Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.     

Electronystagmographic findings among 127 dizzy patients: correlation with the aetiology of dizziness

Electronystagmography (ENG) was performed on 127 dizzy patients and the findings were compared with the diagnosis obtained with a comprehensive neurological test battery. ENG was found to be abnormal in 49 (39%) of the patients: 19 with unilateral vestibular hyporeactivity, eight with directional preponderance, 12 with spontaneous or undirectional positional nystagmus, eight with abnormal smooth pursuit, and 13 with other abnormalities. Among the patients with abnormal ENGs, established central nervous system lesions were found in 28 cases (19 of these infratentorial lesions); nine peripheral vestibular lesions and five undefined vestibular lesions were found. Patients with normal ENGs showed fewer peripheral vestibular lesions and more dizziness of psychogenic aetiology. Almost half the patients with infratentorial lesions had normal ENGs. Patients with rotatory vertigo had fewer ENG abnormalities than those with other types of dizziness. These results suggest that ENG alone is of limited value in the diagnosis of dizziness. A comprehensive test battery is needed to establish the diagnosis.     

Peripheral nerve injury and Raynaud's syndrome following electric shock

A truck driver was injured by a high-voltage line of 10,000 volts when holding a metallic bar in both hands. Initially no neurological abnormalities were found, but during the following few weeks increasing sensory and minor motor symptoms developed in the right upper extremity. After one year numbness of the right thigh and leg appeared, as well as attacks of white finger in both hands. Repeated examinations showed progressive abnormalities of the median and ulnar nerves in both hands. No other cause for Raynaud's syndrome was discovered. The late high-voltage effects, presumably indirect, are suggested to be of multifactorial etiology.     

Operative versus closed treatment of primary dislocation of the patella Similar 2-year results in 125 randomized patients

To assess whether initial surgery is beneficial for patients with primary dislocation of the patella, we carried out a prospective randomized study. Knee stability was examined under anesthesia, and associated injuries were excluded by diagnostic arthroscopy. 55 patients then had closed treatment and 70 patients were operated on with individually adjusted proximal realignment procedures.

Surgery gave no benefit based on 2 years of follow-up. The subjective result was better in the non-operative group in respect of mean Houghston VAS knee score (closed 90, operative 87), but similar in terms of the patient's own overall opinion and mean Lysholm II knee score. Recurrent instability episodes (redislocation or recurrent subluxation) occurred in 20 nonoperated and in 18 operated patients. Of these, 15 and 12, respectively, then suffered redislo-cations. Function was better after closed treatment. Serious complications occurred after surgery in 4 patients.

In conclusion, the recurrence of patellar dislocation may be more frequent than reported, whatever the form of treatment. Routine operative management cannot be recommended for primary dislocation of the patella.     

The value of CT and very low field MRI in the etiological diagnosis of dizziness

A total of 79 dizziness patients were examined by either computed tomography (CT), or very low field magnetic resonance imaging (MRI), or both. In most cases, the patients were selected for the neuroimaging because preliminary clinical examination had suggested central nervous system (CNS) involvement. Abnormal CT or MRI findings with probable clinical relevance to the etiology of dizziness were obtained in 34%. The most common abnormalities were atrophy, infarction, and demyelination.; 29% of the CT scans and 40% of the MRI showed relevant abnormalities. The present results emphasize the diagnostic usefulness of head CT and MRI when dizziness of CNS etiology is suspected.     

Depression-executive dysfunction syndrome in stroke patients.

OBJECTIVE: It has been suggested that executive dysfunction could be the core defect in patients with geriatric or vascular depression, and that this depression-dysexecutive syndrome (DES) might be related to frontal-subcortical circuit dysfunction. The authors tested this hypothesis in 158 poststroke patients, of whom 21 had both depression and executive dysfunction. Methods: In this cross-sectional cohort study, a neurological, psychiatric, and neuropsychological examination was carried out 3 months after ischemic stroke, and brain infarcts, white-matter changes, and brain atrophy were recorded by MRI. RESULTS: The 21 patients with DES had significantly more brain infarcts affecting their frontal-subcortical circuit structures than the 137 patients without DES, or the 41 patients with depression but without executive dysfunction. Patients with DES also had more severe depressive symptoms and worse psychosocial functioning, and they coped less well in complex activities of daily living. CONCLUSIONS: DES is a valid concept and may define a subgroup of poststroke patients with frontal-subcortical pathology and with distinct prognosis and treatment options.     

