Patterns of knee osteoarthritis management in general practice: a retrospective cohort study using electronic health records.

OBJECTIVE: This study determined patterns of knee osteoarthritis (OA) management by general practitioners (GPs) using routine healthcare data from Dutch general practices from 2011 to 2019. DESIGN: A retrospective cohort study was conducted using the Integrated Primary Care Information database between 2011 and 2019. Electronic health records (EHRs) of n = 750 randomly selected knee OA patients (with either codified or narrative diagnosis) were reviewed against eligibility criteria and n = 503 patients were included. Recorded information was extracted on GPs' management from six months before to three years after diagnosis and patterns of management were analysed. RESULTS: An X-ray referral was the most widely recorded management modality (63.2%). The next most widely recorded management modalities were a referral to secondary care (56.1%) and medication prescription or advice (48.3%). Records of recommendation of/referral to other primary care practitioners (e.g. physiotherapists) were found in only one third of the patients. Advice to lose weight was least common (1.2%). Records of medication prescriptions or recommendation of/referral to other primary care practitioners were found more frequently in patients with an X-ray referral compared to patients without, while records of secondary care referrals were found less frequently. Records of an X-ray referral were often found in narratively diagnosed knee OA patients before GPs recorded a code for knee OA in their EHR. CONCLUSION: These findings emphasize the importance of better implementing non-surgical management of knee OA in general practice and on initiatives for reducing the overuse of X-rays for diagnosing knee OA in general practice.

Coverage-dependent desorption kinetics of water on a well-ordered alumina thin film surface.

We have developed an experimental and analytical setup for thermal desorption spectroscopy of solid water films on surfaces. We obtain the coverage-dependent desorption kinetics of water molecules from a well-defined ultra-thin alumina/NiAl(110) surface in the coverage range of 0-2 monolayers. We use a novel deconvolution technique to eliminate the pumping delay of water vapor in the vacuum system, which has previously hindered the accurate estimation of desorption kinetic parameters, such as activation energy and pre-exponential factor. The coverage-dependent Arrhenius analysis reveals that the desorption activation energy decreases with increasing coverage in the sub-monolayer range, indicating that the water-water interaction is not attractive. We also find that the pre-exponential factor for the second layer is higher than that for the sub-monolayer. We explain this difference in terms of transition state theory and propose that entropic effects play a significant role in water desorption kinetics.

Menstrual Suppression in Adolescent and Young Adult Transgender Males.

OBJECTIVE: To describe time to cessation of menses in adolescent and young adult transgender males with testosterone and/or other hormonal therapies DESIGN: Retrospective chart review SETTING: Tertiary children's hospital PARTICIPANTS: Patients, aged 10-24, who began gender-affirming hormonal therapy between January 2013 and January 2019 (n = 220) INTERVENTION(S): None MAIN OUTCOME MEASURE(S): Time to cessation of menses RESULTS: Most patients identified as transgender male or transmasculine (211/220, 95.9%), with an average age of 15.8 (±1.9) years. Approximately 53.6% (118/220) of patients reported regular menstrual cycles; 18.2% (40/220) reported irregular cycles. Median time to cessation of menses for all patients was 182 days. Patients treated with testosterone alone (n = 105) reported a median time to cessation of menses of 151 days. Patients who concurrently began testosterone and norethindrone acetate (NETA) (n = 5) had a median time to cessation of menses of 188 days, compared with 168 days for those on testosterone and depot medroxyprogesterone acetate (DMPA, n = 15). In 15 patients who began testosterone, a progestin therapy was later added to induce menstrual suppression, and the median time to cessation of menses was 168 days (+DMPA, n = 4) or 56 days (+NETA, n = 11). Patients treated with NETA (n = 14) or depot leuprolide (n = 11) reported a median time to cessation of menses of 78 days or 77 days, respectively. Considerable variability in prescribing patterns was noted in the remaining 36.4% of patients (n = 80). CONCLUSION: Patients used a variety of different hormonal regimens for menstrual suppression. Less than half achieved cessation of menses within 6 months. NETA and depot leuprolide users reported the most rapid cessation of menses.

