Incidence of motor neuron disease/amyotrophic lateral sclerosis in South Africa: a 4-year prospective study.

BACKGROUND AND PURPOSE: Little is known about the epidemiological features of amyotrophic lateral sclerosis (ALS) in sub-Saharan Africa, and data from the region are limited to clinical series or case reports. The aim of the study was to investigate the incidence rate and presentation of ALS in an ethnically diverse region of South Africa. METHODS: We performed a 4-year prospective incidence study in the Western Cape Province of South Africa between 1 July 2014 and 30 June 2018, and used a two-source capture-recapture method for case ascertainment. Age- and sex-adjusted incidence rates (ASAIRs) were calculated using the 2010 US population as the reference. RESULTS: A total of 203 incident cases were identified over the study period, resulting in a crude incidence rate (IR) of 1.09 [95% confidence interval (CI) 0.94-1.24] per 100 000 person-years in the at-risk population (aged >15 years). Capture-recapture analysis resulted in an estimated IR of 1.11 (95% CI 1.01-1.22) per 100 000 person-years. The ASAIR was 1.67 (95% CI 1.09-2.26) overall; 1.99 (95% CI 1.60-2.39) for men and 1.37 (95% CI 1.06-1.68) for women. When analysed separately, there was a substantial difference in ASAIRs between the different population groups, with the highest in the European ancestry group (2.62; 95% CI 2.49-2.75), the lowest in the African ancestry group (0.56, 95% CI 0.0-1.23), and an ASAIR in between these two in the mixed ancestry group (1.09, 95% CI 0.80-1.37). CONCLUSION: The overall incidence of ALS in the Western Cape Province of South Africa appears to be lower than in North African and Western countries, but higher than in Asian countries. As suggested by previous epidemiological studies, ALS may be less frequent in people of African ancestry.

The functionality of African-specific variants in the TGFB1 regulatory region and their potential role in HIVAN.

BACKGROUND: Transcription of transforming growth factor beta-1 (TGF-ß1) is regulated by a polymorphic promoter region containing African-specific single nucleotide polymorphisms (SNPs). Some of these SNPs have higher frequencies among Southern Africans compared to other African populations and their functionality has only been partially studied. Due to the high prevalence of HIV-associated nephropathy (HIVAN) in Africans we hypothesized that functional African TGFB1-promoter SNPs may contribute to HIVAN pathogenesis. METHODS: The functionality of the TGFB1 -1347 C>T variant and African-specific variants (-1287 G>A, -1154 C>T, -387 C>T and -14 G>A) were examined by measuring reporter gene expression in kidney and fibroblast cell lines co-transfected with TGFB1-promoter constructs and an HIV-Tat expression vector. TGF-ß1 immunohistochemical staining was performed on kidney biopsies with HIVAN (n = 18) and compared to control biopsies without HIVAN or tubulointerstitial disease (n = 12) using semi-quantitative and digital image analysis. HIVAN cases were genotyped for TGFB1 -1347 and -387 SNP variants. RESULTS: TGFB1-promoter haplotypes containing the African -387 T-allele resulted in ~ five-fold repression of TGFB1-promoter activity compared to -387 C haplotypes (p ≤ 0.024). HIV-Tat upregulated TGFB1-promoter activity for haplotypes containing -1347 T and -387 T in transfected renal cells (≈ 1.6-fold; p ≤ 0.030) and fibroblasts (≈ 1.3-fold; p ≤ 0.016). The renal interstitium from HIVAN biopsies, compared to HIV-positive and -negative controls, differed in the semi-quantitative TGF-ß1 staining and digital optical density analyses. The TGFB1 -1347 and -387 genotypes in HIVAN cases were similar to population controls. CONCLUSION: African-specific haplotypes lower TGFB1-promoter activity and expression levels and HIV-Tat upregulates TGFB1 promoter activity irrespective of the haplotype.

Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor.

Several studies have demonstrated the expression of odorant receptors (OR) in various human tissues and their involvement in different physiological and pathophysiological processes. However, the functional role of ORs in the human heart is still unclear. Here, we firstly report the functional characterization of an OR in the human heart. Initial next-generation sequencing analysis revealed the OR expression pattern in the adult and fetal human heart and identified the fatty acid-sensing OR51E1 as the most highly expressed OR in both cardiac development stages. An extensive characterization of the OR51E1 ligand profile by luciferase reporter gene activation assay identified 2-ethylhexanoic acid as a receptor antagonist and various structurally related fatty acids as novel OR51E1 ligands, some of which were detected at receptor-activating concentrations in plasma and epicardial adipose tissue. Functional investigation of the endogenous receptor was carried out by Ca2+ imaging of human stem cell-derived cardiomyocytes. Application of OR51E1 ligands induced negative chronotropic effects that depended on activation of the OR. OR51E1 activation also provoked a negative inotropic action in cardiac trabeculae and slice preparations of human explanted ventricles. These findings indicate that OR51E1 may play a role as metabolic regulator of cardiac function.

