Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders.

Hypermobile Ehlers-Danlos syndrome (EDS) and hypermobility spectrum disorders are the most common symptomatic joint hypermobility conditions seen in clinical practice. The 2017 International Classification of the Ehlers-Danlos syndromes replaced previous terms for symptomatic joint hypermobility with hypermobile EDS and introduced the term hypermobility spectrum disorders for patients not meeting diagnostic criteria for hypermobile EDS. Both are diagnosed by applying the 2017 diagnostic criteria, which also excludes other less common conditions presenting with joint hypermobility such as other forms of EDS and heritable connective tissue disorders. Hypermobile EDS is inherited in an autosomal dominant pattern, but it does not have a known genetic mutation to help with diagnosis. Clinical features of hypermobile EDS include joint hypermobility, skin findings, and joint pains or recurrent dislocations. Hypermobile EDS and, less commonly, hypermobility spectrum disorders may also be associated with several extra-articular symptoms, including anxiety disorders, chronic pain, fatigue, orthostatic intolerance, functional gastrointestinal disorders, and pelvic and bladder dysfunction. The central goals of therapy are managing symptoms, preventing joint injury, and educating patients about their condition. Based on limited evidence, patients with hypermobile EDS/hypermobility spectrum disorders may benefit from physical and occupational therapy, psychological support, and self-management. Primary care physicians play a key role not only in initial recognition, diagnosis, and patient education, but by virtue of their ongoing relationship they can also help oversee and coordinate the multidisciplinary team many of these patients require.

Diagnosis of acute stroke.

Stroke can be categorized as ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Awakening with or experiencing the abrupt onset of focal neurologic deficits is the hallmark of the diagnosis of ischemic stroke. The most common presenting symptoms of ischemic stroke are speech disturbance and weakness on one-half of the body. The most common conditions that can mimic a stroke are seizure, conversion disorder, migraine headache, and hypoglycemia. Taking a patient history and performing diagnostic studies will usually exclude stroke mimics. Neuroimaging is required to differentiate ischemic stroke from intracerebral hemorrhage, as well as to diagnose entities other than stroke. The choice of neuroimaging depends on availability of the method, the patient's eligibility for thrombolysis, and presence of contraindications. Subarachnoid hemorrhage presents most commonly with sudden onset of a severe headache, and noncontrast head computed tomography is the imaging test of choice. Cerebrospinal fluid inspection for bilirubin is recommended if subarachnoid hemorrhage is suspected in a patient with a normal computed tomography result. Public education about common presenting stroke symptoms may improve patient knowledge and clinical outcomes.

Diagnostic approach to patients with tinnitus.

Tinnitus, a common symptom encountered in family medicine, is defined as the perception of noise in the absence of an acoustic stimulus outside of the body. Because tinnitus is a symptom and not a disease, its underlying cause must be determined to best help patients. Although tinnitus is often idiopathic, sensorineural hearing loss is the most common identified cause. It can also be caused by other otologic, vascular, neoplastic, neurologic, pharmacologic, dental, and psychological factors. More serious causes, such as Meniere disease or vestibular schwannoma, can be excluded during the evaluation. History and physical examination of the head, eyes, ears, nose, throat, neck, and neurologic system guide subsequent evaluation. Almost all patients with tinnitus should undergo audiometry with tympanometry, and some patients require neuroimaging or assessment of vestibular function with electronystagmography. Supportive counseling should begin during the initial evaluation to help patients cope with tinnitus. Counseling may also improve the chances of successful subsequent treatment.

Elephant shark sequence reveals unique insights into the evolutionary history of vertebrate genes: A comparative analysis of the protocadherin cluster.

