Development of a new high sensitivity mechanical switch for augmentative and alternative communication access in people with amyotrophic lateral sclerosis.

BACKGROUND: People with Amyotrophic Lateral Sclerosis (PwALS) in the advanced phase are critically affected by an almost total loss of mobility and severe communication problems. Scanning access based on the patient's interaction with a sensor (or switch) that intercepts even a weak body movement is a valid communication aid. However, its use becomes limited with the progressive decline of residual movements. To overcome this problem, we designed a new sensor, the Lever Magnetic-spring Mechanical Switch (LeMMS), allowing repeated activation/release cycles requiring a very small activation force. METHODS: The LeMMS was applied and validated in a group of 20 PwALS in an advanced stage of disease. All subjects were regular users of communication aids employing other sensors, but which they could no longer operate their sensors (different from LeMMS). Patients were assessed at baseline (t0) and after one (t1), 6 (t2) and 12 (t3) months. Assessment at t0 included administration of standardized clinical scales, the Click-Test-30 counting the maximum number of LeMMS activations in 30 s, and thumb/fingers strength assessment with the Kendall scale. The QUEST 2.0-Dev questionnaire was administered at t1. Some use-related information and the Click-Test-30 were collected at t1, t2 and t3. RESULTS: After one training session, all patients could operate the LeMMS with minimal residual movement of one finger. At t1, they used it on average 5.45 h/day. The mean score of the QUEST 2.0-Dev was 4.63, suggesting strong satisfaction with the LeMMS. Regarding Click-Test-30 scores, no significant difference was found between t0 and t1, but performance at t2 and t3 declined significantly (p < 0.005 vs. t0). At t3, 9/20 patients were still able to use their communication aid. CONCLUSIONS: This new switch sensor can enable PwALS to use their communication aids for a prolonged time even in the advanced phase of disease. It is easy to use, reliable and cheap, thus representing an intermediate alternative to more sophisticated and costly devices.

Enhancing the usefulness of the Mini-BESTest for measuring dynamic balance: a Rasch validation study.

BACKGROUND: Recently, a new balance scale, the Mini-BESTest, was introduced. This scale can be administered in about 15 min, and focuses on "dynamic balance". In spite of the recently increased use of this scale, further psychometric studies seem called for to enhance confidence in its use in different fields of clinical practice and research. AIM: To re-examine through Rasch analysis the metric properties of the Mini-BESTest and provide a nomogram that allow to quickly transform raw scores of the scale into linear estimates of dynamic balance. DESIGN: Observational cross-sectional study. SETTING: Rehabilitation hospital. POPULATION: A total of 234 patients were consecutively admitted with a variety of neurological diseases causing balance impairment. METHODS: Internal construct validity was assessed by determining how well data fit the Rasch model. Reliability was estimated for both persons and items. Scale unidimensionality and local independence of items were analysed performing a principal component analysis (PCA) on the standardized residuals. Also, a differential item functioning (DIF) analysis was run to assess the stability of item calibration across subsamples of patients. RESULTS: All 14 items of Mini-BESTest fitted the "dynamic balance" construct, i.e., the mean of the squared residuals for both the infit and outfit was between 0.8 and 1.2. The person abilities-item difficulty matching was very good. The reliability indices of the Mini-BESTest were as follows: person separation index=3.24 and person reliability=0.91; item separation index=12.00 and item reliability=0.99. The PCA of standardized residuals showed that the variance attributable to the Rasch factor was good (68%) and the eigenvalue of the unexplained variance in the first contrast was just 1.9, thus confirming the unidimensionality of the scale. No DIF was found across gender and age groups. CONCLUSION: The reliability indexes confirmed their high values, giving a high degree of confidence in the consistency of both person-ability and item-difficulty estimates. Results allowed to transform the ordinal summed raw scores of the Mini-BESTest into interval-level measurements using a nomogram. Since no significant local dependence between items was found, this means that each Mini-BESTest item is appropriate for measuring the variable of interest (dynamic balance) and not redundant. DIF analysis showed the stability of item hierarchy and difficulty among subsamples of patients of different gender and age. CLINICAL REHABILITATION IMPACT: This study further increases confidence in use of the Mini-BESTest for clinical assessment of dynamic balance in patients undergoing rehabilitation.

