Objective measurement of oral function in adults with spinal muscular atrophy.

BACKGROUND: Impairment of bulbar function in adult individuals with spinal muscular atrophy (SMA) usually is not assessed by established motor scores. Measurements of oral function including quantitative muscle and endurance tests are able to detect subtle changes. The aim of this study was to systematically evaluate the measurement of maximum bite force and endurance, maximum tongue pressure and endurance, as well as maximum mouth opening in adult individuals with SMA types 2 and 3. METHODS: Data from oral function tests in 43 individuals were analyzed. Differences in oral function between individuals with different SMA types and numbers of SMN2 copies were tested. Spearman´s rho correlations among oral function measures themselves as well as with established clinical outcome scales were analyzed. RESULTS: The absolute maximum measures of oral function (maximum bite force, maximum tongue pressure, maximum mouth opening) were able to discriminate between individuals with different SMA types, individuals with a different number of SMN2 copies and with different walking abilities. The pairwise correlations of the absolute maximum measures of oral function were fair to moderate in size; the same was true for their correlations with the established motor scores. All correlations assessing endurance measures of oral function were weaker and statistically insignificant. CONCLUSIONS: Among the oral function tests maximum tongue pressure and maximum mouth opening are particulary promising as clinical and sensitive outcome measures for clinical trials. Oral function tests may supplement existing motor scores, in particular concerning specific questions about bulbar function or in severely affected non-ambulatory individuals where mild (treatment-related) changes would otherwise remain undetected. Trial registration DRKS, DRKS00015842. Registered 30 July 2019, https://drks.de/search/de/trial/DRKS00015842.

Combinatorial ASO-mediated therapy with low dose SMN and the protective modifier Chp1 is not sufficient to ameliorate SMA pathology hallmarks.

Spinal muscular atrophy (SMA) is a devastating genetically inherited neuromuscular disorder characterized by the progressive loss of motor neurons in the spinal cord, leading to muscle atrophy and weakness. Although SMA is caused by homozygous mutations in SMN1, the disease severity is mainly determined by the copy number of SMN2, an almost identical gene that produces ~10% correctly spliced SMN transcripts. Recently, three FDA- and EMA-approved therapies that either increase correctly spliced SMN2 transcripts (nusinersen and risdiplam) or replace SMN1 (onasemnogen abeparvovec-xioi) have revolutionized the clinical outcome in SMA patients. However, for severely affected SMA individuals carrying only two SMN2 copies even a presymptomatic therapy might be insufficient to fully counteract disease development. Therefore, SMN-independent compounds supporting SMN-dependent therapies represent a promising therapeutic approach. Recently, we have shown a significant amelioration of SMA disease hallmarks in a severely affected SMA mouse carrying a mutant Chp1 allele when combined with low-dose of SMN antisense oligonucleotide (ASO) treatment. CHP1 is a direct interacting partner of PLS3, a strong protective modifier of SMA. Both proteins ameliorate impaired endocytosis in SMA and significantly restore pathological hallmarks in mice. Here, we aimed to pharmacologically reduce CHP1 levels in an ASO-based combinatorial therapy targeting SMN and Chp1. Chp1 modulation is a major challenge since its genetic reduction to ~50% has shown to ameliorate SMA pathology, while the downregulation below that level causes cerebellar ataxia. Efficacy and tolerability studies determined that a single injection of 30 µg Chp1-ASO4 in the CNS is a safe dosage that significantly reduced CHP1 levels to ~50% at postnatal day (PND)14. Unfortunately, neither electrophysiological predictors such as compound muscle action potential (CMAP) or motor unit number estimation (MUNE) nor histological hallmarks of SMA in neuromuscular junction (NMJ), spinal cord or muscle were ameliorated in SMA mice treated with Chp1-ASO4 compared to CTRL-ASO at PND21. Surprisingly, CHP1 levels were almost at control level 4-weeks post injection, indicating a rather short-term effect of the ASO. Therefore, we re-administrated Chp1-ASO4 by i.c.v. bolus injection at PND28. However, no significant improvement of SMA hallmarks were seen at 2 month-of-age either. In conclusion, in contrast to the protective effect of genetically-induced Chp1 reduction on SMA, combinatorial therapy with Chp1- and SMN-ASOs failed to significantly ameliorate the SMA pathology. Chp1-ASOs compared to SMN-ASO proved to have rather short-term effect and even reinjection had no significant impact on SMA progression, suggesting that further optimization of the ASO may be required to fully explore the combination.

