High-dimensional versus conventional propensity scores in a comparative effectiveness study of coxibs and reduced upper gastrointestinal complications.

PURPOSE: High-dimensional propensity score (hd-PS) adjustment has been proposed as a tool to improve control for confounding in pharmacoepidemiological studies using longitudinal claims databases. We investigated whether hd-PS matching improved confounding by indication in a study of Cox-2 inhibitors (coxibs) and traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and their association with the risk of upper gastrointestinal complications (UGIC). METHODS: In a cohort study of new users of coxibs and tNSAIDs we compared the effectiveness of these drugs to reduce UGIC using hd-PS matching and conventional propensity score (PS) matching in the German Pharmacoepidemiological Research Database. RESULTS: The unadjusted rate ratio (RR) of UGIC for coxib users versus tNSAID users was 1.21 [95 % confidence interval (CI) 0.91-1.61]. The conventional PS matched cohort based on 79 investigator-identified covariates resulted in a RR of 0.84 (0.56-1.26). The use of the hd-PS algorithm based on 900 empirical covariates further decreased the RR to 0.62 (0.43-0.91). CONCLUSIONS: A comparison of hd-PS matching versus conventional PS matching resulted in improved point estimates for studying an intended treatment effect of coxibs versus tNSAIDs when benchmarked against results from randomized controlled trials.

Histological, hormonal and biomolecular analysis of the pathogenesis of ovine Prolapsus vaginae ante partum.

The objectives of the present study were to evaluate the hormonal profiles, histology of the vagina and biomolecular analysis of connective tissue of ewes with and without vaginal prolapse. Blood samples from the jugular vein and biopsies of the vaginal tissue were taken from five late term pregnant, unaffected animals, four sheep during parturition and six ewes suffering from vaginal prolapse ante partum. The blood samples were submitted for determining the concentration of the steroid hormones progesterone by automatic luminescence immunoassay and estradiol-17ß by the sequence test. Investigations in the mRNA-expression including the estimation of the transcript levels of the α(2)-chain of collagen I, the collagenolytic metalloproteinase 1 (MMP 1), the tissue inhibitor of MMP 1 (TIMP 1) and the estrogen receptor α were carried out by using semiquantitative reverse transcription-PCR. Additionally, the histology of the vaginal wall of ewes with and without vaginal prolapse and animals intra partum was assessed. Because of a right-skewed distribution, data were logarithmised and described using the geometric mean (xg) and the dispersion factor (DF). The average progesterone concentration of affected ewes (xg = 19.35 ng/ml, DF 1.33) was above those of control animals ante (xg = 10.44 ng/ml, DF 1.58) and intra partum (xg = 9.24 ng/ml, DF 1.92). Compared to the pregnant control group (xg = 20.13 pg/ml, DF 1.49) the plasma levels of 17ß-estradiol in animals suffering from ante partum vaginal prolapse (xg = 27.81 pg/ml, DF 1.56) appeared to be slightly increased, but the difference was without statistical significance. The analysis of mRNA expression revealed a difference in the ante partum collagen metabolism in affected sheep. In prolapsed tissue the α2-chain of collagen I showed a decreased expression level in relation to the control animals in late-term pregnancy (P < 0.01). The average mRNA synthesis of MMP 1 or TIMP 1 in affected ewes was higher or lower, respectively, than the synthesis in healthy, late-term pregnant sheep. Significant differences were not observed. The production of transcripts of the estrogen receptor α was significantly decreased within the group of affected sheep compared to the unaffected pregnant ewes. Histological assessment showed that oedema was only detected in the subepithelial zone of the vaginal wall of intra partum sheep. There was no evidence for an inflammation of the prolapsed vaginal tissue since infiltration of leucocytes was present in all samples equally. The thickest vaginal epithelium due to hyperplasia of the epithelial cells was observed in sheep suffering from ante partum vaginal prolapse (xg = 83.95 µm, DF 1.21). This difference was statistically significant between the ante (xg = 31.12 µm, DF 1.22) and intra partum groups (xg = 33.27 µm, DF 1.24). Peripheral concentrations of progesterone and estradiol-17ß seem to have no influence on the occurrence of vaginal prolapse in ewes. Regarding histology of the vaginal wall in combination with the expression of local estrogen receptors, it was determined that there is neither a pronounced oedema nor an overexpression of the estrogen receptor α in affected animals, which means that no local estrogenic effect provokes the prolapse of vaginal tissue. The biomolecular analysis led to the new result, that ewes suffering from vaginal prolapse show alterations in the antepartal metabolism of vaginal connective tissue.

