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A Harms

Publications and source records attributed to A Harms.

18 recordsLinked to original sources
PubMed2006

A meta-regression analysis of treatment effect modifiers in trials with flexible-dose oral sildenafil for erectile dysfunction in broad-spectrum populations.

Several trials and reviews provide evidence for the efficacy of phosphodiesterase-5 inhibitors in the treatment of erectile dysfunction (ED). However, little is known about the impact of treatment effect modifiers other than concomitant diseases. Our objective was to identify patient and trial characteristics as well as methodological and publication-related issues that are associated with the treatment effect measured in flexible-dose randomized controlled trials of oral sildenafil for ED. The MEDLINE and the Cochrane Central databases were searched for efficacy trials of sildenafil. Thirteen trials fulfilled all inclusion criteria. A series of meta-regression and graphical analyses were performed to test the impact of possible effect modifiers. Treatment effect was influenced by mean baseline disease severity and mean duration of the disease. These associations were at least partly mediated by placebo response. Trial duration, age of patients and etiology of ED in patients did not have any significant influence on the treatment effect. The year of publication of primary trials was also related to trial findings. Our analysis adds important data to enable the control of confounding variables in future trials and meta-analyses. It might also help the individual to assess the unbiased efficacy and true innovative potential of available and forthcoming pharmacological agents.

Administration, Oral↗
PubMed2001

Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

BACKGROUND & AIMS: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations of both copies of the autoimmune regulator (AIRE) gene. It is characterized by susceptibility to mucocutaneous candidiasis and multiple autoimmune lesions. A serious disease component is hepatitis. To identify diagnostic autoantibodies for APECED hepatitis, sera from 64 patients with APECED were screened for autoantibodies established in the diagnosis of idiopathic autoimmune hepatitis, and for autoantibodies against 10 cytochrome P450s. METHODS: Screening methods were indirect immunofluorescence, Western blot, Ouchterlony gel diffusion, enzyme-linked immunosorbent assay, and immunoprecipitation. RESULTS: Anti-liver microsomal antibodies were detected in 50% of the patients with APECED hepatitis and 11% of those without hepatitis. Prevalences of antinuclear, smooth muscle, anti-liver cytosol, anti-soluble liver protein/liver pancreas, and anti-CYP2D6 autoantibodies were 9%, 6%, 3%, 0%, and 0%, respectively. CYP1A1, CYP2B6, CYP1A2, and CYP2A6 were identified as autoantigens. Thirty percent of patients with anti-CYP2A6 and 100% of patients with anti-CYP1A2 were affected by hepatitis. Despite the high specificity of anti-CYP1A2 for APECED hepatitis, its sensitivity was low (50%). Anti-CYP2A6 and anti-CYP1A2 were not detected in patients with autoimmune hepatitis (N = 68) or nonhepatitic controls (N = 81). CONCLUSIONS: Anti-CYP1A2 is a highly specific but insensitive marker for APECED hepatitis. No clinical correlation was observed for anti-CYP2A6. Autoimmune hepatitis and APECED hepatitis are characterized by different molecular targets of autoantibodies with no overlap.

Adolescent↗
PubMed2001

Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1.