Wakefulness impairs selective consolidation of relevant trauma-associated memories resulting in more frequent intrusions.

Recent studies show that sleep reduces intrusive memories after analog trauma. This effect is assumed to be caused by sleep's impact on memory consolidation. However, the underlying processes of this phenomenon have not been uncovered. Thus, the current study investigates the hypothesis that sleep reduces intrusive memories by supporting the selective consolidation of relevant memories. Seventy-five participants were exposed to traumatic picture stories before nocturnal sleep or wakefulness during daytime. Memory for relevant and irrelevant trauma-associated stimuli was assessed prior to and after the retention period. Consistent with the hypothesis, results demonstrate reduced memory loss for relevant as opposed to irrelevant trauma-associated stimuli after sleep but not after wakefulness. Moreover, an incremental retention benefit for relevant trauma-associated stimuli was negatively correlated with the number of intrusive trauma memories after wakefulness. These results suggest that lack of sleep impairs selective gating of relevant trauma-associated memories, thereby enhancing intrusion development after trauma.

Clinical, electrophysiological and genetic characteristics of childhood hereditary polyneuropathies.

BACKGROUND: Hereditary polyneuropathies are heterogeneous group of diseases of the peripheral nervous system. In this study, we investigated the demographic, clinical, electrophysiological, and genetic characteristics of hereditary polyneuropathy patients diagnosed and followed up in our tertiary center clinic in Izmir, Turkey. METHODS: Patients who were diagnosed with hereditary polyneuropathies during nerve conduction studies in our center were evaluated retrospectively. RESULTS: In a total of 1484 nerve conduction studies, 207 patients were diagnosed with polyneuropathy. Ninety-nine of those patients were determined to have hereditary polyneuropathy, 52 of which were male and 47 were female. Sixty-nine patients with hereditary polyneuropathy were compatible with axonal and 30 were compatible with demyelinating polyneuropathy. Genetic analysis was performed in 69 patients, and 49 of those patients were genetically diagnosed, leading to a diagnosis rate of 71%. CONCLUSIONS: Advances in genetics have led to an increase in the heterogeneity of hereditary polyneuropathies, causing difficulties in the use of existing classifications. Although typical mutations expected in childhood-onset polyneuropathies are seen less frequently, polyneuropathies are frequently encountered as findings of complex, multisystemic diseases.

Hydrogen interactions with low-index surface orientations of tungsten.

We report on density functional theory calculations that have been performed to systematically investigate the hydrogen-surface interaction as a function of surface orientation. The interactions that were analyzed include stable atomic adsorption sites, molecular hydrogen dissociation and absorption energies, migration pathways and barriers on tungsten surfaces, and the saturation coverage limits on the (1 1 1) surface. Stable hydrogen adsorption sites were found for all surfaces. For the reconstructed W(1 0 0), there are two primary adsorption sites: namely, the long-bridge and short-bridge sites. The threefold hollow site (3F) was found to be the most stable for W(1 1 0), while the bond-centered site between the first and second layer was found to be most stable for the W(1 1 1) surface. No bound adsorption sites for H2 molecules were found for the W surfaces. Hydrogen (H) migration on both the (1 0 0) and (1 1 0) surfaces is found to have preferred pathways for 1D motion, whereas the smallest migration barrier for net migration of H on the W(1 1 1) surface leads to 2D migration. Although weaker H interactions are predicted for the W(1 1 1) surface compared to the (1 0 0) or (1 1 0) surfaces, we observe higher H surface concentrations of Θ = 4.0 at zero K, possibly due to the corrugated surface structure. These results provide insight into H adsorption, surface saturation coverage and migration mechanisms necessary to describe the evolution from the dilute limit to concentrated coverages of H.

Respiratory muscle endurance training reduces chronic neck pain: A pilot study.

