Culturally adapted psychosocial interventions (CaPSI) for early psychosis in a low-resource setting: study protocol for a large multi-center RCT.

BACKGROUND: Psychosis treatment guidelines recommend cognitive behaviour therapy (CBT) and family intervention (FI), for all patients with first episode psychosis (FEP), though guidance borrows heavily from literature in adults from high income countries. To our knowledge, there are few randomized controlled trials (RCTs) examining the comparative effect of these commonly endorsed psychosocial interventions in individuals with early psychosis from high-income countries and no such trials from low and middle-income countries (LMICs). The present study aims to confirm the clinical-efficacy and cost-effectiveness of delivering culturally adapted CBT (CaCBT) and culturally adapted FI (CulFI) to individuals with FEP in Pakistan. METHOD: A multi-centre, three-arm RCT of CaCBT, CulFI, and treatment as usual (TAU) for individuals with FEP (n = 390), recruited from major centres across Pakistan. Reducing overall symptoms of FEP will be the primary outcome. Additional aims will include improving patient and carer outcomes and estimating the economic impact of delivering culturally appropriate psychosocial interventions in low-resource settings. This trial will assess the clinical-efficacy and cost-effectiveness of CaCBT and CulFI compared with TAU in improving patient (positive and negative symptoms of psychosis, general psychopathology, depressive symptoms, quality of life, cognition, general functioning, and insight) and carer related outcomes (carer experience, wellbeing, illness attitudes and symptoms of depression and anxiety). CONCLUSIONS: A successful trial may inform the rapid scale up of these interventions not only in Pakistan but other low-resource settings, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority groups with FEP. TRIAL REGISTRATION: NCT05814913.

Profiling the human hair follicle immune system in lichen planopilaris and frontal fibrosing alopecia: can macrophage polarization differentiate these two conditions microscopically?

BACKGROUND: Frontal fibrosing alopecia (FFA) is traditionally regarded as a variant of lichen planopilaris (LPP) based on histological features. Distinct clinical presentation, demographics and epidemiology suggest that differing pathogenic factors determine the final phenotype. OBJECTIVES: To map the hair follicle immune system in LPP and FFA by systematically comparing key inflammatory markers in defined hair follicle compartments. METHODS: Lesional scalp biopsies from LPP and FFA and healthy controls were stained with the following immunohistochemical markers: CD1a and CD209, CD4, CD8, CD56, CD68, CD123, CXCR3, forkhead box (FOX)P3, mast cell tryptase and cKit. Macrophage polarization was explored using CD206, CD163, CD86, receptor for advanced glycation end products (RAGE), interleukin (IL)-4 and IL-13 on paired lesional and nonlesional LPP and FFA samples. RESULTS: Increased numbers of CD8+ , CXCR3+ and FOXP3+ T cells and CD68+ macrophages were identified in the distal hair follicle epithelium and perifollicular mesenchyme in both LPP and FFA compared with controls. In both LPP and FFA, total and degranulated mast cells and CD123+ plasmacytoid dendritic cells were increased in the perifollicular mesenchyme adjacent to the bulge and infundibulum, whereas numbers of CD1a+ and CD209+ dendritic cells were significantly reduced in the infundibulum connective tissue sheath. However, only with CD68 staining was a significant difference between LPP and FFA identified, with greater numbers of CD68+ cells in LPP samples. Furthermore, the identified macrophage polarization markers downregulated CD86 and upregulated CD163 and IL-4 expression in lesional LPP compared with FFA samples. CONCLUSIONS: This comparative immunopathological analysis is the first to profile systematically the hair follicle immune system in LPP and FFA. Our analysis highlights a potential role of macrophages in disease pathobiology and suggests that macrophage polarization may differ between LPP and FFA, allowing microscopic differentiation. Linked Comment: Kinoshita-Ise. Br J Dermatol 2020; 183:419-420.

Demographic and clinical correlates of suicidal ideation in individuals with at-risk mental state (ARMS): A study from Pakistan.

