Genome-wide screen to identify genetic loci associated with cognitive decline in late-life depression.

OBJECTIVE: This study sought to conduct a comprehensive search for genetic risk of cognitive decline in the context of geriatric depression. DESIGN: A genome-wide association study (GWAS) analysis in the Neurocognitive Outcomes of Depression in the Elderly (NCODE) study. SETTING: Longitudinal, naturalistic follow-up study. PARTICIPANTS: Older depressed adults, both outpatients and inpatients, receiving care at an academic medical center. MEASUREMENTS: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery was administered to the study participants at baseline and a minimum of twice within a subsequent 3-year period in order to measure cognitive decline. A GWAS analysis was conducted to identify genetic variation that is associated with baseline and change in the CERAD Total Score (CERAD-TS) in NCODE. RESULTS: The GWAS of baseline CERAD-TS revealed a significant association with an intergenic single-nucleotide polymorphism (SNP) on chromosome 6, rs17662598, that surpassed adjustment for multiple testing (p = 3.7 × 10-7; false discovery rate q = 0.0371). For each additional G allele, average baseline CERAD-TS decreased by 8.656 points. The most significant SNP that lies within a gene was rs11666579 in SLC27A1 (p = 1.1 × 10-5). Each additional copy of the G allele was associated with an average decrease of baseline CERAD-TS of 4.829 points. SLC27A1 is involved with processing docosahexaenoic acid (DHA), an endogenous neuroprotective compound in the brain. Decreased levels of DHA have been associated with the development of Alzheimer's disease. The most significant SNP associated with CERAD-TS decline over time was rs73240021 in GRXCR1 (p = 1.1 × 10-6), a gene previously linked with deafness. However, none of the associations within genes survived adjustment for multiple testing. CONCLUSIONS: Our GWAS of cognitive function and decline among individuals with late-life depression (LLD) has identified promising candidate genes that, upon replication in other cohorts of LLD, may be potential biomarkers for cognitive decline and suggests DHA supplementation as a possible therapy of interest.

Lolium perenne peptide immunotherapy is well tolerated and elicits a protective B-cell response in seasonal allergic rhinitis patients.

BACKGROUND: Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short-course treatment with adjuvant-free Lolium perenne peptides (LPP) following a 6-week dose-escalation protocol. METHODS: In a prospective, dose-escalation study, 61 grass pollen-allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG4 and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8). RESULTS: No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG4 levels were higher at V6 (8.1-fold, P < .001) and V8 (12.2-fold, P < .001) than at V1. The sIgE:sIgG4 ratio decreased at V6 (-54.6%, P < .001) and V8 (-71.6%, P < .001) compared to V1. The absolute decrease in IgE-facilitated allergen binding was 18% (P < .001) at V6 and 25% (P < .001) at V8. CONCLUSION: Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.

Influence of hyperoxia on diastolic myocardial and arterial endothelial function.

OBJECTIVE: Hyperoxia is known to influence cardiovascular and endothelial function, but it is unknown if there are differences between younger and older persons. The aim of this study was to monitor changes in myocardial diastolic function and flow-mediated dilatation (FMD) in younger and elderly volunteers, before and after exposure to relevant hyperbaric hyperoxia. METHODS: 51 male patients were separated into two groups for this study. Volunteers in Group 1 (n=28, mean age 26 ±6, "juniors") and Group 2 (n=23, mean age 53 ±9, "seniors") received standard HBO2 protocol (240kPa oxygen). Directly before and after hyperoxic exposure in a hyperbaric chamber we took blood samples (BNP, hs-troponin-t), assessed the FMD and echocardiographic parameters with focus on diastolic function. RESULTS: After hyperoxia we observed a high significant decrease in heart rate and systolic/diastolic FMD. Diastolic function varied in both groups: E/A ratio showed a statistically significant increase in Group 1 and remained unchanged in Group 2. E/e' ratio showed a slight but significant increase in Group 1, whereas e'/a' ratio increased in both groups. Deceleration time increased significantly in all volunteers. Isovolumetric relaxation time remained unchanged and ejection fraction showed a decrease only in Group 2. There were no changes in levels of BNP and hs-troponin-t in either group. CONCLUSION: Hyperoxia seems to influence endothelial function differently in juniors and seniors: FMD decreases more in seniors, possibly attributable to pre-existing reduced vascular compliance. Hyperoxia-induced bradycardia induced a more pronounced improvement in diastolic function in juniors. The ability of Group 1 to cope with hyperoxia-induced effects did not work in the same manner as with Group 2.