BACKGROUND: Patients with chronic neck pain show also respiratory dysfunctions. OBJECTIVE: To investigate the effects of respiratory muscle endurance training (RMET) on chronic neck pain. METHODS: In this pilot study (single-subject design: 3 baseline measurements, 4 measurements during RMET), 15 neck patients (49.3 ± 13.7 years; 13 females) conducted 20 sessions of home-based RMET using a SpiroTiger® (normocapnic hyperpnoea). Maximal voluntary ventilation (MVV), maximal inspiratory (Pimax) and expiratory (Pemax) pressure were measured before and after RMET. Neck flexor endurance, cervical and thoracic mobility, forward head posture, chest wall expansion and self-assessed neck disability [Neck Disability Index (NDI), Bournemouth questionnaire] were weekly assessed. Repeated measure ANOVA (Bonferroni correction) compared the first and last baseline and the last measurement after RMET. RESULTS: RMET significantly increased MVV (p= 0.025), Pimax (p= 0.001) and Pemax (p< 0.001). During RMET, neck disability significantly decreased (NDI: p= 0.001; Bournemouth questionnaire: p= 0.002), while neck flexor endurance (p< 0.001) and chest wall expansion (p< 0.001) increased. The changes in respiratory and musculoskeletal parameters did not correlate. CONCLUSIONS: RMET emerged from this pilot study as a feasible and effective therapy for reducing disability in patients with chronic neck pain. The underlying mechanisms, including blood gas analyses, need further investigation in a randomized controlled study.

[Prostate biopsy: Procedure in the clinical routine]. / Prostatabiopsie : Durchführung im klinischen Alltag.

Over the last decade there has been a 25% decrease in the mortality rates for prostate cancer. The reasons for this significant decrease are most likely associated with the application of urological screening tests. The main tools for early detection are currently increased public awareness of the disease, prostate-specific antigen (PSA) tests and transrectal ultrasound (TRUS) guided topographically assignable biopsy sampling. Together with the histopathological results these features provide essential information for risk stratification, diagnostics and therapy decisions. The evolution of prostate biopsy techniques as well as the use of PSA testing has led to an increased identification of asymptomatic men, where further clarification is necessary. Significant efforts and increased clinical research focus on determining the appropriate indications for a prostate biopsy and the optimal technique to achieve better detection rates. The most widely used imaging modality for the prostate is TRUS; however, there are no clearly defined standards for the clinical approach for each individual biopsy procedure, dealing with continuous technical optimization and in particular the developments in imaging. In this review the current principles, techniques, new approaches and instrumentation of prostate biopsy imaging control are presented within the framework of the structured educational approach.

Respiratory dysfunction in patients with chronic neck pain - influence of thoracic spine and chest mobility.

Patients with chronic neck pain exhibit various musculoskeletal deficits and respiratory dysfunction. As there is a link between thoracic and cervical spine motion, the aim of this study was to investigate the relationship between thoracic spine and chest mobility with respiratory function and neck disability. Nineteen patients with chronic neck pain (7 male, 46.6 ± 10.5 years) and 19 healthy subjects (7 male, 46.5 ± 9.9 years) participated. Spirometry was conducted to determine maximal voluntary ventilation (MVV), maximal inspiratory (Pimax) and maximal expiratory pressure (Pemax). Thoracic spine mobility was measured using the Spinal Mouse(®). Chest expansion was assessed by subtracting chest circumference during maximal inspiration and expiration. Neck function was investigated by examining range of motion, forward head posture, neck flexor muscle synergy endurance and self-assessment (Neck disability index (NDI)). Correlation analyses and multiple linear regression analyses were conducted using MVV, Pimax and Pemax as independent variables. Thoracic spine mobility during flexion and chest expansion correlated significantly to MVV (r = 0.45 and 0.42), all neck motions (r between 0.39 and 0.59) and neck muscle endurance (rS = 0.36). Pemax and Pimax were related to NDI (r = -0.58 and -0.46). In the regression models, chest expansion was the only significant predictor for MVV, and Pemax was determined by neck muscle endurance. These results suggest that chronic neck pain patients should improve the endurance of the neck flexor muscles and thoracic spine and chest mobility. Additionally, these patients might benefit from respiratory muscle endurance training, possibly by increasing chest mobility and Pemax.