BACKGROUND: Suicide is a major public health concern and one of the leading causes of mortality worldwide. People with an at-risk-mental-state (ARMS) for psychosis are more vulnerable to psychiatric co-morbidity and suicide, however, there are limited data from low-middle-income countries. The present study aimed to identify the prevalence of depressive symptoms and suicidal ideation along with sociodemographic and clinical correlates of suicidal ideation in individuals with ARMS from Pakistan. METHOD: Participants between the age of 16 and 35 years who met the criteria for ARMS based on the Comprehensive Assessment of At-Risk Mental State (CAARMS), were recruited from the community, general practitioner clinics and psychiatric units across Pakistan (n = 326). Montgomery and Asberg Depression Rating Scale (MADRS) and Social-Occupational-Functional-Assessment-Scale (SOFAS) were administered to participants. RESULTS: The prevalence of depressive symptoms and suicidal thoughts in the sample at baseline were 91.1% (n = 297) and 61.0% (n = 199), respectively. There were significant mean differences between groups (mean difference [95% CI]; p-value) without suicidal ideation and with suicidal ideation on measures of MADRS (-5.47 [-7.14, -3.81]; p < .001), CAARMS non-bizarre ideas (-0.29 [-0.47, -0.11]; p = .002) and perceptual abnormalities (-0.23 [-0.41, -0.04]; p = .015). CONCLUSION: These findings indicate that suicidal ideation and depressive symptoms are highly prevalent in individuals with ARMS in Pakistan. Given the pivotal developmental stages that ARMS presents, and the poor outcomes associated with co-morbid depression, there is an urgent need to prioritize the development of low-cost and scalable evidence-based interventions to address psychiatric comorbidity and suicidality in the ARMS population in Pakistan.

Site-specific immunophenotyping of keloid disease demonstrates immune upregulation and the presence of lymphoid aggregates.

BACKGROUND: Keloid disease (KD) is a common fibroproliferative disorder of unknown aetiology. T cells and macrophages are increased in KD and are thought to contribute to its pathogenesis. However, while a link between inflammation and fibrotic disorders is well known for other disorders, it remains undetermined in KD. OBJECTIVES: Systematically to immunophenotype the inflammatory infiltrate of KD in situ in a site-specific manner, and to compare this with normal skin and scar tissue. METHODS: Sixty-eight keloid cases were screened for the presence of all three (intralesional, perilesional and extralesional) keloid-associated specific tissue sites. Subsequently, a complete set of 25 keloid biopsies (from different patients) was compared with normal skin (n = 11) and normal scar (n = 11) samples and subjected to systematic, site-specific quantitative immunohistomorphometry and histochemistry, using a range of immunological markers of B cells, T cells, macrophages, mast cells (MCs) and Langerhans cells. RESULTS: T cells, B cells, degranulated and mature MCs (coexpressing OX40 ligand) and alternative macrophages (M2) were all significantly increased in intralesional and perilesional KD sites compared with normal skin and scar tissue (P < 0·05). Additionally, 10 of 68 KD cases (15%) showed the presence of distinctive lymphoid aggregates, which resembled mucosa-associated lymphoid tissue (MALT). CONCLUSIONS: The increased number and activity of MCs and M2 may implicate inflammation in the fibrotic process in KD. The distinct KD-associated lymphoid aggregate resembles MALT, for which we propose the term 'keloid-associated lymphoid tissue' (KALT). It may perpetuate inflammatory stimuli that promote KD growth. KALT, MCs and M2 are promising novel targets for future KD therapy.

Lichen planopilaris following hair transplantation and face-lift surgery.

Cosmetic surgical procedures, including hair transplantation and face-lift surgery, are becoming increasingly popular. However, there is very little information regarding the associated development of dermatological conditions following these procedures. Lichen planopilaris (LPP) is an uncommon inflammatory hair disorder of unknown aetiology that results in permanent alopecia and replacement of hair follicles with scar-like fibrous tissue. Frontal fibrosing alopecia (FFA), a variant of LPP, involves the frontal hairline and shares similar histological findings with those of LPP. We report 10 patients who developed LPP/FFA following cosmetic scalp surgery. Seven patients developed LPP following hair transplantation, and three patients developed FFA following face-lift surgery. In all cases there was no previous history of LPP or FFA. There is currently a lack of evidence to link the procedures of hair transplantation and cosmetic face-lift surgery to LPP and FFA, respectively. This is the first case series to describe this connection and to postulate the possible pathological processes underlying the clinical observation. Explanations include Koebner phenomenon induced by surgical trauma, an autoimmune process targeting an (as yet, unknown) hair follicle antigen liberated during surgery or perhaps a postsurgery proinflammatory milieu inducing hair follicle immune privilege collapse and follicular damage in susceptible individuals.

Does collapse of immune privilege in the hair-follicle bulge play a role in the pathogenesis of primary cicatricial alopecia?