[Studies on the recovery of pharmaceutical drug substances from surfaces made of defined stainless-steel alloys]. / Wiederfindungsuntersuchungen von Arzneistoffen an definierten Edelstahloberflächen.

Facilities for the manufacturing of pharmaceutical drug substances on the pilot-plant and the industrial scale as well as chemical reactors and vessels used for chemical work-up mainly consist of alloyed stainless steel. The influence of the alloy composition and the surface condition, i.e. of the roughness of the stainless-steel materials, on the adsorption of structurally diverse steroidal substances and, hence, on the quality of the products was studied. In general, stainless-steel alloys with smooth, not so rough surfaces are to be favored as reactor material. However, it was demonstrated in this study that, on account of the weak interaction between active substances and steel materials, mechanically polished materials of a medium roughness up to approx. 0.4 microm can be employed instead of the considerably more cost-intensive electrochemically polished stainless-steel surfaces. The type of surface finishing up to a defined roughness, then, has no influence on the quality of these pharmaceutical products. Substances that, because of their molecular structure, can function as "anions" in the presence of polar solvents, are adsorbed on very smooth surfaces prepared by electrochemical methods, forming an amorphous surface film. For substances with this structural characteristics, the lower-cost mechanically polished reactor materials of a medium roughness up to approx. 0.5 microm should be used exclusively.

[Results of surgery for congenital Brown's syndrome]. / Operationsergebnisse bei kongenitalem Brown-Syndrom.

BACKGROUND: There are various surgical procedures for the treatment of congenital ("true") Brown's syndrome. We have evaluated the effects of a superior oblique tendon recession. PATIENTS AND METHODS: In a retrospective study, we evaluated the files of 22 patients who received surgery for congenital Brown's syndrome in our department. A recession of the superior oblique tendon was performed, when there was a hypotropia in primary position with an abnormal head posture and a significant elevation deficit in adduction, and when these findings did not improve spontaneously. The squint angles (alternate prism and cover test), the monocular motility and the abnormal head posture at distance fixation were assessed. The measurements were performed 1 day before and 3 months after surgery. Thirteen patients were examined 2 - 10 years after surgery. RESULTS: At the time of surgery, the patients were 4 - 17 years old (median 7 years), 13 were male, in 15 patients, the right eye was concerned. Eight patients had an additional esotropia, one patient was exotropic. The vertical deviation in straight gaze was 0 - 12 deg (median 7 deg). The elevation of the eye was restricted to - 10 deg (below horizontal) to 15 deg (median 0 deg) in adduction and to 10 - 35 deg (median 25 deg) in abduction. Sixteen patients had an abnormal head posture. The superior oblique tendon was recessed by 10 mm, in some patients with an additional loop (6x0 polyester). Nine patients received simultaneous surgery for their eso/exotropia. At the end of the operation, the elevation of the eye in adduction (forced duction test) was free. Three months postoperatively, the vertical deviation was 0 - 6 deg (median 1 deg). Twelve patients did not show any abnormal head posture. Inspite of free passive motility, the monocular elevation in adduction was only slightly improved to - 5 to 15 deg (median 5 deg). At the late control, the hypotropia (0 - 4 deg, median 0 deg) and the elevation in adduction (5 - 35 deg, median 15 deg) were significantly improved. CONCLUSION: The recession of the superior oblique tendon is an effective and safe surgical procedure for congenital Brown's syndrome. The efficiency of the procedure is individually variable. Presumably, this variability was caused by the heterogenous etiology of Brown's syndrome rather than by surgical technique. The hypotropia and the abnormal head posture were reduced immediately after surgery, while the delayed improvement of active elevation in adduction often remained incomplete. Postoperative forced upgaze training may be beneficial.