The mechanisms driving the immune-mediated destruction of hepatic tissues in autoimmune hepatitis (AIH) are unknown. Recently the autoimmune regulator (AIRE), a gene associated with the development of the autoimmune polyglandular syndrome type 1 (APS-1), was cloned. About 15% to 20% of APS-1 patients develop hepatitis. However, the role of AIRE mutations in AIH, primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC) is not known. To address this issue patients with AIH (n = 94), PSC (n = 60), and PBC (n = 30) were analyzed for the presence of mutations in exons 6, 8, and 10 of AIRE by single stranded conformation polymorphism and sequence analysis. Autoantibody patterns of patients with defects in AIRE were analyzed by indirect immunofluorescence, enzyme-linked immunosorbent assay and Western blot. Heterozygous mutations of AIRE were identified in 3 patients: a patient with PBC and a patient with AIH type 1 carried a R257X mutation, and a patient with AIH type 2, diabetes mellitus type 1 (IDDM), thyroid disease, and atrophic gastritis carried a G305S mutation in the first PHD ring finger domain of the AIRE protein. None of the 3 patients with a defective AIRE allele showed autoantibodies, which are known to associate with APS-1. These findings show a differential genetic association of autoimmune liver diseases and hepatitis in APS-1. The subgroup of patients with heterozygous mutations in AIRE does not represent patients with an incomplete APS-1 syndrome. However, the Aire gene defect showed that genes involved in the induction of immunologic tolerance provide candidates for etiologic factors in autoimmune liver diseases.

Adolescent↗
PubMed2001

Acute immune thrombocytopenia (ITP) in childhood: retrospective and prospective survey in Germany.

Treatment of acute childhood immune thrombocytopenia (ITP) is controversial. For information on the present situation in Germany, a retrospective and a prospective survey were carried out. In the retrospective survey, questionnaires were sent to all German pediatric hospitals asking about local policies for handling ITP and whether in the preceding year (starting on October 1995) death or ICH had occurred; 86% answered. In the prospective survey, 94% responded to the mailings ("have you seen a case of ITP?") sent in monthly intervals between October 1, 1996 and September 30, 1997; 89% of the questionnaires were retrieved. In the retrospective survey, no deaths and no ICH were reported. If only mild bleedings, such as skin bleeds alone (or additional mild mucous membrane bleeding) were present, 20.5% (26.4%) preferred the "watchful waiting" regimen (supportive care), irrespective of the platelet count; 79.5% (73.6%) would treat if the platelet counts were <5 x 10(9)/L, 73.5% (67.9%) if < 10, 35.9% (33.6%) if < 20, and 4.2% (2.6%) if <30. Of the treaters, 50.5% would prefer immunoglobulins (Ig), 24.4% glucocorticosteroids (GC), and 20.5% GC and/or Ig. Generally, a rise in platelets, most frequently >50 x 10(9)/L was considered as therapeutic success. In the prospective survey, from the reported 323 children an annual incidence of 2.16 per 100,000 children was calculated. The incidence depended on age and gender, being highest for boys younger than 2 years with 5.8 (girls 3.42) and low with 0.44 for boys (girls 0.89) older than l4 years. About 60% of the patients had a preceding infection. Although 83% had a platelet count <20 x 10(9)/L (56% <10 x 10(9)/L), almost all (97.5%) had only mild bleeding symptoms; 2.5% had serious bleeding symptoms requiring blood transfusion or nasal packing, none had ICH, and no death was reported. The mean platelet count on admission was 11.348 (lowest count 8.253) x 10(9)/L. Sixty-one percent received Ig, 19% GC (both either alone or as first choice), 6% Ig plus GC, and 14% no treatment. Side effects were reported in 22% of the children treated with Ig. The retrospective survey mirrored the uncertainty in regard to treatment. The prospective survey provided new aspects on incidence, age, and gender distribution. Although almost all patients had only mild bleeding symptoms, most received Ig and/or GC. The decision to treat depended mainly on the platelet count. From these surveys, conclusions about the effectiveness of treatment cannot be drawn. Recommendations based primarily on platelet counts must be reconsidered.

Acute Disease↗
PubMed2000

Mass spectrometric resolution of reversible protein phosphorylation in photosynthetic membranes of Arabidopsis thaliana.