Misoprostol for primary versus secondary prevention of postpartum haemorrhage: a cluster-randomised non-inferiority community trial.

OBJECTIVE: To assess whether secondary prevention, which preemptively treats women with above-average postpartum bleeding, is non-inferior to universal prophylaxis. DESIGN: A cluster-randomised non-inferiority community trial. SETTING: Health sub-centres and home deliveries in the Bijapur district of Karnataka, India. POPULATION: Women with low-risk pregnancies who were eligible for delivery with an Auxiliary Nurse Midwife at home or sub-centre and who consented to be part of the study. METHODS: Auxiliary Nurse Midwifes were randomised to secondary prevention using 800 mcg sublingual misoprostol administered to women with postpartum blood loss ≥350 ml or to universal prophylaxis using 600 mcg oral misoprostol administered to all women during the third stage of labour. MAIN OUTCOME MEASURES: Postpartum haemoglobin ≤7.8 g/dl, mean postpartum blood loss and postpartum haemoglobin, postpartum haemorrhage rate, transfer to higher-level facilities, acceptability and feasibility of the intervention. RESULTS: Misoprostol was administered to 99.7% of women as primary prevention. In secondary prevention, 92 (4.7%) women had postpartum bleeding ≥350 ml, of which 90 (97.8%) received misoprostol. The proportion of women with postpartum haemoglobin ≤7.8 g/dl was 5.9 and 8.8% in secondary and primary prevention clusters, respectively [difference -2.9%, one-sided 95% confidence interval (CI) <1.3%]. Postpartum transfer and haemorrhage rates were low (<1%) in both groups. Shivering was more common in primary prevention clusters (P = 0.013). CONCLUSION: Secondary prevention of postpartum haemorrhage with misoprostol is non-inferior to universal prophylaxis based on the primary outcome of postpartum haemoglobin. Secondary prevention could be a good alternative to universal prophylaxis as it medicates fewer women and is an acceptable and feasible strategy at the community level. TWEETABLE ABSTRACT: Secondary prevention of postpartum haemorrhage with misoprostol is non-inferior to universal prophylaxis.

Dose-time dependency of hyperbaric hyperoxia-induced DNA strand breaks in human immune cells visualized with the comet assay.

PURPOSE: Hyperbaric oxygen exposure may induce dose-dependent DNA damage in peripheral blood mononuclear cells (PBMCs), and repetitive exposures of man may have protective cellular effects. METHOD: PBMCs, freshly isolated from non-divers and pure oxygen divers, were exposed to ambient air (21kPa) and hyperoxia at different levels: 100kPa, 240kPa, 400kPa and 600kPa) for up to 6.5 hours in an experimental pressure chamber. DNA double-strand breaks were studied in the comet assay by calculating the "tail moment" and an alternative "Yes or No" method for damaged nuclei. Previously, the experimental procedure had been optimized for human cell experiments: Pre-tests assured that DNA damage could be considered to be oxygen-induced; and cell viability remained over 95% during exposure time. RESULTS: Visible DNA damage increased with the partial pressure of oxygen (pO2) and exposure time dose-dependently. Linear regressions revealed r2 between 0.61 and 0.98 with the Yes/No method, and significant differences in slopes from control. Tail moment showed similar results, but with less accuracy. The PBMCs of oxygen divers exposed to 400kPa pO2 (up to six hours) showed a significant lower slope in the linear regression. CONCLUSION: Oxygen induces dose-dependent DNA double-strand breaks, and the Yes/No discrimination is superior to the tail moment in linearity and accuracy. Oxygen diver PBMCs seem to be more resistant to hyperbaric oxygen.

