Hypoxia-inducible factors activator, roxadustat, increases pulmonary vascular resistance in rats.

Activators of hypoxia inducible factors (HIFs), such as roxadustat, are promising agents for anemia treatment. However, since HIFs are also involved in the regulation of the pulmonary circulation, we hypothesized that roxadustat increases pulmonary vascular resistance and vasoconstrictor reactivity. Using isolated, cell-free solution perfused rat lungs, we found perfusion pressure-flow curves to be shifted to higher pressures by 2 weeks of roxadustat treatment (10 mg/kg every other day), although not as much as by chronic hypoxic exposure. Vasoconstrictor reactivity to angiotensin II and acute hypoxic challenges was not altered by roxadustat. Since roxadustat may inhibit angiotensin-converting enzyme 2 (ACE2), we also tested a purported ACE2 activator, diminazene aceturate (DIZE, 0.1 mM). It produced paradoxical, unexplained pulmonary vasoconstriction. We conclude that the risk of serious pulmonary hypertension is not high when roxadustat is given for 14 days, but monitoring is advisable.

A man who became breathless after tiling a bathroom.

Inhalational lung injury should be considered in patients presenting with acute respiratory symptoms and a history of occupational or recreational exposure to toxic substances. We present the case of a 29-year-old patient who developed pneumonitis following usage of waterproofing sealant spray in an enclosed space, despite the use of a dust mask. The patient was managed with oxygen therapy, corticosteroids and bronchodilators. He made a complete clinical recovery with resolution of almost all changes seen on computerised tomography (CT) imaging within 7 days.

Idiopathic Pulmonary Arterial Hypertension Unmasked by Pregnancy.

A 31-year old woman presented to the acute medical unit 9 days post-partum with shortness of breath and peripheral oedema. Initially suspected to have either a pulmonary embolism or post-partum cardiomyopathy, she proceeded to have imaging including a CT Pulmonary angiogram and echocardiogram, which were suggestive of pulmonary hypertension and severe right heart failure. Her history and other investigations did not reveal any obvious cause for this. She was transferred to a specialist centre where she was diagnosed with Idiopathic Pulmonary Arterial Hypertension (IPAH), previously known as primary pulmonary hypertension. Shortness of breath during pregnancy and in the postpartum period is a relatively common acute medical presentation. Whilst IPAH is a rare diagnosis, it carries a high mortality rate, particularly in pregnancy, and requires prompt specialist investigation, diagnosis and management.

Neutrophil elastase and endogenous inhibitors in Behçet's disease saliva.

Behçet's disease (BD) is a vasculitis of unknown aetiology typified by chronic recurrent oral ulcers and systemic inflammatory manifestations. Neutrophils, and specifically their protease neutrophil elastase (NE), have been implicated in its pathology. Although NE is an effective anti-microbial, excessive NE can damage host tissue. Recurrent oral ulceration is a primary BD symptom, therefore we hypothesized that excessive neutrophil infiltration evidenced by increased NE and a reduction in specific endogenous inhibitors, secretory leucocyte protease inhibitor (SLPI) and alpha1-anti-trypsin (α1AT) contributes to BD mucosal instability. NE, SLPI and α1AT were quantified in saliva from BD patients with active oral ulcers (BDa) and quiet without ulcers (BDq), recurrent aphthous stomatitis (RASa; RASq) and healthy controls (HC). Although BDq saliva had marginally higher median NE levels (1112 ng/ml) compared to both RASq (1043 ng/ml) and HC (999 ng/ml), SLPI was significantly reduced in BDq (P < 0·01). Despite decreased SLPI protein, mRNA expression was significantly increased in BDq buccal epithelial swabs compared to RASq and HC (P < 0·05, P < 0·001). NE remained enzymatically active, although α1AT levels were at least eight times higher than SLPI in all groups, suggesting that α1AT does not have a primary role in counteracting NE in saliva. Furthermore, NE levels in BDa patients medicated with both azathioprine (AZA) and colchicine (COLC) were significantly lower than those on COLC (P = 0·0008) or neither (P = 0·02), indicating that combining AZA + COLC may help to regulate excessive NE during ulceration. This study showed that enzymatically active NE coupled with reduced SLPI in BD saliva may contribute to recurrent oral ulcerations.

Three-dimensional conformal radiotherapy versus intensity modulated radiotherapy with simultaneous integrated boost in the treatment of locally advanced head and neck carcinoma.