The use of mass spectrometry to characterize the phosphorylome, i.e. the constituents of the proteome that become phosphorylated, was demonstrated using the reversible phosphorylation of chloroplast thylakoid proteins as an example. From the analysis of tryptic peptides released from the surface of Arabidopsis thylakoids, the principal phosphoproteins were identified by matrix-assisted laser desorption/ionization and electrospray ionization mass spectrometry. These studies revealed that the D1, D2, and CP43 proteins of the photosystem II core are phosphorylated at their N-terminal threonines (Thr), the peripheral PsbH protein is phosphorylated at Thr-2, and the mature light-harvesting polypeptides LCHII are phosphorylated at Thr-3. In addition, a doubly phosphorylated form of PsbH modified at both Thr-2 and Thr-4 was detected. By comparing the levels of phospho- and nonphosphopeptides, the in vivo phosphorylation states of these proteins were analyzed under different physiological conditions. None of these thylakoid proteins were completely phosphorylated in the steady state conditions of continuous light or completely dephosphorylated after a long dark adaptation. However, rapid reversible hyperphosphorylation of PsbH at Thr-4 in response to growth in light/dark transitions and a pronounced specific dephosphorylation of the D1, D2, and CP43 proteins during heat shock was detected. Collectively, our data indicate that changes in the phosphorylation of photosynthetic proteins are more rapid during heat stress than during normal light/dark transitions. These mass spectrometry methods offer a new approach to assess the stoichiometry of in vivo protein phosphorylation in complex samples.

Arabidopsis↗
PubMed2000

Distribution and inducibility by 3-methylcholanthrene of family 1 UDP-glucuronosyltransferases in the rat gastrointestinal tract.

UDP-Glucuronosyltransferases (UGT) catalyze the glucuronidation of a broad spectrum of endobiotic and xenobiotic substrates. The resulting glucuronides are more hydrophilic, facilitating renal and biliary excretion. Apart from hepatic glucuronidation, high rates of gastrointestinal glucuronidation have been observed. The aim of this study was to characterize the expression of family 1 UGTs (UGT1A) in liver, kidney, and all parts of the rat gastrointestinal tract by reverse transcription polymerase reaction (RT-PCR), Northern blot, and xenobiotic induction experiments. RT-PCR experiments were performed with primers specific for all known rat UGT1A mRNAs. UGT1A1, UGT1A6, and UGT1A7 were expressed in liver, kidney, and the gastrointestinal tract. UGT1A5 transcripts were detected in liver, but not in kidney or gastrointestinal tissue. In contrast, UGT1A2 and UGT1A3 were not expressed in liver or kidney, but were detected in intestine. Low levels of UGT1A3 were detectable in duodenum and jejunum. UGT1A2 was abundantly expressed in the small intestine; expression levels in the stomach and the large intestine were low. Quantitative evaluation of RNA levels by Northern blot revealed expression in gradients, with highest UGT1A mRNA levels in duodenum and decreasing levels in the small and large intestine. Only UGT1A6 was expressed at high levels in the rectum. Rats treated with 3-methylcholanthrene (3-MC) displayed a 10-fold induction of hepatic UGT1A6 and UGT1A7 mRNAs. In gastric tissues and in intestine, induction was 4-fold and 2-fold, respectively. In contrast to the constitutive expression of UGT1A7 in kidney, UGT1A6 was inducible in the liver. Effects of 3-MC on UGT1A1 expression revealed downregulation in the liver and highly variable effects in duodenum and stomach. This study demonstrates tissue-specific expression and tissue-specific induction patterns in rat liver, kidney, and gastrointestinal tract, which may represent the physiological basis of tissue-specific glucuronidation in rats.

Animals↗
PubMed2000

[Reliability of basic geriatric assessment].

