Cognitive Performance Measures in Bioelectromagnetic Research - Critical Evaluation and Recommendations

<p>Abstract</p> <p>Background</p> <p>The steady increase of mobile phone usage has led to a rising concern about possible adverse health effects of radio frequency electromagnetic field (RF EMF) exposure at intensities even below the existing safety limits. Accumulating evidence suggests that pulse-modulated RF EMF may alter brain physiology. Yet, whereas effects on the human electroencephalogram in waking and sleep have repeatedly been shown in recent years, results on cognitive performance are inconsistent.</p> <p>Methods</p> <p>This review compares 41 provocation studies regarding the effects of RF EMF exposure similar to mobile telephones on cognitive performance measures in humans. The studies were identified via systematic searches of the databases Pub Med and ISI Web of Science and were published in peer-reviewed journals between 1998 and the end of 2009.</p> <p>Results</p> <p>Based on a critical discussion within the scope of methodological standards it is concluded that state-of-the-art-methods in bio-electromagnetic research on RF EMF effects and cognition have neither been specified nor fully implemented over the last 10-11 years. The lack of a validated tool, which reliably assesses changes in cognitive performance caused by RF EMF exposure, may contribute to the current inconsistencies in outcomes. The high variety of findings may also be due to methodological issues such as differences in sample size and the composition of study groups, experimental design, exposure setup as well as the exposure conditions, and emphasizes the need for a standardized protocol in bioelectromagnetic research.</p> <p>Conclusions</p> <p>At present, no underlying biological mechanism has been identified which mediates the effects on brain functioning as observed in electroencephalographic (EEG) studies. A future aim must be to identify this mechanism as well as a reliable exposure protocol in order to gain more insights into possible behavioral and related health consequences of high-frequency EMF exposure.</p

Mitochondrial disease and endocrine dysfunction

Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial diseases and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial diseases, but other endocrine manifestations in these patients can include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Although mitochondrial endocrine dysfunction frequently occurs in the context of multisystem disease, some mitochondrial disorders are characterized by isolated endocrine involvement. Furthermore, additional monogenic mitochondrial endocrine diseases are anticipated to be revealed by the application of genome-wide next-generation sequencing approaches in the future. Understanding the mitochondrial basis of endocrine disturbance is key to developing innovative therapies for patients with mitochondrial diseases

Multicentric Castleman's disease as a cause for unclear febrile episodes in a 55-year-old HIV-infected man

Our case illustrates the difficulties involved in diagnosing multicentric Castleman's disease (MCD) in a human immunodeficiency virus-infected man with febrile episodes and malaise. In the absence of well-established treatment protocols, we have chosen a new treatment algorithm with rituximab, etoposide, and valganciclovir, which led to the remission of clinical symptoms. Yet, we advocate focused exploration for MCD in immunosuppressed patients with unclear febrile episodes, as recent advances in treatment are promisin

Characteristics and outcome of 16 periprosthetic shoulder joint infections

Purpose: Shoulder arthroplasties are increasingly performed, but data on periprosthetic joint infections (PJI) in this anatomical position are limited. We retrospectively investigated the characteristics and outcome of shoulder PJI after primary arthroplasty from 1998 to 2010 in a single centre. Methods: Periprosthetic joint infection was defined as periprosthetic purulence, presence of sinus tract or microbial growth. A Kaplan-Meier survival method was used to estimate relapse-free survival of prosthesis. Results: From 1,571 primary shoulder prostheses, we evaluated 16 patients with a PJI at different stages, i.e, early (n=4), delayed (n=6) and late (n=6) infections. The median patient age was 67 (range 53-86) years, and 69% were females. The most commonly isolated microorganism was Propionibacterium acnes in 38% of patients (monobacterial in four and polymicrobial in two patients). In 14 of the 16 patients, surgical interventions consisting of debridement and implant retention (6 patients), exchange (7) and explantation (1) were performed. Four patients had a relapse of infection with P. acnes (n=3) or Bacteroides fragilis (n=1). The relapse-free survival of the prosthesis was 75% (95% confidence interval 46-90%) after 1 and 2years, 100% in six patients following the treatment algorithm for hip and knee PJI and 60% in 10 patients not followed up. All but one of the relapses were previously treated without exchange of the prosthesis. Conclusions: As recommended for hip and knee PJI, we suggest treating shoulder PJI with a low-grade infection by microorganisms such as P. acnes with an exchange of the prosthesis. Cohort studies are needed to verify our result

New Technologies for the Identification of Novel Genetic Markers of Disorders of Sex Development (DSD)

Although the genetic basis of human sexual determination and differentiation has advanced considerably in recent years, the fact remains that in most subjects with disorders of sex development (DSD) the underlying genetic cause is unknown. Where pathogenic mutations have been identified, the phenotype can be highly variable, even within families, suggesting that other genetic variants are influencing the expression of the phenotype. This situation is likely to change, as more powerful and affordable tools become widely available for detailed genetic analyses. Here, we describe recent advances in comparative genomic hybridisation, sequencing by hybridisation and next generation sequencing, and we describe how these technologies will have an impact on our understanding of the genetic causes of DSD