[Hernia repair at the groin - who undergoes which surgical intervention?]. / Leistenhernienreparation - Wo wird wie operiert?

BACKGROUND: Within the Guidelines of the European Hernia Society (EHS), there are disctinct statements about where and how inguinal hernia has to be surgically approached. In ASA-I and -II patients, it is recommended to perform the operation in an outpatient clinic setting. Male patients older than 30 years of age should undergo preferably surgical intervention using a mesh. In this context, there are two basic questions: "Are these recommendations already implemented in daily surgical practice (?)" and "Are these guidelines the road to success (?)", which are to be commented based on i) data from two registries, ii) data obtained in the surgical practice of the first author and iii) a selective literature search. MATERIAL AND METHODS: An analysis was made of prospectively obtained data from two German registries (Herniamed registry [H-med]; Quality Assurance Inguinal Hernia Registry [QIHR]) and a consecutive and representative patient cohort of a single surgical practice [Surg-Pract] specialised in hernia surgery. Main results and concluding remarks are discussed in light of data reported in the literature. RESULTS: Proportions of hernia repair in an outpatient clinic setting were substantially different among the 3 groups (as follows): H-med (22.3 %), QIHR (62.7 %), Surg-Pract (80.5 %) whereas the percentages of ASA-I and -II patients differed only slightly: H-med (83.4 %), QIHR (89.5 %) and Surg-Pract (88.3 %). Recurrency rates after 12 months were 0.6 % (QIHR) and 0.7 % (Surg-Pract), respectively. In Surg-Pract, for 30 % of hernia repairs, "only" suturing for reconstruction was used. CONCLUSION: In ASA-I and -II patients, a substantial proportion of individuals can be surgically treated in an outpatient clinic setting with no disadvantages regarding high surgical quality and favourable outcome. Data from the national H-med indicated a much lower percentage of such patients than internationally reported and, in addition, a disproportionately high rate of endoscopic procedures. Moreover, reimbursement for hernia repair in an outpatient clinic setting is much worse in Germany compared with international standards, and, interestingly, there is by a factor of 1/3 an above average number of hospital beds in Germany compared with the OECD countries.

Influence of hyperoxia and physical exercise on *OH-radical stress in humans as measured by dihydroxylated benzoates (DHB) in urine.

BACKGROUND: Hyperoxia and physical exercise are known to produce reactive oxygen species (ROS), and the *OH radical is the most aggressive among them. However, knowledge is limited about *OH stress during physical work under hyperoxic conditions. METHODS: This study monitored *OH stress in human volunteers before and after a total of 135 exposures to ambient air (control), different levels of hyperoxia at rest and challenging open-water closed-circuit dives by measurement of dihydroxylated benzoates (DHB) with HPLC by electrochemical detection in urine. RESULTS: Changes in DHB in urine after control were only 3.43 +/- 4.8% (n = 9). After exposures to 100 kPa oxygen (O2) for 110 minutes DHB revealed increases in urine of 23.14 +/- 5.12% (n = 9); exposures to 240 kPa O2 for 90 minutes increases of 22.38 +/- 8.91% (n = 8); and 280 kPa 02 for 30 minutes of 21.92 +/- 10.76% (n = 17). Closed-circuit dives in open water (45-54 minutes of 125-160 kPa O2) revealed DHB increases of 66.34 +/- 25.73% (n = 92). All results differed significantly from control (p < 0.001). The closed-circuit dives also differed significantly from all exposures to hyperoxia without exercise (p < 0.001). Standardization of "oxygen burden" during each exposure (pO2 x exposure time x VO2) allowed for comparison of different exposures vs. DHB changes and revealed goodness of linear fit of r2 = 0.432 (p < 0.0001). CONCLUSIONS: Increases in urine DHB after exposures to different levels of hyperoxia at rest and during exercise are consistent with *OH stress that is greater during exercise than at rest, although other interpretations are possible. Standardization of the individual "oxygen burden" for a given exposure may become useful in future for the estimation of *OH stress.

Physical exercise might influence the risk of oxygen-induced acute neurotoxicity.

