Dystrophin deficiency disrupts muscle clock expression and mitochondrial quality control in mdx mice.

Impaired oxidative capacity and mitochondrial function contribute to the dystrophic pathology in muscles of patients with Duchenne muscular dystrophy (DMD) and in relevant mouse models of the disease. Emerging evidence suggests an association between disrupted core clock expression and mitochondrial quality control, but this has not been established in muscles lacking dystrophin. We examined the diurnal regulation of muscle core clock and mitochondrial quality control expression in dystrophin-deficient C57BL/10ScSn-Dmdmdx (mdx) mice, an established model of DMD. Male C57BL/10 (BL/10; n = 18) and mdx mice (n = 18) were examined every 4 h beginning at the dark cycle. Throughout the entire light-dark cycle, extensor digitorum longus (EDL) muscles from mdx mice had decreased core clock mRNA expression (Arntl, Cry1, Cry2, Nr1d2; P < 0.05) and disrupted mitochondrial quality control mRNA expression related to biogenesis (decreased; Ppargc1a, Esrra; P < 0.05), fission (increased; Dnm1l; P < 0.01), fusion (decreased; Opa1, Mfn1; P < 0.05), and autophagy/mitophagy (decreased: Bnip3; P < 0.05; increased: Becn1; P < 0.05). Cosinor analysis revealed a decrease in the rhythmicity parameters mesor and amplitude for Arntl, Cry1, Cry2, Per2, and Nr1d1 (P < 0.001) in mdx mice. Diurnal oscillations in Esrra, Sirt1, Map1lc3b, and Sqstm1 were absent in mdx mice, along with decreased mesor and amplitude of Ppargc1a mRNA expression (P < 0.01). The expression of proteins involved in mitochondrial biogenesis (decreased: PPARGC1A, P < 0.05) and autophagy/mitophagy (increased: MAP1LC3BII, SQSTM1, BNIP3; P < 0.05) were also dysregulated in tibialis anterior muscles of mdx mice. These findings suggest that dystrophin deficiency in mdx mice impairs the regulation of the core clock and mitochondrial quality control, with relevance to DMD and related disorders.

Seeking healthcare services post-stroke: a qualitative descriptive study exploring family caregiver and stroke survivor perspectives in an asian setting.

AIM: Exploration of the healthcare journey post-stroke is incomplete without acknowledging the crucial role of family caregivers. With limited literature documenting the role of caregivers in the healthcare journey post-stroke, we aimed to describe the healthcare experiences of family caregivers and stroke survivors across different caregiver identities in Singapore. METHODS: We conducted a qualitative descriptive study involving semi-structured interviews with transcripts analysed using thematic analysis. 26 stroke survivors and 35 family caregivers purposively sampled from multiple settings. RESULTS: Findings were summarized into seeking care and experience of healthcare encounters. Seeking care comprised of the following themes: factors influencing seeking care, decision to seek care and role of caregiver in seeking care. Experience of healthcare encounters comprised of the following themes: service around the patient, service with care and role of caregiver in healthcare encounters. CONCLUSION: Multi-dimensional role of caregivers in healthcare experience emerged as a major finding. Unique to our Asian context, as per the participants' accounts, family caregivers seemed to be central in healthcare decision-making for stroke survivors, with adult-child caregivers commonly reported being engaged in collaborative decision-making. While spousal caregivers preferred a relational healthcare experience, adult-child caregivers preferred a transactional one. Practical implications include equipping caregivers with skillset to make healthcare decisions, provision of supportive decision-making environment for caregivers and reinforcing communication aspects in the medical, nursing and allied healthcare curriculum to improve healthcare experience.

Support system diversity among family caregivers of stroke survivors: a qualitative study exploring Asian perspectives.

BACKGROUND: Caregiving is a global phenomenon which is bound to increase in tandem with the aging population worldwide. Stroke is a condition common in older people that requires complex caregiving necessitating provision of adequate support to the caregivers. Past literature consists of limited accounts of types and organization of support arrangements needed by different caregivers. We aimed to describe the support system of caregivers of stroke survivors in Singapore, highlighting differences across the different caregiver identities (i.e. spouse, adult-child, etc.). METHODS: We conducted a qualitative descriptive study in the community setting involving 61 purposively sampled and recruited stroke survivors and caregivers. Semi-structured interviews were conducted, and transcripts were analysed using thematic analysis. RESULTS: Our findings were summarized across the following 4 themes: 1) cultural influence and caregiving; 2) caregiver support system with the following sub-themes: 2.1) dyadic caregiver support type, 2.2) extended caregiver support type, 2.3.) distributed caregiver support type and 2.4) empowering caregiver support type; 3) breaks in care of stroke survivor and 4) complex relationship dynamics. We operationalized the caregiver support system as comprising of type, people and activities that enable the caregiver to participate in caregiving activities sustainably. While spouse caregivers preferred dyadic and extended support systems positioning themselves in a more central caregiving role, adult-child caregivers preferred distributed support system involving family members with paid caregivers playing a more central role. CONCLUSIONS: Our findings highlight caregiver identity as a surrogate for the differences in the caregiver support systems. Practical implications include imparting relationship-building skills to the stroke survivor-caregiver dyads to sustain dyadic support system and educating clinicians to include differences in caregiving arrangements of stroke survivors in practising family-centred care.

