Risk of connective tissue disease, morphoea and systemic vasculitis in patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) has been associated with auto-inflammatory conditions, yet the risk of developing connective tissue disease (CTD), morphoea and systemic vasculitis has not been well-characterized. OBJECTIVES: We sought to evaluate the risk of developing CTD, morphoea and systemic vasculitis in patients with HS. METHODS: Using claims data, we identified patients with HS and used 2 : 1 risk-set sampling to identify patients without HS. Patients with existing CTD were excluded. Patient follow-up lasted until first occurrence of the following events: the occurrence of outcome (i.e. systemic lupus erythematosus, morphoea, systemic sclerosis, Sjogren's Syndrome and systemic vasculitis), death, disenrolment or end of data stream. Hazard ratios (HR) of developing CTD, morphoea and systemic vasculitis were computed after 1 : 1 propensity score (PS) matching. RESULTS: After 2 : 1 risk-set sampling, we identified 78 122 HS patients and 156 247 non-HS comparators. The mean follow-up was 540 days. After PS matching, HS patients had an increased risk of systemic lupus erythematosus HR = 1.63 (1.31-2.03) and morphoea HR = 2.02 (1.32-3.11), compared to non-HS patients. We did not observe an increased risk for systemic sclerosis HR = 0.90 (0.59-1.44), Sjogren's Syndrome HR = 0.91 (0.73-1.14) or systemic vasculitis HR = 0.87 (0.64-1.20). CONCLUSION: In this population-based study, we observed an increased risk of developing systemic lupus erythematous and morphoea subsequent to a first-recorded diagnosis of hidradenitis suppurativa.

Propensity scores for confounder adjustment when assessing the effects of medical interventions using nonexperimental study designs.

Treatment effects, especially when comparing two or more therapeutic alternatives as in comparative effectiveness research, are likely to be heterogeneous across age, gender, co-morbidities and co-medications. Propensity scores (PSs), an alternative to multivariable outcome models to control for measured confounding, have specific advantages in the presence of heterogeneous treatment effects. Implementing PSs using matching or weighting allows us to estimate different overall treatment effects in differently defined populations. Heterogeneous treatment effects can also be due to unmeasured confounding concentrated in those treated contrary to prediction. Sensitivity analyses based on PSs can help to assess such unmeasured confounding. PSs should be considered a primary or secondary analytic strategy in nonexperimental medical research, including pharmacoepidemiology and nonexperimental comparative effectiveness research.

Signatures of the Z = 82 shell closure in α-decay process.

In recent experiments at the velocity filter Separator for Heavy Ion reaction Products (SHIP) (GSI, Darmstadt), an extended and improved set of α-decay data for more than 20 of the most neutron-deficient isotopes in the region from lead to thorium was obtained. The combined analysis of this newly available α-decay data, of which the (186)Po decay is reported here, allowed us for the first time to clearly show that crossing the Z = 82 shell to higher proton numbers strongly accelerates the α decay. From the experimental data, the α-particle formation probabilities are deduced following the Universal Decay Law approach. The formation probabilities are discussed in the framework of the pairing force acting among the protons and the neutrons forming the α particle. A striking resemblance between the phenomenological pairing gap deduced from experimental binding energies and the formation probabilities is noted. These findings support the conjecture that both the N = 126 and Z = 82 shell closures strongly influence the α-formation probability.

A triplet of differently shaped spin-zero states in the atomic nucleus 186Pb

Understanding the fundamental excitations of many-fermion systems is of significant current interest. In atomic nuclei with even numbers of neutrons and protons, the low-lying excitation spectrum is generally formed by nucleon pair breaking and nuclear vibrations or rotations. However, for certain numbers of protons and neutrons, a subtle rearrangement of only a few nucleons among the orbitals at the Fermi surface can result in a different elementary mode: a macroscopic shape change. The first experimental evidence for this phenomenon came from the observation of shape coexistence in 16O (ref. 4). Other unexpected examples came with the discovery of fission isomers and super-deformed nuclei. Here we find experimentally that the lowest three states in the energy spectrum of the neutron deficient nucleus 186Pb are spherical, oblate and prolate. The states are populated by the alpha-decay of a parent nucleus; to identify them, we combine knowledge of the particular features of this decay with sensitive measurement techniques (a highly efficient velocity filters with strong background reduction, and an extremely selective recoil-alpha-electron coincidence tagging methods). The existence of this apparently unique shape triplet is permitted only by the specific conditions that are met around this particular nucleus.