OBJECTIVE: Hyperoxia can induce acute neurotoxicity with generalized seizures. Hyperoxia-induced reduction in cerebral blood flow velocity (CBFV) might be protective. It is unclear whether dynamic exercise during hyperoxia can overcome CBFV-reduction and thus possibly increase the risk of neurotoxicity. METHODS: We studied CBFV with both-sided transcranial Doppler with fixed transducer-position and heart rate under increasing hyperoxic conditions in nine professional military oxygen divers. The divers performed dynamic exercise on a bicycle-ergometer in a hyperbaric chamber (ergometries I-III, 21kPa, 100kPa, 150kPa pO2), with continuous blood pressure (ergometries I, II), end-tidal CO2 (PetCO2; ergometry I) being measured. RESULTS: Systolic (CBFVsyst) and diastolic CBFV (CBFVdiast) readings at rest decreased with increasing pO2. During exercise, CBFVsyst and CBFVdiast significantly increased in parallel with increasing pO2, despite reduced flow velocities at rest. ERGOMETRY I: CBFVsyst increased from 65.0 +/- 11.3 cm/second at rest to 80.2 +/- 23.4cm/s during maximum workload (n.s.), diastolic from 14.5 +/- 4.1 cm/second to 15.6 +/- 7.5 cm/s (n.s.). PetCO2 increased from 43.4 +/- 7.8mmHg to 50.0 +/- 7.5mmHg. ERGOMETRY II: CBFVsyst increased from 58.2 +/- 16.5 cm/second to 99.7 +/- 17.0 cm/s (p<0.001), diastolic from 14.0 +/- 10.7 cm/second to 29.4 +/- 11.1 cm/second (p<0.01). ERGOMETRY III: CBFVsyst increased from 54.4 +/-15.0cm/second to 109.4 +/- 22.3cm/s (p<0.001), diastolic from 14.7 +/- 10.4 cm/second to 35.5 +/- 9.3 cm/second (p<0.01). INTERPRETATION: Physical exercise overrules the decrease in CBFV during hyperoxia and leads to even higher CBFV-increases with increasing pO2. A tendency towards CO2 retainment with elevated PetCOz may be causative and thus heighten the risk of oxygen-induced neurotoxicity.

Treatment of HIV-related primary central nervous system lymphoma with AZT high dose, HAART, interleukin-2 and foscarnet in three patients.

PURPOSE: Combined immunomodulatory and antiviral treatment was administered to three patients with newly diagnosed HIV-associated primary central nervous system lymphoma (PCNSL) in an attempt to improve outcomes. PATIENTS AND METHODS: Three patients from our institution who were recently diagnosed with HIV-associated PCNSL received intravenous azidothymidine (AZT) 1.6 gr. bid for two weeks, followed by oral AZT 250mg bid from day 15. In addition, complementary highly active antiretroviral therapy (HAART) with a second nucleoside reverse transcriptase inhibitor (NRTI) plus one protease inhibitor (PI) and interleukin 2 (IL-2) subcutaneously 2 million units twice daily (bid) plus foscarnet 90mg/kg bid were administered on days 1-14. One patient received anti-Epstein-Barr virus (EBV)-maintenance therapy with ganciclovir, followed by cidofovir. RESULTS: All patients experienced progressive disease while on induction therapy, and switched early to whole-brain radiation therapy (WBRT) as second line-treatment. No grade 3 or 4 toxicities were observed. Two patients died on days 50 and 166 respectively due to progressive disease. The third patient with histo?logically proven lymphoproliferation and only suspected PCNSL remained alive at 53 months. He was on HAART and remained clinically and neurologically stable. CONCLUSION: Although IL-2, HAART, high-dose AZT and foscarnet are used for other HIV-related conditions, they did not demonstrate benefit in lymphoma remission for 2 HIV- associated PCNSL patients. The third patient went into delayed remission after additional radiotherapy and was in good clinical and neurological health status over 53 months after diagnosis.

A single exposure to hyperbaric oxygen increases levels of circulating nucleosomes but does not induce mononuclear cell apoptosis in divers.