This study investigates the Geriatric Basis Assessment (GBA) in terms of its reliability. Data from 1037 patients were collected. The reliability was estimated relating to the lambda 2 coefficient. It is necessary to define the items in different categories: the first variable means valuation 1 of each item and not 2, 3, 4; the second variable means valuation 1, 2 against 3, 4; the third variable means the valuation 1, 2, 3 and not 4. The table shows only little difference concerning the lambda 2 coefficients. In conclusion, 80% of the variability of the GBA items can be explained by differences in the patients themselves, while 20% is due to the inaccurate assessment system. For 343 patients, data for both Barthel index and GBA were available. As presumed, correlations between Barthel and connected GBA items were observed. However, the correlations were too weak to predict the Barthel scores from the corresponding GBA item accurately enough. The Barthel index appears to include similar, but not exactly the same aspects as the GBA. The reliability of the Barthel index (lambda 2 = 0.89 for the first variable) is slightly higher compared to the GBA but it is not suitable as a criterion of validity. Both the validity of the GBA and the Barthel index can not be determined lacking an external measure. As an example, a suitable criterion of validity could be the reintegration into the familiar surroundings preceding the hospital stay. When developing the GBA, it was not assumed that geriatric patients could be correctly diagnosed on the basis of an overall score alone or to allocate them to adequate care using that score as a sole indicator. Crucial for these purposes is the test profile as a whole, including the impairments, disabilities handicaps, and last but not least the diseases of the individual patient. Furthermore, the depiction of the GBA profile at admission and discharge allows one to identify those items, on which therapy has a significant influence and those which remain more or less stable. As presumed, items with minor initial deficits (e.g., motivation, eyesight, hearing, depression, capability of verbal expression, situative adaptability, understanding) showed only small differences between admission and discharge. On the other hand, items strongly influenced by geriatric treatment were, e.g., mobility (walking, transfer), functions of internal medicine, and domestic care. Prognostically significant are those items which are crucial for reintegration and describe a deficiency but cannot be altered reliably. Such items are the person, to whom the patient relates most closely, situative adaptability, motivation, orientation, capability of verbal expression, and possibly depression. All of these parameters are more difficult to influence than the activities of daily living assessed by the Barthel index. Further investigations should clarify whether the GBA can be a reliable tool for allocating a patient to adequate care. However, the requirement for such a criterion of validity is that this allocation is truly optimal for the patient.

Activities of Daily Living↗
PubMed2000

Development of a 5-hydroxytryptamine(2A) receptor binding assay for high throughput screening using 96-well microfilter plates.

A high throughput screening method for the analysis of 5-hydroxytryptamine(2A) (5-HT(2A)) receptor binding parameters has been developed, using 96-well filter plates of the Millipore MultiScreen system in combination with a MicroBeta PLUS microplate scintillation counter. MAFB filter plates (GF/B filter over a Durapore membrane) were used because of the lower nonspecific binding of the radioligand to GF/B filter material than to GF/C filters. Comparing different scintillation cocktails, highest counting efficiency and shortest equilibration time were detected with Betaplatescint, after drying the plates at 50 degrees C for 2 h. Measuring the plates without the plastic underdrain increased the counting efficiency by about 39% as compared with counting the plate with the underdrain intact. Presoaking the wells with 0.5% polyethyleneimine for 2 h reduced the nonspecific binding to the filter material by about 50%. A linear relationship of protein concentration and radioligand binding was established up to a protein concentration of 165 microg of protein/well. In the assays, 70 microg of protein/well was generally used, which has turned out to be favorable with respect to the number of counts obtained. When a higher concentration of protein was used, the period of time needed to aspirate the plate was too long because of obstruction of the filter material. Receptor-radioligand equilibration was reached after about 20 min at concentrations less than 0.05 nM [(3)H]ketanserin-HCl; at higher concentrations it was reached after about 10 min. Saturation analysis of [(3)H]ketanserin-HCl resulted in a mean B(max) of 393 fmol/mg protein and a K(D) of 2.0 nM using rat frontal cortex as a receptor source. Competition experiments with known 5-HT(2A) receptor ligands-DOB-HCl (K(i) = 59 nM), DOET-HCl (K(i) = 137 nM), DOM-HCl (K(i) = 533 nM), DMT (K(i) = 1,985 nM), and TMA-HCl (K(i) = 22,340 nM)-were in accordance with literature values.