Cartilaginous fishes are the oldest living phylogenetic group of jawed vertebrates. Here, we demonstrate the value of cartilaginous fish sequences in reconstructing the evolutionary history of vertebrate genomes by sequencing the protocadherin cluster in the relatively small genome (910 Mb) of the elephant shark (Callorhinchus milii). Human and coelacanth contain a single protocadherin cluster with 53 and 49 genes, respectively, that are organized in three subclusters, Pcdhalpha, Pcdhbeta, and Pcdhgamma, whereas the duplicated protocadherin clusters in fugu and zebrafish contain >77 and 107 genes, respectively, that are organized in Pcdhalpha and Pcdhgamma subclusters. By contrast, the elephant shark contains a single protocadherin cluster with 47 genes organized in four subclusters (Pcdhdelta, Pcdhepsilon, Pcdhmu, and Pcdhnu). By comparison with elephant shark sequences, we discovered a Pcdhdelta subcluster in teleost fishes, coelacanth, Xenopus, and chicken. Our results suggest that the protocadherin cluster in the ancestral jawed vertebrate contained more subclusters than modern vertebrates, and the evolution of the protocadherin cluster is characterized by lineage-specific differential loss of entire subclusters of genes. In contrast to teleost fish and mammalian protocadherin genes that have undergone gene conversion events, elephant shark protocadherin genes have experienced very little gene conversion. The syntenic block of genes in the elephant shark protocadherin locus is well conserved in human but disrupted in fugu. Thus, the elephant shark genome appears to be less prone to rearrangements compared with teleost fish genomes. The small and "stable" genome of the elephant shark is a valuable reference for understanding the evolution of vertebrate genomes.

Institutional support for handheld computing: clinical and educational lessons learned.

Handheld computing devices, or personal digital assistants (PDAs), are used often in the health care setting. They provide a convenient way to store and carry either personal or reference information and can be used to accomplish other tasks associated with patient care. This article reports clinical and educational lessons learned from a longitudinal institutional initiative designed to provide medical students with PDAs to facilitate patient care and assist with clinical learning.

Teaching evidence-based medicine skills: an exploratory study of residency graduates' practice habits.

BACKGROUND AND OBJECTIVES: The long-term effect of teaching critical appraisal (CA) and evidence-based medicine (EBM) skills is unknown. This study explores long-term behaviors and learner satisfaction after a 3-year longitudinal CA/EBM curriculum. METHODS: Telephone interviews were conducted with 1996-1998 graduates of an academic family medicine residency program with an established CA/EBM curriculum. The graduates were all in clinical practice. RESULTS: Ten of 17 graduates met inclusion criteria and consented to be interviewed. Their age range was 31-58, and all had been in practice 3 to 5 years. Six were female. Most participants did not regularly practice CA or use EBM skills. Instead, colleagues were the most commonly used information source. Time constraints and clinical production pressure were the primary barriers to practicing EBM. Despite not practicing CA and EBM, participants generally were satisfied with their training in these skills. Respondents said they used continuing education meetings and reading journals to keep current. CONCLUSIONS: In this study, residents instructed in CA and EBM skills did not regularly practice these skills. Time and workload pressures appear to be major barriers to these behaviors. Those training residents to integrate EBM into clinical practice should evaluate short- and long-term clinically oriented behaviors to assure educational effectiveness.

Learning PDA skills online is feasible and acceptable to clerkship students.

BACKGROUND: The feasibility and acceptability of teaching medical students to use PDA clinical decision support tools via a Web-based course have not been previously evaluated. METHODS: A total of 119 third-year family medicine clerkship students completed a baseline survey on PDA use, attended an introductory PDA lecture, and were invited to voluntarily access a Web-based course through Blackboard. All students had been previously issued with PDAs in their second year. RESULTS: At baseline, 95% of students reported having removed their PDA from its box, 59% reported using it weekly, and 71% had loaded medical applications. From August 2006--March 2007, 36 students accessed the course 610 times (range 8-54). The PDA cases comprised 63% of hits, course resources 30% of hits, and course information 6% of hits. Students evaluated the course equally to other clerkship didactics. CONCLUSIONS: It is feasible and acceptable to students to teach PDA decision support tools in an online course. In our setting, for the minority of students who chose to learn online, the format was successful and met their needs.

Sequencing and comparative analysis of fugu protocadherin clusters reveal diversity of protocadherin genes among teleosts.

BACKGROUND: The synaptic cell adhesion molecules, protocadherins, are a vertebrate innovation that accompanied the emergence of the neural tube and the elaborate central nervous system. In mammals, the protocadherins are encoded by three closely-linked clusters (alpha, beta and gamma) of tandem genes and are hypothesized to provide a molecular code for specifying the remarkably-diverse neural connections in the central nervous system. Like mammals, the coelacanth, a lobe-finned fish, contains a single protocadherin locus, also arranged into alpha, beta and gamma clusters. Zebrafish, however, possesses two protocadherin loci that contain more than twice the number of genes as the coelacanth, but arranged only into alpha and gamma clusters. To gain further insight into the evolutionary history of protocadherin clusters, we have sequenced and analyzed protocadherin clusters from the compact genome of the pufferfish, Fugu rubripes. RESULTS: Fugu contains two unlinked protocadherin loci, Pcdh1 and Pcdh2, that collectively consist of at least 77 genes. The fugu Pcdh1 locus has been subject to extensive degeneration, resulting in the complete loss of Pcdh1gamma cluster. The fugu Pcdh genes have undergone lineage-specific regional gene conversion processes that have resulted in a remarkable regional sequence homogenization among paralogs in the same subcluster. Phylogenetic analyses show that most protocadherin genes are orthologous between fugu and zebrafish either individually or as paralog groups. Based on the inferred phylogenetic relationships of fugu and zebrafish genes, we have reconstructed the evolutionary history of protocadherin clusters in the teleost fish lineage. CONCLUSION: Our results demonstrate the exceptional evolutionary dynamism of protocadherin genes in vertebrates in general, and in teleost fishes in particular. Besides the 'fish-specific' whole genome duplication, the evolution of protocadherin genes in teleost fishes is influenced by lineage-specific gene losses, tandem gene duplications and regional sequence homogenization. The dynamic protocadherin clusters might have led to the diversification of neural circuitry among teleosts, and contributed to the behavioral and physiological diversity of teleosts.

Genetic analysis of DJ-1 in a cohort Parkinson's disease patients of different ethnicity.

Mutations in the DJ-1 gene have been described in autosomal recessive Parkinson's disease patients (ARPD) of European ancestry and young onset (YOPD) Ashkenazi Jewish and Afro-Caribbean patients. There is little information on the prevalence of DJ-1 mutations amongst Asian PD populations. In this study, we examined for DJ-1 mutations in consecutive YOPD and ARPD in a multi-ethnic cohort (Chinese, Malays, and Indians) of PD patients in a tertiary referral center. Sequence analysis of all the exons and the exon and intron boundaries of the DJ-1 gene were carried out. We did not find any DJ-1 mutations in these patients. A number of intronic variants with genotype frequency ranging from 15 to 90% were detected. Unlike Parkin, pathogenic DJ-1 mutations appear to be restricted to certain populations and are unlikely to be of clinical importance in our Asian cohort.

Analysis of MDR1 haplotypes in Parkinson's disease in a white population.

The MDR1 multidrug transporter is important in regulating environmental xenobiotics and hence may play a causative role in Parkinson's disease (PD). MDR1 haplotype comprising 2677 G > T/A and 3435 C > T may be protective against PD. Using a case control methodology, we investigated the association of MDR1 haplotypes (single nucleotide polymorphisms (SNPs) 2677 G > T/A and 3435 C > T) in a Polish PD population. Seven SNPs, extending from the promoter to exon 28 of the MDR1 gene in 158 PD patients and 139 healthy controls were evaluated. Specifically we examined the association of haplotypes containing SNPs 2677 G > T/A and 3435 C > T and risk of PD. The multivariate logistic regression model was used to evaluate the effects of the covariates on the phenotypes. Haplotypes' frequencies were estimated using the Expectation-Maximization algorithm. The frequency of each individual SNPs; -41 A > G (intron -1), -145 C > G (exon 1), -129 T > C (exon 1), 1236 T > C (exon 12), 2677 G > T/A (exon 21), 3435 C > T (exon 26), and 4036 A > G (exon 28) did not differ between PD and controls. However, there was a trend towards significance in PD patients having the haplotype 2677G-3435C (p < 0.09, chi-square 2.85, odds ratio 0.25, 95% CI 0.06-1.08). Haplotype constructs of the other loci did not differ significantly between the two groups. There was a weak protective effect of the haplotype 2677G-3435C in our white population. However, the MDR1 haplotypes did not generally modulate the risk of PD.

Updating clinical knowledge: an evaluation of current information alerting services.