The treatment of locally advanced head and neck cancer (LAHNC) requires a multimodality approach. Radiotherapy with combination of chemotherapy are demonstrated to be effective, however, the treatment intensification leads to increased toxicity at the same time. The implementation of three-dimensional conformal radiotherapy (3D-CRT) allowed to irradiate the treatment volume more precisely with better surrounding healthy tissue sparing. Intensity modulated radiotherapy (IMRT) facilitated higher conformity in dose shaping to target volume. IMRT with simultaneous integrated boost (IMRT-SIB) offered the possibility to deliver individualized dose levels within one fraction and enabled escalation of the dose per fraction and radiotherapy acceleration. The aim of our study was to compare the technique of 3D-CRT and IMRT-SIB in the treatment of LAHNC and evaluate the treatment outcome and the treatment-related toxicity. 262 patients in 3D-CRT group and 263 patients in IMRT-SIB group underwent the radical treatment for LAHNC between 1/1998 and 12/2016. No statistically significant differences in locoregional control (LCR) and overall survival (OS) were found between the two groups. Acute toxicity and xerostomia were significantly reduced in the patients treated by IMRT-SIB. IMRT-SIB is a safe radiotherapy method where less toxicity was proven without compromising local control and overall survival.

A Chest X-Ray causing confusion.

A 91-year old female presented to Acute Medical Unit with a 2 week history of shortness of breath and haemoptysis. Her past medical history included osteoporosis, depression, irritable bowel syndrome, asthma, cataracts, and a colonic polypectomy. Her medications: Citalopram 10 mg, Co-codamol, Beclomethasone 200 mcg inhaler, Salbutamol MDI inhaler, Omeprazole 20 mg and Alendronic acid. She was an ex-smoker with a 20-pack year history who had stopped smoking 40-years ago. She did not drink alcohol and lived alone independently.

Theta burst stimulation in the treatment of chronic orofacial pain: a randomized controlled trial.

Theta burst stimulation (TBS) is a modified form of high-frequency repetitive transcranial magnetic stimulation (rTMS) with promising effect in chronic pain. The aim of our double-blind, sham-controlled, parallel-group, randomized study was to assess an efficacy of intermittent TBS (iTBS) in the treatment of patients with chronic orofacial pain. Nineteen patients (twelve females) with chronic orofacial pain were prospectively included and randomly assigned to single session of an active (iTBS) or sham (intermediate TBS; imTBS) stimulation delivered to the primary motor cortex (M1) contralateral to painful side. The primary outcome was pain relief assessed using a visual analogue scale (VAS) after stimulation and at the end of two-week follow- up. The secondary outcomes were changes in the quantitative sensory testing (QST). QST set the threshold for thermal and tactile (touch) sensation in the affected facial area. Intermittent TBS, compared with the sham, showed significant improvement in VAS after stimulation, but not at the end of two-week follow-up. Regarding the secondary outcomes (QST), we failed to find any significant difference between iTBS and sham. Our findings demonstrate that iTBS of M1 transiently provides transient and modest subjective pain relief in chronic orofacial pain.

Psychiatrist's adherence: a new factor in relapse prevention of schizophrenia. A randomized controlled study on relapse control through telemedicine system.

