External application of NF-κB inhibitor DHMEQ suppresses development of atopic dermatitis-like lesions induced with DNCB/OX in BALB/c mice

Context: Dehydroxymethylepoxyquinomicin (DHMEQ) which is originally developed as an analog of antibiotic epoxyquinomicin C is a specific and potent inhibitor of NF-κB and has been shown to possess promising potential as an anti-inflammatory and anti-tumor agent.

Objective: This study examines DHMEQ’s effect on therapeutic potential for atopic dermatitis (AD)-like lesions.

Materials and methods: AD lesions were chronically induced by the repetitive and alternative application of 2,4-dinitrochlorobenzene (DNCB) and oxazolone (OX) on ears in BALB/c mice. The mice were then externally treated with DHMEQ ointment. Macroscopic and microscopic changes of the skin lesions were observed and recorded.

Results: DHMEQ inhibited ear swelling and relieved clinical symptoms of the AD-like lesions induced by DNCB/OX in BALB/c mice. Histopathology examination illustrated that it significantly decreased DNCB/OX-induced epidermal thickness, the infiltration of inflammatory cells, and the count of mast cell. The elevated level of immunoglobulin E (IgE) in serum and the mRNA levels of interferon γ (IFN-γ), interleukin 4 (IL-4) and IL-13 in the ear tissues, were also suppressed by DHMEQ.

Discussion and conclusion: This study indicated that DHMEQ would be useful for the treatment of AD.     

Systematic overview of neuroanatomical differences in ADHD: Definitive evidence

Objectives: This article seeks to identify neuroanatomical differences in ADHD through an overview of systematic reviews that report encephalic differences compared to a control group in volume, area, activation likelihood or chemical composition.

Methods: We conducted a systematic search using Cochrane guidelines and PRISMA criteria in PubMed, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects.

Results: Results revealed broad encephalic involvement that includes a functional frontal and cingulate hypoactivation and structural differences in corpus callosum, cerebellum and basal nuclei.

Conclusions: ADHD symptoms might be due to a multi-network unbalanced functioning hypothesis.     

Inhibitory deterioration may contribute to hallucinations in Alzheimer's disease

Introduction. Although delusions and hallucinations are relatively common symptoms in individuals with Alzheimer's disease (AD), very little is known regarding underlying mechanisms. We examined whether these manifestations could be underpinned by psychological distress and executive impairments.

Methods. Thirty-one participants with probable mild AD and 33 healthy older adults were administered a neuropsychological and clinical battery assessing delusions, hallucinations, anxiety, depression, episodic memory and executive functions (shifting, updating and inhibition).

Results. Prevalence of delusions and hallucinations were significantly higher in AD participants compared to control participants. Further, hallucinations in AD participants were significantly correlated with poor inhibition, with the latter uniquely predicting the former, as compared to other variables. In addition, hallucinations in AD participants were associated with depression, a relationship that was further mediated by inhibition.

Conclusion. Hallucinations in individuals with AD seem to be related to difficulties suppressing irrelevant thoughts, resulting in these irrelevant thoughts becoming confused with ongoing reality.     

New developments in work-related asthma

Introduction: Work-related asthma includes two subtypes: occupational asthma or asthma caused by specific agents (sensitizers or irritants) in the workplace, and work-exacerbated asthma or pre-existing asthma worsened by workplace exposures.

Areas covered: This review provides an update on the definitions and the clinical features of the different work-related asthma subtypes as well as new insights into their etiology and the pathophysiological mechanisms involved. The diagnosis of work-related asthma should be made on objective basis using a constellation of clinical, physiologic and allergologic tests. Specific inhalation challenge with the suspected occupational agent(s) remains as the reference standard for diagnosis. A literature search was performed using the following terms: work-related asthma, occupational asthma, work-exacerbated asthma, irritant-induced asthma and etiological agents.

Expert commentary: Studies focusing on the biological effects and mechanisms of environmental exposures in the development of sensitizer-induced or irritant-induced asthma in various workplace settings are of greatest interest. An integrative approach that combines clinical parameters with component-resolved diagnosis as well as inflammatory biomarkers appears to be very promising. Occupational allergy provides a good opportunity to understand the complex relationships between exposure to allergens in the workplace, interaction with genes and the co-exposures to other factors in the working environment.     

