Layer-specific reduced neuronal density in the orbitofrontal cortex of older adults with obsessive–compulsive disorder

Brain Structure and Function - Neurobiological models have provided consistent evidence of the involvement of cortical–subcortical circuitry in obsessive–compulsive disorder (OCD). The...     

A functionally relevant IRF5 haplotype is associated with reduced risk to Wegener’s granulomatosis

Wegener’s granulomatosis (WG), characterized by systemic vasculitis and granulomatous inflammation, is a rare chronic rheumatic condition potentially sharing some etiopathological principles with other autoimmune disorders, e.g., rheumatoid arthritis (RA) and systemic lupus erythomatosus (SLE). Several large association studies have identified genetic risk factors for RA and SLE. Thereof, we have evaluated the relevance of the most promising ones in WG. 22 single nucleotide polymorphisms (SNPs) within or in the vicinity of CCL21, CD40, CDK6, IL21, IL2RB, IRF5, KIF5A, KLF12, MMEL1, PRKCQ, STAT4, TNFAIP3, and TRAF1/C5 have been genotyped in >600 German WG cases and >800 matched controls. While most polymorphisms did not show suspicious effects on WG susceptibility, SNPs representing TNFAIP3 (rs6922466, p = 0.032, odds ratio (OR) 0.83, 95% confidence interval (CI) 0.7–-0.98) and CDK6 (rs42041, p = 0.0201, OR 1.21, 95% CI 1.03–1.43) revealed nominally significant differences in allele distribution. The strongest association was detected for a functionally relevant four SNP haplotype of IRF5, which comprised a protective effect (p = 0.0000897, p _corrected = 0.0012, OR 0.73, 95% CI 0.62–0.85) similar to those previously seen in RA and SLE. Thus, we suggest that WG, SLE, and RA share some, but not many, genetic risk factors, which supports models of partly overlapping etiopathogical mechanisms in these disorders.     

A Japanese patient with a mild Lenz–Majewski syndrome

We report on a sclerosing bone dysplasia, associated with cutis laxa, enamel dysplasia, and mental retardation. The patient was a 17-year-old Japanese boy of normal height and muscular build. Cutis laxa with prominent veins in the scalp and abdominal wall and delayed eruption of permanent teeth attracted the attention of clinicians in infancy and adolescence, respectively. The clinical manifestations included a progeroid facial appearance with prognathism, wrinkled skin, and interdigital webbing. The intelligence quotient was estimated at 60. Enamel dysplasia was histologically confirmed. Skeletal changes included calvarial hyperostosis, sclerosis of the skull base, an enlarged, sclerotic mandible, broad clavicles and ribs, and diaphyseal undermodeling of the tubular bones. Metaepiphyseal sclerosis or longitudinal striation was found in the long bones. Metaphyseal equivalents of the axial skeleton showed dense osteosclerosis. These clinical and radiological manifestations overlapped with those of Lenz-Majewski syndrome. Unlike the classical phenotype of the disorder, however, he did not show brachymesophalangy with proximal symphalangism or growth failure. The present case may be considered to fall in the mildest end in the phenotypic continuum of Lenz-Majewski syndrome, suggesting that the clinical spectrum of the disorder may be broader than currently thought.     

Serum mannose–binding lectin (MBL) concentrations are reduced in non-pregnant women with previous adverse pregnancy outcomes

Mannose-binding lectin (MBL) is an important component of the innate immunity, and it is responsible not only for opsonization of micro-organisms, but also for efferocytosis. The aim of this study was to investigate whether MBL concentrations and lectin complement pathway activity are altered in non-pregnant women with previous adverse pregnancy outcomes. Patients were divided into four groups on the basis of their history of pregnancy complications, including control patients who had uncomplicated pregnancies and term deliveries (control, n = 33), and three groups of patients with a history of pregnancy complications, including preterm labour (n = 29), recurrent miscarriage (n = 19) or unexplained intrauterine foetal death (IUFD; n = 17). All women enrolled in the study had an interval of three to six months following their previous pregnancy, and they agreed to have a blood sample taken. We found significantly higher MBL concentrations and functional activity of the lectin complement pathway in healthy controls who had previous uneventful term pregnancies (1341 ng/mL; activity 100% (IQR: 62%-100%)), compared to women with the history of IUFD (684 ng/mL, P = .008; activity 8.5% (IQR: 0%-97.8%), P = .011), recurrent miscarriage (524 ng/mL, P = .022; activity 44% (IQR: 4%-83%), P = .011) or preterm labour (799 ng/mL, P = .022; activity 62.5% (IQR: 0%-83%), P = .003). Our results suggest that inadequate function of the complement lectin pathway is associated with a higher risk of preterm labour, recurrent miscarriage and unexplained intrauterine foetal death.     

