Short course of grass allergen peptides immunotherapy over 3 weeks reduces seasonal symptoms in allergic rhinoconjunctivitis with/without asthma: A randomized,multicenter, double‐blind,placebo‐controlled trial

Background

Immunotherapy with peptide hydrolysates from Lolium perenne (LPP) is an alternative treatment for seasonal allergic rhinitis with or without asthma. The aim of this study was to assess the clinical efficacy and safety of a cumulative dose of 170 μg LPP administered subcutaneously over 3 weeks.

Methods

In a randomized, double‐blind, placebo‐controlled trial, 554 adults with grass pollen rhinoconjunctivitis were randomized (1:2 ratio) to receive 8 subcutaneous injections of placebo or 170 μg LPP administered in increasing doses in 4 visits over 3 weeks. The primary outcome was the combined symptom and medication score (CSMS) measured over the peak pollen season. Reactivity to conjunctival provocation test (CPT) and quality of life (QOL) was assessed as secondary endpoints.

Results

The mean reduction in CSMS in the LPP vs placebo group was ?15.5% (P = .041) during the peak period and ?17.9% (P = .029) over the entire pollen season. LPP‐treated group had a reduced reactivity to CPT (P < .001) and, during the pollen season, a lower rhinoconjunctivitis QOL global score (P = .005) compared with placebo group. Mostly mild and WAO grade 1 early systemic reaction (ESR) were observed ≤30 minutes in 10.5% of LPP‐treated patients, whereas 3 patients with a medical history of asthma (<1%) experienced a serious ESR that resolved with rescue medication.

Conclusion

Lolium perenne pollen peptides administered over 3 weeks before the grass pollen season significantly reduced seasonal symptoms and was generally safe and well‐tolerated.

     

Lolium perenne peptide immunotherapy is well tolerated and elicits a protective B‐cell response in seasonal allergic rhinitis patients

Background

Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short‐course treatment with adjuvant‐free Lolium perenne peptides (LPP) following a 6‐week dose‐escalation protocol.

Methods

In a prospective, dose‐escalation study, 61 grass pollen–allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG₄ and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8).

Results

No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG₄ levels were higher at V6 (8.1‐fold, P < .001) and V8 (12.2‐fold, P < .001) than at V1. The sIgE:sIgG₄ ratio decreased at V6 (?54.6%, P < .001) and V8 (?71.6%, P < .001) compared to V1. The absolute decrease in IgE‐facilitated allergen binding was 18% (P < .001) at V6 and 25% (P < .001) at V8.

Conclusion

Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.

     

Dog saliva – an important source of dog allergens

Background

Allergy to dog (Canis familiaris) is a worldwide common cause of asthma and allergic rhinitis. However, dander extract in routine diagnostics is not an optimal predictor of IgE‐mediated dog allergy. Our objective was to evaluate saliva as an allergen source for improved diagnostics of allergy to dog.

Methods

IgE‐binding proteins in dog saliva and dander extract were analysed by immunoblot and mass spectrometry (LC‐MS/MS) using pooled or individual sera from dog‐allergic patients (n = 13). Sera from 59 patients IgE positive to dander and 55 patients IgE negative to dander but with symptoms to dog were analysed for IgE against saliva and dander by ELISA. Basophil stimulation with dog saliva and dander extract was measured by flow cytometry among three dog‐allergic patients. Additionally, IgE‐binding protein profiles of saliva from different breeds were investigated by immunoblot.

Results

Greater number and diversity of IgE‐binding proteins was found in saliva compared to dander extract and varied among dog breeds. In saliva, Can f 1, 2, 3 and 6 were identified but also four new saliva allergen candidates. The majority of the 59 dog dander–positive sera (n = 44) were IgE positive to dog saliva. Among patients IgE negative to dander, but with symptoms to dog, 20% were IgE positive to saliva. The biological activity of saliva was confirmed by basophil degranulation.

Conclusions

Dog saliva is an allergen source for improved diagnostics of dog allergy. The IgE‐binding protein profile of saliva from different dogs varies.