[Dissociated near reflex and accommodative convergence excess]. / Dissoziierte Naheinstellungs- trias mit akkommodativem Konvergenzexzess.

We report on an 8-year-old boy whose near reflex could be elicited exclusively when the left eye was fixing (LF) but not when the right eye was fixing (RF). With RE +1.25/-1.25/169 degrees and LE +1.0/-0.75/24 degrees, the visual acuity was 1.0 OU at 5 m and RE 0.5, LE 1.0 at 0.3 m improving to 1.0 OU by a near addition of 3.0 D. Stereopsis was 100 degrees (Titmus test). The prism and cover test revealed an esophoria of 4 degrees at 5 m. At 3 m there was an esophoria of 6 degrees (RF) and an esotropia of 28 degrees (LF), compensating to an esophoria of 3 degrees (RF/LF) with a near addition of 3.0 D. Accommodation and the pupillary near reaction (OU) were hardly elicitable during RF. During LF, retinoscopy revealed an accommodation of 8 D (OU) and the pupils constricted normally. Correction by bifocal glasses yielded orthotropia with random dot stereopsis at near.

Epilepsy surgery in children with focal cortical dysplasia (FCD): results of long-term seizure outcome.

The purpose of this study was to assess the effect of epilepsy surgery on seizure outcome in children and adolescents under 18 years with intractable epilepsy due to focal cortical dysplasia. We analysed clinical data, such as age at seizure onset, epilepsy course, localisation of focus from presurgical evaluation, MRI, tissue pathology and seizure outcome in 68 patients 6 months to 9 years after epilepsy surgery. Seizure outcome was classified according to the Engel classification. Mean age at seizure onset was 7 months, ranging from the first days of life to 7 years. All patients had medically intractable epilepsy. Localisation of the lesion was predominantly extratemporal: posterior (uni- or multilobar) 43 %, frontal without central region 26 %, multilobar involving central area 19 % and temporal in 12 %. MRI signs typically seen in cortical dysplasia (FCD) such as localised blurring of gray-white matter junction was found in 68 %, dysgyria in 62 %, thickening of the cortical ribbon in 46 % and T2 signal elongation of the subcortical white matter in 40 % of the patients' MRI. Age at surgery ranged from 5 months to 16 years; 14 patients were under 2 years when operated on. In 34 patients (6 patients under 3 years) subdural grid electrode evaluation was performed prior to surgery. Pathology revealed focal cortical dysplasia without balloon cells (type I) in 60 %, FCD of the balloon cell subtype (type II) in 40 % of the specimens. Postoperative complications were subdural hygroma in 5 and an increased motor deficit in 2 patients. Up to two years after epilepsy surgery 50 % of the children were seizure free (Engel class I), 10 % Engel class II, 33 % Engel class III and 7 % unchanged (Engel class IV). Long-term seizure outcome (> 3 years post surgery) in 32 patients showed similar results (class I 50 %, class II 19 %, class III 28 %, class IV 3 %). Complete resection of the dysplastic lesion was significantly correlated with favorable seizure outcome, whereas seizure outcome was not significantly different in patients with mild (type I) or balloon cell (type II) FCD. Children operated after 6 years of age had no better outcome than children operated in infancy or at preschool age. Epilepsy surgery resulted in good (class I and II) seizure control in 60 % of children with intractable epilepsy due to focal cortical dysplasia.

Effects of in vivo nitroglycerin treatment on activity and expression of the guanylyl cyclase and cGMP-dependent protein kinase and their downstream target vasodilator-stimulated phosphoprotein in aorta.