ALK protein expression in pulmonary adenocarcinoma of Tunisian patients

Background. It is now necessary to determine ALK status in order to use targeted therapy. Aim: herein, we assess immunohistochemical profile of ALK protein in a series of Tunisian patients with pulmonary adenocarcinoma.

Materials and Methods. ALK protein expression was studied applying the D5F3 antibody with a fully automated Ventana CDx technique on a series of 19 patients.

Results. Positive ALK expression was found in one case (5.2%) corresponding to a papillary adenocarcinoma which showed a strong granular and homogenous cytoplasmic staining. The patient was a 30-years-old woman.

Conclusion. The frequency of positive ALK expression based on immunohistochemistry in our series was similar to that reported in the world literature.     

Down the rabbit hole: assessing the influence of schizotypy on the experience of the Barbie Doll Illusion

Introduction: “Body swapping” illusions have been used to explore factors contributing to the experience of “owning” an artificial body. Preliminary research indicated that those people diagnosed with schizophrenia experience more vivid illusions of this kind than do “normal” individuals.

Objectives: Here, we explored whether participants who rated themselves “high” on the cognitive-perceptual factor of the Schizotypal Personality Questionnaire (SPQ) experienced a more compelling sense of immersion in a variation of the body swapping illusion: The Barbie Doll Illusion. We also hypothesised that these individuals would experience a change in size perception when immersed in the illusion.

Method: Forty-four participants wore a pair of Head-Mounted Display goggles connected to a video-camera, and thus a doll’s body replaced their own body in their visual field. In two conditions, touch was either applied synchronously or asynchronously to the doll’s and each participant’s leg. After each condition, participants filled out a questionnaire relating to their experience in the illusion. When both conditions were completed, they filled out the SPQ.

Results: Our first hypothesis was confirmed, which suggested that people with higher cognitive-perceptual SPQ scores do indeed experience a more compelling Barbie Doll Illusion; however, our second hypothesis was not supported.

Conclusion: Our study demonstrated, for the first time, that proneness to the positive and interpersonal factors of schizotypy in a normal population is sufficient to produce a compelling sense of swapping bodies.     

Testing times: identifying puberty in an identified skeletal sample

Background: Identifying the onset of puberty in skeletal remains can provide evidence of social changes associated with the onset of adulthood.

Aim: This paper presents the first test of a skeletal method for identifying stages of development associated with the onset of puberty in a skeletal sample of known age and cause of death.

Materials and methods: Skeletal methods for assessing skeletal development associated with changes associated with puberty were recorded in the identified skeletal collection in Coimbra, Portugal. Historical data on the onset of menarche in this country are used to test the method.

Results: As expected, females mature faster than their male counterparts. There is some side asymmetry in development. Menarche was found to have been achieved by an average age of 15.

Conclusions: Asymmetry must be taken into account when dealing with partially preserved skeletons. Age of menarche is consistent, although marginally higher, than the age expected based on historical data for this time and location. Skeletal development in males could not be tested against historical data, due to the lack of counterpart historical data. The ill health known to be present in this prematurely deceased population may have delayed skeletal development and the onset of puberty.     

The Orientalisation of North Africa: New hints from the study of autosomal STRs in an Arab population

Background: Recent genomic analyses suggest that the current North African gene pool was mainly influenced by population flow coming from the East that altered the genetic structure of autochthonous Berber populations. Such genetic flow has not been extensively addressed yet using North African populations of Middle-eastern origin as reference.

Aim: To discern the Middle-eastern component in the genetic background of Tunisian Arabs and evaluate the extent of gene flow from the Middle East into North African autochthonous Berber populations.

Subjects and methods: This study has examined 113 Tunisians of well-known Arabian origin from Kairouan region, using 15 autosomal Short Tandem Repeats (STRs) loci.

Results: No deviations from Hardy-Weinberg equilibrium were observed and all loci presented high levels of heterozygosity. Principal coordinate and STRUCTURE analyses were consistent in clustering together North African and Middle Eastern populations, likely reflecting the recent gene flow from the East dating back to the Arab conquest period. This demographic migration and the Arabisation process that submerged the original Berber language and customs seems to have be accompanied by substantial gene flow and genetic admixture.