Use of the Levonorgestrel Intrauterine Device in an Adolescent with Type IV Vascular Ehlers-Danlos Syndrome and Heavy Menstrual Bleeding, a Case Report.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a group of connective tissue disorders of altered collagen synthesis. People with vascular EDS are at increased risk for vascular and hollow viscous rupture. Heavy menstrual bleeding (HMB) is common among adolescents with EDS. The levonorgestrel intrauterine device (LNG-IUD) is an effective treatment option for HMB; however, its use in patients with vascular EDS has historically been avoided due to perceived risk of uterine rupture. This is the first known case report on use of the LNG-IUD in an adolescent with vascular EDS. CASE: A 16-year-old female with vascular EDS and HMB underwent placement of the LNG-IUD. Placement of the device was performed in the operating room under ultrasound guidance. At the 6-month follow-up, the patient reported significant improvement in bleeding and high satisfaction. No complications were identified at the time of placement or follow-up. SUMMARY AND CONCLUSION: LNG-IUD may be a safe and effective option for menstrual management in individuals with vascular EDS.

Occurrence of comorbidity following osteoarthritis diagnosis: a cohort study in the Netherlands.

OBJECTIVE: To determine the risk of comorbidity following diagnosis of knee or hip osteoarthritis (OA). DESIGN: A cohort study was conducted using the Integrated Primary Care Information database, containing electronic health records of 2.5 million patients from the Netherlands. Adults at risk for OA were included. Diagnosis of knee or hip OA (=exposure) and 58 long-term comorbidities (=outcome) were defined by diagnostic codes following the International Classification of Primary Care coding system. Time between the start of follow-up and incident diagnosis of OA was defined as unexposed, and between diagnosis of OA and the end of follow-up as exposed. Age and sex adjusted hazard ratios (HRs) comparing comorbidity rates in exposed and unexposed patient time were estimated with 99.9% confidence intervals (CI). RESULTS: The study population consisted of 1,890,712 patients. For 30 of the 58 studied comorbidities, exposure to knee OA showed a HR larger than 1. Largest positive associations (HR with (99.9% CIs)) were found for obesity 2.55 (2.29-2.84) and fibromyalgia 2.06 (1.53-2.77). For two conditions a HR < 1 was found, other comorbidities showed no association with exposure to knee OA. For 26 comorbidities, exposure to hip OA showed a HR larger than 1. The largest were found for polymyalgia rheumatica 1.81 (1.41-2.32) and fibromyalgia 1.70 (1.10-2.63). All other comorbidities showed no associations with hip OA. CONCLUSION: This study showed that many comorbidities were diagnosed more often in patients with knee or hip OA. This suggests that the management of OA should consider the risk of other long-term-conditions.

Estimating incidence and prevalence of hip osteoarthritis using electronic health records: a population-based cohort study.

OBJECTIVE: To determine the incidence and prevalence of hip osteoarthritis (OA) in electronic health records (EHRs) of Dutch general practices by using narrative and codified data. METHOD: A retrospective cohort study was conducted using the Integrated Primary Care Information database. An algorithm was developed to identify patients with narratively diagnosed hip OA in addition to patients with codified hip OA. Incidence and prevalence estimates among people aged ≥30 were assessed from 2008 to 2019. The association of comorbidities with codified hip OA diagnosis was analysed using multivariable logistic regression. RESULTS: Using the hip OA narrative data algorithm (positive predicted value = 72%) in addition to codified hip OA showed a prevalence of 1.76-1.95 times higher and increased from 4.03% in 2008 to 7.34% in 2019. The incidence was 1.83-2.41 times higher and increased from 6.83 to 7.78 per 1000 person-years from 2008 to 2019. Among codified hip OA patients, 39.4% had a previous record of narratively diagnosed hip OA, on average approximately 1.93 years earlier. Hip OA patients with a previous record of spinal OA, knee OA, hypertension, and hyperlipidaemia were more likely to be recorded with a hip OA code. CONCLUSION: This study using Dutch EHRs showed that epidemiological estimates of hip OA are likely to be an underestimation. Using our algorithm, narrative data can be added to codified data for more realistic epidemiological estimates based on routine healthcare data. However, developing a valid algorithm remains a challenge, possibly due to the diagnostic complexity of hip pain in general practice.

The utility of a standardised breath sampler in school age children within a real-world prospective study.