The W520X mutation in the TSHR gene brings on subclinical hypothyroidism through an haploinsufficiency mechanism.

BACKGROUND: TSHR is a G-protein-coupled seven transmembrane domain receptor that activates the two major signal transduction pathways: the Gαs/adenylate cyclase and the Gαq/11/phospholipase C pathways. Inactivating mutations in the TSHR gene have been demonstrated to be responsible for subclinical hypothyroidism, a disorder characterized by elevated serum TSH concentrations despite normal thyroid hormones levels. AIM: We identified in a child a nonsense mutation (W520X) in the third transmembrane domain of the TSHR that causes the lack of the C-terminus portion of the receptor. The functional significance of this variation was assessed in vitro. MATERIAL/SUBJECT AND METHODS: The W520X mutation was introduced into the pSVL vector containing the wild-type sequence of TSHR gene. Wild-type and mutated vectors were expressed in Chinese Hamster Ovary (CHO) cells, and cAMP, inositol phosphate (IP), immunofluorescence and FACS analyses were performed. RESULTS: Transfection with pSVL-TSHR vector induced basal cAMP and IP production in the absence of TSH stimulation, indicating a constitutive activity for the TSHR. An impairment of receptor function was demonstrated by the observation that cells expressing the mutant TSHR exhibited a lower second messenger production with respect to the wild-type, despite a normal expression of the receptor at the cell surface. CONCLUSIONS: The mechanism through which the W520X mutation exerts its effect is more likely haploinsufficiency rather than a dominant-negative effect. This could explain the phenotype of our patient, who has a hormonal pattern in the range of a mild subclinical hypothyroidism, without an overt disease phenotype.

A novel recessive splicing mutation in the POU1F1 gene causing combined pituitary hormone deficiency.

BACKGROUND: Mutations in the gene encoding the pituitary transcription factor POU1F1 (Pit-1, pituitary transcription factor-1) have been described in combined pituitary hormone deficiency (CPHD). AIM: The aim of this study was the characterisation of the molecular defect causing CPHD in a patient born to consanguineous parents. SUBJECT AND METHODS: The case of a 12.5-yr-old girl presenting with severe growth failure at diagnosis (-3 SD score at 3 months) and deficiency of GH, PRL, and TSH was investigated for the presence of POU1F1 gene mutations by denaturing high performance liquid chromatography analysis. RESULTS: A novel mutation adjacent to the IVS2 splicing acceptor site (IVS2-3insA) was identified in the patient at the homozygous state. Analysis of patient's lymphocyte mRNA and an in vitro splicing assay revealed the presence of 2 aberrant splicing products: a) deletion of the first 71 nucleotides of exon 3, altering the open reading frame and generating a premature stop codon, b) total exon 3 skipping resulting in an in frame deleted mRNA encoding a putative protein lacking part of the transactivation domain and of the POUspecific homeodomain. Notably, the patient's relatives heterozygous for the mutation had PRL levels under the normal range with no evident clinical symptoms. CONCLUSIONS: The IVS2- 3insAmutation, responsible for CPHD at the homozygous state, causes the presence of 2 aberrant splicing products encoding non-functional products. In the heterozygotes one normal allele might not guarantee a complete pituitary function.

Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review.

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1,000 male births. It is a complex disorder associated with genetic and environmental factors and can be part of genetic syndromes. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation. It is caused by mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1). To date, 68 deletion/mutation-positive cases have been reported. Genitourinary anomalies are common in MWS. Here we report that hypospadias is common in males with this syndrome. In 39 patients where this information was available, hypospadias was present in 46% of patients (18/39). In the 3 Italian male cases reported here, hypospadias was always present. MWS should be considered by endocrinologists in patients with hypospadias associated with developmental delays/mental retardation, in particular in the presence of a distinct facial phenotype.