Late-onset X-linked adrenal hypoplasia (DAX-1, NR0B1): two new adult-onset cases from a single center

PURPOSE: DAX-1 (NR0B1) is an orphan nuclear receptor, which plays a critical role in development and regulation of the adrenal gland and hypothalamo-pituitary-gonadal axis. Mutations in NR0B1 lead to adrenal hypoplasia congenita (AHC), hypogonadotropic hypogonadism (HH) and azoospermia in men. Presentation is typically with adrenal insufficiency (AI) during infancy or childhood. To date only eight cases/kindreds are reported to have presented in adulthood. METHODS: We describe two new cases of men with DAX-1 mutations who presented in adulthood and who were diagnosed at a large University Hospital. RESULTS: Case 1 presented with AI at 19 years. At 38 years he was diagnosed with HH. Detailed history revealed a brother diagnosed with AI at a similar age. Sequencing of the DAX-1 (NR0B1) gene revealed a heterozygous c.775T > C substitution in exon 1, which changes codon 259 from serine to proline (p.Ser259Pro). Case 2 was diagnosed with AI at 30 years. Aged 37 years he presented with HH and azoospermia. He was treated with gonadotropin therapy but remained azoospermic. Testicular biopsy showed maturational arrest and hypospermatogenesis. Analysis of the NR0B1 gene showed a heterozygous c.836C > T substitution in exon 1, resulting in a change of codon 279 from proline to leucine (p.Pro279Leu). This change alters the structure of the repression helix domain of DAX-1 and affects protein complex interactions with NR5A family members. CONCLUSIONS: We describe two missense mutations within the putative carboxyl-terminal ligand binding domain of DAX-1, presenting with AHC and HH in adulthood, from a single center. DAX-1 mutations may be more frequent in adults than previously recognized. We recommend testing for DAX-1 mutations in all adults with primary AI and HH or impaired fertility where the etiology is unclear

Birth after TESE–ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation

DAX1/NR0B1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) associated with hypogonadotropic hypogonadism (HH). Few data are available concerning testicular function and fertility in men with DAX1 mutations. Azoospermia as well as failure of gonadotrophin treatment have been reported. We induced spermatogenesis in a patient who has a DAX1 mutation (c.1210C>T), leading to a stop codon in position 404 (p.Gln404X). His endocrine testing revealed a low testosterone level at 1.2 nmol/l (N: 12–40) with low FSH and LH levels at 2.1 IU/l (N: 1–5 IU/l) and 0.1 IU/l (N: 1–4 IU/l), respectively. Baseline semen analysis revealed azoospermia. Menotropin (Menopur®:150 IU, three times weekly) and human chorionic gonadotrophin (1500 IU, twice weekly) were used. After 20 months of treatment, as azoospermia persisted, bilateral multiple site testicular biopsies were performed. Histology revealed severe hypospermatogenesis. Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed. Four embryos were obtained and, after a frozen–thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy. We report the first case of paternity after TESE–ICSI in a patient with DAX1 mutation, giving potential hope to these patients to father non-affected children. Furthermore, this case illustrates the fact that patients with X-linked AHC have a primary testicular defect in addition to HH

Testosterone production during puberty in two 46,XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations

BACKGROUND: Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic–pituitary–gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown. SUBJECTS AND METHODS: Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected. RESULTS: Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro. CONCLUSION: Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible

Goal-Directed Personalized Upper Limb Intensive Therapy (PULIT) for Children With Hemiparesis: A Retrospective Analysis

Importance: Children with hemiparesis experience limitations in activities of daily living (ADLs) as a result of upper limb impairments. To address these limitations, we developed a group-based Personalized Upper Limb Intensive Therapy (PULIT) program combining modified constraint-induced movement therapy, bimanual intensive therapy, and exergame-based robotics. Objective: To determine the effectiveness of PULIT in helping children with upper limb impairments achieve individually set goals and enable transfer of the attained motor skills into ADLs. Design: Retrospective analysis. Setting: Day camp at a pediatric rehabilitation clinic in Switzerland. Participants: Twenty-three children with upper limb impairment (unilateral cerebral palsy, n = 16; acquired brain injury, n = 7); 13 boys and 10 girls (M age = 7 yr, 8 mo, SD = 2 yr, 1 mo; Manual Ability Classification System Level I-IV). Intervention: Thirty hours of PULIT over the course of 8 days. Outcomes and measures: Goal attainment scaling (GAS) was assessed on the first and last day of intervention. The Canadian Occupational Performance Measure (COPM) and dexterity tests, such as the Box and Block Test (BBT), were administered 3 wk before and 3 wk after the intervention. Results: Total goal achievement was 85.7%. GAS, parent- and child-rated COPM Performance and Satisfaction, and the BBT of the affected and dominant upper limb improved significantly. Conclusions and relevance: PULIT effectively increases children's dexterity of the impaired and dominant upper limb, improves ADL performance, and achieves individual goals. This retrospective analysis could serve as a basis for a future randomized trial. What This Article Adds: This article informs occupational therapy practitioners about a therapy program that includes conventional and rehabilitation technology interventions and enables children with hemiparesis of the upper limb to improve relevant ADL tasks in 8 days' time

Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency

Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient