Genome-wide scan demonstrates significant linkage for male sexual orientation.

BACKGROUND: Findings from family and twin studies support a genetic contribution to the development of sexual orientation in men. However, previous studies have yielded conflicting evidence for linkage to chromosome Xq28. METHOD: We conducted a genome-wide linkage scan on 409 independent pairs of homosexual brothers (908 analyzed individuals in 384 families), by far the largest study of its kind to date. RESULTS: We identified two regions of linkage: the pericentromeric region on chromosome 8 (maximum two-point LOD = 4.08, maximum multipoint LOD = 2.59), which overlaps with the second strongest region from a previous separate linkage scan of 155 brother pairs; and Xq28 (maximum two-point LOD = 2.99, maximum multipoint LOD = 2.76), which was also implicated in prior research. CONCLUSIONS: Results, especially in the context of past studies, support the existence of genes on pericentromeric chromosome 8 and chromosome Xq28 influencing development of male sexual orientation.

The pre- and post-somatic segments of the human type I spiral ganglion neurons--structural and functional considerations related to cochlear implantation.

Human auditory nerve afferents consist of two separate systems; one is represented by the large type I cells innervating the inner hair cells and the other one by the small type II cells innervating the outer hair cells. Type I spiral ganglion neurons (SGNs) constitute 96% of the afferent nerve population and, in contrast to other mammals, their soma and pre- and post-somatic segments are unmyelinated. Type II nerve soma and fibers are unmyelinated. Histopathology and clinical experience imply that human SGNs can persist electrically excitable without dendrites, thus lacking connection to the organ of Corti. The biological background to this phenomenon remains elusive. We analyzed the pre- and post-somatic segments of the type I human SGNs using immunohistochemistry and transmission electron microscopy (TEM) in normal and pathological conditions. These segments were found surrounded by non-myelinated Schwann cells (NMSCs) showing strong intracellular expression of laminin-ß2/collagen IV. These cells also bordered the perikaryal entry zone and disclosed surface rugosities outlined by a folded basement membrane (BM) expressing laminin-ß2 and collagen IV. It is presumed that human large SGNs are demarcated by three cell categories: (a) myelinated Schwann cells, (b) NMSCs and (c) satellite glial cells (SGCs). Their BMs express laminin-ß2/collagen IV and reaches the BM of the sensory epithelium at the habenula perforata. We speculate that the NMSCs protect SGNs from further degeneration following dendrite loss. It may give further explanation why SGNs can persist as electrically excitable monopolar cells even after long-time deafness, a blessing for the deaf treated with cochlear implantation.

Endogenous α-calcitonin-gene-related peptide promotes exercise-induced, physiological heart hypertrophy in mice.

AIM: It is unknown how the heart distinguishes various overloads, such as exercise or hypertension, causing either physiological or pathological hypertrophy. We hypothesize that alpha-calcitonin-gene-related peptide (αCGRP), known to be released from contracting skeletal muscles, is key at this remodelling. METHODS: The hypertrophic effect of αCGRP was measured in vitro (cultured cardiac myocytes) and in vivo (magnetic resonance imaging) in mice. Exercise performance was assessed by determination of maximum oxygen consumption and time to exhaustion. Cardiac phenotype was defined by transcriptional analysis, cardiac histology and morphometry. Finally, we measured spontaneous activity, body fat content, blood volume, haemoglobin mass and skeletal muscle capillarization and fibre composition. RESULTS: While αCGRP exposure yielded larger cultured cardiac myocytes, exercise-induced heart hypertrophy was completely abrogated by treatment with the peptide antagonist CGRP(8-37). Exercise performance was attenuated in αCGRP(-/-) mice or CGRP(8-37) treated wild-type mice but improved in animals with higher density of cardiac CGRP receptors (CLR-tg). Spontaneous activity, body fat content, blood volume, haemoglobin mass, muscle capillarization and fibre composition were unaffected, whereas heart index and ventricular myocyte volume were reduced in αCGRP(-/-) mice and elevated in CLR-tg. Transcriptional changes seen in αCGRP(-/-) (but not CLR-tg) hearts resembled maladaptive cardiac phenotype. CONCLUSIONS: Alpha-calcitonin-gene-related peptide released by skeletal muscles during exercise is a hitherto unrecognized effector directing the strained heart into physiological instead of pathological adaptation. Thus, αCGRP agonists might be beneficial in heart failure patients.

Incidence of paroxysmal atrial tachycardias in patients treated with cardiac resynchronization therapy and continuously monitored by device diagnostics.

AIMS: Little is known about the incidence of paroxysmal atrial tachycardias (PAT) in patients with heart failure (HF). The availability of cardiac resynchronization therapy (CRT) devices with extended diagnostics for AT enables continuous monitoring of PAT episodes. The aim of the study was to assess the incidence over time of PAT in HF patients treated with CRT. METHODS AND RESULTS: Consecutive patients in NYHA functional class III or IV despite optimal drug therapy, QRS duration > or = 130 ms, left ventricular ejection fraction < or = 35%, and left ventricular end-diastolic dimension > or = 55 mm were eligible for enrolment. Patients with permanent or persistent atrial fibrillation (AF) were not included in the study. The first follow-up examination was performed 2 weeks after implantation, to optimize atrial sensing and CRT. Subsequent follow-up examinations were carried out 15 and 28 weeks after implantation, to collect the telemetric data. A total of 173 patients (67 +/- 11 years, M 116) were enrolled. Complete arrhythmia monitoring data were available from 120 patients over a mean follow-up of 183 +/- 23 days. Atrial tachycardia episodes were detected through telemetry in 25 of 120 patients (21%) during at least one follow-up examination. Atrial tachycardia episodes were recorded in 29 and 17% (P = NS) of patients with and without previous history of AF, respectively. CONCLUSION: More than 20% of the overall HF patient population treated with CRT suffer PAT episodes. Paroxysmal atrial tachycardia may interfere with response to CRT. Therefore, telemetric data may be relevant to drive the appropriate therapy in each patient.

[Diagnostics of primary ciliary dyskinesia]. / Diagnostik der primären Ziliendyskinesie.

Primary ciliary dyskinesia (PCD) is an autosomal recessive inherited disease characterized by abnormal ciliary motion and impaired mucociliary clearance. The prevalence of PCD is approximately 1 : 15 000 - 1 : 20 000 in live births. Cilia dysfunction is also implicated in a wider spectrum of diseases due to impaired organ genesis and body symmetry. Cilia are highly conserved in animals and show complex structures containing more than 250 proteins for their formation. Recent studies have begun to locate the PCD genes in the genome and characterize functional mutations. Specific diagnosis of the ciliary dysfunction requires physiological measurements as well as light- and electron microscopy. Abnormalities in ciliary motion and ultrastructural studies can be performed with nasal mucosal epithelium.

Iodide iontophoresis as a treatment for dry eye syndrome.

BACKGROUND/AIMS: Among the causes related to the development or perpetuation and aggravation of dry eye disease, oxidative reactions may have a role in the pathogenesis of this disorder. Antioxidants, such as iodide, have shown a strong effect in preventing the oxidative damage to constituents of the anterior part of the eye. In this clinical trial the effectiveness of iodide iontophoresis and iodide application without current in moderate to severe dry eye patients was compared. METHODS: 16 patients were treated with iodide iontophoresis and 12 patients with iodide application without current for 10 days. Subjective improvement, frequency of artificial tear application, tear function parameters (break up time, Schirmer test without local anaesthesia), vital staining (fluorescein and rose bengal staining) as well as impression cytology of the bulbar conjunctiva were evaluated before treatment, 1 week, 1 month, and 3 months after treatment. RESULTS: A reduction in subjective symptoms, frequency of artificial tear substitute application, and an improvement in certain tear film and ocular surface factors could be observed in both groups. A stronger positive influence was seen after application of iodide with current (iontophoresis), as observed in a distinct improvement in break up time, fluorescein and rose bengal staining, and in a longer duration of this effect compared with the non-current group. No significant change in Schirmer test results and impression cytology were observed in both groups. CONCLUSIONS: Iodide iontophoresis has been demonstrated to be a safe and well tolerated method of improving subjective and objective dry eye factors in patients with ocular surface disease.

Anti-oxidative capacity of various artificial tear preparations.

BACKGROUND: Increased UV radiation and ozone exposure may cause "dry eyes of environmental origin", if the normal anti-oxidative capacity of the tear film can no longer cope with the oxidative stress. The use of artificial tears with an adequate anti-oxidative effect may be beneficial in the treatment of dry eyes caused by environmental factors. METHODS: The anti-oxidative capacity of various commercial artificial tear preparations was determined with a modified TRAP procedure. The two preparations with the strongest anti-oxidative effect were then examined for their protective effects against UV or ozone exposure in a hyaluronate model. RESULTS: Of 19 artificial tear preparations tested, only 6 showed strong to moderate anti-oxidative effects. All others were at best weakly anti-oxidative or had no anti-oxidative effect at all. Some of them even acted as oxidants. Although the two most strongly anti-oxidative preparations performed somewhat differently on UV and ozone exposure, they were both found to be highly protective against these important oxidative stress factors. CONCLUSIONS: The anti-oxidative capacity of artificial tear preparations varies widely. While some are strong anti-oxidants, others are less active or even act as oxidants. If the carefully elicited history of patients with dry eyes suggests that noxious environmental factors may be causally involved, artificial tears which are not just lubricants or contain wetting agents, but act as anti-oxidants, should be chosen for treatment from the many commercially available preparations. Such an etiology-oriented concept would probably improve the success rate of treatment for dry eyes.