PURPOSE: Clinicians are overwhelmed by the sheer magnitude of new clinical information that is available on a daily basis. Despite the availability of information tools for finding this information and for updating clinical knowledge, no study has examined the quality of current information alerting services. METHODS: We developed a 7-item checklist based on the principles of evidence-based medicine and assessed content validity with experts and face validity with practicing clinicians and clinician researchers. A list of clinical information updating tools (push tools) was generated in a systematic fashion and the checklist was used to rate the quality of these tools by two independent raters. Prior to rating all instruments, the raters were trained to achieve good agreement (>80%) by applying the checklist to two sets of three randomly selected tools. Descriptive statistics were used to describe the quality of the identified tools and inter-rater reliability was assessed using Intraclass Correlation (ICC). RESULTS: Eighteen tools were identified using our systematic search. The average quality of these tools was 2.72 (range 0-7). Only two tools met all suggested criteria for quality. Inter-rater reliability for the 7-item checklist was .82 (ICC). CONCLUSIONS: We developed a checklist that can be used to reliably assess the quality of clinical information updating tools. We found many shortcomings in currently available clinical knowledge updating tools. Ideally, these tools will evolve in the direction of applying basic evidence-based medicine principles to new medical information in order to increase their usefulness to clinicians.

A systematic process to prioritize prevention activities sustaining progress toward the reduction of military injuries.

BACKGROUND: To sustain progress toward injury reduction and other health promotion goals, public health organizations need a systematic approach based on data and an evaluation of existing scientific evidence on prevention. This paper describes a process and criteria developed to systematically and objectively define prevention program and policy priorities. METHODS: Military medical surveillance data were obtained and summarized, and a working group of epidemiology and injury experts was formed. After reviewing the available data, the working group used predefined criteria to score leading military unintentional injury causes on five main criteria that assessed factors contributing to program and policy success: (1) importance of the problem, (2) effectiveness of existing prevention strategies, (3) feasibility of establishing programs and policies, (4) timeliness of implementation and results, and (5) potential for evaluation. Injury problems were ranked by total median score. RESULTS: Causes with the highest total median scores were physical training (34 points), military parachuting (32 points), privately-owned vehicle crashes (31 points), sports (29 points), falls (27 points), and military vehicle crashes (27 points). CONCLUSIONS: Using a data-driven, criteria-based process, three injury causes (physical training, military parachuting, and privately owned-vehicle crashes) with the greatest potential for successful program and policy implementation were identified. Such information is useful for public health practitioners and policymakers who must prioritize among health problems that are competing for limited resources. The process and criteria could be adapted to systematically assess and prioritize health issues affecting other communities.

Acute stroke diagnosis.

Stroke can be categorized as ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Awakening with or experiencing the abrupt onset of focal neurologic deficits is the hallmark of ischemic stroke diagnosis. The most common presenting symptoms for ischemic stroke are difficulty with speech and weakness on one half of the body. Many stroke mimics exist; two of the most common are a postictal seizure and hypoglycemia. Taking a detailed history and performing ancillary testing will usually exclude stroke mimics. Neuroimaging is required to differentiate ischemic stroke from intracerebral hemorrhage, as well as to diagnose entities other than stroke. The choice of neuroimaging depends on its availability, eligibility for acute stroke interventions, and the presence of patient contraindications. Subarachnoid hemorrhage presents most commonly with severe headache and may require analysis of cerebrospinal fluid when neuroimaging is not definitive. Public education of common presenting stroke symptoms is needed for patients to activate emergency medical services as soon as possible after the onset of stroke.

Diagnosis of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease affects more than 26 million adults in the United States. Family physicians provide care for most of these patients. Cigarette smoking is the leading risk factor for chronic obstructive pulmonary disease, although other risk factors, including occupational and environmental exposures, account for up to one in six cases. Patients presenting with chronic cough, increased sputum production, or progressive dyspnea should be evaluated for the disease. Asthma is the disease most often confused with chronic obstructive pulmonary disease. The diagnosis of chronic obstructive pulmonary disease is based on clinical suspicion and spirometry confirmation. A forced expiratory volume in one second/forced vital capacity ratio that is less than 70 percent, and that is incompletely reversible with the administration of an inhaled bronchodilator, suggests chronic obstructive pulmonary disease. Disease severity is classified by symptomatology and spirometry. Joint guidelines from the American Thoracic Society and the European Respiratory Society recommend a single quantitative test for alpha1-antitrypsin deficiency in patients diagnosed with chronic obstructive pulmonary disease who remain symptomatic despite bronchodilator therapy. Other advanced testing is usually not necessary.