Clinical assessment of children with asthma is problematic, and non-invasive biomarkers are needed urgently. Monitoring exhaled volatile organic compounds (VOCs) is an attractive alternative to invasive tests (blood and sputum) and may be used as frequently as required. Standardised reproducible breath-sampling is essential for exhaled-VOC analysis, and although the ReCIVA (Owlstone Medical Limited) breath-sampler was designed to satisfy this requirement, paediatric use was not in the original design brief. The efficacy of the ReCIVA at sampling breath from children has been studied, and 90 breath-samples from 64 children (5-15 years) with, and without asthma (controls), were collected with two different ReCIVA units. Seventy samples (77.8%) contained the specified 1 l of sampled-breath. Median sampling times were longer in children with acute asthma (770.2 s, range: 532.2-900.1 s) compared to stable asthma (690.6 s, range: 477.5-900.1 s;p= 0.01). The ReCIVA successfully detected operational faults, in 21 samples. A leak, caused by a poor fit of the face mask seal was the most common (15); the others were USB communication-faults (5); and, a single instance of a file-creation error. Paediatric breath-profiles were reliably monitored, however synchronisation of sampling to breathing-phases was sometimes lost, causing some breaths not to be sampled, and some to be sampled continuously. This occurred in 60 (66.7%) of the samples and was a source of variability. Importantly, multi-variate modelling of untargeted VOC analysis indicated the absence of significant batch effects for eight operational variables. The ReCIVA appears suitable for paediatric breath-sampling. Post-processing of breath-sample meta-data is recommended to assess the quality of sample-acquisition. Further, future studies should explore the effect of pump-synchronisation faults on recovered VOC profiles, and mask sizes to fit all ages will reduce the potential for leaks and importantly, provide higher levels of comfort to children with asthma.

Does thrombolysis for pulmonary embolism reduce the risk of chronic complications?

We assessed the efficacy of thrombolysis in avoiding long-term complications. Notes of patients thrombolysed for PE in the 2-year period were reviewed. The initial CTPA and echocardiogram results before thrombolysis were compared to the results of follow up imaging repeated after 6 months. Twenty-two patients were thrombolysed for PE. 14 patients had sub-massive PE and 8 patients had massive PE. The right ventricle (RV) was dilated on pre-thrombolysis echocardiogram in 16 patients. On follow up echocardiography all patients with massive PE (6 studies) had a normal RV size, with pulmonary artery pressures (PAP) of 29mmHg. Follow up echocardiography of patients with submassive PE (13 studies) showed 11 patients with a normal RV, with PAP of 28 mmHg.

Associations of preconception Body Mass Index in women with PCOS and BMI and blood pressure of their offspring.

Women with polycystic ovary syndrome (PCOS) have unfavorable metabolic profiles. Their offspring may be affected by such risks. The objective of the current study was to disclose associations between preconception health of these women and health of their offspring. 74 women diagnosed with PCOS according to the Rotterdam criteria were screened systematically before conception. Cardiovascular health of their offspring was assessed at 2.5-4 (n = 42) or at 6-8 years of age (n = 32). Multivariate linear regression analysis was performed with adjustments for potential confounders. In the primary analyses the association between preconception Body Mass index (BMI) and offspring BMI was evaluated. Secondly associations between preconception blood pressure, androgens, insulin-resistance (HOMA-IR), and LDL-cholesterol in women with PCOS and BMI and blood pressure of offspring were assessed. Results show that preconception BMI of women with PCOS was positively associated with sex- and age-adjusted BMI of their offspring at 6-8 years of age (ß = 0.55 (95% CI: 0.12 to 0.97), p = .012). No other significant associations were found. In conclusion, our data suggest that preconception BMI in PCOS is significantly associated with offspring BMI at 6-8 year of age. If this suggestion could be confirmed this may provide an opportunity for improving the future health of these children.

Can increased vigilance for chronic kidney disease in hospitalised patients decrease late referral and improve dialysis-free survival?

BACKGROUND: Insufficient vigilance for renal insufficiency is associated with late referral, increased morbidity and mortality. The present study examines whether increased vigilance for chronic kidney disease (CKD) leads to quicker referral to and better follow-up by a nephrologist, and whether it is associated with an improved outcome. METHODS: Patients with an eGFR < 45 ml/min/1.73 m2 during hospitalisation at the Ghent University Hospital were enrolled during a period of 100 days. The patients were interviewed about their awareness of CKD. Both the patients and their general practitioner were subsequently informed about CKD. The primary endpoint was the number of patients referred for nephrological follow-up within three months. The secondary endpoint was need for dialysis and mortality from any cause one year after inclusion. RESULTS: Of the 72 included patients, 54 had proven CKD, with eGFR consistently < 45 ml/min/1.73 m2 during at least three months before inclusion. Merely 65% was aware of having CKD and only 41% was in regular nephrological follow-up. After intervention, the percentage of patients with CKD in follow-up increased from 41% to 71% (p = 0.002). The proportion reaching the secondary endpoint was significant lower in the patients who were referred quickly than in those who were not (p = 0.015). Similarly, the proportion was significant lower in the patients who received nephrological follow-up than in those who did not (p = 0.006). CONCLUSION: Vigilance for CKD is poor. Simple interventions to augment the vigilance for CKD, as presented in this study, lead to a quicker referral to and follow-up by a nephrologist, which may result in better outcome.