Recent reports that hyperbaric oxygenation (HBO2) induced apoptosis in T-cell lines raised concern about a possible immunosuppressive effect of HBO2. Nucleosomes, DNA fragments wrapped around a histone core, have been observed in the circulation in diseases with increased cell death such as sepsis. Our aim was to investigate, whether HBO2 increases circulating nucleosomes as a marker of cell death and induces apoptosis of peripheral blood mononuclear cells in vivo. After informed consent 29 healthy volunteers were exposed to a 30 minute dive at 2.8 atmospheres absolute in a pressure chamber under resting conditions, while breathing 100% oxygen. Samples were obtained before and 24 hours after exposure. Circulating nucleosomes were measured in serum. Caspase-3 activation, Bcl-2 expression and mRNA of Bcl-2, Bcl-xl and Bax were analyzed in mononuclear cell extracts. Nucleosomes were elevated markedly 24h after exposure (p<0.01), while caspase-3 was not activated significantly. mRNA levels of Bcl-2, Bcl-xl and Bax were not altered. In conclusion, while evidence of elevated levels of circulating nucleosomes was found, mononuclear cell apoptosis was not affected by a single exposure to hyperbaric oxygen.

Monitoring of CBFV and time characteristics of oxygen-induced acute CNS toxicity in humans.

BACKGROUND: Hyperbaric oxygen can cause central nervous system (CNS) toxicity with seizures. We tested the hypothesis that CNS toxicity could be predictable by cerebral blood flow velocity (CBFV) monitoring. METHOD: We monitored 369 mandatory oxygen tolerance tests (30 min, 280 kPa O(2)) by video-documentation and since May 2005 by additional CBFV registration (n = 61). RESULTS: The onset of early manifestations of CNS toxicity was documented in 11 of 369 tests within 22 +/- 3 min. These included twitches and/or agitation, 6 of 11 and tonic-clonic seizures in 5 of 11 cases. In both cases with CBFV monitoring, an increase in CBFV preceded symptom onset, once followed by seizure, once without seizure after timely oxygen reduction. CONCLUSIONS: During exposure to 280 kPa oxygen at rest a constant delay of approximately 20 min precedes the onset of central nervous oxygen toxicity. An increase in CBFV may indicate the impending seizure.

Viewpoint: the type A- and the type B-variants of Decompression Sickness.

BACKGROUND: Symptoms of neurological decompression incidents (DCS/AGE) can be severe or mild. It is unknown if these differences of symptom presentation represent different clinical entities or if they represent just the spectrum of DCS/AGE. METHODS: 267 cases with DCS/AGE were compared retrospectively and classified into two subgroups, the Type A-DCS/AGE for cases with a severe and often stroke-like symptomatology and the Type B-DCS/AGE for those with milder and sometimes even doubtful neurological symptoms. The main outcome measures were the number of hyperbaric treatments (HTs) needed and the clinical outcome. RESULTS: 42 patients with DCS/AGE were classified as Type A- and 225 patients met the criteria for a Type B-DCS/AGE. Patients with Type A-lesions were more severely affected, needed more hyperbaric treatments and had a less favorable outcome than patients with the Type B-variant. CONCLUSIONS: The Type A- and the Type B-DCS/AGE are likely to be different entities with better clinical outcome in the Type B-variant and possibly significant differences in the underlying pathophysiologies of both variants. Future studies with a particular focus on the up to now inadequately investigated Type B-DCS/AGE are necessary to elucidate such differences in the pathophysiology.

Neuroprotection by oxygen in acute transient focal cerebral ischemia is dose dependent and shows superiority of hyperbaric oxygenation.