[Conclusions and consequences from registries: the Polytrauma Register of the German Society of Trauma Surgery]. / Lehren und Konsequenzen aus Sammelregistern: Das Polytraumaregister der DGU.

In the trauma register of the German society of traumatology until now 5353 patients have been analysed. The mean age was 38.5 years, the proportion of blunt injuries was 94.3%. The mean ISS was 24.8%, the emergency doctor arrived in the middle 22.4 minutes after the accident. The stay of the emergency doctor lasted 32.9 minutes and the transport from the place of accident to the hospital took 18.3 minutes. The rate of intubation through the emergency doctor was 58.3%. The mean stay at hospital was 31.1 days, at the intensive car unit 13.1 days with a mean time of 8.7 days artificial respiration. In comparing the years we saw an improvement of outcome throughout all participating hospitals. Future aims of the trauma register are to increase the quality of life after trauma, to guarantee an adequate quality of treatment, to analyse costs and to include all German hospitals in the trauma register.

Mitochondrial defects by intracellular calcium overload versus endothelial cold ischemia/reperfusion injury.

Questions as to the critical stress factor and primary targets of cold ischemia/reperfusion (CIR) injury were addressed by comparing mitochondrial defects caused by (1) CIR injury and (2) intracellular Ca2+ overload. CIR was simulated in transformed human umbilical vein endothelial cell cultures (tEC) by 8 h cold anoxia in University of Wisconsin solution and reoxygenation at 37 degrees C. Intracellular Ca2+ concentrations were changed by permeabilization of suspended cells with digitonin in culture medium (RPMI, 0.4 mM Ca2+). Binding of free Ca2+ by ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid in RPMI or mitochondrial incubation medium served as controls. Extracellular Ca2+ protected the cell membrane against permeabilization. Mitochondrial functions were determined before and after permeabilization of the cell membrane. After CIR, mitochondrial respiratory capacity declined, but oxygen consumption remained coupled to adenosine triphosphate (ATP) production. In contrast, Ca2+ overload caused uncoupling of mitochondrial respiration. High intracellular Ca2+ overload, therefore, does not reproduce cold ischemia/reperfusion injury in endothelial cells.

[The internal fixation of fractures in children]. / Intramedulläre Osteosynthesen beim Kind.

The internal fixation of fractures of shaft bones was spread out by a group of surgeons working together with Prevot. The principle of this method is a three point load carrying paragraph sign(entry point, height of fracture and cancellous bone of the metaphysis of the opposite fracture part). From 1996 to 1999 86 children with fractures of the humerus, the fore-arm and the femur were operated in the technique of intramedullary nailing. The fractures affected the humerus to 3.5 %, the fore-arm to 65.1 % and the femoral shaft to 31.4 %. The postoperative duration of stay in hospital after internal fixation of the fore-arm in the proximal and middle third lasted 7.2 days, the duration of immobilisation in a cast took 13.7 days. 96 % of the patients showed very good and good results after operation. The average stay in hospital for patients with femoral shaft fractures was 14.4 days. 17 weeks after operation the intramedullary nails were removed. At the time of first full weight bearing the legs showed an average shortening of 1.2 cm. The fractures of the humerus healed without any restriction of movements. Internal fixation is a minimal invasive operation technique with low risks and small operating trauma. Due to the stability a early mobilisation is possible. The reported results in the literature are all good. The only problem can be caused by too long nails irritating the skin.

Ultrastructural analysis of human endothelial cells after hypothermic storage in organ preservation solutions.