A Novel Mutation in a Patient with Hyperparathyroidism–Jaw Tumour Syndrome

Hyperparathyroidism–jaw tumour syndrome (HPT-JT) is a rare variant of familial hyperparathyroidism, characterized by primary hyperparathyroidism (PHPT) due to one or multiple parathyroid adenomas, and benign tumours of the mandible and maxilla. It has an autosomal dominant pattern of inheritance, and is associated with mutations that deactivate the cell division cycle protein 73 homolog (CDC73) gene, also known as hyperparathyroidism 2 (HRPT2), located on the long arm of chromosome 1, that encodes for the tumour suppressor protein parafibromin. In the majority of cases, PHPT is the presenting symptom, but up to 30 % of HPT-JT cases initially present with an ossifying fibroma of the maxillofacial bones. HPT-JT may result in severe hypercalcemia-related complications and an elevated risk of parathyroid carcinoma. For this reason, early identification of the disease is important. We present the case of a 23-year-old woman who was found to have jaw tumours and was later diagnosed with PHPT. Genetic analysis revealed a novel mutation in exon 1 of CDC73. This report contributes to the understanding of the genetics of this rare syndrome. It also highlights the fact that HPT-JT should be considered and CDC73 mutation analysis should be performed in cases of early-onset PHPT associated with ossifying fibromas of the jaw.     

Can we rely on simulated patients’ satisfaction with their consultation for assessing medical students’ communication skills? A cross-sectional study

Background

In medical education, teaching methods offering intensive practice without high utilization of faculty resources are needed. We investigated whether simulated patients’ (SPs’) satisfaction with a consultation could predict professional observers’ assessment of young doctors’ communication skills.

Methods

This was a comparative cross-sectional study of 62 videotaped consultations in a general practice setting with young doctors who were finishing their internship. The SPs played a female patient who had observed blood when using the toilet, which had prompted a fear of cancer. Immediately afterwards, the SP rated her level of satisfaction with the consultation, and the scores were dichotomized into satisfaction or dissatisfaction. Professional observers viewed the videotapes and assessed the doctors’ communication skills using the Arizona Communication Interview Rating Scale (ACIR). Their ratings of communication skills were dichotomized into acceptable versus unacceptable levels of competence.

Results

The SPs’ satisfaction showed a predictive power of 0.74 for the observers’ assessment of the young doctors and whether they reached an acceptable level of communication skills. The SPs’ dissatisfaction had a predictive power of 0.71 for the observers’ assessment of an unacceptable communication level. The two assessment methods differed in 26 % of the consultations. When SPs felt relief about their cancer concern after the consultation, they assessed the doctors’ skills as satisfactory independent of the observers’ assessment.

Conclusions

Accordance between the dichotomized SPs’ satisfaction score and communication skills assessed by observers (using the ACIR) was in the acceptable range.These findings suggest that SPs’ satisfaction scores may provide a reliable source for assessing communication skills in educational programs for medical trainees (students and young doctors).Awareness of the patient’s concerns seems to be of vital importance to patient satisfaction.