ACCESSIBLE SUMMARY: Exposure to psychotic states has detrimental effects on the long-term outcome of schizophrenia and brain integrity. Therefore, improving relapse prevention is a key component of long-term management of schizophrenia. Previous studies using continuous monitoring of an individual's early signs of relapse and adopting preventative pharmacological interventions, when early signs are detected, showed promising clinical results in terms of relapse risk reduction. This 18-month multi-centre parallel randomized controlled, open label, trial with telemedicine relapse prevention programme ITAREPS failed to show superiority of maintenance plus prodrome-based targeted medication strategy over treatment as usual. The study, marked by low investigator's adherence, confirmed that absence of pharmacological intervention at early stage of prodrome, critically influenced the risk of relapse. This and previous randomized controlled trials with telemedicine programme ITAREPS suggested that substantial improvement in relapse prevention in schizophrenia is likely to be unattainable under current clinical settings. Future preventive strategies in schizophrenia would require rapid pharmacological intervention upon occurrence of subclinical prodromal symptoms that are undetectable under conventional outpatient practice. Studies with ITAREPS suggested that integration of telemedicine relapse prevention systems and visiting nurse service might together represent practical solution capable to address those requirements. ABSTRACT: The Information Technology Aided Relapse Prevention Programme in Schizophrenia (ITAREPS) presents a telemedicine solution for weekly monitoring and management of schizophrenia. This study aims to evaluate the effectiveness of the programme in reducing the number of hospitalizations during the 18-month multi-centre parallel randomized controlled, open label, trial. Outpatients with schizophrenia or schizoaffective disorder were randomized to the active (n = 74) or control group (n = 72). In the active arm, investigators increased the antipsychotic dose upon occurrence of prodrome announced by the system. Intention-to-treat analysis showed no between-group difference in the hospitalization-free survival rate [Kaplan-Meier method; hazard ratio (HR) = 1.21, 95% confidence interval (CI): 0.56-2.61, P = 0.6). In a post hoc multivariate Cox proportional hazards model, out of 13 potential predictors, only ITAREPS-related variables (number of alerts without pharmacological intervention/HR = 1.38, P = 0.042/ and patient non-adherence with ITAREPS /HR = 1.08, P = 0.009/) increased the risk of hospitalization. In this trial ITAREPS was not effective. The results in context with previous ITAREPS studies suggest non-adherence of both psychiatrists and patients as the main reasons for the failure of this preventive strategy. Tertiary prevention in schizophrenia have to be regarded a major challenge, warranting the need for implementation of strategies with more active participation of both patient and treating psychiatrist.

White matter changes in first episode psychosis and their relation to the size of sample studied: a DTI study.

BACKGROUND: White matter abnormality has been recently proposed as a pathophysiological feature of schizophrenia (SZ). However, most of the data available has been gathered from chronic patients, and was therefore possibly confounded by factors such as duration of the disease, and treatment received. The extent and localization of these changes is also not clear. METHODS: We examined a population of early stage SZ patients using diffusion tensor imaging (DTI). 77 SZ patients and 60 healthy controls (HCs) were included in the analysis using Tract-Based Spatial Statistics (TBSS). We have also analyzed 250 randomly created subsets of the original cohort, to investigate the relation between the result of TBSS analysis, and the size of the sample studied. RESULTS: We have found a significant decrease in fractional anisotropy (FA) in the patient group. This change is present in most major white matter (WM) tracts including the corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, and posterior thalamic radiation. Furthermore, we identified a clear trend towards an increase in the number and spatial extent of significant voxels reported, with an increasing number of subjects included in the analysis. CONCLUSION: Our study shows that FA is significantly decreased in patients at an early stage of schizophrenia, and that the extent of this finding is dependent on the size of studied sample; therefore underpowered studies might produce results with false spatial localization.

Optical clearing in collagen- and proteoglycan-rich osteochondral tissues.

OBJECTIVE: Recent developments in optical clearing and microscopy technology have enabled the imaging of intact tissues at the millimeter scale to characterize cells via fluorescence labeling. While these techniques have facilitated the three-dimensional (3D) cellular characterization within brain and heart, study of dense connective tissues of the musculoskeletal system have been largely unexplored. Here, we quantify how optical clearing impacted the cell and tissue morphology of collagen-, proteoglycan-, and mineral-rich cartilage and bone from the articulating knee joint. METHODS: Water-based fructose solutions were used for optical clearing of bovine osteochondral tissues, followed by imaging with transmission and confocal microscopy. To confirm preservation of tissue structure during the clearing process, samples were mechanically tested in unconfined compression and visualized by cryo-SEM. RESULTS: Optical clearing enhanced light transmission through cartilage, but not subchondral bone regions. Fluorescent staining and immunolabeling was preserved through sample preparations, enabling imaging to cartilage depths five times deeper than previously reported, limited only by the working distance of the microscope objective. Chondrocyte volume remained unchanged in response to, and upon the reversal, of clearing. Equilibrium modulus increased in cleared samples, and was attributed to exchange of interstitial fluid with the more viscous fructose solution, but returned to control levels upon unclearing. In addition, cryo-SEM-based analysis of cartilage showed no ultrastructural changes. CONCLUSION: We anticipate large-scale microscopy of diverse connective tissues will enable the study of intact, 3D interfaces (e.g., osteochondral) and cellular connectivity as a function of development, disease, and regeneration, which have been previously hindered by specimen opacity.

Direct noninvasive measurement and numerical modeling of depth-dependent strains in layered agarose constructs.