The neuroprotective effect of oxygen after acute stroke in rats has been shown previously. However, the question of optimal dosing still remains unanswered. Thus, we investigated the use of oxygen at different concentrations by either normobaric oxygenation (NBO) or hyperbaric oxygenation (HBO) at different pressures in a model of transient ischemia/reperfusion in rats. Animals underwent 90 min of middle cerebral artery occlusion (MCAO) followed by 90 min of reperfusion before oxygen treatment. Oxygen was applied either by NBO (100% O(2); 1.0 absolute atmosphere, ATA) or HBO (100% O(2); 1.5, 2.0, 2.5 or 3.0 ATA) for 1 h. Primary endpoints were infarct volume and clinical outcome measured 24 h and 7 days following the MCAO. A statistically significant and long-lasting reduction in infarct volume was seen in the HBO 2.5 ATA and 3.0 ATA groups over a period of 7 days. The reduced infarct volume was accompanied with a statistically significant improvement in clinical outcome in the high-dose oxygen-treated groups. The presented data indicate that oxygen is a highly neuroprotective molecule in transient focal cerebral ischemia in rats, when applied early and at high doses. The effect is dose dependent and shows a superiority of HBO over NBO, when the primary endpoints infarct volume reduction and clinical outcome are analyzed. These data are important for the development of new acute stroke treatment studies in humans.

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Evaluation of plants used for antimalarial treatment by the Maasai of Kenya.

Semi-structured interviews with three Maasai herbalists led to the identification and collection of 21 species of plants used to treat malaria. Extracts were evaluated using in vitro antimalarial and cytotoxicity assays. Of the species tested, over half were antiplasmodial (IC50<10 microg/ml), and all but one (Gutenbergia cordifolia Benth.) displayed selectivity for the malaria parasite Plasmodium falciparum as indicated by a lack of cytotoxicity (ED50>20 microg/ml) against cultured KB cells. The results of this preliminary investigation support the traditional knowledge of Maasai herbalists and justify ethnomedical inquiry as a promising method, specifically, in antimalarial therapy, to yield leads for drug discovery.

Noninvasive myocardial contractility monitoring with seismocardiography during simulated dives.

OBJECTIVE: To determine if bradycardia during hyperbaric exposure is accompanied by a negative influence on myocardial contractility. METHODS: Accelerometer-based registration of myocardial compression waves with Seismocardiography (SCG) for noninvasive contractility monitoring. Comparative pulmonary artery (PA) catheter study (9 ICU-patients, mean = 67ys) with ejection-fraction (EF) equivalent versus sum of g-values of contraction phase in SCG, and Preload (leg-positioning). Test with monitoring of changes in Contractility Index (ContrI) derived from the SCG-power spectrum (contraction phases, area under curve). Hyperbaric chamber study (0.6MPa dive-simulation) in 14 healthy divers. Quantitative SCG-(ContrI, power spectra) and ECG-recording. RESULTS: Correlation between changes in EF (PA catheter) and in the g-values (SCG) was r(SP) = 0.87 (p < 0.0001). ContrI increased in the leg-positioning test parallel to preload increase, heart rate remained stable. During hyperbaric exposure (0.6MPa) heart rate decrease was highly significant (68 to 58 min(-1); p < 0.001), ContrI and power spectra remained nearly unchanged, SCG registration was noise free. CONCLUSIONS: Hyperoxic bradycardia during simulated dives is not accompanied by impaired contractility measured with SCG, which is concordant to findings with invasive methods in current literature. SCG is suitable for noninvasive and stress free contractility monitoring and patient surveillance in a hyperbaric chamber.

Plastidic (Pho1-type) phosphorylase isoforms in potato (Solanum tuberosum L.) plants: expression analysis and immunochemical characterization.

Higher plants contain two types of phosphorylase (EC 2.4.1.1). One type is plastidic (Phol) and the other resides in the cytosol (Pho2). For Solanum tuberosum L., two highly homologous Pho1-type sequences (designated as Pho1a and Pho1b, respectively) have been described that occur both in a homodimeric, (Pho1a)2, and a heterodimeric, Pho1a-Pho1b, state [U. Sonnewald et al. (1995) Plant Mol Biol 27:567 576; T. Albrecht et al. (1998) Eur J Biochem 251:981-991]. We present a spatial and temporal analysis of the expression patterns of the Pho1-type phosphorylases in S. tuberosum. Expression was analyzed at transcript, protein and activity levels. The specificity of both the probes and the antibodies used was carefully determined to ensure selectivity of detection. For both the Pho1a and Pho1b probes the degree of cross-hybridization was estimated. Peptide scanning identified the epitopes of the anti-Pho 1a and anti-Pho 1b antibodies. Expression of the two Pho1-type genes was analyzed in various organs of the potato plant. In all organs studied the Pho1a transcript levels exceeded those of Pho1b. Furthermore, leaves of a given developmental stage were sampled during the light period and were analyzed for transcript and protein levels and for various carbohydrate pools as well. The data show that in leaves the Pho1a gene expression closely corresponds to starch accumulation, suggesting that the enzyme fulfils a metabolic function within the process of starch biosynthesis. In tubers, Pho1a is constitutively expressed in the parenchyma cells whereas expression of the Pho1b, gene is restricted to cells in close vicinity of the vascular tissue.