BACKGROUND: Chronic in vivo treatment with nitroglycerin (NTG) induces tolerance to nitrates and cross-tolerance to nitrovasodilators and endothelium-derived nitric oxide (NO). We previously identified increased vascular superoxide formation and reduced NO bioavailability as one causal mechanism. It is still controversial whether intracellular downstream signaling to nitrovasodilator-derived NO is affected as well. METHODS AND RESULTS: We therefore studied the effects of 3-day NTG treatment of rats and rabbits on activity and expression of the immediate NO target soluble guanylyl cyclase (sGC) and on the cGMP-activated protein kinase I (cGK-I). Tolerance was induced either by chronic NTG infusion via osmotic minipumps (rats) or by NTG patches (rabbits). Western blot analysis, semiquantitative reverse transcription-polymerase chain reaction, and Northern blot analysis revealed significant and comparable increases in the expression of sGC alpha(1) and beta(1) subunit protein and mRNA. Studies with the oxidative fluorescent dye hydroethidine revealed an increase in superoxide in the endothelium and smooth muscle. Stimulation with NADH increased superoxide signals in both layers. Although cGK-I expression in response to low-dose NTG was not changed, a strong reduction in vasodilator-stimulated phosphoprotein (VASP) serine239 phosphorylation (specific substrate of cGK-I) was observed in tolerant tissue from rats and rabbits. Concomitant in vivo and in vitro treatment with vitamin C improved tolerance, reduced oxidative stress, and improved P-VASP. CONCLUSIONS: We therefore conclude that increased expression of sGC in the setting of tolerance reflects a chronic inhibition rather than an induction of the sGC-cGK-I pathway and may be mediated at least in part by increased vascular superoxide.

Aging and chronic hypertension decrease expression of rat aortic soluble guanylyl cyclase.

We analyzed the influence of aging and genetic hypertension on the function and expression of soluble guanylyl cyclase (sGC) in the aortas of prehypertensive and old spontaneously hypertensive rats (SHR) as well as in age-matched normotensive Wistar-Kyoto rats (WKY). The expression of heterodimeric sGC (alpha(1) and beta(1)) was assessed at the mRNA and protein level, and its function was assessed by the relaxant responses of phenylephrine-contracted endothelium-denuded aortic rings to the nitric oxide (NO) donor sodium nitroprusside. The vasodilator potency of sodium nitroprusside was significantly reduced (P<0.05) with age (3- to 6-fold increase in the EC(50) in old WKY and SHR compared with their young counterparts) as well as with hypertension (3-fold increase in old SHR compared with age-matched WKY), whereas the vasodilator potency of sodium nitroprusside did not differ between young SHR and WKY. A similar influence of aging and hypertension on NO-stimulated GC activity was revealed at the GC expression level: Whereas the beta(1) protein content was similar in young rats of both strains, old WKY exhibited 60% lower and old SHR exhibited 80% lower beta(1) subunit protein compared with young rats (P<0.05). Moreover, the abundance of alpha(1) and beta(1) mRNA (assessed by reverse transcriptase-polymerase chain reaction) was similar in young rats but was 2.5-fold (alpha(1)) and 4.3-fold (beta(1)) lower in old SHR compared with old WKY. In conclusion, our findings show that both aging and hypertension decrease sGC expression and its NO-dependent activation in aortic tissue. Downregulation of sGC may therefore contribute to arterial dysfunction in senescence and chronic hypertension.

Control of proven pulmonary and suspected CNS aspergillus infection with itraconazole in a patient with chronic granulomatous disease.

An 11-year-old boy with chronic granulomatous disease caused by cytochrome b deficiency developed right upper lung lobe aspergillosis. Intracerebral lesions developed on maximum doses of flucytosine and amphotericin B. Treatment with 16 mg/kg oral itraconazole was followed by a dramatic clinical improvement and almost complete disappearance of the intracerebral lesions. Plasma itraconazole levels were between 40 and 3440 ng/ml depending on concomitant medication. Toxicity was restricted to transient elevation of alkaline phosphatase and gamma glutamyl transferase. We conclude that further trials with itraconazole are justified in high risk patients in whom conventional therapy has failed.