Animals↗
PubMed1990

Calcium channel blockers for kidney protection.

Acute postischemic renal failure (ARF) is a major complication in surgery and in particular in renal transplantation. Calcium channel blockers (CCBs) are able to prevent or ameliorate ARF in different experimental models when given before ischemic injury. Because ARF, which is observed in 20-60% of graft recipients, carries the risk of undetected rejections and nephrotoxic injury and is also expensive, we tested the hypothesis, suggested by animal experiments, that there is also a beneficial effect of CCBs when given after ischemic injury. A total of 134 recipients of first or second cadaver grafts were randomly assigned to a diltiazem pretreatment (DZ) or control (C) group. Kidney grafts were pretreated immediately prior to transplantation by reperfusion with 500 ml Euro-Collins (preservation fluid), with or without DZ. The DZ patients also received a 74-h infusion of DZ (0.12 mg/kg/h), starting 2 h prior to surgery. DZ was continued (90 mg b.i.d. p.o.) until day 30. Immunosuppression consisted of low-dose steroids and cyclosporine A (CSA) (10 mg/kg p.o.). CSA was instituted 6 h after surgery and later adjusted to achieve whole-blood trough levels of 300-600 ng/ml [by polyclonal radioimmunoassay (RIA)]. A total of 129 patients were available for efficacy analysis. There were no significant differences concerning donor demographics, human lymphocyte antigen (HLA) match, or ischemic times. ARF was defined as a need for dialysis in the first week. Our data show a significant reduction in ARF in grafts pretreated with DZ.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1978

Determination of the position of electroimmune precipitates of antigen--antibody systems on their respective quantitative precipitation curves.

Using corresponding monospecific antisera from the rabbit, the precipitation curves for albumin, alpha-1-antitrypsin, haptoglobin 1-1 and fibrinogen were produced. In parallel, four different dilutions of these antigens were examined by line immmunoelectrophoresis, employing the same antisera. The distance of the resulting line immune precipitates from the start served to calculate the amount of antigen-antiserum reacting with each other. After converting these values to the amount of antiserum used for producing the precipitation curves, the 'line antigen/antibody ratios' were drawn into the appropriate precipitation curves. All electroimmune precipitates (in this case, the 'line immune precipitates') were found to be located on the side of antigen excess of their corresponding precipitation curve.

Animals↗
PubMed1975

Electrophoretic separation of serum proteins on cellulose acetate followed by electrophoresis in antibody - containing agarose gel.

A modification of the crossed immunoelectrophoresis of serum proteins is described in which the first step is carried out on cellulose acetate membranes and the second in antibody-containing agarose gel. The use of a special chamber allows reproducible conditions. The cellulose acetate membranes with the protein fractions separated in the first step can, if desired, be stored at minus 20 degrees C until further use. The technique of reversed intermediate gel has been worked out and employed for the identification of the Laurell peaks and their localization in the pherogram. Crossed immunoelectrophoresis with cellulose acetate and agarose is simple, provides reproducible results and requires no apparatus other than a special gel chamber.

Antibodies↗
PubMedDate not supplied

Persistent mechanical allodynia following injury of the hand. Treatment through mobilization of the nervous system.

Mechanical allodynia (MA) following hand injury is a well-documented clinical problem. The purpose of this pilot study was to examine the relationship between hand MA and the upper limb tension test (ULTT). The ULTT mechanically stresses the neural structures from the C5/6/7 neural foramina to the median nerve distally. This study examined 29 subjects with unilateral hand MA before and after a 2-week neural self-mobilization programme. There was a significant difference between the subjects' affected and unaffected sides when tested using the ULTT, both in reproduction of symptoms and in reduced range of motion of the ULTT. Following the self-mobilization program, there was an improvement in the range of the ULTT, and subjects reported a reduction in their symptoms. Complete recovery was not obtained in all cases. The results of this study suggest that the ULTT is a useful tool both in assessment and treatment of subjects with hand MA.