     

Omalizumab rapidly improves angioedema‐related quality of life in adult patients with chronic spontaneous urticaria: X‐ACT study data

Background

The X‐ACT study aimed to examine the effect of omalizumab treatment on quality of life (QoL) in chronic spontaneous urticaria (CSU) patients with angioedema refractory to high doses of H₁‐antihistamines.

Methods

In X‐ACT, a phase III, double‐blind, placebo‐controlled study, CSU patients (18‐75 years) with ≥4 angioedema episodes during the 6 months before inclusion were randomized (1:1) to receive omalizumab 300 mg or placebo every 4 weeks for 28 weeks. Angioedema‐related QoL, skin‐related QoL impairment, and psychological well‐being were assessed.

Results

Ninety‐one patients were randomized and 68 (omalizumab, n = 35; placebo, n = 33) completed the 28‐week treatment period. At baseline, the mean (SD) total Angioedema QoL (AE‐QoL; 56.2 [18.7] and 59.9 [19.2]) and Dermatology Life Quality Index (DLQI; 14.6 [5.7] and 16.6 [7.3]) score were high in the omalizumab and placebo group, respectively. At Week 4 (after the first treatment), the least squares mean difference in the AE‐QoL and DLQI score between groups was ?17.6 (P < .001) and ?7.2 (P < .001), respectively. Significant QoL improvements in the omalizumab vs placebo groups continued until Week 28, but returned to placebo levels at the follow‐up visit. The mean (SD) baseline 5‐item World Health Organization Well‐being Index was 10.0 (5.5, omalizumab) and 7.7 (5.3, placebo), which increased above the depression threshold (<13) from Week 4 and throughout with omalizumab but not placebo treatment. Compared to placebo, omalizumab was also associated with decreased fear of suffocation due to angioedema.

Conclusions

Our findings support omalizumab treatment in patients with severe H1‐antihistamine‐refractory CSU with angioedema.

     

50 years of rational‐emotive and cognitive‐behavioral therapy: A systematic review and meta‐analysis

Objective

Rational emotive behavior therapy (REBT), introduced by Albert Ellis in the late 1950s, is one of the main pillars of cognitive‐behavioral therapy. Existing reviews on REBT are overdue by 10 years or more. We aimed to summarize the effectiveness and efficacy of REBT since its beginnings and investigate the alleged mechanisms of change.

Method

Systematic search identified 84 articles, out of which 68 provided data for between‐group analyses and 39 for within‐group analyses.

Results

We found a medium effect size of REBT compared to other interventions on outcomes (d = 0.58) and on irrational beliefs (d = 0.70), at posttest. For the within‐group analyses, we obtained medium effects for both outcomes (d = 0.56) and irrational beliefs (d = 0.61). Several significant moderators emerged.

Conclusion

REBT is a sound psychological intervention. Directions for future studies are outlined, stemming from the limitations of existing ones.

     

Expression of MAGE‐A and NY‐ESO‐1 cancer/testis antigens is enriched in triple‐negative invasive breast cancers

Aims

A better understanding of the expression of cancer/testis antigens (CTAs) in breast cancer might enable the identification of new immunotherapy options, especially for triple‐negative (TN) tumours, which lack expression of the conventional therapeutic targets oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The aim of this study was to quantify the expression of MAGE‐A and NY‐ESO‐1 CTAs in breast cancer, and relate this to known clinicopathological parameters.

Methods and results

We surveyed MAGE‐A and NY‐ESO‐1 expression in an unselected cohort of 367 breast tumours (of which 65 were TN), with accompanying clinical follow‐up data, by using immunohistochemical analysis of tissue microarrays. Relevant to their potential as vaccine targets in breast cancer, MAGE‐A was expressed in 13% of cases, and NY‐ESO‐1 in 3.8%, with the majority of tumours showing fairly homogeneous staining within individual tissue cores (~85% of cases with staining in >75% of tumour cells). Most NY‐ESO‐1‐positive cases also expressed MAGE‐A (P = 2.06 × 10^?9), and both were strongly associated with the TN phenotype (P < 0.0001), with the most proliferative and poorly differentiated cases, in paticular, showing genomic instability. This was characterised by coexpression of c‐Kit and TTK, and overexpression of p53.