Nanoscope based on nanowaveguides.

The far field spatial resolution of conventional optical lenses is of the order of the wavelength of light, due to loss in the far field of evanescent, near electromagnetic field components. We show that subwavelength details can be restored in the far field with an array of divergent nanowaveguides, which map the discretized, subwavelength image of an object into a magnified image observable with a conventional optical microscope. We demonstrate in simulations that metallic nanowires, nanocoaxes, and nanogrooves can be used as such nanowaveguides. Thus, an optical microscope capable of subwavelength resolution - a nanoscope - can be produced, with possible applications in a variety of fields where nanoscale optical imaging is of value.

First-principles study of the structure and band structure of Ga2Se3.

Our first-principles calculations show that the ordering of stoichiometric cation vacancies in Ga2Se3 has a large influence on the bandgap, up to 0.55 eV. Therein, the zigzag-line vacancy-ordered Ga2Se3 has the maximum bandgap (∼2.56 eV direct bandgap), and the straight-line vacancy-ordered Ga2Se3 has the minimum bandgap (∼1.99 eV indirect bandgap) at 0 K, according to scGW calculations. The bandgap difference (0.55 eV) is almost the same for normal density functional theory (DFT) calculations, hybrid DFT calculations and GW calculations. The calculation results are consistent with the experimental bandgap range of 2.0-2.6 eV at room temperature. Also, hydrostatic pressure (<9 GPa) tends to increase the bandgap, consistent with the experiments in the literature.

[Development and evaluation of a German version of the Tegner activity scale for measuring outcome after anterior cruciate ligament injury]. / Entwicklung und Evaluation einer deutschen Version der Tegner Aktivitätsskala zur Erfassung der Funktion nach einer Verletzung des vorderen Kreuzbands.

BACKGROUND: The aim of this study is to provide a valid and reliable German version of the Tegner activity scale (Tegner-G). The Tegner activity scale assesses on 11 levels the activity in sports (competitive and recreational) and work of patients with anterior cruciate ligament injuries. The English original version was elaborated in Sweden and contains sports that are unknown in German-speaking countries. METHODS: The translation and adaptation was conducted in several steps according to the guidelines in the literature. The validity (discriminative validity and content validity) and (absolute and relative) reliability were determined in 46 patients after reconstruction of the anterior cruciate ligament and in 20 healthy subjects. The patients were divided into an acute group (< 3 months after operation; 11 men; 30.9 ± 8.3 years) and a chronic group (3 - 12 months after operation; 18 men; 31.3 ± 11.6 years). All subjects filled in the scale two times within 3 - 7 days. For the additional determination of the relation between activity and function, they also filled in the German version of the Lysholm score (Lysholm-G). RESULTS: The three groups differed significantly from each other (Kruskal-Wallis test: χ2 = 27.95, p < 0.001; post hoc Mann-Whitney U tests: acute-chronic p < 0.001; acute-control p < 0.001; chronic-control p = 0.003). There was a floor effect in the acute patient group. The intraclass correlation coefficients indicated a high relative reliability (ICC2,1 > 0.9). The minimal detectable change was 1.4 points. The relation between activity (Tegner-G) and function (Lysholm-G) was stronger in the acute than in the chronic patient group (ρ = 0.77 and ρ = 0.60, respectively). CONCLUSION: The psychometric properties of the Tegner-G are comparable to those of the English original version. The Tegner-G is thus valid and reliable for the German-speaking part of Switzerland. The application in other German-speaking countries probably requires adaptations for some of the sports included. The relation between activity and function changes depending on time since operation. This confirms that a comprehensive assessment of the outcome after an anterior cruciate ligament injury requires the separate assessment of both parameters.

First-principles study of bubble nucleation and growth behaviors in α U-Zr.