Contraluminal p-aminohippurate transport in the proximal tubule of the rat kidney. VII. Specificity: cyclic nucleotides, eicosanoids.

Using the stop-flow peritubular capillary microperfusion method the inhibitory potency (apparent Ki values) of cyclic nucleotides and prostanoids against contraluminal p-aminohippurate (PAH), dicarboxylate and sulphate transport was evaluated. Conversely the contraluminal transport rate of labelled cAMP, cGMP, prostaglandin E2, and prostaglandin D2 was measured and the inhibition by different substrates was tested. Cyclic AMP and its 8-bromo and dibutyryl analogues inhibited contraluminal PAH transport with an app. Ki,PAH of 3.4, 0.63 and 0.52 mmol/l. The respective app. Ki,PAH values of cGMP and its analogues are with 0.27, 0.04 and 0.05 mmol/l, considerably lower. None of the cyclic nucleotides tested interacted with contraluminal dicarboxylate, sulphate and N1-methylnicotinamide transport. ATP, ADP, AMP, adenosine and adenine as well as GTP, GDP, GMP, guanosine and guanine did not inhibit PAH transport while most of the phosphodiesterase inhibitors tested did. Time-dependent contraluminal uptake of [3H]cAMP and [3H]cGMP was measured at different starting concentrations and showed facilitated diffusion kinetics with the following parameters for cAMP: Km = 1.5 mmol/l, Jmax = 0.34 pmol S-1 cm-1, r (extracellular/intracellular amount at steady state) = 0.91; for cGMP: Km = 0.29 mmol/l, Jmax = 0.31 pmol S-1 cm-1, r = 0.55. Comparison of app. Ki,cGMP with app. Ki,PAH of ten substrates gave a linear relation with a ratio of 1.83 +/- 0.5. All prostanoids applied inhibited the contraluminal PAH transport; the prostaglandins E1, F1 alpha, A1, B1, E2, F2 alpha, D2, A2 and B2 with an app. Ki,PAH between 0.08 and 0.18 mmol/l. The app. Ki of the prostacyclins 6,15-diketo-13,14-dihydroxy-F1 alpha (0.22 mmol/l) and Iloprost (0.17 mmol/l) as well as that of leukotrienes B4 (0.2 mmol/l) was in the same range, while the app. Ki,PAH of the prostacyclins PGI2 (0.55 mmol/l), 6-keto-PGF1 alpha (0.77 mmol/l) and 2,3-dinor-6-keto-PGF1 alpha (0.57 mmol/l) as well as that of thromboxane B2 (0.36 mmol/l) was somewhat higher. None of these prostanoids inhibited contraluminal dicarboxylate transport and only PGB1, E2 and D2 inhibited contraluminal sulphate transport (app. Ki,SO4(2-) 5.4, 11.0, 17.9 mmol/l respectively). Contraluminal influx of labelled PGE2 showed complex transport kinetics with a mixed Km = 0.61 mmol/l and Jmax of 4.26 pmol S-1 cm-1. It was inhibited by probenecid, sulphate and indomethacin. Contraluminal influx of PGD2, however, was only inhibited by probenecid. The data indicate that cyclic nucleotides as well as prostanoids are transported by the contraluminal PAH transporter. For prostaglandin E2 a significant uptake through the sulphate transporter occurs in addition.(ABSTRACT TRUNCATED AT 400 WORDS)

Contraluminal organic anion and cation transport in the proximal renal tubule: V. Interaction with sulfamoyl- and phenoxy diuretics, and with beta-lactam antibiotics.