Conclusion: This study represents an additional step to obtain a comprehensive understanding of the complex demographic history of North African populations.     

Implementation of a prospective pregnancy registry for antiretroviral based HIV prevention trials

Background: Safety data on pregnancy and fetal outcomes among women in HIV prevention trials are urgently needed to inform use of effective antiretroviral agents for HIV prevention. We describe an effective, efficient, and novel method to prospectively collect perinatal safety data concurrent with on-going parent clinical trials.

Methods: The Microbicide Trials Network (MTN)-016 study is a multinational prospective pregnancy exposure registry designed to capture pregnancy and neonatal outcomes. Studies currently contributing data to this registry included phase I and II safety trials with planned exposures to candidate HIV prevention agents, as well as phase IIB and III efficacy trials capturing data on pregnancy and infant outcomes following inadvertent fetal exposure during study participation.

Results: To date, participants from two phase I studies and two effectiveness trials have participated in MTN-016, resulting in 420 pregnant women and 381 infants enrolled. Infant retention has been high, with 329 of 381 (86%) infants completing the 12-month follow-up visit.

Conclusion: In a research setting context, it is feasible to establish and implement a prospective, multinational HIV chemoprophylaxis pregnancy registry that will generate pregnancy exposure data in a robust fashion.     

Pregnane X Receptor Polymorphisms and Risk of Inflammatory Bowel Disease: A Meta-Analysis

Background: Pregnane X receptor (PXR) gene polymorphisms have been widely studied in terms of the association with inflammatory bowel disease (IBD), with inconsistent results.

Objective: The present meta-analysis was performed to assess the association between PXR gene polymorphisms and the susceptibility of IBD, Crohn’s disease (CD), and ulcerative colitis (UC).

Methods: PubMed, Wanfang, and CNKI databases were searched for eligible studies before November 1, 2016. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to calculate the various genetic models using either a fixed-effect or a random-effect model. The heterogeneity of the included studies was examined with Cochran Q and I² statistics. Begg’s rank correlation test and Egger’s linear regression test were used to assess the publication bias.

Results: A total of six studies with 4248 cases and 3853 controls were included in this meta-analysis. Three PXR gene polymorphisms were evaluated: rs1523127, rs2276707, and rs6785049. Our analyses of rs1523127, rs2276707, and rs6785049 suggested that PXR gene polymorphism had no obvious influence on the risk of IBD in Caucasians. Subgroup analyses based on disease type showed similar results.

Conclusion: Our meta-analysis revealed that PXR gene polymorphism may not be significantly associated with IBD susceptibility. However, the number of original studies was limited and further studies with large samples are needed to verify the results.

Abbreviations: PXR = pregnane X receptor, IBD = inflammatory bowel disease, CD = Crohn’s disease, UC = ulcerative colitis, ORs = pooled odds ratios, 95% CIs = 95% confidence intervals, NOS = Newcastle–Ottawa scale, HWE = Hardy–Weinberg equilibrium.     

Unusual sleep experiences and dissociation as mediators between sleep quality and proneness to hallucinations in a nonclinical population sample: a preliminary study

Introduction: The purpose of this study was to examine the relationship of sleep quality to proneness to hallucinations and the mediating role of dissociation and unusual sleep experiences in a nonclinical sample.

Methods: One hundred and seventy-seven participants completed a questionnaire on sleep quality, a dissociative experiences scale, an unusual sleep experiences scale and a hallucination proneness scale.

Results: The results showed a significant positive association between quality of sleep and hallucination proneness, dissociation and unusual sleep experiences, and that dissociation and unusual sleep experiences fully mediated between sleep quality and hallucination proneness.

Conclusions: Our study highlights the importance of variables related to sleep quality and unusual sleep experiences and dissociation in understanding hallucinations, and the importance of taking these variables into consideration in designing intervention directed at reducing distress caused by hallucinations.     

Memory and executive functions correlates of self-awareness in traumatic brain injury

Objective: The purpose of this study was to investigate the contribution of executive functions (EF) components and episodic and working memory variables, as well as clinical and demographic factors, to awareness of cognitive ability in traumatic brain injury (TBI).

Methods: Sixty-five TBI patients (mild: n?=?26; moderate/severe: n?=?39) took part in the study. Independent stepwise regression models were calculated for EF and memory predictors, with awareness being measured by patient/informant discrepancy in the Patient Competency Rating Scale.