Bubble nucleation and growth is responsible for swelling in metallic fuels such as U-Zr. Computational modeling is useful for understanding and ultimately developing mitigation strategies for the swelling behavior of the fuel. However, the relevant fundamental parameters are not currently available. In our previous work, the formation energy and migration barrier of uranium vacancies and interstitials in α U have been obtained by first-principles calculations, and the calculated diffusion activation energy agrees reasonably well with the experimental results, within 0.1 eV (Huang and Wirth 2011 J. Phys.: Condens. Matter 23 205402). In this paper, the formation energy and migration barrier of Xe, Zr, Pu, in addition to the binding energy of small vacancy clusters, Xe-vacancy clusters, and small interstitial clusters are investigated. These are among the essential data essential for the analysis and computational modeling of swelling in metallic nuclear fuel.

Whole body vibration added to endurance training in obese women - a pilot study.

Whole body vibration (WBV) training is an increasingly popular training method that is strongly promoted for weight loss, but scientific data on its effectiveness, particularly in obese subjects, are sparse. 14 obese women (BMI: 37.4 ± 1.3 kg/m2) randomized to 2 different groups (each n=7) participated in a 6-week endurance training program that was either combined or not combined with additional WBV training. Anthropometric measures, phase angle and body composition (assessed by bioelectrical impedance analysis; BIA), and resting energy expenditure (REE) were obtained before and after the training program. Body weight did not change during the training period (P=0.87), but waist circumference decreased in both groups (P=0.007; WBV: -3.4 ± 1.4 cm; no-WBV: -1.7 ± 0.7 cm) independent of WBV training (P=0.29 for group×time interaction). BIA revealed an enhancing effect of WBV training in comparison to no-WBV training on the phase angle (+0.20 ± 0.12° vs. -0.19 ± 0.12°; P=0.04) and calculated body cell mass (+0.8 ± 0.2 vs. -0.3 ± 0.4 kg; P=0.02), while calculated percentage fat mass decreased in both conditions (P=0.05) to similar extent (P=0.59; WBV: -0.8 ± 0.2%; no-WBV: -0.4 ± 0.5%). REE increased across the training (P=0.01; WBV: +77 ± 33 kcal/24 h; no-WBV: +68 ± 34 kcal/24 h), with this increase again not depending on WBV condition (P=0.85). Results of our pilot study in obese women provide preliminary evidence for a beneficial effect of WBV, when added to endurance training, on the bioelectrical phase angle, an increasingly recognized marker of individual's health status.

Structural characterization of epitaxial Cr(x)Mo(1-x) alloy thin films.

To develop a model system containing regularly spaced misfit dislocations for studies of the radiation resistance of nanoscale defects, epitaxial thin films of Cr, Mo, and Cr(x)Mo(1-x) alloys were deposited on MgO(001) by molecular beam epitaxy. Film compositions were chosen to vary the lattice mismatch with MgO. The film structure was investigated by x-ray diffraction (XRD), Rutherford backscattering spectrometry (RBS) and scanning transmission electron microscopy (STEM). Epitaxial films with reasonably high crystalline quality and abrupt interfaces were achieved at a relatively low deposition temperature, as confirmed by STEM. However, it was found by XRD and RBS in the channeling geometry that increasing the Mo content of the CrMo alloy films degraded the crystalline quality, despite the improved lattice match with MgO. XRD rocking curve data indicated that regions of different crystalline order may be present within the films with higher Mo content. This is tentatively ascribed to spinodal decomposition into Cr-rich and Mo-rich regions, as predicted by the Cr(x)Mo(1-x) phase diagram.

Is a positive clinical outcome after exercise therapy for chronic non-specific low back pain contingent upon a corresponding improvement in the targeted aspect(s) of performance? A systematic review.