Nuclear Dynamics and Electronic Effects of Hydrogen on Solid Surfaces.

Hydrogen is involved in a variety of chemical processes on surfaces. While hydrogen exhibits vibrational and rotational dynamics in its adsorption state, it in some cases undergoes diffusion into the substrate as well as on the surface, and participates in chemical reactions. Furthermore, hydrogen exchanges an electron with surfaces having a significant effect on the surface electronic structure. In this personal account, we review our recent studies on surface nuclear dynamics of hydrogen, hydrogen transport across surfaces, catalytic hydrogenation/isotope exchange reactions, and charge transfer between the surface and hydrogen by using a depth-resolved technique of nuclear reaction analysis and a quantum-state-selective detection of resonance enhanced multiphoton ionization in combination with surface science techniques. As a future prospect, we refer to ultraslow µ spin rotation spectroscopy for a direct probe of the hydrogen charge state at surfaces.

Confinement and inhomogeneous broadening effects in the quantum oscillatory magnetization of quantum dot ensembles.

We report on the magnetization of ensembles of etched quantum dots with a lateral diameter of 460 nm, which we prepared from InGaAs/InP heterostructures. The quantum dots exhibit 1/B-periodic de-Haas-van-Alphen-type oscillations in the magnetization M(B) for external magnetic fields B > 2 T, measured by torque magnetometry at 0.3 K. We compare the experimental data to model calculations assuming different confinement potentials and including ensemble broadening effects. The comparison shows that a hard wall potential with an edge depletion width of 100 nm explains the magnetic behavior. Beating patterns induced by Rashba spin-orbit interaction (SOI) as measured in unpatterned and nanopatterned InGaAs/InP heterostructures are not observed for the quantum dots. From our model we predict that signatures of SOI in the magnetization could be observed in larger dots in tilted magnetic fields.

Mass spectral characterisation of a polar, esterified fraction of an organic extract of an oil sands process water.

RATIONALE: Characterising complex mixtures of organic compounds in polar fractions of heavy petroleum is challenging, but is important for pollution studies and for exploration and production geochemistry. Oil sands process-affected water (OSPW) stored in large tailings ponds by Canadian oil sands industries contains such mixtures. METHODS: A polar OSPW fraction was obtained by silver ion solid-phase extraction with methanol elution. This was examined by numerous methods, including electrospray ionisation (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS) and ultra-high-pressure liquid chromatography (uHPLC)/Orbitrap MS, in multiple ionisation and MS/MS modes. Compounds were also synthesised for comparison. RESULTS: The major ESI ionisable compounds detected (+ion mode) were C15-28 SO3 species with 3-7 double bond equivalents (DBE) and C27-28 SO5 species with 5 DBE. ESI-MS/MS collision-induced losses were due to water, methanol, water plus methanol and water plus methyl formate, typical of methyl esters of hydroxy acids. Once the fraction was re-saponified, species originally detected by positive ion MS, could be detected only by negative ion MS, consistent with their assignment as sulphur-containing hydroxy carboxylic acids. The free acid of a keto dibenzothiophene alkanoic acid was added to an unesterified acid extract of OSPW in known concentrations as a putative internal standard, but attempted quantification in this way proved unreliable. CONCLUSIONS: The results suggest the more polar acidic organic SO3 constituents of OSPW include C15-28 S-containing, alicyclic and aromatic hydroxy carboxylic acids. SO5 species are possibly sulphone analogues of these. The origin of such compounds is probably via further biotransformation (hydroxylation) of the related S-containing carboxylic acids identified previously in a less polar OSPW fraction. The environmental risks, corrosivity and oil flow assurance effects should be easier to assess, given that partial structures are now known, although further identification is still needed.

Preconception predictors of gestational diabetes: a multicentre prospective cohort study on the predominant complication of pregnancy in polycystic ovary syndrome.