BACKGROUND: The hair-follicle bulge has recently been added to a growing list of human tissue compartments that exhibit a complex combination of immunosuppressive mechanisms, termed immune privilege (IP), which seem to restrict immune-mediated injury in specific locations. As epithelial hair-follicle stem cells (eHFSC) reside in the hair-follicle bulge region, it is conceivable that these IP mechanisms protect this vital compartment from immune-mediated damage, thereby ensuring the ongoing growth and cyclic regeneration of the hair follicle. Primary cicatricial alopecias (PCA) are a group of inflammatory hair disorders that result in hair-follicle destruction and permanent alopecia. Growing evidence suggests that eHFSC destruction is a key factor in the permanent follicle loss seen in these conditions. AIM: To explore the possible role of bulge IP collapse in PCA pathogenesis. METHODS: We report three clinically distinct cases of PCA. Immunohistochemical analyses of paired biopsies from lesional and uninvolved scalp skin were compared using recognized markers of IP. RESULTS: Immunohistochemical investigation found increased expression of major histocompatibility complex (MHC) classes I and II and of beta2-microglobulin in the bulge region of lesional follicles compared with uninvolved follicles in each case. Further, expression of the bulge marker keratin 15 was reduced in lesional skin in two of the cases. CONCLUSIONS: This small series represents our first preliminary attempts to ascertain whether bulge IP collapse may play a role in PCA pathogenesis. We present standard parameters relating to hair-follicle IP in the bulge region of three patients with distinct PCA variants, and show the presence of features consistent with bulge IP collapse in each case.

A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis.

NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (ß = -2.5; [95% CI -4.7 to -0.4]), whereas negative symptoms were unaffected by treatment (ß = -0.39; [95% CI -2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

How not to get scar(r)ed: pointers to the correct diagnosis in patients with suspected primary cicatricial alopecia.

Primary cicatricial alopecias (PCAs) are a rare, but important, group of disorders that cause irreversible damage to hair follicles resulting in scarring and permanent hair loss. They may also signify an underlying systemic disease. Thus, it is of paramount importance that clinicians who manage patients with hair loss are able to diagnose these disorders accurately. Unfortunately, PCAs are notoriously difficult conditions to diagnose and treat. The aim of this review is to present a rational and pragmatic guide to help clinicians in the professional assessment, investigation and diagnosis of patients with PCA. Illustrating typical clinical and histopathological presentations of key PCA entities we show how dermatoscopy can be profitably used for clinical diagnosis. Further, we advocate the search for loss of follicular ostia as a clinical hallmark of PCA, and suggest pragmatic strategies that allow rapid formulation of a working diagnosis.

Minimising metabolic and cardiovascular risk in schizophrenia: diabetes, obesity and dyslipidaemia.

People with schizophrenia are at greater risk of obesity, Type 2 diabetes, dyslipidaemia and hypertension than the general population. This results in an increased incidence of cardiovascular disease (CVD) and reduced life expectancy, over and above that imposed by their mental illness through suicide. Several levels of evidence from data linkage analyses to clinical trials demonstrate that treatment-related metabolic disturbances are commonplace in this patient group, and that the use of certain second-generation antipsychotics may compound the risk of developing the metabolic syndrome and CVD. In addition, smoking, poor diet, reduced physical activity and alcohol or drug abuse are prevalent in people with schizophrenia and contribute to the overall CVD risk. Management and minimization of metabolic risk factors are pertinent when providing optimal care to patients with schizophrenia. This review recommends a framework for the assessment, monitoring and management of patients with schizophrenia in the UK clinical setting.

Orbital cellulitis following implantation of aqueous drainage devices.

PURPOSE: Orbital cellulitis (OC) as a complication of implanted aqueous drainage devices (ADD) for glaucoma is an uncommon phenomenon. The authors report two cases of infectious OC in patients with a history of congenital glaucoma and placement of ADD. METHODS: Clinical records of two patients with ADD who subsequently developed OC were reviewed for presenting symptoms, signs, medical and surgical management, and final outcome. RESULTS: In the first case, an 11-year-old girl was found to have evidence of OC 9 days after the implantation of a Krupin-Denver valve. In the second case, a 14-month-old girl presented with similar findings 8 months following the implantation of an Ahmed valve. In both cases, ultrasonography demonstrated evidence of orbital inflammation and in one patient computed tomography scan was consistent with OC. In both cases, prompt institution of systemic antibiotics resulted in resolution of the clinical signs. In the first case, diagnosis was made early and the patient was promptly treated with systemic antibiotics, resulting in resolution of her symptoms without the need for implant removal. Because of the delayed presentation in the second case, an infected implant had to be removed to achieve resolution in addition to aggressive with antibiotics treatment. CONCLUSIONS: Although rare, infectious OC may occur following implantation of ADD. Early recognition and intervention may be required to achieve resolution of the infection.

Development of early choroidal neovascular membrane in a young myope after LASIK.

PURPOSE: To describe development of early choroidal neovascular membrane (CNVM) after laser-assisted in situ keratomileusis (LASIK) procedure in a young myopic patient that was successfully managed by photodynamic therapy (PDT). METHODS: A retrospective interventional case report. RESULTS: A 20-year-old woman with myopic astigmatism underwent uneventful LASIK surgery resulting in best-corrected visual acuity (BCVA) of 20/20 bilaterally. One week later, the patient presented with decreased VA in the right eye and was found to have clinical evidence of central serous chorioretinopathy (CSC). She was treated with systemic corticosteroids without any improvement. Two weeks after LASIK, the patient's VA was 20/200 and clinical evidence of early CNVM was confirmed by fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT). PDT resulted in the regression of her CNVM with improvement in her VA and OCT findings. CONCLUSIONS: Systemic corticosteroids may enhance CNVM in patients with LASIK-induced early CNVM. PDT may be effective in the resolution of LASIK-induced CNVM.