Molecular and immunodiagnostic investigations on bovine neosporosis in Switzerland.

Neospora caninum has gained considerable attention through its role in the aetiology of bovine abortion. Due to its close phylogenetic relationship with Toxoplasma gondii, respective unequivocal differential diagnosis deserves special consideration. In order to evaluate the diagnostic performance of molecular and immunodiagnostic techniques and to provide insights into the epidemiological significance of bovine neosporosis in Switzerland, we conducted a study on 83 cases of bovine abortion: of these, 24 (29%) foetal brains were positive by Neospora-PCR, six of these foetuses were simultaneously seropositive in Neospora-IFAT and/or somatic antigen-ELISA. Conversely, four (5%) foetal brains were considered positive by Toxoplasma-PCR, two of which were also seropositive in the Toxoplasma-P30-ELISA and/or direct agglutination test. The seroprevalence in 1689 cattle sera obtained from 113 diary farms was 11.5% (95% confidence interval: 9.2-13.8) by Neospora-somatic antigen-ELISA were and 10.7% (95% confidence interval: 8.3-12.6) by Toxoplasma-P30-ELISA. From the same samples, 1.1%, less than statistically expected, were positive in both ELISA. Within selected groups of cow-calf farms, the seroprevalence determined using the Neospora-somatic antigen-ELISA was 14% (95% confidence interval 5.0-23.0) for dams and 15% (95% confidence interval: 3.0-28.0) for offspring calves. Seroprevalences determined by Toxoplasma-P30-ELISA were 8% (95% confidence interval: 4.0-12.0) for dams and 3% (95% confidence interval: 0.3-6.0) for calves. None of the sera gave a positive reaction in both ELISA. Our data indicated that prenatal neosporosis appears as an important cause of bovine abortion in Switzerland.

Endometrial cytohistology by aspiration technic and by Gravlee Jet Washer: a comparative study.

An office procedure of intrauterine aspiration yielded a 99% diagnostic accuracy in 100 patients admitted for either curettage or hysterectomy. After correlation with surgical diagnosis, no false-positive or false-negative results were found. The method provides tissue for cell blocks adequate for histologic diagnosis of endometrial adenocarcinoma and its precursors. The major advantage of this technic in comparison with the Gravlee Jet Washer is its low cost. Moreover, in this study, it proved to be less painful, superior for cell block preparation, and yielded more satisfactory specimens. As a screening procedure for asymptomatic patients at risk, this intrauterine aspiration technic holds promise and must be evaluated by further studies.

Negligible systemic absorption of topical isotretinoin cream: implications for teratogenicity.

The objective of the study was to assess the extent of systemic exposure of retinoic acid metabolites after excessive application of 0.1% isotretinoin cream in patients with photodamaged skin. This was a single-center, open-label, noncomparative, multiple-dose study of isotretinoin cream. Eighteen female patients with photodamaged skin received a 10 g topical application of isotretinoin cream once daily to a surface area of approximately 2,300 cm2 for 42 days. The patients were not allowed to have high vitamin A-containing foods, vitamin A supplements, or concomitant medications during the entire study period. Plasma levels of four retinoic acids (isotretinoin, tretinoin, 4-oxo-isotretinoin, and 4-oxo-tretinoin) were evaluated after 42 days of isotretinoin application and compared with baseline (pretreatment) levels. The mean area under the curve (AUC) in plasma increased by 48% (+/-SE 9.2) and 77% (+/-13) from the 24-hour pretreatment baseline level for isotretinoin and 4-oxo-isotretinoin, respectively, after treatment with excessive amounts of isotretinoin cream, suggesting systemic absorption of isotretinoin cream. This increase in systemic exposure of retinoic acids was less than that reported earlier after the U.S. recommended daily allowance of 5,000 i.u. of vitamin A supplementation (isotretinoin 141 +/- 19% and 4-oxo-isotretinoin 171 +/- 27%). The minimal systemic availability of isotretinoin cream compared with the U.S. recommended daily allowance for vitamin A supplements provides reasonable evidence for lack of its potential teratogenic risk.

A newly discovered xenobiotic metabolic pathway: ethyl ester formation.

Formation of etretinate, ethyl ester of acitretin, can be confirmed in vitro and in vivo using acitretin as the substrate. Etretinate was identified by LC/MS. The in vitro incubation was performed using rat and human liver 12,000 g supernatant, and the in vivo experiment was conducted in rats after oral dosing of acitretin. The ethyl ester formation was greatly enhanced by addition of or dosing with ethanol.