     

cAMP–PKA inhibition of SK3 channel reduced both Ca2+ entry and cancer cell migration by regulation of SK3–Orai1 complex

SK3 channel mediates the migration of various cancer cells. When expressed in breast cancer cells, SK3 channel forms a complex with Orai1, a voltage-independent Ca²⁺ channel. This SK3–Orai1 complex associates within lipid rafts where it controls a constitutive Ca²⁺ entry leading to cancer cell migration and bone metastases development. Since cAMP was found to modulate breast cancer cell migration, we hypothesized that this could be explained by a modulation of SK3 channel activity. Herein, we study the regulation of SK3 channel by the cAMP–PKA pathway and the consequences for SK3-dependent Ca²⁺ entry and cancer cell migration. We established that the beta-adrenergic receptor agonist, isoprenaline, or the direct adenylyl cyclase activator forskolin alone or in combination with the PDE4 inhibitor, CI-1044, decreased SK3 channel activity without modifying the expression of SK3 protein at the plasma membrane. Forskolin and CI-1044 reduced the SK3-dependent constitutive Ca²⁺ entry and the SK3-dependent migration of MDA-MB-435s cells. PKA inhibition with KT 5720 reduced: (1) the effect of forskolin and CI-1044 by 50 % on Ca²⁺ entry and (2) SK3 activity by inhibiting the serine phosphorylation of SK3. These cAMP-elevating agents displaced Orai1 protein outside lipid rafts in contrast to SK3, which remained in the lipid rafts fractions. All together, these results show that activation of the cAMP–PKA pathway decreases SK3 channel and SK3–Orai1 complex activities, leading to a decrease in both Ca²⁺ entry and cancer cell migration. This work supports the potential use of cAMP-elevating agents to reduce cancer cell migration and may provide novel opportunities to address/prevent bone metastasis.     

KAT6A Syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants

PurposePathogenic variants in KAT6Ahave recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported.MethodsWe obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review.ResultsWe identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location forde novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype– phenotype correlations show that late-truncating pathogenic variants (exons 16–17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction.ConclusionOur data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.     

A Chinese patient with KBG syndrome and a 9q31.2–33.1 microdeletion

KBG syndrome is characterized by postnatal short stature, macrodontia, facial and hand anomalies, delayed bone age and intellectual disability. KBG syndrome is an infrequently reported autosomal dominant condition caused by a mutation or haploinsufficiency of ANKRD11 at 16q24.3. We report on a patient, who showed many manifestations of KBG syndrome and was found to harbor a de novo ANKRD11 mutation, c.362T > A (p.Met121Lys). As the patient showed additional characteristics not occurring in KBG syndrome, a CGH array was performed which showed a de novo microdeletion of 9q31.2–q33.1. The majority of findings in our patient can be explained by the combined ANKRD11 mutation and 9q31.2–33.1 deletion. The case demonstrates well the need for comparing an abnormal genotype with a detailed phenotype analysis and the need for further studies in case the phenotype is unusual for the genotype.     

A reduced IL2R (CD25) expression level in first and second degree female relatives of autoimmune thyroid disease patients. A sign of a poor capability to preserve tolerance?

There is room for immune markers other than TPO-Abs to identify an increased risk to develop autoimmune thyroid disease (AITD). Our aim was to test the hypothesis that activation of CD4+ T cells is such marker in relatives of AITD patients, who have an increased risk to develop AITD. We established a controlled study on 20 TPO-Ab positive and 20 TPO-Ab negative euthyroid female relatives. All these cases had at least one 1st or 2nd degree relative with a documented autoimmune hyper- or hypothyroidism in whom we studied the percentages of circulating subsets of activated (MHC class-II, CD25 (IL-2R), CD71 or CD69+) CD4+ T cells and the level of the soluble (s)-IL2R in serum. We found that euthyroid female relatives did not show an activation of their T cell system, but a reduced expression of CD25 on CD4+ T cells. The level of the shed IL2R in serum was also lower in comparison with levels found in healthy control females. A reduced T cell activity was found in both TPO-Ab positive and negative relatives. In conclusion, female relatives with at least one 1st or 2nd degree relative with an AITD show signs of a reduced expansion capability of their T cell pool. It is hypothesized that this reduced expansion capability may affect T cell tolerance mechanisms more than T effector mechanisms.     