Results: Models with EF variables indicated that semantic verbal fluency and age are the best predictors of awareness, whereas models including mnemonic functions suggested verbal delayed episodic recall and TBI severity as predictors.

Conclusions: These results are discussed in relation to clinical implications, such as the need to focus efforts of rehabilitation in the cognitive abilities related to awareness, and theoretical models.     

Clinical and immunological studies for 105 Japanese seropositive patients of epidermolysis bullosa acquisita examined at Kurume University

Objectives: Using our serological diagnostic criteria, we selected 105 Japanese patients with epidermolysis bullosa acquisita (EBA), an autoimmune bullous disease (AIBD) reacting with type VII collagen, from our cohort of 5063 AIBD patients.

Methods: We examined the patients clinically and immunologically.

Results: We found diversity of clinical manifestations in both cutaneous and oral mucosal lesions and a high rate of inflammatory-type EBA patients in Japan. Common treatments were systemic steroids, followed by immunosuppressives, DDS, tetracycline/minocycline and colchicine. Immunological studies revealed that indirect immunofluorescence of 1M-NaCl-split skin, immunoblotting of dermal extract, and type VII collagen ELISA were sensitive methods, with possible multiplicity of circulating autoantibodies against other basement membrane autoantigens.

Conclusion: The present study analyzed the largest cohort of EBA patients, confirming the scarcity of EBA (only 105 of the 5063 AIBD patients), and showed that the three serological tests are useful for the diagnosis of EBA.     

Interferon β-1a and β-1b for patients with multiple sclerosis: updates to current knowledge

Introduction: Although multiple sclerosis (MS) remains incurable, interferon beta (IFNβ) has been at the forefront of treatment for many years. Different formulations of IFNβ allow for different levels of exposure: low-dose/frequency with some agents, and high-dose/frequency with others.

Areas covered: This review article discusses existing and emerging efficacy and safety data for IFNβ in MS. Clinical evidence of IFNβ efficacy has been generated and accumulated over many decades. During this time, key clinical trials have demonstrated the benefits of high-dose and/or high-frequency dosing of IFNβ-1a or β-1b, compared with lower levels of exposure, on outcome measures such as relapse rates, disability progression, disease progression and magnetic resonance imaging lesion outcomes.

IFNβ therapy is well tolerated and has one of the best characterized safety profiles of all first line therapies. The overall severity of adverse events (AEs) does not appear to be affected by different IFNβ exposures. Typical AEs that patients may experience with IFNβ are mild, reversible and manageable.

Expert commentary: IFNβ is one of the best characterized treatments for MS, with a large body of clinical and real-world evidence supporting the risk-benefit profile. High-dose/frequency regimens may provide better long-term outcomes.     

Harpagoside-induced anaphylactic reaction in an IgE-independent manner both in vitro and in vivo

Background: Harpagoside (HAR) is an active component of Scrophularia ningpoensis (SN), which has anti-inflammatory and anti-immune effects. SN is used widely in China to treat various diseases. Recently, SN has been used as a traditional Chinese medicine injection and used clinically. However, allergic responses to these injections are frequently reported.

Aim: We examined whether the main component of SN, HAR, is associated with the allergic reaction to SN.

Methods: This study assessed the effects of HAR in mice and mast cell activation to characterize its anaphylactic effects and underlying mechanisms. Mice hindpaw swelling, serum allergy factor detection, enzyme-linked immunosorbent assays, and degranulation assays were performed to measure allergic mediators both in vivo and in vitro.

Results: The present study indicated that HAR induced paw swelling, interleukin-6, inositol triphosphate, tumor necrosis factor-α, and histamine increases in mice. Our in vitro data also showed that HAR induced β-hexosaminidase, inositol triphosphate, and interleukin-6 release, leading to mast cell degranulation. In contrast, neither C48/80 nor HAR induced local anaphylaxis in STOCK Kit^W-sh/HNihrJaeBsmJNju mice.

Conclusions: HAR is a potential sensitization compound in SN, and these results provide information for the safe clinical use of SN.     