Determination of the N-methyl-D-aspartate receptor NR2B subunit blocker Ro 63-1908 in rat, cynomolgus monkey and human plasma by high-performance liquid chromatography with column switching and fluorescence detection.

A HPLC method with automated column switching was developed and validated for the determination of Ro 63-1908 in rat and cynomolgus monkey plasma. Human plasma was used for calibration and was also included in the validation process. Ro 63-1908 belongs to a class of neuroprotective N-methyl-D-aspartate (NMDA) receptor blockers which were in development for the treatment of stroke and traumatic brain injury. The method involves deproteinisation of plasma samples with ethanol and direct injection of the supernatant (1.4 ml) into the HPLC column-switching system. To prevent a breakthrough of the analyte and the internal standard on the precolumn (Purospher RP-18, 75x4 mm) due to the high ethanol content, the injection solution was diluted, on-line, using an additional pump and a T-piece. 1% ammonium acetate-ethanol (100:2, v/v) was used as mobile phase for injection, as well as for on-line dilution, resulting in pre-concentration of the analyte and the internal standard on the precolumn. As Purospher RP-18 is a non-endcapped stationary phase with a special selectivity for amines, the analyte and the internal standard could then be selectively eluted with 30% acetonitrile (without any buffer in the mobile phase) and transferred to the analytical column [consisting of two coupled columns (125+250x4 mm) packed with Superspher 60 RP-select B], where they were separated by gradient elution and detected by fluorescence detection. Compared to the use of a 125 mm long precolumn and dilution of the supernatant with ammonium acetate prior to injection, the 75 mm precolumn and the on-line dilution procedure allowed about one third shorter run times (21 min) and, therefore, a higher sample throughput. The limit of quantification was 1 ng/ml using 0.4 ml plasma. The method was applied to more than 670 plasma samples from pharmacokinetic and toxicokinetic studies and is also suitable for other matrices and NMDA receptor blockers.

Determination of several N-methyl-D-aspartate receptor blockers in plasma and brain by a selective high-performance liquid chromatographic method with column switching.

A general procedure is presented for the determination of several N-methyl-D-aspartate (NMDA) receptor open-channel and subtype-selective blockers, which have been evaluated and developed as neuroprotective drugs for the treatment of brain stroke and trauma. The method involves deproteination of plasma with ethanol, or homogenization of brain samples in ethanol, dilution of the supernatant with ammonium acetate and direct injection into an HPLC column-switching system. Although the investigated NMDA receptor blockers are all tertiary amines, they have quite different structures. However, they are all concentrated on the first column (Purospher RP-18, 125 x 4 mm), whereas polar interfering compounds are washed out with 1% ammonium acetate-acetic acid-acetonitrile (100:1:5, v/v/v). Due to the special selectivity of the Purospher RP-18 material, the analytes and the internal standard are then selectively eluted with 25% acetonitrile (without any buffer in the mobile phase) and transferred to the analytical column (Superspher 60 RP-select B, 250 x 4 mm), where they are separated by gradient elution and detected by UV or fluorescence detection. The low degree of interference allowed the development of sensitive methods with quantification limits of 5 ng/ml for animal plasma (0.4 ml used), 0.5 ng/ml for human plasma (1 ml used) and 50 ng/g for brain tissue (200 mg used).

Determination of the arotinoid mofarotene in human, rat and dog plasma by high-performance liquid chromatography with automated column switching and ultraviolet detection.

A sensitive and specific high-performance liquid chromatographic method was developed and validated for the determination of the third-generation retinoid (arotinoid) mofarotene (Ro 40-8757) in human, rat and dog plasma, using direct injection of deproteinated plasma samples, automated column switching (on-line solid-phase extraction) and ultraviolet detection. Plasma (0.5 ml) was deproteinated by adding ethanol (1 ml) containing the internal standard Ro 42-8659 (200 ng/ml). After centrifugation, 0.9 ml of the supernatant were directly injected onto a precolumn packed with C18 Corasil 37-50 microns. Polar plasma components were washed out from the precolumn using 1% ammonium acetate-acetic acid-acetonitrile (900:9:100, v/v/v). After valve switching, the pre-concentrated compounds were transferred to the analytical column (C18) in the backflush mode, separated by gradient elution and detected at 300 nm. The retention times (total run times) were approximately 15 and 20 min for the internal standard and mofarotene, respectively. The method was linear in the range 10-1000 ng/ml with a limit of quantification of 10 ng/ml. The mean recoveries were 80.4%, 81.7% and 77.8% (range 10-1000 ng/ml) and the inter-assay precision was 2.7% (range 20-1000 ng/ml), 1.5% and 2.0% (both range 100-1000 ng/ml) for human, rat and dog plasma, respectively. Mofarotene was found to be stable in human, rat and dog plasma stored at -20 degrees C for 3 months and 22 degrees C for 24 h. The method was successfully applied to clinical, pharmacokinetic and toxicokinetic studies.