Conclusions

MAGE‐A and NY‐ESO‐1 are frequently expressed in TN breast cancer (~47% and 17% of TN cases, respectively), suggesting that targeting them could be feasible in this patient group. Expression is reasonably homogeneous in positive cases, suggesting that immunohistochemical analysis of tissue biopsies would be a reliable companion biomarker.

     

Enhancing group cognitive‐behavioral therapy for hoarding disorder with between‐session Internet‐based clinician support: A feasibility study

Objective

Hoarding disorder (HD) is difficult to treat. In an effort to increase efficacy and engagement in cognitive‐behavioral therapy (CBT), we developed and evaluated a novel intervention comprising group CBT combined with between‐session Internet‐based clinician support for people with HD.

Method

Twenty participants with HD received group CBT combined with an Internet‐support system enabling therapist–participant communication between group sessions.

Results

The treatment was associated with a significant reduction on the Saving Inventory—Revised (SI‐R) and a large effect size (Cohen's d = 1.57) was found at posttreatment. Treatment gains were maintained at the 3‐month follow‐up. Group attendance was high and no participants dropped out from treatment prematurely. Between‐session motivational support from the therapist was most frequently mentioned as the main strength of the system.

Conclusion

The results of this study support adding Internet‐based clinician support to group CBT for HD to increase treatment adherence and, potentially, improve the overall efficacy of CBT.

     

The prevalence of atopic dermatitis beyond childhood: A systematic review and meta‐analysis of longitudinal studies

Background

There are sparse and conflicting data regarding the long‐term clinical course of atopic dermatitis (AD). Although often described as a childhood disease, newer population‐based estimates suggest the prevalence of pediatric and adult disease may be similar.

Methods

Our objective was to determine whether there is a decline in the prevalence of AD in population‐based cohorts of patients followed longitudinally beyond childhood. We conducted a systematic review and meta‐analysis including studies assessing AD prevalence across 3 or more points in time. The primary outcome was weighted overall risk difference (percentage decrease in AD prevalence).

Results

Of 2080 references reviewed, 7 studies with 13 515 participants were included. Participants were assessed at 3‐6 time points, ranging from age 3 months to 26 years. The percentage decrease in prevalence after age 12 was 1%, which was not significantly different from zero (95% confidence interval ?2%‐5%). Similar results were found with other age cut‐offs.

Conclusion

The prevalence of AD in longitudinal birth cohort studies is similar in childhood and adolescence/early adulthood.

     

TRPV1 antagonists that cause hypothermia,instead of hyperthermia,in rodents: Compounds’ pharmacological profiles,in vivo targets,thermoeffectors recruited and implications for drug development

Aim

Thermoregulatory side effects hinder the development of transient receptor potential vanilloid‐1 (TRPV1) antagonists as new painkillers. While many antagonists cause hyperthermia, a well‐studied effect, some cause hypothermia. The mechanisms of this hypothermia are unknown and were studied herein.

Methods

Two hypothermia‐inducing TRPV1 antagonists, the newly synthesized A‐1165901 and the known AMG7905, were used in physiological experiments in rats and mice. Their pharmacological profiles against rat TRPV1 were studied in vitro.

Results

Administered peripherally, A‐1165901 caused hypothermia in rats by either triggering tail‐skin vasodilation (at thermoneutrality) or inhibiting thermogenesis (in the cold). A‐1165901‐induced hypothermia did not occur in rats with desensitized (by an intraperitoneal dose of the TRPV1 agonist resiniferatoxin) sensory abdominal nerves. The hypothermic responses to A‐1165901 and AMG7905 (administered intragastrically or intraperitoneally) were absent in Trpv1^?/? mice, even though both compounds evoked pronounced hypothermia in Trpv1^+/+ mice. In vitro, both A‐1165901 and AMG7905 potently potentiated TRPV1 activation by protons, while potently blocking channel activation by capsaicin.