The REVAMP trial to evaluate HIV resistance testing in sub-Saharan Africa: a case study in clinical trial design in resource limited settings to optimize effectiveness and cost effectiveness estimates

Background: In sub-Saharan Africa, rates of sustained HIV virologic suppression remain below international goals. HIV resistance testing, while common in resource-rich settings, has not gained traction due to concerns about cost and sustainability.

Objective: We designed a randomized clinical trial to determine the feasibility, effectiveness, and cost-effectiveness of routine HIV resistance testing in sub-Saharan Africa.

Approach: We describe challenges common to intervention studies in resource-limited settings, and strategies used to address them, including: (1) optimizing generalizability and cost-effectiveness estimates to promote transition from study results to policy; (2) minimizing bias due to patient attrition; and (3) addressing ethical issues related to enrollment of pregnant women.

Methods: The study randomizes people in Uganda and South Africa with virologic failure on first-line therapy to standard of care virologic monitoring or immediate resistance testing. To strengthen external validity, study procedures are conducted within publicly supported laboratory and clinical facilities using local staff. To optimize cost estimates, we collect primary data on quality of life and medical resource utilization. To minimize losses from observation, we collect locally relevant contact information, including Whatsapp account details, for field-based tracking of missing participants. Finally, pregnant women are followed with an adapted protocol which includes an increased visit frequency to minimize risk to them and their fetuses.

Conclusions: REVAMP is a pragammatic randomized clinical trial designed to test the effectiveness and cost-effectiveness of HIV resistance testing versus standard of care in sub-Saharan Africa. We anticipate the results will directly inform HIV policy in sub-Saharan Africa to optimize care for HIV-infected patients.     

Turkish Cypriot paternal lineages bear an autochthonous character and closest resemblance to those from neighbouring Near Eastern populations

Background: Cyprus is an island in the Eastern Mediterranean Sea with a documented history of human settlements dating back over 10,000 years.

Aim: To investigate the paternal lineages of a representative population from Cyprus in the context of the larger Near Eastern/Southeastern European genetic landscape.

Subjects and methods: Three hundred and eighty samples from the second most populous ethnic group in Cyprus (Turkish Cypriots) were analysed at 17 Y-chromosomal short tandem repeat (Y-STR) loci.

Results: A haplotype diversity of 0.9991 was observed, along with a number of allelic variants, multi-allelic patterns and a most frequent haplotype that have not previously been reported elsewhere. Pairwise genetic distance comparisons of the Turkish Cypriot Y-STR dataset and Y-chromosomal haplogroup distribution with those from Near East/Southeastern Europe both suggested a closer genetic connection with the Near Eastern populations. Median-joining network analyses of the most frequent haplogroups also revealed some evidence towards in situ radiation.

Conclusion: Turkish Cypriot paternal lineages seem to bear an autochthonous character and closest genetic connection with the neighbouring Near Eastern populations. These observations are further underscored by the fact that the haplogroups associated with the spread of Neolithic Agricultural Revolution from the Fertile Crescent (E1b1b/J1/J2/G2a) dominate (>70%) the Turkish Cypriot haplogroup distribution.     

Morphology and age-related changes in calcospherites of human teeth: an ultrastructural study

Background: Dentine has been examined extensively for age-related physiological changes, but there are limited data on age-related changes at ultrastructural level of dentine.

Aim: The present study aimed to examine age-related ultrastructural changes in calcospherites of human dentine under the scanning electron microscope.

Materials and methods: Thirty single rooted teeth of North Western adult Indians (18–75 years) were collected from the Department of Oral Health Sciences, PGIMER, Chandigarh. Labiolingual sections were prepared and morphology of calcospherites was studied at different locations (coronal, cervical, midroot and apical) of the tooth.

Results: Morphologically, four types (I [small, unfused and discrete], II [partially fused and globular], III [large, completely fused] and IV [structureless]) of calcospherites were seen in the sample. With advancing age, type I calcospherites approached neighbouring crystals and changed their form to type II, which ultimately coalesced and transformed to type III. Results revealed that among different age groups (young, middle and old), calcospherites of only type I, II and III showed statistically significant differences in their shapes using Pearson’s Chi-square test. Statistically non-significant differences were obtained in the shapes at different locations of the tooth.

Conclusions: Results showed that calcospherites get fused as age advances. There is a change in the shape of calcospherites based on the location of the tooth.