Optic nerve avulsion from door-handle trauma in children.

AIM: To report severe visual loss caused by optic nerve avulsion (ONA) in children with door-handle trauma. METHODS: Clinical records at a tertiary eye care hospital, of 14 children who sustained severe visual loss as a result of door-handle injuries, were reviewed. The data were analysed for location, presenting symptoms and signs, diagnostic studies, intervention, and the cause of visual loss. RESULTS: There were 11 males and three females with an average age of 8 years and an average height of 125 cm. The place of trauma was home in 11 and school in three children. Presenting visual acuity (VA) was light perception (LP) in five patients and no light perception (NLP) in nine. All the 14 children had evidence of ONA and four patients had ruptured eye globes that required initial repair. The diagnosis of ONA was made clinically or by imaging studies and confirmed histopathologically in eyes that were enucleated. Average follow up was 28.8 months (range 4 months to 8 years). Final VA was LP in one patient and NLP in 13 patients, eight eyes required enucleation for painful blind eye or to achieve optimal cosmesis. CONCLUSION: ONA was the common cause of visual loss in children who sustained ocular trauma caused by door-handles.

Progressive severe visual loss after long-term withdrawal from thioridazine treatment.

PURPOSE: To report advanced thioridazine-induced retinopathy in a 50-year-old woman with evidence of progressive severe loss of vision over 30 years after withdrawal from thioridazine treatment. METHODS: The ocular fundus examination revealed areas of retinal pigment epithelium (RPE) clumping as well as generalized atrophy of the RPE and choroid. The patient experienced visual loss to the level of no light perception in both eyes despite the fact that the funduscopic appearances of her optic nerves and retinal vasculature remained relatively normal. CONCLUSIONS: This case demonstrates that severe progressive visual loss can occur several years after the cessation of chronic thioridazine treatment.

Characteristics of "reverse tolerance" to amphetamine-induced locomotor stimulation in mice.

The characteristics of chronically administered amphetamine on the locomotor and anticonvulsant effects were studied in adult CF-1 mice. The influence of dose of the drug and interdose interval on the development of "reverse tolerance" to the locomotor stimulation was investigated, in addition to the selectivity of the response and the persistence of the change in pharmacodynamics. Once-daily treatment with 6 mg/kg amphetamine for 4 weeks resulted in a 2-3 fold increase in locomotor activity. The increase in responsiveness, however, was limited to the first period of 2 weeks and there was no subsequent change in pharmacodynamics during the last 2 weeks of treatment. After 36 days of withdrawal, the response had not returned to that of control, illustrating the persistence of the effect. The results of varying the interdose interval indicated that "reverse tolerance" occurred even when the interval was as long as 14 days. These results represent additional evidence of the persistence of the phenomenon. Selectivity of the changes in the CNS was illustrated by the cross-reactivity with a motor-stimulant dose of cocaine but not with that of morphine. Selectivity was also demonstrated by the failure of "reverse tolerance" to develop to the anticonvulsant effects of amphetamine, which also appear to be mediated dopaminergically.

Effect of mono- and diaminopyridines on release of [3H]norepinephrine from isolated guinea-pig atrium.

Neurochemical evidence has been obtained that 4-aminopyridine, 3,4-diaminopyridine and 3,3-dimethyl-1-(4-amino-3-pyridyl)urea HBr (LF-14), concentration-dependently enhanced the stimulation-evoked release of [3H]norepinephrine ([3H]NE) from isolated guinea-pig atrium. The effects of aminopyridines, compounds known to inhibit potassium channels, were Ca0-dependent. High pressure liquid chromatography, combined with radiochemical detection, indicated that the increased stimulated release of radioactivity was due to [3H]NE. Since the aminopyridines studied also enhanced the release of [3H]NE from atrium treated with cocaine, a blocker of uptake1, it seems likely that the increased release of NE caused by the aminopyridines is due to the enhanced release of NE from sympathetic axon terminals and not to the inhibition of reuptake. It is probable that the sympathomimetic cardiac effects (positive inotropic and chronotropic effect) of aminopyridines observed in animal experiments is due to the increased release of NE, caused by these compounds.

Bilateral ptosis and lower eyelid ectropion secondary to cutaneous leishmaniasis.

A 73-year-old white woman had a 14-month history of an extensive, disfiguring facial lesion involving the cheeks, nose, and eyelids, resulting in exposure keratopathy. A biopsy of the facial lesion established the diagnosis of cutaneous leishmania, and the lesion responded to treatment with itraconazole.