Biomechanical factors play an important role in the growth, regulation, and maintenance of engineered biomaterials and tissues. While physical factors (e.g. applied mechanical strain) can accelerate regeneration, and knowledge of tissue properties often guide the design of custom materials with tailored functionality, the distribution of mechanical quantities (e.g. strain) throughout native and repair tissues is largely unknown. Here, we directly quantify distributions of strain using noninvasive magnetic resonance imaging (MRI) throughout layered agarose constructs, a model system for articular cartilage regeneration. Bulk mechanical testing, giving both instantaneous and equilibrium moduli, was incapable of differentiating between the layered constructs with defined amounts of 2% and 4% agarose. In contrast, MRI revealed complex distributions of strain, with strain transfer to softer (2%) agarose regions, resulting in amplified magnitudes. Comparative studies using finite element simulations and mixture (biphasic) theory confirmed strain distributions in the layered agarose. The results indicate that strain transfer to soft regions is possible in vivo as the biomaterial and tissue changes during regeneration and maturity. It is also possible to modulate locally the strain field that is applied to construct-embedded cells (e.g. chondrocytes) using stratified agarose constructs.

Repetitive transcranial magnetic stimulation in the treatment of chronic orofacial pain.

Repetitive transcranial magnetic stimulation (rTMS) is non-invasive neuromodulation method. We applied rTMS for the treatment of farmacoresistant chronic orofacial pain. We compared the effect of 10 Hz and 20 Hz stimulation. The study included 23 patients for 20 Hz stimulation and 36 patients for 10 Hz stimulation with pharmacotherapy resistant chronic facial pain aged 33-65 years with pain duration of at least 6 months. Monitoring of treatment effects was performed within 15 minutes of each rTMS application (days 1-5) and finally stimulation (active vs. sham coil). If compared with data with 10 Hz rTMS study (n=36) and with 20 Hz rTMS (n=23) trials using a parallel design. Only the results obtained in a series of five rTMS treatments in the first step (active n=24, sham n=12), that 20 Hz frequency rTMS using a higher intensity (95 % of motor threshold) to be equally effective relative to VAS (Visual analogue scale) and QST (quantitative sensory testing). In conclusions, the better results with the relief of orofacial pain were obtained with 20 Hz stimulation if compared with 10 Hz stimulation. It was proved with subjective (VAS) and objective evaluation (QST). rTMS can be used in the treatment of chronic intractable pain.

Differences in onset of disease and severity of psychopathology between toxoplasmosis-related and toxoplasmosis-unrelated schizophrenia.

OBJECTIVE: Toxoplasmosis is a lifelong parasitic disease that appears to be associated to schizophrenia. However, no distinguishing attributes in Toxoplasma-infected schizophrenia patients have been described as yet. METHOD: We searched for differences in symptom profile, cognitive performance and treatment response between 194 Toxoplasma-free and 57 (22.7%) Toxoplasma-infected schizophrenia patients treated in Prague Psychiatric Centre between 2000 and 2010. RESULTS: Infected and non-infected patients differed in severity of symptoms (P = 0.032) measured with the Positive and Negative Symptom Scale (PANSS). Infected patients scored higher in positive subscale of PANSS, but not in the general and negative subscales. Infected men scored higher also in Total PANSS score, and negative, reality distortion, disorganisation and cognitive scores. Higher PANSS scores of positive, negative and disorganised psychopathology were associated with the lower titres of anti-Toxoplasma antibodies suggesting that psychopathology deteriorates with duration of parasitic infection. Infected patients remained about 33 days longer in hospital during their last admission than uninfected ones (P = 0.003). Schizophrenia started approximately 1 year earlier in infected men and about 3 years later in infected women, no such difference was observed in uninfected subjects. CONCLUSION: Latent toxoplasmosis in schizophrenia may lead to more severe positive psychopathology and perhaps less favourable course of schizophrenia.

The early improvement of depressive symptoms as a potential predictor of response to antidepressants in depressive patients who failed to respond to previous antidepressant treatments. Analysis of naturalistic data.