Conclusion

TRPV1 antagonists cause hypothermia by an on‐target action: on TRPV1 channels on abdominal sensory nerves. These channels are tonically activated by protons and drive the reflectory inhibition of thermogenesis and tail‐skin vasoconstriction. Those TRPV1 antagonists that cause hypothermia further inhibit these cold defences, thus decreasing body temperature.

Significance

TRPV1 antagonists (of capsaicin activation) are highly unusual in that they can cause both hyper‐ and hypothermia by modulating the same mechanism. For drug development, this means that both side effects can be dealt with simultaneously, by minimizing these compounds’ interference with TRPV1 activation by protons.

     

Patients’ care dependency in mental health care: Development of a self‐report questionnaire and preliminary correlates

Objectives

Patients’ dependency on the therapist or treatment has received little empirical attention. To examine care dependency, we aimed to develop a theory‐driven questionnaire based on three hypothetical dimensions (passive–submissive dependency; active‐emotional dependency; and lack of perceived alternatives) and to provide a preliminary exploration of several correlates of care dependency.

Method

Care dependency, perceived social support, therapeutic alliance, remoralization, and symptom severity were measured in a large cross‐sectional sample of 742 outpatients with various psychiatric disorders. Test–retest reliability was established in a smaller patient sample.

Results

Findings indicated a reliable questionnaire measuring three unidimensional subscales of care dependency (i.e., submissive dependency, need for contact, and lack of perceived alternatives; α’s .74, .81, and .86 respectively; r_t1,t2’s .78, .76, and .80, respectively). These subscales were all positively correlated with each other and with patients’ self‐proclaimed care dependency, but divergent from patients’ trait dependency and symptoms of a dependent personality disorder. Moreover, higher levels of care dependency were correlated with lower levels of remoralization and more symptoms severity, and with a better therapeutic alliance.

Conclusions

A reliable and valid questionnaire was developed to measure patients’ care dependency. Future studies are needed to determine whether care dependency covers an unwanted side‐effect or a crucial ingredient of an effective treatment.

     

Increased FXYD1 and PGC‐1α mRNA after blood flow‐restricted running is related to fibre type‐specific AMPK signalling and oxidative stress in human muscle

Aim

This study explored the effects of blood flow restriction (BFR) on mRNA responses of PGC‐1α (total, 1α1, and 1α4) and Na⁺,K⁺‐ATPase isoforms (NKA; α_1‐3, β_1‐3, and FXYD1) to an interval running session and determined whether these effects were related to increased oxidative stress, hypoxia, and fibre type‐specific AMPK and CaMKII signalling, in human skeletal muscle.

Methods

In a randomized, crossover fashion, 8 healthy men (26 ± 5 year and 57.4 ± 6.3 mL kg^?1 min^?1) completed 3 exercise sessions: without (CON) or with blood flow restriction (BFR), or in systemic hypoxia (HYP, ~3250 m). A muscle sample was collected before (Pre) and after exercise (+0 hour, +3 hours) to quantify mRNA, indicators of oxidative stress (HSP27 protein in type I and II fibres, and catalase and HSP70 mRNA), metabolites, and α‐AMPK Thr¹⁷²/α‐AMPK, ACC Ser²²¹/ACC, CaMKII Thr²⁸⁷/CaMKII, and PLBSer¹⁶/PLB ratios in type I and II fibres.

Results

Muscle hypoxia (assessed by near‐infrared spectroscopy) was matched between BFR and HYP, which was higher than CON (~90% vs ~70%; P < .05). The mRNA levels of FXYD1 and PGC‐1α isoforms (1α1 and 1α4) increased in BFR only (P < .05) and were associated with increases in indicators of oxidative stress and type I fibre ACC Ser²²¹/ACC ratio, but dissociated from muscle hypoxia, lactate, and CaMKII signalling.