In order to study the interaction of sulfamoyl- and phenoxy diuretics as well as of beta-lactam antibiotics with the contraluminal anion and cation transport systems the inhibitory potency of these substances against the influx of 3H-para-aminohippurate, 14C-succinate, 35S-sulfate and 3H-N1-methylnicotinamide into cortical tubular cells have been determined. 1.) 2-, 3- and 4-sulfamoylbenzoate inhibit contraluminal PAH influx. N-dipropyl substitution to yield probenecid or ring-substitution to yield furosemide and piretanide augment the inhibitory potency. However, hydrochlorothiazide and acetazolamide exert only a moderate inhibitory potency. Succinate transport was inhibited by furosemide only. Sulfate transport was inhibited by furosemide and 3-sulfamoyl-4-phenoxybenzoate as well as by probenecid, piretanide, hydrochlorothiazide and acetazolamide. 2.) Phenoxyacetate, -propionate, and -butyrate exert increasing inhibition against PAH transport. The weed-killers 2,4-dichloro-, and 2,4,5-trichlorophenoxyacetate (2,4 D and 2,4,5 T) had a similar inhibitory potency, while ethacrynic acid showed a lower and the uricosuric tienilic acid a higher inhibitory potency. None of the compounds of this group interact with contraluminal succinate transport, and only the multiring-substituted compounds 2,4 D, 2,4,5 T, ethacrynic and tienilic acid interact slightly with the sulfate transporter. 3.) The monocarboxylic penicillins benzylpenicillin and phenoxymethylpenicillin as well as the dicarboxylic ticarcillin interact with the contraluminal PAH transport. The aminopenicillin ampicillin had a lower, and apalcillin a higher inhibitory potency than monocarboxylic penicillin. Benzylpenicillin showed small inhibition against succinate transport and ticarcillin against sulfate transport. 4.) The monocarboxylic cephalosporine, 6315 S Shionogi, and the aminocephalosporines, cephalexin and cefadroxil, showed an app. Ki.PAH as the comparable penicillins. The zwitterions cephaloridine and cefpirome did not interact with the PAH transporter, but with the organic cation (NMN) transporter. Amongst the amino-thiazol-containing compounds cefotaxime, ceftriaxone, and cefodizime, increasing interaction with the PAH transporter was seen dependent of a second ionizable anionic group. Compounds with two ionizable anionic groups (cefsulodin, ceftriaxone, cefodizime) exert also a small inhibitory potency against sulfate transport. None of the cephalosporins interacted with the dicarboxylate transporter. The interaction pattern of the tested compounds is in accordance with the specificity requirements for the contraluminal transporters depending on electrical charge and hydrophobicity.

Contraluminal para-aminohippurate (PAH) transport in the proximal tubule of the rat kidney. IV. Specificity: mono- and polysubstituted benzene analogs.

In order to study the specificities of the contraluminal anion transport systems, the inhibitory potency of substituted benzene analogs on influx of [3H]PAH, [14C]succinate, and [35S]sulfate from the interstitium into cortical tubular cells has been determined in situ: (1) Contraluminal [3H]PAH influx is moderately inhibited by benzene-carboxylate and benzene-sulfonate, and strongly by benzene-dicarboxylates, -disulfonates and carboxy-benzene-sulfonates, if the substituents are located at positions 1 and 3 or 1 and 4. The affinity of the PAH transporter to polysubstituted benzoates increases with increasing hydrophobicity, decreasing electron density at the carboxyl group and decreasing pKa. Similar dependencies are observed for phenols. Benzaldehydes which do not carry an ionic negative charge are accepted by the PAH-transporter, if they possess a second partially charged aldehyde or NO2-group. (2) Contraluminal [14C]succinate influx is inhibited by benzene 1,3- or 1,4-dicarboxylates, -disulfonates and 1,3- or 1,4-carboxybenzene-sulfonates. Monosubstituted benzoates do not interact with the dicarboxylate transporter, but NO2-polysubstituted benzoates do. Phenol itself and 2-substituted phenol interact weakly possibly due to oligomer formation. (3) The contraluminal sulfate transporter interacts only with compounds which show a negative group accumulation such as 3,5-dinitro- or 3,5-dichloro-substituted salicylates. The data are consistent with three separate anion transport systems in the contraluminal membrane: The PAH transporter interacts with hydrophobic molecules carrying one or two negative charges (-COO-, -SO3-) or two or more than two partial negative charges (-OH, -CHO, -SO2NH2, -NO2). The dicarboxylate transporter requires two electronegative ionic charges (-COO-, -SO3-) at 5-9 A distance or one ionic and several partial charges (-Cl, -NO2) at a favourable distance. The sulfate transporter interacts with molecules which have neighbouring electronegative charge accumulation.