BACKGROUND: Protection of vascular endothelium is a critical factor in organ preservation for transplantation. This study aims at a morphological assessment of endothelial cell injury in a comparison of storage solutions, using a cell culture model of cold preservation and rewarming. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were cultured in monolayer and exposed to hypothermic storage in University of Wisconsin (UW), histidine-tryptophane-ketoglutarate (HTK), and EuroCollins solutions for 6 h and subsequent rewarming for 30 min or 6 h. Alterations of subcellular structures and cell-cell contacts were analyzed by transmission electron microscopy (TEM) and light microscopic assessment after actin and nuclear staining. RESULTS: Structural alterations of mitochondria, endoplasmic reticulum, nuclei, and cytoskeletal fibers as well as disruption of intercellular contacts were found after cold storage in HTK and EuroCollins solutions. In contrast, storage in UW solution resulted in minimum changes of stress fibers only. A rapid rearrangement of structural alterations was achieved during rewarming in cell culture medium in all experimental groups. CONCLUSIONS: Preservation of endothelial cell structure is best achieved by UW solution. Ultrastructural cell damage is a direct consequence of hypothermic storage and is fully reversible during rewarming after short storage times.

Color discrimination in patients with keratoconjunctivitis sicca before and after artificial tear application.

BACKGROUND: The precorneal tear film is of decisive importance for the optical quality of the cornea. Poor stability of this film causes not only dry eye symptoms, but also has negative effects on optical functions of the eye, as previous studies on visual acuity, field test performance and contrast sensitivity have shown. METHODS: 60 patients with dry eyes randomized into 2 groups of 30 underwent color vision testing with the Lanthony Desaturated 15 Hue test before and after instillation of artificial tear (test group) or physiological saline (control group) drops. RESULTS: The improvement in color discrimination in the group given artificial tear treatment was found to be slightly better than in the saline group but in both groups this improvement was not of statistical significance. CONCLUSION: Even though an unstable tear film adversely affects the optics of the eye and even mildly degraded optics can affect spatial visual tasks, color discrimination performance on tasks such as the Lanthony D-15 test does not appear to be markedly impaired.

Mitochondrial oxygen affinity, respiratory flux control and excess capacity of cytochrome c oxidase.

The oxygen affinity of the enzyme system involved in mitochondrial respiration indicates, in relation to intracellular oxygen levels and interpreted with the aid of flux control analysis, a significant role of oxygen supply in limiting maximum exercise. This implies that the flux control coefficient of mitochondria is not excessively high, based on a capacity of mitochondrial oxygen consumption that is slightly higher than the capacity for oxygen supply through the respiratory cascade. Close matching of the capacities and distribution of flux control is consistent with the concept of symmorphosis. Within the respiratory chain, however, the large excess capacity of cytochrome c oxidase, COX, appears to be inconsistent with the economic design of the respiratory cascade. To address this apparent discrepancy, we used three model systems: cultured endothelial cells and mitochondria isolated from heart and liver. Intracellular oxygen gradients increase with oxygen flux, explaining part of the observed decrease in oxygen affinity with increasing metabolic rate in cells. In addition, mitochondrial oxygen affinities decrease from the resting to the active state. The oxygen affinity in the active ADP-stimulated state is higher in mitochondria from heart than in those from liver, in direct relationship to the higher excess capacity of COX in heart. This yields, in turn, a lower turnover rate of COX even at maximum flux through the respiratory chain, which is necessary to prevent a large decrease in oxygen affinity in the active state. Up-regulation of oxygen affinity provides a functional explanation of the excess capacity of COX. The concept of symmorphosis, a matching of capacities in the respiratory cascade, is therefore complemented by 'synkinetic' considerations on optimum enzyme ratios in the respiratory chain. Accordingly, enzymatic capacities are matched in terms of optimum ratios, rather than equal levels, to meet the specific kinetic and thermodynamic demands set by the low-oxygen environment in the cell.

A rare cause of complete "spectacle hematoma".

Both subconjunctival and orbital hemorrhages as well as bleeding into the eyelids may occur in a variety of conditions, including vascular disease, abnormal blood composition, systemic disease, and the so-called Valsalva maneuver. A case of complete spontaneous "spectacle hematoma" after vigorous paroxysmal coughing is reported.

Iodine distribution in a porcine eye model following iontophoresis.

Iodine distribution was studied in isolated porcine eyes after iontophoresis using 131I-labelled solutions and chemical methods. After a 15-min treatment with a therapeutically used iodine brine, the iodine content in the ocular tissues showed the following rank order: cornea > retina > vitreous body > anterior chamber fluid > lens. Replacement of the brine by 0.15 M NaI increased the uptake values in a different way, but the same rank order was maintained. The increase was highest in the cornea (5.6-fold) and only about 2-fold in the lens, nevertheless approaching now the level of 10(-4) M, a concentration which was regarded as being optimal for the antioxidant effect of I-. Among the other eye components, the relatively high iodine enrichment of the retina was remarkable. The data are discussed with respect to a possible protective, antioxidative and OH-scavenging efficacy of I- and to previous results in the literature concerning iodine uptake in ocular tissues.