Phorbol ester and epidermal growth factor receptors in human breast cancer.

Recently hormone - dependent mammary carcinoma cell lines were shown to exhibit in vitro significantly lower protein kinase C (PKC) activities and epidermal growth factor receptor (EGF-R) as compared to hormone - independent cell lines. Measurements of EGF-R levels in primary human breast cancer biopsies were determined by [125I]-EGF binding. The EGF binding correlated inversely with the estrogen (ER) (p less than 0.001), progesterone receptor (PR) (p less than 0.005) contents and with the age of the patients. In contrast, the amounts of PKC, determined by phorbol ester binding, correlated inversely only with the PR (p less than 0.001), but not with the ER (p = 0.065). There was, however, a significant inverse correlation (p less than 0.05) between phorbol ester binding and ER levels if ER positive biopsies but with a PR negative value (i.e. with a non functional estrogen receptor) were excluded from statistical analysis. These data suggest an inverse relationship between the EGF-R or the phorbol ester receptor and the steroid receptor system in human breast cancer.

Microdose intravaginal levonorgestrel contraception: a multicentre clinical trial. I. Contraceptive efficacy and side effects. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation.

A multicentre clinical trial, including 19 centres in 13 countries, assessed the contraceptive efficacy and clinical acceptability of a Silastic 382 vaginal ring releasing 20 micrograms of levonorgestrel for at least 90 days. A total of 1005 women entered the study and 8176.74 woman-months of experience was gathered. The rate of intrauterine pregnancy at one year of use was 3.6 per 100 women (95% confidence interval 2.2-5.0), and of ectopic pregnancy, 0.2% (one case). The principal reasons for discontinuation were menstrual disturbances (17.2% at one year), vaginal symptoms (6.0%) and repeated expulsion of the ring (7.1%). The pregnancy rate with this 20 micrograms levonorgestrel-releasing vaginal ring compares favourably with that of a low estrogen combination oral contraceptive tested by WHO and is less than half that of a progestogen-only oral contraceptive in a WHO randomized study. It is concluded that the WHO intravaginal ring releasing an average of 20 micrograms of levonorgestrel per 24 hours is an effective method of contraception for at least one year of use.

Microdose intravaginal levonorgestrel contraception: a multicentre clinical trial. II. Expulsions and removals. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation.

This paper investigates the relationship between expulsions and removals, and demographic characteristics of 1005 women from 19 centres using a vaginal ring releasing 20 micrograms levonorgestrel per 24 hours. Emphasis is placed on discontinuations of method use due to expulsions, on the number and rate of expulsions, and the time at which the first expulsion occurred. The overall life-table discontinuation rate due to expulsion was 7.1% at one year. Life-table discontinuation rates increased with parity and were highest in Asian and lowest in European women. In respect to the number of expulsions experienced by women (expulsions did not necessarily lead to discontinuation), the women of high parity and those from Asia and Europe have the highest rates. The life-table first expulsion rate is 29% at one year. Such rates are highest in Chinese and Asian women. Following a first expulsion, the second expulsion rate is 45% by the end of the subsequent six months. The majority of first expulsions occur at defaecation (134 or 57% of 234 women), urination (12%) and during menstruation (17%). Rings were removed by 121 (12%) women on 201 occasions and for a variety of reasons. The main medical reasons were vaginal discharge and irritation, bleeding pain and dyspareunia. Others removed the ring during defaecation, intercourse or because the ring came out of place. Women also removed rings for curiosity, to show their husbands and to clean.

Microdose intravaginal levonorgestrel contraception: a multicentre clinical trial. III. The relationship between pregnancy rate and body weight. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation.

This paper investigates the relationship between pregnancy rates and body weight of 1005 women using a vaginal ring releasing 20 micrograms levonorgestrel per 24 hours. While the overall pregnancy rate at one year was 3.7%, it was found that women have an increasing risk of pregnancy with increasing body weight. For example, a woman of 40 kg has an estimated pregnancy rate of 1.7% in contrast to 9.8% for a woman of 80 kg weight.