Conclusion

Blood flow restriction augmented exercise‐induced increases in muscle FXYD1 and PGC‐1α mRNA in men. This effect was related to increased oxidative stress and fibre type‐dependent AMPK signalling, but unrelated to the severity of muscle hypoxia, lactate accumulation, and modulation of fibre type‐specific CaMKII signalling.

     

Treatment of allergic rhinitis using mobile technology with real‐world data: The MASK observational pilot study

Background

Large observational implementation studies are needed to triangulate the findings from randomized control trials as they reflect “real‐world” everyday practice. In a pilot study, we attempted to provide additional and complementary insights on the real‐life treatment of allergic rhinitis (AR) using mobile technology.

Methods

A mobile phone app (Allergy Diary, freely available in Google Play and Apple App stores) collects the data of daily visual analog scales (VAS) for (i) overall allergic symptoms, (ii) nasal, ocular, and asthma symptoms, (iii) work, as well as (iv) medication use using a treatment scroll list including all medications (prescribed and over the counter (OTC)) for rhinitis customized for 15 countries.

Results

A total of 2871 users filled in 17 091 days of VAS in 2015 and 2016. Medications were reported for 9634 days. The assessment of days appeared to be more informative than the course of the treatment as, in real life, patients do not necessarily use treatment on a daily basis; rather, they appear to increase treatment use with the loss of symptom control. The Allergy Diary allowed differentiation between treatments within or between classes (intranasal corticosteroid use containing medications and oral H1‐antihistamines). The control of days differed between no [best control], single, or multiple treatments (worst control).

Conclusions

This study confirms the usefulness of the Allergy Diary in accessing and assessing everyday use and practice in AR. This pilot observational study uses a very simple assessment (VAS) on a mobile phone, shows novel findings, and generates new hypotheses.

     

Epidemiology of atopic dermatitis in adults: Results from an international survey

Background

There are gaps in our knowledge of the prevalence of adult atopic dermatitis (AD).

Objective

To estimate the prevalence of AD in adults and by disease severity.

Methods

This international, cross‐sectional, web‐based survey was performed in the United States, Canada, France, Germany, Italy, Spain, United Kingdom, and Japan. Adult members of online respondent panels were sent a questionnaire for AD identification and severity assessment; demographic quotas ensured population representativeness for each country. A diagnosis of AD required subjects to be positive on the modified UK Working Party/ISAAC criteria and self‐report of ever having an AD diagnosis by a physician. The proportion of subjects with AD who reported being treated for their condition was determined and also used to estimate prevalence. Severity scales were Patient‐Oriented SCORAD, Patient‐Orientated Eczema Measure, and Patient Global Assessment.

Results

Among participants by region, the point prevalence of adult AD in the overall/treated populations was 4.9%/3.9% in the US, 3.5%/2.6% in Canada, 4.4%/3.5% in the EU, and 2.1%/1.5% in Japan. The prevalence was generally lower for males vs females, and decreased with age. Regional variability was observed within countries. Severity varied by scale and region; however, regardless of the scale or region, proportion of subjects reporting severe disease was lower than mild or moderate disease.

Conclusions

Prevalence of adult AD ranged from 2.1% to 4.9% across countries. Severe AD represented a small proportion of the overall AD population regardless of measure or region.

     

The D‐vitamin metabolite 1,25(OH)2D in serum is associated with disease activity and Anti‐Citrullinated Protein Antibodies in active and treatment naïve,early Rheumatoid Arthritis Patients

Rationale

Sufficient levels of vitamin D seem to be essential for proper immune function, and low levels might be associated to disease activity in Rheumatoid Arthritis (RA ). Most studies investigate only 25OHD and not the physiologically active vitamin D metabolite, 1,25(OH )₂D.

