Critical reflections on the concept and impact of "scaling up" in Global Mental Health.

The field of Global Mental Health (GMH) aims to address the global burden of mental illness by focusing on closing the "treatment gap" faced by many low- and middle-income countries (LMICs). To increase access to services, GMH prioritizes "scaling up" mental health services, primarily advocating for the export of Western centred and developed biomedical and psychosocial "evidence-based" approaches to the Global South. While this emphasis on scalability has resulted in the increased availability of mental health services in some LMICs, there have been few critical discussions of this strategy. This commentary critically appraises the scalability of GMH by questioning the validity and sustainability of its approach. We argue that the current approach emphasizes the development of mental health services and interventions in "silos," focusing on the treatment of mental illnesses at the exclusion of a holistic and contextualized approach to people's needs. We also question the opportunities that the current approach to GMH offers for the growth of mental health programmes of local NGOs and investigate the potential pitfalls that scalability may have on NGOs' impact and ability to innovate. This commentary argues that any "scaling up" of mental health services must place sustainability at the core of its mission by favouring the growth and development of local solutions and wider forms of support that prioritize social inclusion and long-lasting mental health recovery.

An unusual case of stridor: supraglottic inverted papilloma.

Inverted papillomas are rare benign neoplasms that typically originate in the sinonasal area of middle-aged men. We report the first case of a supraglottic inverted papilloma presenting with stridor.

The long noncoding RNA MALAT1 suppresses miR-211 to confer protection from ultraviolet-mediated DNA damage in vitiligo epidermis by upregulating sirtuin 1.

BACKGROUND: The absence of melanocytes poses a challenge for long-term tissue homeostasis in vitiligo. Surprisingly, while individuals with Fitzpatrick phototypes I-II (low melanin content) have a higher incidence of melanoma and nonmelanoma skin cancer, people with vitiligo are at a decreased risk for the same. OBJECTIVES: To understand the molecular mechanisms that protect vitiligo skin from ultraviolet (UV)-induced DNA damage by (i) characterizing differentially expressed microRNAs in lesional vs. nonlesional epidermis and (ii) identifying their upstream regulators and downstream gene targets. METHODS: Genome-wide microRNA profiling of nonlesional and lesional epidermis was performed on five individuals with stable nonsegmental vitiligo using next-generation RNA sequencing. The relevance of the upstream regulator and downstream target gene of the most differentially expressed microRNA was studied. RESULTS: Our study found sirtuin1 (SIRT1), an NAD-dependent deacetylase, to be a direct target of miR-211 - the most significantly downregulated microRNA in lesional epidermis. Inhibition of SIRT1 with EX-527 downregulated keratin 10 and involucrin, suggesting that SIRT1 promotes keratinocyte differentiation. Overexpression of miR-211 mimic led to a significant increase in γ-H2AX positivity and cyclobutane pyrimidine dimer (CPD) formation, hallmarks of UVB-mediated DNA damage. These effects could be ameliorated by the addition of resveratrol, a SIRT1 activator. Furthermore, a long noncoding RNA, MALAT1, was identified as a negative upstream regulator of miR-211. Overexpression of MALAT1 resulted in increased expression of SIRT1 and a concomitant removal of UVB-induced CPDs in primary keratinocytes. CONCLUSIONS: These findings establish a novel MALAT1-miR-211-SIRT1 signalling axis that potentially confers protection to the 'amelanotic' keratinocytes in vitiligo.

Reducing the rate of fistula: does a fibrin sealant act as an adjunct in pharyngeal closure? A two-centre experience.

BACKGROUND: Pharyngocutaneous fistula is a troublesome complication. Recently, synthetic materials such as fibrin sealant have been used as a secondary measure to treat fistula. This work assessed whether the primary use of fibrin sealant can reduce the rate of fistula. METHOD: A retrospective review of 50 cases from 2 centres was completed. Tisseel was an adjunct to primary closure in all cases. RESULTS: In the first centre, 3 out of 34 cases developed pharyngocutaneous fistula (fistula rate of 9 per cent). All three were salvage cases. In the second centre, 0 out of 16 cases developed a fistula. CONCLUSION: The incidence of pharyngocutaneous fistula post-radiation and post-chemoradiotherapy in laryngectomy cases has been quoted as 23 per cent and 34 per cent respectively. This study represents the first patient series on the use of fibrin sealant as an adjunct in primary closure following laryngectomy. The results are promising, encouraging the use of Tisseel as an adjunct to meticulous closure.