STUDY QUESTION: Can we develop an adequate preconception prediction model to identify those women with polycystic ovary syndrome (PCOS) who have an increased risk of developing gestational diabetes mellitus (GDM) during subsequent pregnancy? STUDY ANSWER: The risk of developing GDM in women with PCOS can be adequately predicted prior to conception by a prediction model. WHAT IS KNOWN ALREADY: Women with PCOS are at increased risk of pregnancy complications, especially GDM. GDM has serious short-term and long-term effects on mother and baby. STUDY DESIGN, SIZE, DURATION: This study is a part of a multicentre prospective cohort study, which was conducted between April 2008 and April 2012. A total of 326 women with PCOS were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and a wish to conceive were included prior to conception and followed until 6 weeks after delivery. Maternal, neonatal and birth complications were reported. A multivariate model was developed to predict the most common pregnancy complication, GDM, by using univariate and multivariate logistic regression of preconception patient characteristics. The area under the curve (AUC) of the receiver-operating characteristic was used to test the performance of the model. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 189 women (58%) achieved an ongoing pregnancy (8% multiples) and delivered a live-born neonate. One or two maternal complications occurred in 62 (33%) pregnant women, mainly GDM (n = 41; 22%) and pregnancy-induced hypertension (n = 14; 7%). In children, one or two complications were observed in 49 (26%) of 206 children born, e.g. premature delivery (n = 23; 12%) and small for gestational age (n = 15; 8%). The preconception prediction model for GDM performed well (AUC 0.87, 95% CI 0.81-0.93). First-degree relatives with type 2 diabetes mellitus, serum levels of fasting glucose, fasting insulin, androstenedione and sex hormone-binding globulin before conception were identified as predictors. LIMITATIONS, REASONS FOR CAUTIONS: The prediction model has not yet been externally validated in another group of patients. Also, there were missing data for some of the determinants, which were accounted for by multiple imputation. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS who achieve a pregnancy have an increased risk of GDM. The prediction model can be used to identify women particularly at risk for GDM who should be monitored closely to enable preventative measures that may reduce the risk of developing GDM and its adverse consequences. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for the study. M.A.W., S.M.V.V., A.J.G., A.F. and M.P.H.K. have nothing to disclose. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, European Society of Human Reproduction and Embryology and MSD. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, Merck-Serono, MSD, Organon, Schering Plough, Sharp & Dome and Serono. M.J.C. has received grant support from the following companies (in alphabetic order): Illumina and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Ferring, Ova-Science, PregLem SA, Roche and Watson Laboratories. TRIAL REGISTRATION NUMBER: NCT00821379 [Clinicaltrials.gov].

The incidence of Barrett's oesophagus and oesophageal adenocarcinoma in the United Kingdom and The Netherlands is levelling off.

BACKGROUND: Barrett's oesophagus (BO) is a risk factor for oesophageal adenocarcinoma (OAC). Several studies report increasing incidences of BO with substantial variation. AIM: To determine age- and sex-stratified incidence rates (IR) of BO and OAC. METHODS: Cohort study using two primary care databases in the United Kingdom (UK) and the Netherlands (NL) (2000-2012). BO and OAC cases were identified using disease-specific READ codes (UK) and free-text search with manual validation (NL). Age- and sex-specific incidence rates (IRs) were calculated for both BO and OAC. RESULTS: From the study population of 6,885,420 subjects in the UK, we identified 12,312 incident BO and 40 (0.3%) subsequent incident OAC cases. There were 1383 incident BO, and subsequent 5 (0.4%) incident OAC cases among the 1,487,191 subjects in the NL. The IR of BO increased linearly with age: 15.6/100,000 PYs (UK) and 23.7/100,000 PYs (NL) for patients aged 40-44 years, increasing to 85.6/100,000 PYs (UK) and 87.0/100,000 PYs (NL) for 70-74 years. In both the UK and the NL, IR of BO was 2-4 times higher in males than females across all age groups. With respect to calendar time, the IR of BO increased by 35% (UK) and 41% (NL) from 2000 to 2003, after which IRs remained stable until 2012. CONCLUSIONS: The incidence rates of BO in the UK and the NL increased until 2003, but levelled off thereafter. Around 0.3% of patients with BO developed OAC at least 1 year after BO diagnosis. These findings may help tailor endoscopic surveillance strategies among patients with BO.

Lesion location and repeatable battery for the assessment of neuropsychological status performance in acute ischemic stroke.