Contraluminal para-aminohippurate transport in the proximal tubule of the rat kidney. III. Specificity: monocarboxylic acids.

In order to study the specificity of the contraluminal para-aminohippurate (PAH) transport system, the inhibitory potency of monocarboxylates on the 3H-PAH influx from the interstitium into cortical tubular cells in situ has been determined. The following was found: if a homologous series of fatty acids with increasing chain length is tested, inhibition of contraluminal PAH influx is first seen with valerate (app. Ki 1.4 mmol/l), increasing up to nonanoate (app. Ki 0.06 mmol/l) and remaining in this range up to duodecanoate, the last compound of this series which is sufficiently water-soluble. Similarly, the inhibitory potency of aromatic monocarboxylates increases with increasing hydrophobicity. If the fatty acids are esterified, their inhibitory potency is lost. If they are transformed to the respective aldehydes their inhibitory potency is preserved at a reduced degree. Introduction of a hydrophobic methyl-, ethyl-, or propyl-group increases the inhibitory potency. A beta-, but not an alpha-oxo-group augments the inhibitory potency of phenylpropionate analogs, an OH group diminishes it, and a NH2 group abolishes it. Among phenyl-fatty acids an increase in affinity is observed from phenyl- less than benzoylamine- less than phenoxy- less than benzoyl-acetate and -propionate. All monocarboxylate compounds, so far tested, do not inhibit contraluminal sulfate and Na+/succinate influx. The data indicate that the PAH transporter interacts with monocarboxylates and also with aldehydes which have a hydrophobic moiety. An additional oxo-group facilitates the interaction. Thus, the benzoyl compounds show the highest affinity observed.

Contraluminal para-aminohippurate (PAH) transport in the proximal tubule of the rat kidney. I. Kinetics, influence of cations, anions, and capillary preperfusion.

In order to study the characteristics of contraluminal para-aminohippurate transport into proximal tubular cells the stopped flow capillary perfusion method was applied. The disappearance of 3H-para-aminohippurate from the capillary perfusate at different concentrations and contact times was measured and saturation type behaviour was found with a Km of 0.08 +/- 0.01 (SE) mmol/l, Jmax of 1.1 +/- 0.1 pmol X s-1 X cm-1 and r, the final extracellular/intracellular distribution ratio of 0.93 +/- 0.03. Omission of Na+ from the capillary test perfusate caused a small reduction of contraluminal PAH uptake at small transport rates (0.1 mmol/l PAH in the test perfusate) but not at high transport rates (1.0 mmol/l PAH in the test perfusate). Change of K+ between 0 and 40 mmol/l and pH between 6.0 and 8.0 did not influence contraluminal PAH uptake. Isotonic replacement of chloride by gluconate, nitrate, sulfate, phosphate, methanesulfonate or increase in bicarbonate to 50 mmol/l did not influence PAH uptake at small transport rates. But isotonic sulfate and phosphate, as well as 50 mmol/l HCO3- and 25 mmol/l Hepes in isotonic solutions reduced PAH uptake at high transport rates. Addition of 5 mmol/l Ca2+, Mg2+, Mn2+, Ba2+, Cd2+ to isotonic Na+-gluconate solution did not influence PAH uptake except for Mg2+ and Mn2+ which inhibited uptake at small transport rates only. Preperfusion of the peritubular capillaries with rat serum, Na+ gluconate (Ca2+- + Mg2+-free), Na+ gluconate (Ca2+- + Mg2+-free) plus 10 mmol/l lactate or pyruvate or 0.1 mmol/l 2-oxoglutarate did not influence PAH uptake at small PAH transport rates, but inhibited at high transport rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Contraluminal para-aminohippurate (PAH) transport in the proximal tubule of the rat kidney. II. Specificity: aliphatic dicarboxylic acids.