Differential expression pattern of the antiapoptotic proteins, Bcl-2 and FLIP, in experimental arthritis.

OBJECTIVE: To examine the relationship between apoptosis and the expression of antiapoptotic proteins in the pathogenesis of experimental inflammatory arthritis. METHODS: Clinical and histologic assessment of adjuvant-induced arthritis (AIA) was performed over a 42-day period. The induction of apoptosis was measured by TUNEL analysis, and the antiapoptotic proteins, Bcl-2 and FLIP, were examined by immunohistochemistry with the use of monospecific antibodies. The percentage of Bcl-2- and FLIP-positive cells was correlated with histologic markers of AIA. RESULTS: Arthritis developed by day 14 following adjuvant injection. Few TUNEL-positive cells were observed between days 0 and 21, indicating that apoptosis did not occur at these time points. An increase in the number of TUNEL-positive cells was observed at day 28, particularly outside sites of cartilage or bone erosion, which dramatically declined by day 35. Immunohistochemical analyses of Bcl-2 and FLIP revealed that the synovium was positive for Bcl-2 and FLIP on day 0. On day 14, Bcl-2 was present at the sites of early erosions and correlated with the erosion and inflammation scores. FLIP was also highly expressed at sites of erosion and was localized to the pannus starting on day 21. Although TUNEL positivity peaked at day 28, a time point in which Bcl-2 and FLIP were present, the areas that displayed intense positivity for expression of Bcl-2 and FLIP were TUNEL negative. In addition, the number of neutrophils in the synovial lining and pannus significantly decreased from day 28 to day 35, suggesting that the cells undergoing apoptosis were neutrophils. Furthermore, at day 42 when TUNEL-positive cells were absent, Bcl-2 expression was diminished, while FLIP remained highly expressed in the pannus. CONCLUSION: The overall percentage of TUNEL-positive cells in the ankle was <1% except on days 28 and 35 post-adjuvant injection, suggesting that in AIA, similar to rheumatoid arthritis, a lack of apoptosis may contribute to disease progression. Furthermore, Bcl-2 and FLIP are temporally and differentially expressed during the pathogenesis of AIA. Inhibition of these molecules may augment synovial apoptosis and ameliorate the disease.

[Psychological status and motivation for psychosocial intervention in patients with allergic disorders]. / Psychisches Befinden und Motivation zu psychosozialen Interventionen bei Patienten mit allergischen Erkrankungen.

The aim of this study was to compare the psychological stress of patients with different forms of immediate type hypersensitivity and urticaria. Moreover, the patients' motivation for different forms of psychological treatment was assessed and an indication for psychosocial support was defined. 228 consecutive inpatients with insect venom allergies (ins), food intolerance (food), drug hypersensitivities (dru) and urticaria (urt) were evaluated by validated questionnaires regarding psychological strain and motivation for psychosocial treatments. Patients with food intolerance and urticaria showed significantly elevated psychological stress and higher motivation for psychosocial support as compared to those with insect venom allergies and drug intolerance. Patient education was the favourite technique for the patients (food 78%, urt 57%, dru 24%, ins 17%), followed by relaxation treatment. The most important predictors for the motivation were the wish for self-responsibility, a feeling of helplessness and social limitations. If strong indication criteria are applied, psychosocial support is indicated in only small subgroups of each patient group. In spite of that, the management of allergic disease should consider the potential need for psychosocial support.