Objective

To investigate associations between serum level of vitamin D metabolites and disease activity parameters in 160 inflammatory active and treatment naïve early RA patients. Serum level of vitamin D metabolites (25OHD ₂, 25OHD ₃ and 1,25(OH )₂D) was measured by isotope dilution mass spectrometry and radio‐immunoassays at baseline. Disease characteristics were gender, number of tender joints, number of swollen joints, DAS 28‐CRP , HAQ , VAS ‐scores, CRP , erosive status (Total Sharp Score; TSS ), ACPA and IgM‐RF ‐status. Associations were evaluated using Spearman's and Wilcoxon rank‐sum tests. The study was registered in clinical trials; trial registration number: NCT 00209859.

Findings

Statistically significant inverse associations were found between the active metabolite 1,25(OH )₂D and DAS 28‐CRP (P  = 0.004, rho = −0.23), HAQ (P  = 0.005, rho = −0.22), CRP (P  = 0.001, rho = −0.25), VAS _{patient‐pain} (P  = 0.008, rho = −0.21), and a positive association was found to ACPA ‐status (P  = 0.04).

Conclusion

The vitamin D metabolite 1,25(OH )₂D was inversely associated with disease activity and positively associated with ACPA in treatment naïve and inflammatory active early RA . The results indicate that in RA , both the degree of inflammatory activity, and the diagnostic sensitivity and specificity might affect—or might be affected by the level of vitamin 1,25(OH )₂D.

     

Psychosis and sexual abuse: An interpretative phenomenological analysis

Objectives

This study aimed to investigate the first‐person perspective of psychosis sufferers who survived childhood sexual abuse.

Methods

Interpretative phenomenological analysis was employed to explore the experiences of 7 women with a history of sexual abuse and psychosis.

Results

Analysis generated six themes: (a) degradation of self, interlinking shame, guilt, and sometimes disgust; (b) body‐self entrapment, experiencing bodily constraint and distortion; (c) a sense of being different to others, involving interpersonal problems; (d) unending struggle and depression, a pervasive sense of defeat; (e) psychotic condemnations and abuse, describing psychotic phenomena related to harm and sexual abuse; and (f) perception of links to the past, the links made from past abuse to current functioning.

Conclusion

Participants suffered extreme psychological, physical, and interpersonal difficulties past and present. Psychotic experiences reported exhibited themes of condemnation by external entities and reflected the topic of sexual abuse. Participants did not generally link psychosis to their past abusive experiences.

     

Interleukin-33 amplifies IgE synthesis and triggers mast cell degranulation via interleukin-4 in naïve mice

Background

The regulation and function of IgE in healthy individuals and in antigen‐naïve animals is not well understood. IL‐33 administration increases serum IgE in mice with unknown mechanism. We tested the hypothesis that IL‐33 provides an antigen‐independent stimulus for IgE production and mast cell degranulation.

Methods

IL‐33 was administered to naïve wild‐type (WT), nude and ST2^?/?, IL‐4^?/?, IL4Rα^?/? and T‐or B‐cell‐specific IL‐4Rα^?/? mice. IgEand cytokines were quantified by ELISA. T‐ and B‐lymphocyte numbers and CD40L expression were determined by flow cytometry. Anaphylaxis was measured by temperature, mast cell degranulation and histamine release.

Results

IL‐33 enhanced IgE production in naïve WT, T‐IL‐4Rα^?/? but not in ST2^?/?, IL‐4^?/?, IL‐4Rα^?/? or B‐cell‐specific IL‐4Rα^?/? mice, demonstrating IL‐33 specificity and IL‐4 dependency. Moreover, IL‐4 was required for IL‐33‐induced B‐cell proliferation and T‐cell CD40L expression, which promotes IgE production. IL‐33‐induced IL‐4 production was mainly from innate cells including mast cells and eosinophils. IL‐33 increased mast cell surface IgE and triggered degranulation and systemic anaphylaxis in allergen‐naïve WT but not in IL‐4Rα^?/? mice.

Conclusion

IL‐33 amplifies IgE synthesis and triggers anaphylaxis in naïve mice via IL‐4, independent of allergen. IL‐33 may play an important role in nonatopic allergy and idiopathic anaphylaxis.