INTRODUCTION: The effect size for exercise therapy in the treatment of chronic non-specific low back pain (cLBP) is only modest. This review aims to analyse the specificity of the effect by examining the relationship between the changes in clinical outcome (pain, disability) and the changes in the targeted aspects of physical function (muscle strength, mobility, muscular endurance) after exercise therapy. METHODS: We searched for exercise therapy trials for cLBP published up to 15 April 2010 in Medline, Embase, Cochrane Library, Cinahl, and PEDro. Two independent reviewers selected studies according to the inclusion criteria. DATA EXTRACTION: one author extracted the data of the articles. DATA SYNTHESIS: 16 studies with a total of 1,476 participants met the inclusion criteria. There was little evidence supporting a relationship between the changes in pain or physical function and the changes in performance for the following measures: mobility (no correlation in 9 studies, weak correlation in 1 study), trunk extension strength (7 and 2, respectively), trunk flexion strength (4 and 1, respectively) and back muscle endurance (7 and 0, respectively). Changes in disability showed no correlation with changes in mobility in three studies and a weak correlation in two; for strength, the numbers were four (no correlation) and two (weak correlation), respectively. CONCLUSIONS: The findings do not support the notion that the treatment effects of exercise therapy in cLBP are directly attributable to changes in the musculoskeletal system. Future research aimed at increasing the effectiveness of exercise therapy in cLBP should explore the coincidental factors influencing symptom improvement.

[Development and evaluation of a German version of the Lysholm score for measuring outcome after anterior cruciate ligament injuries]. / Entwicklung und Evaluation einer deutschen Version des Lysholm-Scores zur Erfassung der Funktion nach einer Verletzung des vorderen Kreuzbands.

BACKGROUND: The Lysholm score is a questionnaire that assesses knee function after conservatively or operatively treated anterior cruciate ligament (ACL) injuries. Its original version is in English and consists of eight items (limping, support, locking, instability, pain, swelling, stair-climbing, squatting). The aim of this study was to translate the Lysholm score in the German language, to test discriminative validity and reliability of this German version and, thus, to provide a validated German version of the Lysholm score to be applied in further studies. METHODS: The cross-cultural adaptation to the German language was performed according to recommended guidelines in the literature. Validity and reliability of the German version were tested in two patient groups in the acute (< 3 months post incident/operation; n = 12) and late rehabilitation phase after ACL injury (3 - 12 months post incident/operation, n = 16), respectively as well as in a control group without any knee problems (n = 22). The subjects filled in the questionnaire twice within three days. RESULTS: With respect to validity, the control group (total score 96.8 ± 5.1 points) differed significantly from the total patient group (p < 0.001) as well as from the patient group in the acute (75.3 ± 16.8 points) (p < 0.001) and the late (82.7 ± 12.8 Punkte) (p < 0.001) rehabilitation phase, respectively. Test-retest reliability of the total Lysholm score was good for the total patient group (intraclass correlation coefficient (ICC) = 0.82) as well as for the patients in the acute (ICC = 0.82) and in the late (ICC = 0.84) rehabilitation phase, respectively. The Cronbachs Alpha was 0.73. CONCLUSION: The psychometric properties of the German version of the Lysholm score are comparable to the English version. It is a valid and reliable instrument for the objective assessment of rehabilitation outcome after ACL injury at least in the German speaking part of Switzerland. Based on these first results, its application for further research projects in all German speaking countries is recommended.

Development of quantitative and sensitive assessments of physiological and functional outcome during recovery from spinal cord injury: a clinical initiative.

The ability to detect physiological changes associated with treatments to effect axonal regeneration, or novel rehabilitation strategies, for spinal cord injury will be challenging using the widely employed American Spinal Injuries Association (ASIA) impairment scales (AIS) for sensory and motor function. Despite many revisions to the AIS standard neurological assessment, there remains a perceived need for more sensitive, quantitative and objective outcome measures. The purpose of Stage 1 of the Clinical Initiative was to develop these tools and then, in Stage 2 to test them for reliability against natural recovery and treatments expected to produce functional improvements in those with complete or incomplete spinal cord injury (SCI). Here we review aspects of the progress made by four teams involved in Stage 2. The strategies employed by the individual teams were (1) application of repetitive transcranial magnetic stimulation (rTMS) to the motor cortex in stable (chronic) SCI with intent to induce functional improvement of upper limb function, (2) a tele-rehabilitation approach using functional electrical stimulation to provide hand opening and grip allowing incomplete SCI subjects to deploy an instrumented manipulandum for hand and arm exercises and to play computer games, (3) weight-assisted treadmill walking therapy (WAT) comparing outcomes in acute and chronic groups of incomplete SCI patients receiving robotic assisted treadmill therapy, and (4) longitudinal monitoring of the natural progress of recovery in incomplete SCI subjects using motor tests for the lower extremity to investigate strength and coordination.