Radioiodinated Capsids Facilitate In Vivo Non-Invasive Tracking of Adeno-Associated Gene Transfer Vectors.

Viral vector mediated gene therapy has become commonplace in clinical trials for a wide range of inherited disorders. Successful gene transfer depends on a number of factors, of which tissue tropism is among the most important. To date, definitive mapping of the spatial and temporal distribution of viral vectors in vivo has generally required postmortem examination of tissue. Here we present two methods for radiolabeling adeno-associated virus (AAV), one of the most commonly used viral vectors for gene therapy trials, and demonstrate their potential usefulness in the development of surrogate markers for vector delivery during the first week after administration. Specifically, we labeled adeno-associated virus serotype 10 expressing the coding sequences for the CLN2 gene implicated in late infantile neuronal ceroid lipofuscinosis with iodine-124. Using direct (Iodogen) and indirect (modified Bolton-Hunter) methods, we observed the vector in the murine brain for up to one week using positron emission tomography. Capsid radioiodination of viral vectors enables non-invasive, whole body, in vivo evaluation of spatial and temporal vector distribution that should inform methods for efficacious gene therapy over a broad range of applications.

Cytokinesis from nanometers to micrometers and microseconds to minutes.

Cytokinesis, a model cell shape change event, is controlled by an integrated system that coordinates the mitotic spindle signals with a mechanoresponsive cytoskeletal network that drives contractility and furrow ingression. Quantitative methods that measure cell mechanics, mechanoresponse (mechanical stress-induced protein accumulation), protein dynamics, and molecular interactions are necessary to provide insight into both the mechanical and biochemical components involved in cytokinesis and cell shape regulation. Micropipette aspiration, fluorescence correlation and cross-correlation spectroscopy, and fluorescence recovery after photobleaching are valuable methods for measuring cell mechanics and protein dynamics in vivo that occur on nanometer to micron length-scales, and microsecond to minute timescales. Collectively, these methods provide the ability to quantify the molecular interactions that control the cell's ability to change shape and undergo cytokinesis.

ß1-Na(+),K(+)-ATPase gene therapy upregulates tight junctions to rescue lipopolysaccharide-induced acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with diverse disorders and characterized by disruption of the alveolar-capillary barrier, leakage of edema fluid into the lung, and substantial inflammation leading to acute respiratory failure. Gene therapy is a potentially powerful approach to treat ALI/ARDS through repair of alveolar epithelial function. Herein, we show that delivery of a plasmid expressing ß1-subunit of the Na(+),K(+)-ATPase (ß1-Na(+),K(+)-ATPase) alone or in combination with epithelial sodium channel (ENaC) α1-subunit using electroporation not only protected from subsequent lipopolysaccharide (LPS)-mediated lung injury, but also treated injured lungs. However, transfer of α1-subunit of ENaC (α1-ENaC) alone only provided protection benefit rather than treatment benefit although alveolar fluid clearance had been remarkably enhanced. Gene transfer of ß1-Na(+),K(+)-ATPase, but not α1-ENaC, not only enhanced expression of tight junction protein zona occludins-1 (ZO-1) and occludin both in cultured cells and in mouse lungs, but also reduced pre-existing increase of lung permeability in vivo. These results demonstrate that gene transfer of ß1-Na(+),K(+)-ATPase upregulates tight junction formation and therefore treats lungs with existing injury, whereas delivery of α1-ENaC only maintains pre-existing tight junction but not for generation. This indicates that the restoration of epithelial/endothelial barrier function may provide better treatment of ALI/ARDS.

Laparoscopic management of transverse testicular ectopia with persistent mullerian duct syndrome.

A 4-month-old male child presented with right undescended testis and left inguinal hernia with funiculitis. Ultrasonography showed funiculitis on the left side testis along with presence of 1.5 × 1 cm testis like structure just above left testis and empty right scrotal sac without any evidence of mullerian structures. On diagnostic laparoscopy, right testicular vessels were crossing from right to left and had uterus with both testes in left hernia sac. Mobilization of vessels, division of uterus, and hernia repair was done laparoscopically. On the review of literature, there is only one case report of total laparoscopic repair of transversetesticular ectopia (TTE) with hernia without persistent mullerian duct (PMDS). The uniqueness of our case is that it had TTE with hernia and PMDS, which were totally managed by laparoscopy. On 6 months of follow-up, both the testes are palpable in scrotum.