[A 10-year evaluation of geriatric rehabilitation in Rhineland-Palatinate]. / 10 Jahre Evaluation der geriatrischen Rehabilitation in Rheinland-Pfalz.

BACKGROUND: An evaluation of geriatric rehabilitation has been carried out in Rhineland-Palatinate for over 10 years by collecting data of patients absolving an inpatient geriatric rehabilitation program. The aim of the project was to improve the transparency of outcome quality. The procedure is equally supported by geriatric rehabilitation clinics, health insurance companies and the Medical Service of Health Insurance (MDK). MATERIAL AND METHODS: Consented information about the rehabilitation process has been collected from every geriatric rehabilitation clinic in Rhineland-Palatinate. The data were pseudonymized and sent to the MDK in Rhineland-Palatinate for statistical analysis. The dataset included age, diagnosis, life circumstances before rehabilitation, duration of the rehabilitation, therapy implemented and need for support (with or without personal assistance) in eight activities of daily living at the beginning and at the end of rehabilitation. RESULTS: The results of 45,751 participants who underwent rehabilitation between 2005 and 2014 are presented. There was a slight tendency towards an increase in the number of very old geriatric patients undergoing rehabilitation. The average duration of rehabilitation decreased slightly during the observation period, while the frequency of therapy increased. The reduction in the need for assistance during rehabilitation remained constant over the observation period. CONCLUSION: Systematic evaluation improves the transparency of the rehabilitation process.

[Vision Screening in Zurich]. / Sehscreening in der Stadt Zürich.

BACKGROUND: In the city of Zurich, vision screening is performed by school medical services as part of the legally compulsory preventive medical examinations. We retrospectively evaluated the results of the 2011-2012 school year. PATIENTS AND METHODS: Preventive medical examinations by the school medical services were performed in all kindergartens. The examinations were mandatory for first, second and eighth grade children, whilst those for the fourth grade were voluntary. The basic diagnostic testing consisted of monocular visual acuity (Snellen E chart) for all age groups and the stereopsis test (TNO test) in kindergartens. RESULTS: Vision screening was performed on 7499 children. 1471 first graders (55 %), 201 fourth graders (11 %) and 211 eighth graders (12.3 %) did not pass the examinations. In 33.7 % of the children who underwent the follow-up examination from an ophthalmologist, amblyogenic potential was found. CONCLUSIONS: Vision screening by the school medical services enrols most of the children from a single age group. The Snellen E charts used for the monocular distance acuity, together with the TNO stereo test, appear to constitute an effective testing combination. Ophthalmological follow-up examinations of the affected children revealed that one third were afflicted by amblyogenic factors.

Recurrent Miller Fisher syndrome: clinical and laboratory features.

To present two patients with Miller Fisher syndrome (MFS) recurrence after 35 and 44 years and review of the literature on recurring MFS. All identified cases with recurrent MFS were evaluated. Age, gender, clinical features of first and recurrent MFS, course of disease, laboratory findings, therapy and outcome were transformed into tables. Twenty-eight patients (16 men, 12 women; mean age at the first episode 34 years (range 13-57 years); mean age at the latest episode 47 years (range 21-66 years) with a total of 70 MFS episodes were identified. Twenty-one patients had a single recurrence, five patients had two recurrences, one patient had four recurrences and one patient had seven recurrences. The mean interval between attacks was 9.45 years (3 months to 44 years). In 76% of the initial episodes and in 81% of the recurrent episodes, an infectious disease preceded MFS. Additional facial and bulbar symptoms and autonomic disturbances were frequent findings. Cerebrospinal fluid (CSF) and electrodiagnostic findings were unspecific. If tested, autoantibodies against GQ1b had been positive in all episodes. In about half of the patients, immunotherapy was applied. The outcome was favourable in most patients. Recurrence of MFS is a rare quite uniform condition with a mostly favourable prognosis.

[The new S2k AWMF guideline for the treatment of Bell's palsy in commented short form]. / Die neue S2k AWMF Leitlinie zur idiopathischen Fazialisparese in kommentierter Kurzform.

A new S2k AWMF guideline for the treatment of idiopathic facial palsy has been published. An accurate differential diagnosis is indispensable as 25-40% of all facial palsy cases are of non-idiopathic origin. It is explicitly recommended to treat patients with idiopathic facial palsy with steroids. Steroids favour a complete recovery, decrease the risk of synkinesis, autonomic sequelae and contractures. Adjuvant antiviral therapy cannot be recommended. On current data there is not sufficient evidence that the combination of steroids with antiviral drugs has a benefit for the patients. Even when not supported by randomized trials, adjuvant symptomatic therapy to protect the cornea and to avoid complications is recommended. There is no scientific evidence that physical therapy has any benefit but it should be taken into account because of psychological reasons. A benefit of acupuncture has not been proven. If eye closure remains incomplete as result of defective healing, one therapeutic option is lid loading of the upper eye lid. Moreover, in case of severe persistent palsy, several well-established microsurgical nerve and muscle plasty procedures are available.

[Recommendation of an assessment protocol to describe geriatric inpatient rehabilitation of lower limb mobility based on ICF: an interdisciplinary consensus process]. / Empfehlungen für die Durchführung des motorischen Assessments der unteren Extremität zur ICF-basierten Verlaufsbeurteilung der Mobilität in der stationären geriatrischen Rehabilitation: Bericht eines interdisziplinären Konsensusprozesses.

Because of the growing demand of geriatric rehabilitation, objective and clear indication decisions are needed with respect to limited financial resources. The aim of an interdisciplinary consensus group was to critically evaluate the most commonly used tests of functional performance of the lower limbs and to recommend useful tests to document progress of inpatient rehabilitation. Assessment of standing, walking, walking with a dual-task, sit-to-stand transfer, lying-to-sit-to-stand transfer, and stair climbing were recommended to document functional performance of the lower limbs and to describe rehabilitation targets. Future research is needed, because reasonably validated assessment tools do not exist for all of these domains. In addition to a standardized assessment of physical capacity, physical activity and participation with regard to the International Classification of Functioning, Disability, and Health (ICF) context have to be assessed. Body fixed sensors seem to be a promising assessment tool to objectively document progress in rehabilitation.

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis.

Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C>G SNP (odds ratio=8.6; P=0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5'-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C>G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression.

Predictive testing for Huntington disease in a developing country.

Predictive testing for Huntington disease (HD), by means of direct mutation analysis, has been offered at the Division of Human Genetics, University of Cape Town, from 1995. The aim of this study was to compile a comprehensive profile of the participants who had undergone predictive testing in the Western Cape from 1995 to 2005. The sociodemographic data, uptake and outcome of tests were analyzed to inform changes to improve the current genetic counseling services. A retrospective cross-sectional design using a 'multi-method' approach of both qualitative and quantitative methods was used. Data were gathered from the participants' hospital files and genetic database. Psychosocial data were obtained by face-to-face interviews with the participants in their homes or venues of choice. A total of 36 predictive tests were performed. The uptake for predictive testing was approximately 4.5% of the estimated at-risk population. The cohort of 27 individuals comprised 16 females and 11 males. Their mean age was 35.3 years; 6 were mixed ancestry and 21 were White people (European ancestry); 11 tested gene positive, 15 gene negative and 1 was in the reduced penetrance range. The most important issue identified was that the uptake of individuals classified as mixed ancestry was substantially lower than that of the White people possibly due to limited access to the predictive testing program because of the low levels of income and education in the general population of families with HD. Strategies to address these aspects have been incorporated into the program and will be reassessed after 1 year.

Smell and taste disorders in polyneuropathy: a prospective study of chemosensory disorders.

OBJECTIVE: The aim of the study was to assess the occurrence and the frequency of chemosensory dysfunction in patients with polyneuropathy (PNP). METHODS: We performed a prospective observational study. Olfactory function was assessed using the standardized 'Sniffin' Sticks' test to measure odor threshold for phenyl ethyl alcohol, odor discrimination, and odor identification. Gustatory function was assessed using the standardized 'taste strips' test. In addition, we assessed etiology, neurophysiology, and severity of the PNP, and the patients' comorbidities and medication. RESULTS: A total of 53 consecutive patients were enrolled (15 women, 38 men; mean age 61 years); 27 of them (51%) exhibited olfactory dysfunction and 23 of them (43%) gustatory dysfunction. Patients with diabetic PNP had significantly lower taste scores than patients with inflammatory, genetic, or idiopathic PNP. In addition, odor identification was negatively correlated with PNP severity. CONCLUSION: The applied bedside tests are useful to detect chemosensory dysfunction in patients with PNP. Chemosensory dysfunction is quite frequent in these patients.