Microdose intravaginal levonorgestrel contraception: a multicentre clinical trial. IV. Bleeding patterns. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation.

A multicentred clinical trial was conducted in 12 countries to assess the contraceptive efficacy and side effects of a low-dose levonorgestrel-releasing vaginal ring. Contraceptive efficacy and side effects, expulsions and removals, and the relation between pregnancy rate and admission body weight of the women have been reported previously. The effect of ring use on vaginal bleeding patterns as observed from daily menstrual diaries kept by the women is the object of this paper. A total of 1005 women were fitted with the ring and 702 of them provided a menstrual diary suitable for analysis. The description of the bleeding patterns is made using a 90-day reference period approach and following the guidelines published by WHO. In addition the longest bleeding/spotting episode and longest bleeding/spotting-free interval are calculated over the entire diary length. Half of the ring users have vaginal bleeding patterns similar to normal untreated patterns. A quarter experience irregular bleeding, 10% have prolonged cycles and 10% have shortened cycles. Over one year of continuous use, there appears to be no significant trend in these patterns. Users with the worst bleeding patterns tend to discontinue first during the clinical trial and are influenced by their more recent experience of vaginal bleeding irregularities. Life-table analysis of discontinuation rates gives an underestimation of the true incidence of bleeding irregularities. Some comments are made on the limitations of the methods of analysis of menstrual diaries.

Biological structures imaged in a hybrid scanning transmission electron microscope and scanning tunneling microscope.

A hybrid scanning transmission electron microscope (STEM) and scanning tunneling microscope (STM) is described which allows simultaneous imaging of biological structures adsorbed to electron-transparent specimen supports in both modes of scanning microscopy, as demonstrated on uncoated phage T4 polyheads. We further discuss the reproducibility and validity of height data obtained from STM topographs of biomacromolecules and present raw data from topographs of freeze-dried, metal-coated nuclear envelopes from Xenopus laevis oocytes.

Determination of 13-cis-3-hydroxyretinoic acid, all-trans-3-hydroxyretinoic acid and their 4-oxo metabolites in human and animal plasma by high-performance liquid chromatography with automated column switching and UV detection.

A high-performance liquid chromatographic method with automated column switching was developed for the simultaneous determination of 13-cis-3-hydroxyretinoic acid, all-trans-3-hydroxyretinoic acid and their metabolites 13-cis-3-hydroxy-4-oxo-retinoic acid and all-trans-3-hydroxy-4-oxo-retinoic acid in plasma samples from man, rat, dog, rabbit and mouse. The method consists of deproteination of plasma (0.4 ml) with ethanol (1.5 ml), containing the internal standard Ro 12-7310. After centrifugation, 1.4 ml of the supernatant was directly injected onto the precolumn (PC) (4 x 4 mm) packed with LiChrospher 100 RP-18 (5 microm). Ammonium acetate (0.02%)-acetic acid-ethanol (100:3:4, v/v/v) was used as mobile phase M1A during injection, as well as to decrease the elution strength of the injection solution by on-line addition using a T-piece (M1B). After valve switching, the retained components were transferred to the analytical column (AC), separated by gradient elution and detected at 360 nm. Two coupled Purospher 100 RP-18 endcapped columns (both 250 x 4 mm) were used for the separation, together with a mobile phase consisting of acetonitrile-water-10% ammonium acetate-acetic acid, (A), 540:450:2:30 (v/v/v/v), (B), 600:350:2:30 (v/v/v/v), and (C), 950:40:2:30 (v/v/v/v). The method was linear in the range 1-500 ng ml(-1), at least, with a quantification limit of 1 ng ml(-1). The mean recoveries from human plasma were 100-107% and the mean inter-assay precision was 2.0-4.7% (range 1-500 ng ml(-1)). Similar results were obtained for animal plasma. The analytes were stable in the plasma of all investigated species stored at -20 degrees C for 3 months, at least. The method was successfully applied to clinical and toxicokinetic studies.

Malaria prophylaxis and self-therapy in airline crews.

The risk of malaria infection in airline crews is estimated to be 0.5 per 1,000 persons per night in areas with high levels of malaria transmission. Routine chemoprophylaxis for years is not recommended because of possible side effects. Airline crews should therefore use appropriate measures to prevent mosquito bites. In addition, they may need to carry "standby" medication with them to be used for presumptive treatment of a febrile illness if medical attention is not readily available.