INTRODUCTION: Current studies suggest that improvement of depressive symptoms after 2 weeks of treatment could predict the subsequent response. The aim of our study was to compare the predictive effect of early improvement (EI) after 1 and 2 weeks of treatment in patients who had failed to respond to previous antidepressant treatments (≥1 unsuccessful antidepressant trial). METHOD: Seventy-one subjects were treated (≥4 weeks) with various antidepressants chosen according to the judgment of attending psychiatrists. We used three definitions of EI (MADRS reduction ≥20, 25, 30%) at both time points. Areas under curve (AUC) were calculated to compare predictive effect of EI. RESULTS: We found lower MADRS scores in weeks 1 and 2 in responders (≥50% reduction of MADRS, n=35) compared to nonresponders. AUCs of MADRS reduction for response prediction at week 1 and 2 were not significantly different (0.73 vs 0.8; p=0.24). CONCLUSION: The results indicate that improvement of depressive symptoms in the treatment of resistant patients may occur after the first week of treatment. The predictive potential might be comparable to that found after the second week of antidepressant intervention and be clinically meaningful.

Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect.

BACKGROUND: Theta cordance is a novel quantitative electroencephalography (QEEG) measure that correlates with cerebral perfusion. A series of clinical studies has demonstrated that the prefrontal theta cordance value decreases after 1 week of treatment in responders to antidepressants and that this effect precedes clinical improvement. Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, has a unique rapid antidepressant effect but its influence on theta cordance is unknown. METHOD: In a double-blind, cross-over, placebo-controlled experiment we studied the acute effect of ketamine (0.54 mg/kg within 30 min) on theta cordance in a group of 20 healthy volunteers. RESULTS: Ketamine infusion induced a decrease in prefrontal theta cordance and an increase in the central region theta cordance after 10 and 30 min. The change in prefrontal theta cordance correlated with ketamine and norketamine blood levels after 10 min of ketamine infusion. CONCLUSIONS: Our data indicate that ketamine infusion immediately induces changes similar to those that monoamineric-based antidepressants induce gradually. The reduction in theta cordance could be a marker and a predictor of the fast-acting antidepressant effect of ketamine, a hypothesis that could be tested in depressive patients treated with ketamine.

LCMS using a hybrid quadrupole time of flight mass spectrometer for impurity identification during process chemical development of a novel integrase inhibitor.

LCMS incorporating a quadrupole time of flight mass spectrometer was used to identify impurities found in a chemical process development sample of a novel integrase inhibitor, raltegravir. The combination of accurate mass measurement in full scan mode followed by construction of targeted masses for further MSMS interrogation allowed for the determination of atomic composition and connectivity. The fragmentation pattern of raltegravir was used as a model compound, and the product ion spectra of an impurity was compared to both the model fragmentation pattern and the atomic composition generated in the full scan experiment to deduce a structure.

Benefits of periodontal therapy when preterm birth threatens.

There is growing evidence that chronic periodontitis may be a risk factor for pre-term birth. The goal of this intervention study was to determine the effect of periodontal treatment on the pregnancy outcome in women with threatening pre-term birth and initial localized chronic periodontitis. Forty-one women with a singleton pregnancy were enrolled in the study. For this treatment group, oral hygiene instruction and periodontal therapy were provided in the third trimester, while those in the control group (42 persons) did not receive any periodontal treatment. In the treatment group, the mean weight of newborns was 3079.0 g, compared with the control group mean of 2602.4 g. The incidence of pre-term birth and low birthweight in the treatment group was significantly less than in the control group (p = 0.015). Periodontal treatment completed before the 35th week appeared to have a beneficial effect on birth weight and time of delivery.

The Information Technology Aided Relapse Prevention Programme in Schizophrenia: an extension of a mirror-design follow-up.

AIMS: Decreasing a number of hospital admissions is important for improving outcomes for people with schizophrenia. The Information Technology Aided Relapse Prevention Programme in Schizophrenia (ITAREPS) programme enables early pharmacological intervention in psychosis by identification of prodromal symptoms of relapse using home telemonitoring via a phone-to-PC SMS platform. METHODS: This study was a 1-year extension of a previously published mirror-design follow-up evaluation of programme clinical effectiveness. In total, 73 patients with psychotic illness (45 patients from original sample and 28 newly added subjects) collaborating with 56 family members participated in the clinical evaluation. RESULTS: There was a statistically significant 77% decrease in the number of hospitalisations during the mean 396.8 +/- 249.4 days of participation in ITAREPS, compared with the same time period before participation in ITAREPS (Wilcoxon-signed ranks test, p < 0.00001), as well as significantly reduced number of hospitalisation days when in the ITAREPS (2365 hospitalisation days before and 991 days after ITAREPS enrolment respectively, Wilcoxon-signed ranks test, p < 0.003). CONCLUSION: The ITAREPS programme represents an effective tool in the long-term treatment of patients with psychotic disorders.