A uniquely high number of ftsZ genes in the moss Physcomitrella patens.

Plant FtsZ proteins are encoded by two small nuclear gene families (FtsZ1 and FtsZ2) and are involved in chloroplast division. From the moss Physcomitrella patens, four FtsZ proteins, two in each nuclear gene family, have been characterised and described so far. In the recently sequenced P. patens genome, we have now found a fifth ftsZ gene. This novel gene has a genomic structure similar to PpftsZ1-1. According to phylogenetic analysis, the encoded protein is a member of the FtsZ1 family, while PpFtsZ1-2, together with an orthologue from Selaginella moellendorffii, forms a separate clade. Further, this new gene is expressed in different gametophytic tissues and the encoded protein forms filamentous networks in chloroplasts, is found in stromules, and acts in plastid division. Based on all these results, we have renamed the PpFtsZ proteins of family 1 and suggest the existence of a third FtsZ family. No species is known to encode more FtsZ proteins per haploid genome than P. patens.

[OSCE in the neurology clerkship. Experiences at the neurological department of the university hospital Erlangen]. / OSCE in der Neurologie. Erfahrungen an der neurologischen Universitätsklinik Erlangen.

BACKGROUND: In the German medical education program practical examinations at the end of the neurology clerkship are sparsely performed. By this way, motivation for practical learning and a method to assure quality of learning are not used. METHOD: The Anglo-Saxon concept of "objective structured clinical examination" (OSCE) is picked up and implemented as a practical examination at the end of the neurology clerkship of medical students in their 4th and 5th year. A catalogue of learning goals was defined and an OSCE of 5 stations was developed. A standard of a successful examination was defined. In two OSCE stations the competence in clinical decision making and reasoning were tested, in two stations the competence in practical examination skills and in one station the practical skill to perform a lumbar puncture at the phantom. The results of the OSCE stations were analysed for task difficulty, discriminatory power, normalized discrimination index and reliability. Using a questionnaire, the students evaluated the OSCE. RESULTS: N = 123 students (73 female, 50 male) with a mean age of 26.1 years (22 - 46 years) participated. The mean score was 40 +/- 3.6 of a total of 50 points (range 29 - 46). Female students (40.8 +/- 3.1) scored significantly higher than male ones (38.8 +/- 4; p = .002). One student (0.8 %) failed the examination. The difficulty of the stations ranged between 0.63 and 0.91, normalized discrimination index between 0.1 and 0.18 and the discriminatory power from r = 0.25 to r = 0.53. The reliability of the 5 stations was 0.65 (Cronbach's alpha). In the evaluation, the rating for innovation, organisation, length, clarity of the tasks, clinical reality and compatibility with general physician's competence, atmosphere during the examination and fairness was extremely positive. Most students would prefer an OSCE compared with a multiple-choice test. CONCLUSION: An OSCE at the end of the neurology clerkship is feasible. The quantitative analyses of the results are concordant with requirements of medical examinations. The OSCE is positively evaluated by the students.

Effects of peer-assisted training during the neurology clerkship: a randomized controlled study.

OBJECTIVE: To determine the efficacy of peer-assisted clinical skills training for students during their neurology clerkship. METHODS: Students (n = 122) were randomized to get clinical skills training from either student (peer) instructors (experimental group) or from experienced clinical staff (control group). The remaining schedule during the clerkship did not differ between both groups. Primary endpoint was students' practical skills and knowledge tested at the end of the course by a written test and objective structured clinical examination (OSCE). Secondary endpoints were evaluation of the practical training and self-estimated gain in theoretical and practical competence. RESULTS: In the written test, the peer-trained group (n = 66) scored 69.5 +/- 10.2 (95% CI 67-72) points of 100 and the postgraduates-trained group (n = 56) 66.7 +/- 11.4 (95% CI 63.6-69.8) (P = 0.15). In the OSCE the peer-trained group scored 93.7 +/- 6.3 (95% CI 92.1 to 95.2) points of 100 and the postgraduates-trained group 92 +/- 5.1 (95% CI 90.6 to 93.4) (P = 0.11). In the evaluation and self-assessment items, there was no significant difference between the two groups except for the postgraduates' higher competence (P = 0.004). CONCLUSION: Peer-trained students pass written exam and OSCE as efficient as postgraduates-trained students. Self-assessed learning success is equally rated in both groups.

Myasthenia gravis in South Africans: racial differences in clinical manifestations.