Adult↗
PubMedDate not supplied

Efficacy of PDE-5-inhibitors for erectile dysfunction. A comparative meta-analysis of fixed-dose regimen randomized controlled trials administering the International Index of Erectile Function in broad-spectrum populations.

This meta-analytic study aims to estimate the likely improvements of erectile dysfunction (ED) measured by the International Index of Erectile Function (IIEF) at the highest fixed dosages of the three available PDE-5-inhibitors: sildenafil, tadalafil, and vardenafil. MEDLINE and the Cochrane Library were searched electronically for efficacy trials of PDE-5-inhibitors for treating ED. In addition drug manufacturers were contacted to provide unpublished or unrecorded congress proceedings. Randomized, double-blind, placebo-controlled, parallel-group, maximum fixed-dose, broad-spectrum efficacy trials using IIEF were included in the analysis. Data were independently extracted by two reviewers. The results were pooled using weighted mean differences. A formal indirect comparison (including Bonferroni-correction) was conducted to estimate the differences between agents. A total of 14 trials were included in the meta-analysis (three with 100 mg sildenafil, eight with 20-25 mg tadalafil, and three with 20 mg vardenafil). All trials were of good methodological quality. Overall heterogeneity was moderate: I(2)=33.2%, chi(2)=19.47, P=0.11. The funnel plot suggested moderate likelihood of publication bias. Pooled results of IIEF-improvement were for sildenafil 9.65 (95% CI: 8.50, 10.79) points, tadalafil 8.52 (7.61, 9.42) points, and vardenafil 7.50 (6.50, 8.50) points, respectively. Sildenafil proved to be significantly more effective than vardenafil (d=2.15, P=0.006), other pairwise comparisons showed no difference in efficacy. All PDE-5-inhibitors are highly effective in the treatment of ED. At maximum dosage they improve erectile function 7-10 points on the IIEF compared to placebo-treatment. There is evidence that sildenafil might be more efficacious than vardenafil, although this is to be interpreted with caution. To prove higher efficacy truly independent comparative trials are needed.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMedDate not supplied

Beet-vinasse (condensed molasses solubles) as an ingredient in diets for cattle and pigs - nutritive value and limitations.

Sugar beet vinasse, originating as the condensed molasses residue from yeast production, was fed to bulls and pigs to determine the feed value. It contained, per kg dry matter (DM content 66.8%), 293 g crude protein, 305 g N-free extract (therefrom 34.4 g total sugar), and 395 g crude ash. The experiment was carried out with three fattening bulls (German Holstein) and four adult pigs (Gottingen Minipig). In bulls, two balance trials lasting 20 days each (10 days adaptation; 10 days collection) were conducted in which subsequently a basal ration without and with vinasse (14% in DM) was fed. In pigs, the experiment consisted of three 12-day balance trials with the final 5 days as collection period. In the first trial, pigs received a basal diet without vinasse and in the following, a mixed diet with 16 and 43% vinasse (in DM) respectively. Digestibilities of components in vinasse in bulls were: organic matter 73.5%, crude protein 72.6%, and N-free extract 52.3%. In bulls, no influence on faeces quality could be detected while feeding 14% vinasse in DM. While feeding 16% vinasse in DM to pigs, the digestibility of organic matter amounted to 72.3% (crude protein 71.8%; NfE 74.6%). Feeding higher amounts of vinasse (43% in DM) in the diet of pigs, digestibilities were reduced (organic matter: 61.6%), which might be a result of a reduced retention time of the chyme as a result of an osmotically driven diarrhoea because of unexpectedly high sulphate (136 g/kg DM) content in the vinasse. It is concluded that because of organic matter digestibility >70% for cattle and pigs, the use of vinasse in these species in small proportions is reasonable.

Animal Feed↗