Diagnostic and treatment challenges of a case of primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid.

BACKGROUND: Primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid is an extremely rare but aggressive neoplasm diagnosed primarily in elderly men. Until now there are 32 published cases of signet-ring cell carcinoma or histiocytoid carcinoma of the eyelid. We report the clinical, radiographic and histological features of the 33rd reported case of PCSRCC in the eyelid of a 73-year-old male, and review diagnostic and treatment challenges of this rare entity. CASE PRESENTATION: Our case highlights a 73-year-old male who was referred for surgical correction of right eye ptosis that was present for 2 years. Upon assessment, he was noted to have an upper lateral orbital rim mass. Computed tomography (CT) noted ill-defined soft tissue thickening anterior to the right globe, predominantly pre-septal but with slight post-septal extension. The pathology revealed diffusely and deeply infiltrating tumour cells extending through the dermis, subcutis, orbicularis muscle bundles and nerve fibers; the tumour cells were noted to have a monotonous histiocytoid appearance with foamy granular eosinophilic cytoplasm. At high magnification, intracytoplasmic vacuoles and occasional intermixed signet ring cells were identified. Immunohistochemical staining revealed the tumour cells to be AE1/AE3, CK7, GCDFP-15, E-cadherin, androgen receptor stain and GATA3 positive. Final pathology report confirmed the diagnosis of primary cutaneous signet-ring cell/histiocytoid carcinoma. Further imaging failed to identify a distant primary malignancy or metastatic disease. The decision was made to attempt surgical excision of the tumor. After the bulk of the grossly apparent tumor was removed, intraoperative frozen sections were sent. Superficial biopsies of the right periorbital region were performed, which revealed extension significantly further than the gross disease. Thereafter, the patient underwent a wide orbital exenteration with reconstruction using a temporary split-thickness skin graft. Due to positive margins on final permanent sections, the patient underwent further wide resection with free muscle-skin flap reconstruction followed by adjuvant radiation treatment. CONCLUSION: Our case represents the 33rd case of primary signet-ring cell/histiocytoid carcinoma of the eyelid in a 73-year-old male, the first documented case with GATA3 positivity and the second documented case with androgen receptor stain positivity.

Necrobiosis lipoidica with rapid response to doxycycline.

Necrobiosis lipoidica (NL) is a rare granulomatous disease of unknown etiology. Multiple therapies may be used with varying efficacy. We report a pediatric patient with a history of type I diabetes mellitus and NL with minimal response to an ultrapotent topical steroid, topical calcineurin inhibitor, and intralesional triamcinolone, complicated by steroid atrophy, who rapidly responded after addition of doxycycline.

A rare case of orbital granulomatous inflammation from explosive hydraulic oil masquerading as orbital cellulitis.

The differential diagnosis for acute orbital inflammation is broad. We report a case of granulomatous orbital inflammation due to high-pressure oil injury to the orbit presenting as an atypical orbital cellulitis. Here we review the presentation and treatment of orbital inflammation from oil.

Firm, hyperpigmented subcutaneous nodule in the inguinal fold of an infant.

Subcutaneous juvenile xanthogranuloma (JXG) of the inguinal fold, an unusual location, was diagnosed in an infant. Subcutaneous JXG should be included in the differential diagnosis of subcutaneous nodules of the lower body, despite the absence of the characteristic yellowish hue usually associated with JXG.

Catalytic, Enantioselective ß-Protonation through a Cooperative Activation Strategy.

The NHC-catalyzed transformation of unsaturated aldehydes into saturated esters through an organocatalytic homoenolate process has been thoroughly studied. Leveraging a unique "Umpolung"-mediated ß-protonation, this process has evolved from a test bed for homoenolate reactivity to a broader platform for asymmetric catalysis. Inspired by our success in using the ß-protonation process to generate enals from ynals with good E/Z selectivity, our early studies found that an asymmetric variation of this reaction was not only feasible, but also adaptable to a kinetic resolution of secondary alcohols through NHC-catalyzed acylation. In-depth analysis of this process determined that careful catalyst and solvent pairing is critical for optimal yield and selectivity; proper choice of nonpolar solvent provided improved yield through suppression of an oxidative side reaction, while employment of a cooperative catalytic approach through inclusion of a hydrogen bond donor cocatalyst significantly improved enantioselectivity.

Structure-based discovery of LpxC inhibitors.