Radical radiotherapy of inoperable non-small cell lung cancer. Irradiation techniques and tumor characteristics in relation to local control and survival.

The relation between tumor characteristics, irradiation technique, local tumor control and survival was retrospectively studied in 323 patients with non-small cell lung cancer who started radical radiotherapy in 1974-1981. At that time three non-randomized different fractionation schedules were used: 16 x 3.25 Gy, total dose 52 Gy, 3 fractions/week (schedule 1), 11 x 4 Gy, total dose 44 Gy, 2 fractions/week (schedule 2) and 25 x 2 Gy, total dose 50 Gy, 5 fractions/week (schedule 3). The highest survival rates were observed in the patient group treated according to schedule 2. The 2-year survival rate was 30% compared with 18% and 6% in the patients treated according to schedule 1 and 3 respectively. However, this can at least partly be explained by patient selection. A correlation between size of the tumor, target volume and survival was observed: the larger the tumor, the poorer the survival. Pleural effusion showed to be an unfavorable prognostic factor. The prognosis of inoperable lung cancer on the whole remained poor: the 1-year survival rate was 43% and 2-year survival rate 16%. Only 3% of the patients lived at least five years.     

A 5-year retrospective analysis of employer-provided dental care for Finnish male industrial workers

Abstract The treatment-mix, treatment time, and dental status of 268 male industrial workers entitled to employer-provided dental care were studied. The data were collected from treatment records of the covered workers over the 5-year period 1989-93. Treatment time was based on clinical treatment time recorded per patient visit, and the treatment procedure codes were reclassified into a treatment-mix according to American Dental Association categories, with a modification combining endodontics and restorative treatment. The mean number of check-ups followed by prescribed treatment (treatment courses) during the 5 years was 3.7 among those who had entered the in-house dental care program prior to the monitored period (old attenders). Their treatment time was stable, 57–63 min per year, while the first-year mean treatment time (170 min) of those who had entered the program during the study period (new attenders) was significantly higher (P<0.01) than the 5-year mean of the old attenders (61 min). Over the first 2 years, the treatment-mix of the new attenders showed a rise in diagnostic and preventive procedures from one-third to about one-half of all procedures, as it was for the old attenders. The new attenders' mean number of carious teeth (2.7), registered at the initial check-up visit, paralleled the mean recently demonstrated in the similar non-covered population. It was significantly higher than the 5-year mean of the old attenders (0.5) (P<0.001), but declined to the same level after the first year of treatment. It was concluded that the studied program seemed to contribute to a stabilization of treatment-mix, and to the establishment of a shorter annual treatment time within the first 2 years of treatment.     

Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy

The purpose of this work is to evaluate the predictive strength of the relative seriality, parallel and LKB normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis, in a large group of patients following breast cancer radiotherapy, and furthermore, to illustrate statistical methods for examining whether certain published radiobiological parameters are compatible with a clinical treatment methodology and patient group characteristics. The study is based on 150 consecutive patients who received radiation therapy for breast cancer. For each patient, the 3D dose distribution delivered to lung and the clinical treatment outcome were available. Clinical symptoms and radiological findings, along with a patient questionnaire, were used to assess the manifestation of radiation-induced complications. Using this material, different methods of estimating the likelihood of radiation effects were evaluated. This was attempted by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Additionally, the need for an update of the criteria that are being used in the current clinical practice was also examined. The patient material was selected without any conscious bias regarding the radiotherapy treatment technique used. The treatment data of each patient were applied to the relative seriality, LKB and parallel NTCP models, using published parameter sets. Of the 150 patients, 15 experienced radiation-induced pneumonitis (grade 2) according to the radiation pneumonitis scoring criteria used. Of the NTCP models examined, the relative seriality model was able to predict the incidence of radiation pneumonitis with acceptable accuracy, although radiation pneumonitis was developed by only a few patients. In the case of modern breast radiotherapy, radiobiological modelling appears to be very sensitive to model and parameter selection giving clinically acceptable results in certain cases selectively (relative seriality model with Seppenwoolde et al and Gagliardi et al parameter sets). The use of published parameters should be considered as safe only after their examination using local clinical data. The variation of inter-patient radiosensitivity seems to play a significant role in the prediction of such low incidence rate complications. Scoring grades were combined to give stronger evidence of radiation pneumonitis since their differences could not be strictly associated with dose. This obviously reveals a weakness of the scoring related to this endpoint, and implies that the probability of radiation pneumonitis induction may be too low to be statistically analysed with high accuracy, at least with the latest advances of dose delivery in breast radiotherapy.