUS c.1855C > T (p.Pro619Ser) in the TRIM32 gene can be pathological. Summarizing, it can be argued that the cause of the identified disorders is a homozygous variant c.1855C > T (p.Pro619Ser) in TRIM32 gene that causes LGMDR8 in a patient with MS.

Cataract in You-Hoover-Fong syndrome: TELO2 deficiency.

INTRODUCTION: Recently, You, Hoover-Fong, and colleagues described a disease caused by a deficiency of the telomere maintenance 2 gene (TELO2) function. The clinical spectrum includes early-onset global delay, dysmorphic facial features, auditory disorder, and reduced vision. MATERIALS AND METHODS: We report two siblings, diagnosed with You-Hoover-Fong syndrome at the age of 28 and 14 months. Both were genetically studied to find the cause of their developmental delay and microcephaly. RESULTS: The identical compound heterozygous missense mutations in the TELO2gene were found in each. Ophthalmologically, both siblings were diagnosed with progressive congenital bilateral nuclear-lamellar cataracts. CONCLUSIONS: We report nuclear-lamellar cataracts in two siblings diagnosed with You-Hoover-Fong syndrome.

Measuring aggregation in parasite populations.

Aggregation, a fundamental feature of parasite distributions, has been measured using a variety of indices. We use the definition that parasite-host system A is more aggregated than parasite-host system B if any given proportion of the parasite population is concentrated in a smaller proportion of the host population A than of host population B. This leads to indices based on the Lorenz curve such as the Gini index (Poulin's D), coefficient of variation and the Hoover index, all of which measure departure from a uniform distribution. The Hoover index is particularly useful because it can be interpreted directly in terms of parasites and hosts. An alternative view of aggregation is degree of departure from a Poisson (or random) distribution, as used in the index of dispersion and the negative binomial k. These and Lloyd's mean crowding index are reinterpreted and connected back to Lorenz curves. Aggregation has occasionally been defined as the slope from Taylor's law, although the slope appears unrelated to other indices. The Hoover index may be the method of choice when data points are available, and the coefficient of variation when only variance and mean are given.

Physical signs in patients with chronic obstructive pulmonary disease.

We reviewed the various physical signs of chronic obstructive pulmonary disease, their pathogenesis, and clinical importance. We searched PubMed, EMBASE, and the CINAHL from inception to March 2018. We used the following search terms: chronic obstructive pulmonary disease, physical examination, purse-lip breathing, breath sound intensity, forced expiratory time, abdominal paradox, Hoover's sign, barrel-shaped chest, accessory muscle use, etc. All types of studies were chosen. Globally, history taking and clinical examination of the patients is on the wane. One reason can be a significant development in the field of medical technology, resulting in overreliance on sophisticated diagnostic machines, investigative procedures, and medical tests as first-line modalities of patient's management. In resource-constrained countries, detailed history taking and physical examination should be emphasized as one of the important modalities in patient's diagnosis and management. Declining bedside skills and clinical aptitude among the physician is indeed a concern nowadays. Physical diagnosis of chronic obstructive pulmonary disease (COPD) is the quickest and reliable modalities that can lead to early diagnosis and management of COPD patients. Bedside elicitation of physical signs should always be the starting point for any diagnosis and therapeutic approach.

Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome.

BACKGROUND: Very recently, compound heterozygous loss-of-function mutations in TELO2 were shown to underlie the newly-described You-Hoover-Fong syndrome. TELO2 forms part of the co-chaperone triple T complex (TTT complex), which plays an important role in the maturation and stabilization of the phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Patients with mutations in TELO2 present with microcephaly and associated intellectual disability, postnatal growth retardation and dysmorphic features. Here, we describe Danish sisters with two novel mutations in TELO2. In particular, we highlight the clinical features of the 22-year index patient, which are more severe than the original patients described, thereby expanding the clinical spectrum of YHFS. METHODS: The index patient was clinically examined and subsequently exome sequencing on her DNA was performed using the NimbleGen SeqCap EZ Human Exome Library v2.0 enrichment kit on an Illumina HiSeq2000 sequencer. RESULTS: Two novel, compound heterozygous mutations in TELO2 were identified in the index patient and her deceased older sister. Both have clinical features in keeping with the original YHFS patients, although the index patient seems to represent the severe end of the clinical spectrum with very marked prenatal onset growth retardation and microcephaly, severe global developmental delay and facial dysmorphic features. Additional clinical findings include eye anomalies (bilateral congenital cataracts, retinitis pigmentosa, convergent squint), bilateral conductive hearing loss, an abnormal kidney and seizures. CONCLUSION: This report of Danish siblings with YHFS serves to expand the presentation of this new syndrome to include features in keeping with a form of microcephalic primordial dwarfism on the severe end of the clinical spectrum, and adds two novel mutations to the TELO2 mutational spectrum.

Hurst revisited: Are symptoms and signs of functional motor and sensory disorders "dependent on idea"?

INTRODUCTION: Symptoms and signs of functional (psychogenic) motor and sensory disorder are often said to be dependent on the patients' idea of what symptoms should be, rather than anatomy and physiology. This hypothesis has however rarely been tested. MATERIALS AND METHODS: Inspired by a brief experiment carried out in 1919 by neurologist Arthur Hurst we aimed to assess the views of healthy non-medical adults towards paralysis and numbness and their response to tests for functional disorders when asked to pretend to have motor and sensory symptoms. RESULTS: When subjects were asked to pretend they had a paralysed arm 80% thought there would be sensory loss. Of these 60% thought it would have a circumferential (functional) distribution at the wrist, elbow or shoulder. Hoover's sign of functional weakness was only positive in 75% of patients pretending to have leg paralysis with 23% maintaining weakness of hip extension in the feigned weak leg, a rare finding in neurological practice. 20% of subjects managed to continue having their feigned tremor during the entrainment test. 52% of subjects thought there was asymmetry of a tuning fork across their forehead even when no prior instruction had been given. CONCLUSIONS: The study confirmed Hurst's finding that non-medical people generally expect sensory loss to go along with paralysis, especially if the examiner suggests it. When present, it usually conforms to functional patterns of sensory loss. Clinical tests for functional and motor disorders appear to behave somewhat differently in patients asked to pretend to have symptoms suggesting that larger more detailed studies would be worthwhile.