We present data on the phenotypic variation in myasthenia gravis of 205 subjects from a multi-racial South African cohort. Consecutive subjects seen more than twice from 1996 to 2006, were included. Documented observational data included a myasthenia gravis and extra-ocular eye muscle score. Results showed Black subjects were more likely than Whites to develop treatment-resistant complete ophthalmoplegia and ptosis (18% vs. 2%; p=0.041). Of the 14 patients with this phenotype, 13 had generalised disease and positive AChR antibodies. Despite similar sized cohorts, White subjects were more likely than Blacks to develop generalised myasthenia poorly responsive to therapy (p=0.005). There were no significant racial differences in the time between diagnosis to initiation of therapy, or the performance and timing of thymectomy. The racial variation in some phenotypic features of myasthenia gravis and outcome to therapy, highlights the need to study biological factors in different subgroups to develop a more rational approach to immuno-suppressive therapy.

High prevalence of "non-dipping" blood pressure and vascular stiffness in HIV-infected South Africans on antiretrovirals.

BACKGROUND: HIV-infected individuals are at increased risk of tissue inflammation and accelerated vascular aging ('inflamm-aging'). Abnormal diurnal blood pressure (BP) rhythms such as non-dipping may contribute to an increased risk of cardiovascular and cerebrovascular events in HIV infected individuals. However, little data exists on ambulatory blood pressure (ABP) and measures of vascular stiffness in the black African HIV infected population. METHODS: This is a cross-sectional analysis of otherwise well, HIV infected outpatients on ART for >5 years. Study assessments included: 24hr ABP monitoring, pulse wave velocity (PWV) and central aortic systolic pressure (CASP) using a AtCor Medical Sphygmocor device, fasting lipogram, oral glucose tolerance test, high-sensitivity C-reactive protein (hsCRP) and anthropometric data. Patients completed a questionnaire of autonomic symptoms. CD4+ counts and viral loads were obtained from the National Laboratory results system. RESULTS: Sixty seven black participants were included in the analysis of whom 91% (n = 61) were female with a mean age of 42.2 ± 8.6 years. The median duration on ART was 7.5 years (IQR = 6-10), 84% were virally supressed and the median CD4 count was 529.5cells/mm3 (IQR = 372.0-686.5). The majority (67%) were classified as overweight and 76% had an increased waist circumference, yet only 88% of participants were normotensive. A hsCRP level in the high cardiovascular risk category was found in 68% of participants. The prevalence of non-dipping BP was 65%. Interestingly, there was no association on multivariable analysis between dipping status and traditional risk factors for non-dipping BP, such as: obesity, autonomic dysfunction and older age. CONCLUSION: This relatively young cross-sectional sample of predominantly normotensive, but overweight black women on effective ART >5 years showed: a high prevalence of non-dipping BP, inflammation and vascular stiffness. Causality cannot be inferred but cardiovascular risk reduction should be emphasized in these patients.

Taste in dementing diseases and parkinsonism.

Like with many sensory abilities a reduction of taste and smell occurs during aging. Since there are hints to an additional reduction in dementing diseases, we assessed 52 patients, 26 women and 26 men, who were presented to a memory clinic, using the Sniffin' Sticks, Whole Mouth and Taste Strip Tests. While smoking, alcohol consumption, intake of drugs and sex exerted only minor impact, age and the severity of cognitive impairment were of major importance. There was a moderate but significant correlation between the severity of dementia, taste and smell, even if the age effect was partialled out. Notably, patients with Parkinson syndrome showed worse taste and smell abilities than those without. Here the differences were indeed marked enough to play a possible role in making the diagnosis. This exploratory study confirms a mild reduction of gustatory function in dementing diseases over and beyond that of normal aging which--in addition to a reduction of smell--seems to be especially marked in Parkinson syndromes.

Zinc gluconate in the treatment of dysgeusia--a randomized clinical trial.

In the treatment of dysgeusia, the use of zinc has been frequently tried, with equivocal results. The aim of the present randomized clinical trial, which involved a sufficiently large sample, was therefore to determine the efficacy of zinc treatment. Fifty patients with idiopathic dysgeusia were carefully selected. Zinc gluconate (140 mg/day; n=26) or placebo (lactose; n=24) was randomly assigned to the patients. The patients on zinc improved in terms of gustatory function (p <0.001) and rated the dysgeusia as being less severe (p <0.05). Similarly, signs of depression in the zinc group were less severe (Beck Depression Inventory, p <0.05; mood scale, p <0.05). With the exception of the salivary calcium level, which was higher in the zinc patients (p <0.05), no other significant group differences were found. In conclusion, zinc appears to improve general gustatory function and, consequently, general mood scores in dysgeusia patients.