The emergence and spread of multidrug-resistant (MDR) Gram negative bacteria presents a serious threat for public health. Novel antimicrobials that could overcome the resistance problems are urgently needed. UDP-3-O-(R-3-hydroxymyristol)-N-acetylglucosamine deacetylase (LpxC) is a cytosolic zinc-based deacetylase that catalyzes the first committed step in the biosynthesis of lipid A, which is essential for the survival of Gram-negative bacteria. Our efforts toward the discovery of novel LpxC inhibitors are presented herein.

Deep Granuloma Annulare Mimicking Inflamed Cysts in a Teenager.

We describe deep granuloma annulare (DGA) of the forehead mimicking inflamed cysts. Reactive inflammation and sterile purulent drainage may be an underrecognized feature of DGA.

CRIPT exonic deletion and a novel missense mutation in a female with short stature, dysmorphic features, microcephaly, and pigmentary abnormalities.

Mutations in CRIPT encoding cysteine-rich PDZ domain-binding protein are rare, and to date have been reported in only two patients with autosomal recessive primordial dwarfism and distinctive facies. Here, we describe a female with biallelic mutations in CRIPT presenting with postnatal growth retardation, global developmental delay, and dysmorphic features including frontal bossing, high forehead, and sparse hair and eyebrows. Additional clinical features included high myopia, admixed hyper- and hypopigmented macules primarily on the face, arms, and legs, and syndactyly of 4-5 toes bilaterally. Using whole exome sequencing (WES) and chromosomal microarray analysis (CMA), we detected a c.8G>A (p.C3Y) missense variant in exon 1 of the CRIPT gene inherited from the mother and a 1,331 bp deletion encompassing exon 1, inherited from the father. The c.8G>A (p.C3Y) missense variant in CRIPT was apparently homozygous in the proband due to the exon 1 deletion. Our findings illustrate the clinical utility of combining WES with copy number variant (CNV) analysis to provide a molecular diagnosis to patients with rare Mendelian disorders. Our findings also illustrate the clinical spectrum of CRIPT related mutations. © 2016 Wiley Periodicals, Inc.

Discovery of indole inhibitors of chemokine receptor 9 (CCR9).

Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12.

Biarylsulfonamide CCR9 inhibitors for inflammatory bowel disease.

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve.

Verruciform xanthoma.

A 50-year-old man presented with a several month history of a polypoid papule on the scrotum. A dense accumulation of macrophages with foamy cytoplasm was exhibited in the biopsy specimen leading to a diagnosis of verruciform xanthoma.

Patient perceptions of three-dimensional (3D) surface imaging technology and traditional methods used to assess anthropometry.

Background: Obesity and overweight are commonplace, yet attrition rates in weight management clinics are high. Traditional methods of body measurement may be a deterrent due to invasive and time-consuming measurements and negative experiences of how data are presented back to individuals. Emerging new technologies, such as three-dimensional (3D) surface imaging technology, might provide a suitable alternative. This study aimed to understand acceptability of traditional and 3D surface imaging-based body measures, and whether perceptions differ between population groups. Methods: This study used a questionnaire to explore body image, body measurement and shape, followed by a qualitative semi-structured interview and first-hand experience of traditional and 3D surface imaging-based body measures. Results: 49 participants responded to the questionnaire and 26 participants attended for the body measurements and interview over a 2-month period. There were 3 main themes from the qualitative data 1) Use of technology, 2) Participant experience, expectations and perceptions and 3) Perceived benefits and uses. Conclusion: From this study, 3D-surface imaging appeared to be acceptable to patients as a method for anthropometric measurements, which may reduce anxiety and improve attrition rates in some populations. Further work is required to understand the scalability, and the role and implications of these technologies in weight management practice. (University Research Ethics Committee reference number ER41719941).

The BALB/c.mdx62 mouse exhibits a dystrophic muscle pathology and is a model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a devastating monogenic skeletal muscle-wasting disorder. Although many pharmacological and genetic interventions have been reported in preclinical studies, few have progressed to clinical trials with meaningful benefit. Identifying therapeutic potential can be limited by availability of suitable preclinical mouse models. More rigorous testing across models with varied background strains and mutations can identify treatments for clinical success. Here, we report the generation of a DMD mouse model with a CRISPR-induced deletion within exon 62 of the dystrophin gene (Dmd) and the first generated in BALB/c mice. Analysis of mice at 3, 6 and 12 months of age confirmed loss of expression of the dystrophin protein isoform Dp427 and resultant dystrophic pathology in limb muscles and the diaphragm, with evidence of centrally nucleated fibers, increased inflammatory markers and fibrosis, progressive decline in muscle function, and compromised trabecular bone development. The BALB/c.mdx62 mouse is a novel model of DMD with associated variations in the immune response and muscle phenotype, compared with those of existing models. It represents an important addition to the preclinical model toolbox for developing therapeutic strategies.