Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.

Effectiveness of a community-based 3-year advisory program after acquired brain injury.

Objective of this study was to examine the effectiveness of a coordinated, community based 3-year advisory program in 1534 patients with acquired brain injury. Patients and caregivers were offered a coordinated advisory program after discharge from rehabilitation. Patients in the historical control group received standard aftercare. The main outcomes were functional status [Functional Independence Measure (FIM)], and days spent in the acute hospital. The secondary outcome was survival. Patients were comparable for sex (intervention: 41.3% female, control: 38.0%), and younger in the control group (mean age intervention: 55.3, control: 49.6). Functional status at discharge was lower in the intervention group (mean FIM intervention: 66.2, control: 80.3). Patients in the intervention group experienced a moderate gain in FIM. Rate of days in hospital was 15.4 per 1000 person days (intervention) and 15.5 per 1000 person days (control). Patients of the intervention group had an increased rate of days in hospital. A total of 16.0% of patients in the intervention group and 19.3% in the control group died during follow-up. Patients in the intervention had a significant lower mortality risk depending on follow-up period and discharge FIM. The advisory program may be effective for all patients with acquired brain injury.

Changes of epidermal mu-opiate receptor expression and nerve endings in chronic atopic dermatitis.

There is increasing evidence that neuropeptides such as a substance P, neurotrophins or beta-endorphin, an endogenous agonist for mu-opioid receptor, are involved in the pathogenesis of atopic dermatitis in which mental stress and scratching deteriorate the disease. mu-Opioid receptor, a G-protein-coupled receptor, can be downregulated and internalized by agonists and other factors in vitro. In this study, we investigated the regulation of mu-opioid receptor and nerve endings in atopic dermatitis patients. Skin biopsies from atopic dermatitis patients revealed a significant downregulation of mu-opiate receptor expression in epidermis of atopic dermatitis. Permeabilization of the skin showed that the receptor in keratinocytes from atopic dermatitis is internalized. The mRNA expression pattern of the mu-opiate receptor is different in epidermis taken from patients with chronic atopic dermatitis compared to normal skin. In atopic dermatitis, the mRNA is concentrated in the subcorneal layers of the epidermis and in normal skin in the suprabasal layers. Staining of the nerve endings using protein gene product 9.5 shows a different pattern of epidermal nerve endings in normal skin compared to atopic dermatitis. In normal skin, the epidermal nerve endings are rather thick. However, in atopic dermatitis, the epidermal nerve endings are thin and run straight through the epidermis. Based on these observations and combining the 'intensity' and 'pattern' hypothesis, we propose a new theory especially for histamine-unrelated, peripheral induction of chronic pruritus. We suggest that 'itch' is elicited in the epidermal unmyelinated nerve C-fibers and 'pain' in the dermal unmyelinated nerve fibers. The downregulation of the opioid receptor in the epidermis contributes to the chronic itching. We call this new hypothesis the 'layer hypothesis'.

Non-invasive measurement of the cardiovascular effects of chronic hypoxaemia on dogs living at moderately high altitude.

Pulmonary hypertension is a well-recognised condition in dogs, and, among other mechanisms, is caused by hypoxia. In order to evaluate the effect of chronic hypobaric hypoxia on pulmonary arterial pressure in dogs, a colony of 19 clinically and biochemically healthy Greenland sled dogs living permanently at at least 2300 m above sea level (altitude dogs) and 10 clinically healthy Greenland sled dogs living at 700 to 900 m above sea level (control dogs) were examined. Investigations were made of the dogs' packed-cell volume, venous and arterial blood gases, electrocardiogram, blood pressure and echocardiograph, including the calculation of pulmonary arterial pressure by Doppler examination of tricuspid regurgitation. The altitude dogs had a marked arterial hypoxaemia with a mean (sd) oxygen partial pressure of 61.9 (7.4) mmHg and a significantly lower arterial oxygen saturation (90.7 [3.7] per cent) than the control dogs (96.7 [0.8] per cent). In eight of the altitude dogs, tricuspid regurgitation allowed calculation of the systolic pulmonary arterial pressure, which was 29.5 (10.4) mmHg. Eight of the control dogs had tricuspid insufficiency, and their derived systolic pulmonary arterial pressure was significantly lower (17.4 [3.9] mmHg).

Electrophysiological correlates of visual impairments after traumatic brain injury.