Observation of plastoquinone kinetics in photosystem II from delayed fluorescence measurements.

Attempts to account for the variations in photosystem II (PSII) under general conditions result in non-linear and cumbersome models that are difficult to validate and render few insights about the system kinetics. In this research, the authors experimentally show that under certain conditions, linear-system techniques could be applied to advantage for probing some basic kinetic characteristics of the plastoquinones (PQs). The PQ redox states of the reaction centres were represented in a conditionally linear model structure with delayed fluorescence (DF) as a measurable output. DF data were acquired for different plant samples and conditions. After least-squares parameter optimisation, not only could the model closely describe the measured DF, but more significantly, the estimated parameters correctly reflected the expected changes induced by drought or [3-(3,4-dichlorophenyl)-1,1-dimethylurea] (DCMU) stress. Analysis showed that for short-pulse illumination, the PQ kinetic states of the reaction centres in an initially dark-adapted plant leaf can be represented as a time-invariant bilinear system in a five-dimensional state space. The system becomes linear for constant illuminations, but the system matrix and the kinetic behaviour are illumination dependent. In particular, the system behaves differently between lights-on and lights-off conditions. The simplicity of the model structure, nonetheless, permits observation and analysis of the PQ kinetics of PSII reaction centres from DF measurements by using linear-system techniques.

Genotype-phenotype studies in infantile spinal muscular atrophy (SMA) type I in Germany: implications for clinical trials and genetic counselling.

We reviewed the natural history and assessed the SMN2 copy number of 66 patients with infantile spinal muscular atrophy (SMA) type I born between 2000 and 2005 in Germany whose diagnosis was confirmed by a homozygous SMN1 deletion in the first 6 months of life. After excluding patients who had received valproic acid, the median/mean age at disease endpoint was 6.1/7.3 months (range 0.0-34.0). Four (6.1%) patients with one SMN2 copy had severe SMA type '0' with joint contractures and respiratory distress from birth. Median/mean age at onset (months) in 57 (86.3%) patients with two SMN2 copies was 1.2/1.3, and 3.5/3.4 in 5 (7.6%) patients with three SMN2 copies. Median/mean age at disease endpoint was 6.5/7.8 months (range 0.5-30) in patients with two SMN2 copies. All patients with three SMN2 copies were still alive at 10-55 months, two of them under permanent ventilation. Our data are relevant for prognostication and genetic counselling. The observed clinical variability, especially in the group with two SMN2 copies, might be important for clinical trials in SMA I where a possible control group could be defined as follows: age at onset within 4-5 months, age at genetic diagnosis <6 months, two SMN2 copies present, head control in less than 10%, no respiratory distress from birth, disease endpoint either age at death or age at permanent ventilation.

Congenital heart disease is a feature of severe infantile spinal muscular atrophy.

OBJECTIVE: Homozygous deletions/mutations of the SMN1 gene cause infantile spinal muscular atrophy (SMA). The presence of at least one SMN2 gene copy is required for normal embryogenesis. Lack of SMN protein results in degeneration of motor neurons, while extraneuronal manifestations have been regarded as a chance association with SMA. We report on heart defects in the subgroup of congenital SMA type I patients. METHODS: Data were recruited from 65 unselected SMA I patients whose diagnosis had been confirmed genetically within the first 6 months of age. SMN2 copy numbers were analysed retrospectively and correlated with clinical findings including heart malformations. RESULTS: Four (6%) patients had one copy of SMN2, 56 (86%) had two and five (8%) had three SMN2 copies. Three out of four (75%) patients with a single SMN2 copy had congenital SMA with haemodynamically relevant atrial or ventricular septal defects. CONCLUSIONS: Previous case reports of SMA I patients with congenital heart defects did not clarify whether the cardiac malformations were coincidental. Given the respective incidences of congenitally lethal SMA with a single SMN2 copy and of cardiac septal defects in humans, a chance association of both conditions would occur in less than one out of 50 million individuals. Our findings suggest that the SMN protein is relevant for normal cardiogenesis.