A Prospective Study on Anti–endothelial Cell Antibodies in Patients with Systemic Lupus Erythematosus

IgG anti–endothelial cell antibodies (AECA) were detected in 48.5% of patients with active systemic lupus erythematosus (SLE) and in 7% of patients during remission and were associated with the development of diffuse proliferative lupus nephritis. Sixteen AECA-positive patients were prospectively studied for 25.2 ± 2.9 months. Serial AECA levels correlated with disease activity in 10 (62.5%) patients. Seven (43.8%) of 16 patients remained AECA positive during clinical remission. Among four episodes of disease exacerbation and 16 instances of clinical improvement, 85% (17 episodes) were accompanied by corresponding changes in the level of AECA, while corresponding changes in C₃, anti–nuclear antibodies, and anti–double-stranded DNA antibodies were noted in 60, 60, and 80% of cases, respectively (p= not significant). AECA served as the only serologic marker of altered disease activity in five episodes, when C₃, ANA, and anti–double-stranded DNA levels remained unaltered. We conclude that the level of AECA can serve as a marker of disease activity in SLE and that serial monitoring of AECA can complement other serologic parameters in the management of patients.     

Atypical signed language development: A case study of challenges with visual–spatial processing

In signed languages, the articulatory space in front of the signer is used grammatically, topographically, and to depict a real or imagined space around a signer and thus is an important consideration in signed language acquisition. It has been suggested that children who acquire signed languages rely on concomitant visual–spatial development to support their linguistic development. We consider the case of a native-signing deaf adolescent female with average intelligence who had been reported to struggle with spatial aspects of American Sign Language (ASL) as a child. Results of a battery of linguistic and nonlinguistic tests suggest that she has relatively good ASL skills with the exception of some specific difficulties on spatial tasks that require attention to ASL and nonlinguistic topographic space or changes in visual perspective (e.g., classifiers and referential shift). This child has some difficulties with visual–spatial abilities, and we suggest that this has affected her acquisition of those aspects of ASL that are heavily dependent on visual–spatial processing.     

Cerebro-fronto-facial syndrome type 3 with polymicrogyria: A clinical presentation of Baraitser–Winter syndrome

Baraitser–Winter syndrome (BRWS) is a rare condition affecting the development of the brain and the face. The most common characteristics are unusual facial appearance including hypertelorism and ptosis, ocular colobomas, hearing loss, impaired neuronal migration and intellectual disability. BRWS is caused by mutations in the ACTB and ACTG1 genes. Cerebro-fronto-facial syndrome (CFFS) is a clinically heterogeneous condition with distinct facial dysmorphism, and brain abnormalities. Three subtypes are identified. We report a female infant with striking facial features and brain anomalies (included polymicrogyria) that fit into the spectrum of the CFFS type 3 (CFFS3). She also had minor anomalies on her hands and feet, heart and kidney malformations, and recurrent infections. DNA investigations revealed c.586C>T mutation (p.Arg196Cys) in ACTB. This mutation places this patient in the spectrum of BRWS. The same mutation has been detected in a polymicrogyric patient reported previously in literature. We expand the malformation spectrum of BRWS/CFFS3, and present preliminary findings for phenotype–genotype correlation in this spectrum.     

A review of mother–child relational interventions and their usefulness for mothers with schizophrenia

This review evaluates empirical studies that have attempted to improve observed mother-infant relationships in order to inform a potential approach for mothers with schizophrenia, a growing group of vulnerable families where mothers are known to have relational difficulties. Parenting intervention studies in: (1) mothers with a mental disorder; (2) other vulnerable groups were reviewed. Only interventions that empirically evaluated observations of mother-child interaction or child attachment were included, and their potential usefulness for mothers with schizophrenia was examined. Nine studies involved mothers with mental disorder; none involved mothers with psychotic disorder specifically. Overall, approaches that emphasise the mother-child dyad, such as sensitivity-focused behavioural techniques and toddler-parent psychotherapy, were most efficacious for improving maternal sensitivity/child attachment. Although individual psychological therapies are the more conventional treatment, little current evidence suggests that mother-infant relations improve with symptom reduction. The usefulness of the available evidence for informing interventions with mothers with schizophrenia is discussed in the context of their clinical needs. Feasibility studies are needed, which provide a focus on enhancing maternal sensitivity directly within a multi-level support package.     