Our aims were to investigate: (i) the VEP correlates of functional visual impairments following traumatic brain injury (TBI), in particular of the reduced spatial form perception; and (ii) the VEP correlates of visual sustained arousal in TBI patients. We used two approaches: (i) the analysis of latency and amplitude of the peaks; and (ii) the study of the correlations among the latencies of the peaks as a label of temporal synchronization. Thirty-five severe TBI outcome inpatients and 35 matching controls were studied. Pattern-reversal VEPs were recorded at Oz-Fz and Cz-A1, first without counting, then with counting of the reversals. Seven peaks of the waveform at Oz and eight peaks at Cz were measured. We found several differences in amplitude and latency between patients and controls, and between nocount/count. The temporal binding of the peaks within each channel and between the two channels was calculated by correlation matrices, and tested by factor analysis. Results indicated that the synchronization of the peaks within each channel did not differ between patients and controls. The temporal covariation between peaks occurring at Oz and Cz, however, was highly significantly altered in patients. This suggests that visual impairments in TBI patients may be due to a deranged synchronization of the activity of different brain regions.

Elektromagnetische Bioinformation im Frequenzbereich von 100 Hz bis 100 kHz?

Electromagnetic Bioinformation in the Frequency Region between 100 Hz and 100 kHz? A highly sensitive measurement amplifier (BIT device) was constructed in order to detect possible electromagnetic biosignals in the frequency region between 100 Hz and 100 kHz. Even when working with the highest amplification mode of the BIT device, no endogenous electromagnetic biosignals could be detected on the test persons, but only well-known EMG signals. If the BIT device worked in a feedback mode, electromagnetic oscillations beween 1.7 and 2.9 kHz could be generated and oscilloscopically detected; these oscillations are caused by the oscillator system 'BIT - man', depending on the impedance of the human body. Biological effects of the impedance-depending oscillations were investigated in a simple randomized double-blind study. Three anamnestically healthy persons were treated 20 times with their specific oscillations. The physiological effects of this treatment were measured by pulse plethysmography. Nonlinear analysis of the time series indicated significant changes in pulse dynamics of one person. Linear analysis of heart rate variability showed no statistical significance. Our device was only designed for the project described below. It is, therefore, evident that the research results presented in this paper cannot be applied to any of the therapy devices at present on the market.

[Polychemotherapy of ovarian cancer via combined intravenous and intraperitoneal routes. Technic and preliminary results]. / Polychimiothérapie des cancers de l'ovaire par voie mixte intraveineuse et intrapéritonéale. Technique et résultats préliminaires.

20 patients with F.I.G.O. stages III ovarian cancer were entered into a randomised trial between January 1980 and March 1984. After a surgical resection as complete as possible, 10 of these patients received an intravenous chemotherapy with Adriamycin, Vincaleucoblastin Bleomycin, Fluorouracil and Ifosfamid monthly for 10 months. The other 10 patients received the same combined chemotherapy but by a double route: Intravenously and intraperitoneally. The results were judged at "second look surgery". 1 Of the 10 patients who were treated intravenously, 2 who had had a complete surgical resection had no recurrence. Of the remaining 8 patients who had had an incomplete resection, 4 still had residual lesions that could not be removed completely.

Determination of kallikrein by radioimmunoassay in human body fluids.

A sensitive and specific radioimmunoassay for human urinary kallikrein was developed, which allows tissue kallikrein determination in human urine, saliva, pancreatic juice, bile and sweat. In several body fluids a kallikrein-like antigen was found, but not in gastric juice and breast milk. According to gel filtration studies, complex formation of kallikrein with serum proteins or different molecular weight forms of kallikrein in serum and urine may be assumed. Pancreatic kallikrein secretion follows the same pattern after stimulation with secretin and cholecystokinin as trypsin and chymotrypsin in normal individuals. In chronic pancreatitis the kinetic behaviour remains unchanged with respect to the enzyme secretion, but the secretion of kallikrein is reduced to about 20%.

[Simultaneous bilateral avulsion of the quadriceps and Achilles tendons in 1 limb and of the patellar tendon in the other in a hyperparathyroid patient on chronic hemodialysis]. / Avulsion bilatérale simultanée des tendons quadricipital et rotulien et rupture du tendon tricipital chez un hémodialysé hyperparathyroïdien.

A case of simultaneous rupture of three tendons is reported in a patient who had suffered a bilateral nephrectomy six years earlier and was on chronic haemodialysis. The quadriceps tendon and the patellar tendon were repaired surgically. The rupture of the tendo Achillis was left untreated. Six days later a parathyroidectomy was performed; nine months later recovery was excellent. A review of the literature has been made. The role of hyperparathyroidism in the strength of the bone-tendon junction is discussed.