The validity of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was evaluated in a sample of acute ischemic stroke patients. A total of 164 ischemic stroke patients with anterior fossa lesions were divided into groups according to lesion laterality (left, right, or bilateral) and location (cortical versus subcortical) as determined by CT and/or MRI findings. The hypotheses for this study were: (1) that left hemispheric stroke patients would perform better than their counterparts on the Visuospatial/Constructional and Attention Indexes; (2) that right hemisphere stroke patients would outperform their counterparts on the Immediate Memory, Delayed Memory, and Language Indexes; (3) that patients with subcortical lesions would outperform those with cortical lesions on the Language, Immediate Memory, and Delayed Memory indexes; and (4) that patients with cortical lesions would outperform those with subcortical lesions on the Attention and Visuospatial/Constructional Indexes. A multivariate analysis of variance (MANOVA) disclosed significant main effects for both lesion side and location, with no location by side interaction. Group comparisons of the five RBANS index scores disclosed modest effects for side of lesion, with right hemisphere patients outperforming those with left sided and bilateral lesions on the Immediate and Delayed Memory, and Language Index Scores. Right hemisphere stroke patients also outperformed left and bilateral lesion patients on the Attention Index. The left hemisphere patients outperformed the right hemisphere and bilateral patients on the Visuospatial/Constructional Index. The effect for location was significant only for the Visuospatial/Constructional Index where the subcortical patients outperformed the cortical patients.

Sildenafil therapy in secondary pulmonary hypertension: Is there benefit in prolonged use?

BACKGROUND: Sildenafil is of benefit to selected patients with pulmonary hypertension due to parenchymal lung or cardiac disease. We present data from patients with secondary pulmonary hypertension, comparing their right heart catheter results and six minute walking distance to time on treatment. METHODS: 25 patients with symptomatic secondary pulmonary hypertension received sildenafil 50 mg tds in a 5-year period. Underlying causes were chronic inoperable thromboembolic disease (11), COPD (6), interstitial lung disease (5) and valvular heart disease (3). Their cardio-pulmonary haemodynamics were measured with right heart catheterization prior to treatment, post-treatment at 2, 6 and 12 months and subsequently depending upon clinical need. Six-minute walk distance was also measured. RESULTS: Patient age range was 40 to 83 (median 70.5) years. Time of treatment to latest right heart catheter was 2 to 60 (median 17) months and 8 to 61 (median 34) months to clinic follow-up or death. There was a significant reduction in six-minute walk distance from baseline to long term (>12 months) follow-up (p=0.002). Pulmonary vascular resistance was significantly reduced from baseline to 12 months (p=0.049). The mean pulmonary arterial (PA) pressure was significantly reduced at long-term follow-up (p=0.009). 20 patients had an improved PA pressure with treatment. In those with a worsening PA pressure, two had an improvement in cardiac output and six minute walk distance, two had stable cardiac output at 20 and 21 months, and one had measurements taken during a significant illness. Three patients, who had a reduction in PA pressure, subsequently died of progression of underlying illness at 8 months, from myocardial infarction at 34 months, and from aspergillus pneumonia at 59 months. CONCLUSION: Long-term use of sildenafil in patients with secondary forms of pulmonary hypertension is associated with a sustained improvement in cardio-pulmonary haemodynamics. Lack of improvement may be attributed to other factors apart from treatment failure, such as underlying disease progression or unrelated concurrent illness at time of assessment.

Differential effects of stress on adult hippocampal cell proliferation in low and high aggressive mice.

Male wild house mice selected for a long (LAL) or a short (SAL) latency to attack a male intruder generally show opposing behavioural coping responses to environmental challenges. LAL mice, unlike SAL mice, adapt to novel challenges with a highly reactive hypothalamic-pituitary-adrenal axis and show an enhanced expression of markers for hippocampal plasticity. The present study aimed to test the hypothesis that these features of the more reactive LAL mice are reflected in parameters of hippocampal cell proliferation. The data show that basal cell proliferation in the subgranular zone (SGZ) of the dentate gyrus, assessed by the endogenous proliferation marker Ki-67, is lower in LAL than in SAL mice. Furthermore, application of bromodeoxyuridine (BrdU) over 3 days showed an almost two-fold lower cell proliferation rate in the SGZ in LAL versus SAL mice. Exposure to forced swimming resulted, 24 h later, in a significant reduction in BrdU + cell numbers in LAL mice, whereas cell proliferation was unaffected by this stressor in SAL mice. Plasma corticosterone and dentate gyrus glucocorticoid receptor levels were higher in LAL than in SAL mice. However, no differences between the SAL and LAL lines were found for hippocampal NMDA receptor binding. In conclusion, the data suggest a relationship between coping responses and hippocampal cell proliferation, in which corticosterone may be one of the determinants of line differences in cell proliferation responses to environmental challenges.