The biological impact of living with chronic breathlessness – A role for the hypothalamic–pituitary–adrenal axis?

Breathlessness is a common and distressing symptom in advanced cardiorespiratory disease, with recognised psychological, functional and social consequences. The biological impact of living with chronic breathlessness has not been explored. As breathlessness is often perceived as a threat to survival, we propose that episodic breathlessness engages the stress-response, as regulated by the hypothalamic–pituitary–adrenal (HPA) axis. Furthermore, we hypothesise that chronic breathlessness causes excessive stimulation of the HPA axis, resulting in dysfunctional regulation of the HPA axis and associated neuropsychological, metabolic and immunological sequelae. A number of observations provide indirect support for this hypothesis. Firstly, breathlessness and the HPA axis are both associated with anxiety. Secondly, similar cortico-limbic system structures govern both breathlessness perception and HPA axis regulation. Thirdly, breathlessness and HPA axis dysfunction are both independent predictors of survival. There is a need for direct observational evidence as well as experimental data to investigate this hypothesis which, if plausible, could lead to the identification of a new biomarker pathway to support breathlessness research.     

The properties of the Kir6.1–6.2 tandem channel co-expressed with SUR2A

Functional ATP-sensitive K (KATP) channels have an octameric subunit structure with four pore-forming subunits (Kir6.x) and four sulfonylurea receptors (SURx). In the present study, the properties of the heteromeric KATP channel whose pore subunits are composed of Kir6.1 and Kir6.2 were examined using a heterologous expression system. In COS7 cells co-transfected with Kir6.1, Kir6.2 and SUR2A at a ratio of 1:1:2, KATP channels showed various unitary conductances between those of Kir6.1/SUR2A (33.6+/-4.2 pS) and Kir6.2/ SUR2A (67.1+/-1.6 pS). Kir6.1-6.2 tandem protein, constructed by fusing the C-terminus of Kir6.1 to the N-terminus of Kir6.2 with a ten glutamine linker sequence, also formed a channel with an intermediate conductance (58.9+/-1.5 pS). Kir6.2 and Kir6.1-6.2 showed similar sensitivity to ATP4-: half-maximal inhibition (IC50) was obtained at 14.1+/-12.8 microM and 17.6+/-9.6 microM, respectively. In the presence of Mg2+, Kir6. 1-6.2 was significantly less sensitive than Kir6.2 to MgATP (IC50=95.5+/-49.6 microM versus 18.9+/-5.0 microM). These results suggest that Kir6.1 and Kir6.2 are endowed with the potential to form a heteromeric KATP channel, which has a low sensitivity to MgATP.     

Composite pullulan–dextran polysaccharide scaffold with interfacial polyelectrolyte complexation fibers: A platform with enhanced cell interaction and spatial distribution

Hydrogels are highly preferred in soft tissue engineering because they recapitulate the hydrated extracellular matrix. Naturally derived polysaccharides, like pullulan and dextran, are attractive materials with which to form hydrophilic polymeric networks due to their non-immunogenic and non-antigenic properties. However, their inherent hydrophilicity prevents adherent cell growth. In this study, we modified pullulan–dextran scaffolds with interfacial polyelectrolyte complexation (IPC) fibers to improve their ability to support adherent cell growth. We showed that the pullulan–dextran–IPC fiber composite scaffold laden with extracellular matrix protein has improved cell adhesion and proliferation compared to the plain polysaccharide scaffold. We also demonstrated the zero-order release kinetics of the biologics bovine serum albumin and vascular endothelial growth factor (VEGF) incorporated in the composite scaffold. Lastly, we showed that the VEGF released from the composite scaffold retained its capacity to stimulate endothelial cell growth. The incorporation of IPC fibers in the pullulan–dextran hydrogel scaffold improved its functionality and biological activity, thus enhancing its potential in tissue engineering applications.