Salivary gland pathology in the paediatric population: implications for management and presentation of a rare case.

INTRODUCTION: Salivary gland pathology in the paediatric population is rare and can present management challenges regarding both investigation and treatment. METHOD: Case report and review of available literature. RESULTS: A seven-year-old, fit, well girl presented with a two-month history of a painless mass over the left parotid area. Ultrasonography confirmed the presence of a well-defined, 1.5 × 2 cm, predominantly solid lesion with minor internal cystic spaces arising from the superficial part of the gland. Magnetic resonance imaging showed no invasion of the deep lobe or skeletal erosion. Superficial parotidectomy was performed via a facelift incision. Histopathology confirmed a diagnosis of pleomorphic adenoma. Review of the literature emphasised important differences in managing this pathology in the paediatric population when compared with adults. CONCLUSION: We present the youngest reported case of a pleomorphic adenoma of the parotid gland, detail its management, and discuss the general approach to parotid pathology management in the paediatric population.

Is there a change in the epidemiology of nasal fractures in females in the UK?

OBJECTIVE: To determine whether there is a change in the epidemiology of nasal fractures in females in the UK, and the potential contribution of the 'ladette' culture. METHODS: This paper reports a multi-centre retrospective study. Operating theatre data for all females who underwent manipulation of nasal fractures under anaesthesia between 2002 and 2009 were analysed. In addition, the case notes of all females presenting with nasal fractures over a five-year period (2004-2009) were retrospectively reviewed and the cited cause of the fracture was noted. RESULTS: From 2002 to 2009, there was an 825 per cent increase in nasal fractures in women aged 13-20 years. Almost one-quarter of all nasal fractures in one centre was attributed to non-domestic violence. The highest incidence of nasal fractures (67 per cent) was amongst white British females. CONCLUSION: There is an increasing trend in the number of women sustaining nasal fractures in the UK. The cause may be multi-factorial, but could be partially attributed to a rise in ladette culture. Further research on the role of alcohol consumption in this phenomenon is needed.

Success of cricopharyngeal myotomy for specific and non-specific cervical dysphagia.

OBJECTIVE: The present study aimed to compare outcomes of cricopharyngeal myotomy (CPM) in patients with documented cricopharyngeal dysfunction (CPD) and those in whom the diagnosis is complex or in doubt. MATERIALS AND METHODS: Retrospective comparative study of all patients undergoing CPM between 2001 and 2010 at a single UK centre. Patients were classified as having either CPD (n = 15) or non-specific cervical dysphagia (NSCD) (n = 12) based on contrast swallow results. They completed a 10-point visual analogue scale (VAS) questionnaire regarding their ability to swallow solids preoperatively and 6 months postoperatively. Scores were compared between groups, and symptom recurrence at 12 months postoperatively was also noted. RESULTS: The median VAS for all patients in both groups preoperatively was 5.5 and improved postoperatively to 8.0 (p < 0.001), and median preoperative ratings between groups were similar (CPD = 6.0 vs. NSCD = 5.5; p > 0.05). The CPD group scored better postoperatively compared to their NSCD counterparts (CPD = 9.0 vs. NSCD = 7.5; p < 0.001). Recurrence rate at 12 months was lower in CPD (12.5%) compared to NSCD (60%) patients. CONCLUSION: After CPM, patients with CPD showed significant improvement in swallowing solids, as did patients with NSCD, although to a lesser extent. CPD patients experienced better outcomes compared to their NSCD counterparts, including lower complication and recurrence rates. Larger studies are required before CPM can be advocated as the standard of care for NSCD patients.

Visual loss following head and neck surgery.