     

Histopathology of Middle East respiratory syndrome coronovirus (MERS‐CoV) infection – clinicopathological and ultrastructural study

Aims

The pathogenesis, viral localization and histopathological features of Middle East respiratory syndrome – coronavirus (MERS‐CoV) in humans are not described sufficiently. The aims of this study were to explore and define the spectrum of histological and ultrastructural pathological changes affecting various organs in a patient with MERS‐CoV infection and represent a base of MERS‐CoV histopathology.

Methods and results

We analysed the post‐mortem histopathological findings and investigated localisation of viral particles in the pulmonary and extrapulmonary tissue by transmission electron microscopic examination in a 33‐year‐old male patient of T cell lymphoma, who acquired MERS‐CoV infection. Tissue needle biopsies were obtained from brain, heart, lung, liver, kidney and skeletal muscle. All samples were collected within 45 min from death to reduce tissue decomposition and artefact. Histopathological examination showed necrotising pneumonia, pulmonary diffuse alveolar damage, acute kidney injury, portal and lobular hepatitis and myositis with muscle atrophic changes. The brain and heart were histologically unremarkable. Ultrastructurally, viral particles were localised in the pneumocytes, pulmonary macrophages, renal proximal tubular epithelial cells and macrophages infiltrating the skeletal muscles.

Conclusion

The results highlight the pulmonary and extrapulmonary pathological changes of MERS‐CoV infection and provide the first evidence of the viral presence in human renal tissue, which suggests tissue trophism for MERS‐CoV in kidney.

     

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

Aim

Diabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main β‐cell keratins, and knockout of K8 (K8^?/?) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during β‐cell stress and that decreased K8 levels contribute to diabetes susceptibility.

Methods

K8‐heterozygous knockout (K8^+/?) and wild‐type (K8^+/+) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)‐induced β‐cell stress and T2D high‐fat diet (HFD).

Results

Murine K8^+/? endocrine islets express ~50% less K8/K18 compared with K8^+/+. The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, β‐cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8^+/? mice after low‐dose/chronic STZ treatment, and STZ causes more β‐cell damage and polyuria in K8^+/? compared with K8^+/+. K8 appears upregulated 5 weeks after STZ treatment in K8^+/+ islets but not in K8^+/?. K8^+/? mice showed no major susceptibility risk to HFD compared to K8^+/+.

Conclusion

Partial K8 deficiency reduces β‐cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD.

     

Treatment course and its predictors in patients with somatoform disorders: A routine outcome monitoring study in secondary psychiatric care

Aim

Somatoform disorders are common and often chronic. It would be helpful to distinguish those patients who are likely to have a positive treatment course from those who are likely to follow a negative course. Such studies of different somatoform disorders are scarce, especially in secondary psychiatric care. This study examined the 6‐month treatment course of psychological, physical symptoms, and functioning, and its predictors in a naturalistic sample of secondary psychiatric care outpatients with somatoform disorders.

Method

The present study used routine outcome monitoring data of patients with somatoform disorders regarding their 6‐month treatment course of psychological and physical symptoms as well as functioning. The following patient groups were included: total group of somatoform disorders (N = 435), and undifferentiated somatoform disorder (N = 242), pain disorder (N = 102), body dysmorphic disorder (N = 51), and hypochondriasis (N = 40). Measures were Mini‐International Neuropsychiatric Interview plus, Brief Symptom Inventory, Montgomery–?sberg Depression Rating Scale, Brief Anxiety Scale, Short Form Health Survey 36, and Physical Symptom Checklist (PSC).

Results

The study population generally showed high co‐morbidity, especially with anxiety and mood disorders. The PSC total score, body dysmorphic disorder, and hypochondriasis were significant predictors for the treatment course of symptoms (Brief Symptom Inventory), whereas the PSC total score was the only significant predictor for the course of functioning (Short Form Health Survey 36).

Conclusion

Secondary psychiatric care outpatients with somatoform disorders showed high co‐morbidity with anxiety and mood disorders, and an unfavourable 6‐month course of both symptoms and functioning. Clinical implications are discussed, such as additional treatment of co‐morbidity in somatoform disorders.