In order to study the specificity for contraluminal para-aminohippurate (PAH) transport, the inhibitory potency of aliphatic dicarboxylates on 3H-PAH influx, as well as the inhibitory effect on 35SO4(2-)- and 3H-succinate influx, from the interstitium into cortical tubular cells in situ has been determined. The following was found: Testing a homologous series of dicarboxylates--ranging from the 2 C oxalate to the 10 C sebacate--PAH transport was inhibited by succinate (app. Ki 1.35 mmol/l), and all longer dicarboxylates, with high potency (app. Ki 0.05--0.35 mmol/l). Sulfate transport was inhibited only by oxalate (app. Ki 1.1 mmol/l), while dicarboxylate transport was inhibited by succinate, glutarate, adipate and pimelate with decreasing potency (app. Ki 0.04, 0.24, 0.91, 4.0 mmol/l, respectively). PAH transport was inhibited by succinate and glutarate with high potency (app. Ki 1.35 and 0.05 mmol/l), by the correspondent monomethylester to a lesser extent (app. Ki 1.7 and 0.74 mmol/l), but not by the dimethylester. On the other hand, the semialdehyde of succinate with a Ki-value of 1.2 mmol/l, had the same inhibitory potency as succinate itself, while the dialdehyde of glutarate (app. Ki 1.4 mmol/l) was much less potent as glutarate. Introduction of an oxo-, methyl- or sulfhydroxyl-group group onto the 2-position of succinate, or of an oxo-group onto the 2-position of glutarate moderately augmented the inhibitory potency against PAH-uptake. However, introduction of a 2-hydroxy group onto succinate or glutarate in the L-position reduced the inhibitory potency more than in the D-position. Introduction of two methyl-, sulfhydryl- or hydroxyl-groups in the 2-3 position of succinate reduced or abolished its inhibitory potency. The introduction of a 2-amino group onto succinate or glutarate abolished its effect on PAH transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Erythroderma associated with mixed lymphocyte-endothelial cell interaction and Staphylococcus aureus infection.

We report 11 consecutive cases of erythroderma, a high percentage of which were associated with the growth of Staphylococcus aureus in cultures from blood, joint fluid or skin. In biopsies from all the patients we found close morphological associations between lymphocytes and endothelial cells, with some of the lymphocytes showing features of blastoid transformation to T helper lymphocytes. In extreme cases, sheets of T cells, including T helper lymphocytes, formed a syncytium with endothelial cells in the dermis. Marked capillary proliferation was noted both on light and electron microscopy. We suggest that erythroderma is precipitated by antigens such as protein A, a potent T cell mitogen present on the cell surface of Staphylococcus aureus, or by drugs, such as phenytoin. These antigens induce antigen presentation by individual endothelial cells, leading to T helper transformation and lymphocyte proliferation. Endothelial proliferation resulting from lymphocyte-endothelial interaction results in the vascular proliferation associated with this syndrome.

Endothelial cell toxicity in leg ulcers treated with topical hyperbaric oxygen.

We report the clinical and electron-microscopic features of endothelial cell toxicity in patients treated with hyperbaric oxygen for prolonged periods for leg ulcers. The clinical manifestations include the appearance of depressed white areas within the bed of granulation tissue, which correlated with decreased vascularity under light microscopy. Electron-microscopic findings include endothelial cells with serrated nuclear membranes and degenerate mitochondria in the cytoplasm. These changes occurred in all patients subjected to at least 8 weeks of hyperbaric oxygen, even though an intermittent regimen was adopted. The changes reversed after 1-2 weeks of cessation of hyperbaric oxygen.