INTRODUCTION: Non-arteritic ischaemic optic neuritis is a known post-operative complication of ophthalmological and maxillofacial surgery, but has not been widely described as a potential consequence of head and neck surgery. AIM: To highlight non-arteritic ischaemic optic neuritis as a potential risk in patients undergoing head and neck surgery. SUBJECT AND METHOD: Case report of a 60-year-old man undergoing total laryngectomy and bilateral neck dissection for laryngeal squamous cell carcinoma. RESULT: On day 14 post-operatively, the patient suffered substantial oral bleeding secondary to an internal jugulo-neopharyngeal fistula. Following emergency haemostatic measures, the patient was immediately aware of visual disturbances. The ophthalmologists concluded that these were due to non-arteritic ischaemic optic neuritis, caused by acute hypoxaemia secondary to substantial blood loss. CONCLUSION: The prognosis of non-arteritic ischaemic optic neuritis is poor. Thus, it is crucial that otolaryngologists are aware of this complication of head and neck surgery, as immediate diagnosis and treatment can help prevent worsening visual loss.

Internet and e-mail use in ENT: a survey of patient usage and satisfaction.

Nowadays, internet and e-mail are important modes of communication and information. This paper seeks to determine internet usage as a source of health information amongst ENT patients and to investigate whether patients prefer to communicate primarily with the hospital via e-mail. The method used is a questionnaire study and 201 patients attending an ENT clinic completed questionnaires over 2 weeks in December 2010. Of those with internet access (85%), 37% had used it for health information prior to their appointment; 90% rated the information between average and excellent; over half stated they would like doctor-recommended websites. Overall, 8% had previously used e-mail to communicate with healthcare professionals, but 50% stated that they wished to use e-mail in the future. ENT patients are becoming increasingly computer-literate. As healthcare professionals, we must do more to incorporate the internet as a source of reliable healthcare information. Properly implemented, e-mail can become an invaluable method of communication with patients.

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.

The follow-up of patients with head and neck cancer: an analysis of 1,039 patients.

In all cancer specialities, there has been much debate about the best follow-up regime. The provision of a service that meets high standards whilst being cost-effective is increasingly pertinent. The objectives of the study were to examine: whether routine follow-up facilitates early diagnosis and recurrence; whether there is a cohort of patients who require a more intensive follow-up regime; whether follow-up should be customised to individual patients. A total of 1,039 consecutive outpatient consultations were prospectively analysed in a multicentre study. All adult patients who had undergone multidisciplinary, multimodality management for head and neck cancer were included. The case mix was representative of all head and neck tumour sites and stages. Suspicion of recurrence was noted in 10% (n = 96/951) of patients seen routinely. This rose to 68% (n = 60/88) for the subset of patients who had requested an appointment. Most recurrences were found within the first follow-up year (n = 64/156, 54%). Only 0.3% (n = 3/1,039) of asymptomatic patients attending routine appointments were suspected of having a recurrence, and two (0.2%) were found to have an actual recurrence following investigation. Of the total number of patients reporting a new suspicious symptom, recurrence was suspected in 56% (n = 152/270). Patients thus had a 98.1% sensitivity to raising suspicion for a recurrence based on the reporting of new symptoms with a 99.6% negative predictive value. Our data show that the efficiency of the current follow-up regime at detecting suspected recurrence of head and neck cancer is low, suggesting the need for a customised, more focused follow-up regime, tailored to individual cases. Patient education and close relationships with clinicians and allied health-care professionals are essential for early diagnosis and management of cancer recurrence. Follow-up regimes within the first year should be most intensive as recurrence is most likely within this time, and it serves to alleviate patient anxiety in the early post-treatment period. More research needs to be carried out to investigate the role of patient self-reporting and surveillance of cancer recurrence.

Persistent otorrhoea with an abnormal tympanic membrane secondary to squamous cell carcinoma of the tympanic membrane.

OBJECTIVE: The authors present an extremely rare case of carcinoma of the tympanic membrane. METHOD: A case report and review of the literature concerning carcinoma of the tympanic membrane and temporal bone are presented and discussed. RESULTS: The authors present a patient with recurrent otorrhoea and an abnormal tympanic membrane. Biopsy was inconclusive, but resection demonstrated squamous cell carcinoma of the tympanic membrane. We also discuss the investigation, diagnosis, natural history and management of this rare condition, as well as the staging and management of tumours of the temporal bone and the differences between these closely related but prognostically different entities. CONCLUSION: This rare entity can be managed by primary surgical resection if there is no evidence of metastasis.