PINK1 mutations in sporadic early-onset Parkinson's disease.

Pathogenic PINK1 mutations have been described in PARK6-linked Parkinson's disease (PD) patients of Asian origin. However, data on the frequency of PINK1 mutations in sporadic early-onset Parkinson's disease (EOPD) Asian patients are lacking. The objectives of this study were to report the frequency of PINK1 mutations of sporadic EOPD in an Asian cohort comprising of ethnic Chinese, Malays, and Indians, and to highlight a PINK1-positive patient who presented with restless legs symptoms. Eighty consecutive sporadic EOPD patients from the movement disorder clinics of two major tertiary institutions in the country were included. We performed sequence analysis of all the coding and exon-intron junctions of the PINK1 using specific primer sets. In addition, we genotyped polymorphisms detected from the analysis in a group of sporadic PD patients and controls. Three different mutations (two homozygous nonsense and one heterozygous missense) in the putative kinase domain were found in three patients, giving a 3.7% frequency of PINK1 mutations in our EOPD cohort. All the mutations were absent in 200 healthy controls. One patient with a novel homozygous nonsense PINK1 mutation presented unusually with restless legs symptoms. Separately, analysis of the frequency of four PINK1 polymorphisms in a group of sporadic PD and controls did not reveal any significant differences. We highlight a 3.7% frequency of PINK1 mutations in an Asian cohort (ethnic Chinese, Malay, and Indian) of EOPD. The phenotypic spectrum associated with PINK1-positive patients may be wider than previously reported. Polymorphisms of PINK1 do not appear to modulate risk of PD in our population.

Functional COMT variant predicts response to high dose pyridoxine in Parkinson's disease.

Pyridoxal-5-phosphate, the biological active form of pyridoxine, is a cofactor for dopa-decarboxylase (DDC) enzyme. Pyridoxine may augment the conversion of levodopa to dopamine in the periphery and therefore decrease availability of levodopa to the brain. However, this effect can be negated in the presence of a DDC inhibitor, which potentiates plasma levodopa level. A single nucleotide polymorphism at the nucleotide 1947 in the catechol-O-methyltransferase (COMT) gene encodes the high (COMT(H)) and low activity (COMT(L)) forms of the enzyme. In this study, we examined the effect of the COMT(L) allele on the clinical response to pyridoxine in Parkinson's disease (PD) patients. PD patients who were on stable and optimized dose of levodopa were included in this study. Their mean motor and activities of living score improved after high dose pyridoxine (P = 0.09, P = 0.04), and worsened after a washout period (P = 0.005, P = 0.001). Using a multivariate model, the presence of the COMT(L) allele predicted response to pyridoxine, with the best outcome observed in COMT(L/L) homozygotes. Our observational study suggests that the status the functional COMT(L) variant may be potentially useful to select PD patients for high dose pyridoxine therapy.

Alpha-synuclein mRNA expression in sporadic Parkinson's disease.

The expression of alpha-synuclein gene can be influenced by the genomic load and/or epigenetic factors. By using quantitative real-time polymerase chain reaction techniques, we demonstrated that the alpha-synuclein gene mRNA expression in sporadic PD did not differ from healthy controls (median [range] 0.110 ]0.012-0.628] vs. 0.120 [0.028-0.447]; P = 0.15). There was no difference in the alpha-synuclein gene dosage between PD patients with high and low mRNA expression. Multivariate analysis did not reveal age, gender, or cigarette smoking as confounding variables. Our study suggests that there was no significant alteration of alpha-synuclein mRNA expression in our sporadic PD patients compared to controls. However, the role of alpha-synuclein mRNA expression in select groups of sporadic PD patients and its interaction with environmental agents need to be further determined.

Nurr1 mutational screen in Parkinson's disease.

We performed sequence analysis of all the exons and exon-intron boundaries in familial and young-onset Parkinson's disease (PD) in an Asian cohort. None of the patients carried any pathogenic mutations in the Nurr1 gene. We demonstrated a 5 to 10% prevalence of the intron 7 +33 C-->T variant among Malay and Indian PD and healthy controls, suggesting that this variant, which was previously described only in 1 Chinese patient, was not a silent mutation but a common polymorphic variant in some ethnic races.