Stratification of alopecia areata reveals involvement of CD4 T cell populations and altered faecal microbiota.

Alopecia areata (AA) is an immune-mediated disease that causes non-scarring hair loss. Autoreactive CD8 T cells are key pathogenic effectors in the skin, and AA has been associated both with atopy and with perturbations in intestinal homeostasis. This study aimed to investigate mechanisms driving AA by characterizing the circulating immunophenotype and faecal microbiome, and by stratifying AA to understand how identified signatures associated with heterogeneous clinical features of the condition. Flow cytometric analyses identified alterations in circulating B cells and CD4 T cells, while 16S sequencing identified changes in alpha and beta diversity in the faecal microbiome in AA. The proportions of transitional and naïve B cells were found to be elevated in AA, particularly in AA samples from individuals with >50% hair loss and those with comorbid atopy, which is commonly associated with extensive hair loss. Although significant changes in circulating CD8 T cells were not observed, we found significant changes in CD4+ populations. In individuals with <50% hair loss higher frequencies of CCR6+CD4 ("Th17") and CCR6+CXCR3+CD4 ("Th1/17") T cells were found. While microbial species richness was not altered, AA was associated with reduced evenness and Shannon diversity of the intestinal microbiota, again particularly in those with <50% hair loss. We have identified novel immunological and microbial signatures in individuals with alopecia areata. Surprisingly, these are associated with lower levels of hair loss, and may therefore provide a rationale for improved targeting of molecular therapeutics.

Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease-associated psychological morbidity.

BACKGROUND: Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8+ NKG2D+ T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood. OBJECTIVES: To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression. METHODS: We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort. RESULTS: Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression. CONCLUSIONS: Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D+ CD8+ T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood. AA is associated with changes in levels of interleukin (IL)-6, tumour necrosis factor-α, IL-1ß and type 17 cytokines. Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25), in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F. Levels of IL-17E and IL-22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17- and type 2 immune pathways. Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17- and type 2 immune dysregulation, rather than focusing narrowly on the CD8+ T-cell response. An immunological mechanism might contribute directly to the depression observed in people with AA.

Correction to: Update of Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias (International Endohernia Society (IEHS))-Part A.

This article was updated to include the middle initial of author L. N. Jorgensen's name.

Update of Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias (International Endohernia Society (IEHS))-Part A.

In 2014, the International Endohernia Society (IEHS) published the first international "Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias." Guidelines reflect the currently best available evidence in diagnostics and therapy and give recommendations to help surgeons to standardize their techniques and to improve their results. However, science is a dynamic field which is continuously developing. Therefore, guidelines require regular updates to keep pace with the evolving literature. METHODS: For the development of the original guidelines, all relevant literature published up to year 2012 was analyzed using the ranking of the Oxford Centre for Evidence-Based Medicine. For the present update, all of the previous authors were asked to evaluate the literature published during the recent years from 2012 to 2017 and revise their statements and recommendations given in the initial guidelines accordingly. In two Consensus Conferences (October 2017 Beijing, March 2018 Cologne), the updates were presented, discussed, and confirmed. To avoid redundancy, only new statements or recommendations are included in this paper. Therefore, for full understanding both of the guidelines, the original and the current, must be read. In addition, the new developments in repair of abdominal wall hernias like surgical techniques within the abdominal wall, release operations (transversus muscle release, component separation), Botox application, and robot-assisted repair methods were included. RESULTS: Due to an increase of the number of patients and further development of surgical techniques, repair of primary and secondary abdominal wall hernias attracts increasing interests of many surgeons. Whereas up to three decades ago hernia-related publications did not exceed 20 per year, currently this number is about 10-fold higher. Recent years are characterized by the advent of new techniques-minimal invasive techniques using robotics and laparoscopy, totally extraperitoneal repairs, novel myofascial release techniques for optimal closure of large defects, and Botox for relaxing the abdominal wall. Furthermore, a concomitant rectus diastasis was recognized as a significant risk factor for recurrence. Despite insufficient evidence with respect to these new techniques, it seemed to us necessary to include them in the update to stimulate surgeons to do research in these fields. CONCLUSION: Guidelines are recommendations based on best available evidence intended to help the surgeon to improve the quality of his daily work. However, science is a continuously evolving process, and as such guidelines should be updated about every 3 years. For a comprehensive reference, however, it is suggested to read both the initial guidelines published in 2014 together with the update. Moreover, the presented update includes also techniques which were not known 3 years before.

Update of Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias (International Endohernia Society (IEHS)): Part B.

In 2014 the International Endohernia Society (IEHS) published the first international "Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias". Guidelines reflect the currently best available evidence in diagnostics and therapy and give recommendations to help surgeons to standardize their techniques and to improve their results. However, science is a dynamic field which is continuously developing. Therefore, guidelines require regular updates to keep pace with the evolving literature. METHODS: For the development of the original guidelines all relevant literature published up to year 2012 was analyzed using the ranking of the Oxford Centre for Evidence-Based-Medicine. For the present update all of the previous authors were asked to evaluate the literature published during the recent years from 2012 to 2017 and revise their statements and recommendations given in the initial guidelines accordingly. In two Consensus Conferences (October 2017 Beijing, March 2018 Cologne) the updates were presented, discussed, and confirmed. To avoid redundancy, only new statements or recommendations are included in this paper. Therefore, for full understanding both of the guidelines, the original and the current, must be read. In addition, the new developments in repair of abdominal wall hernias like surgical techniques within the abdominal wall, release operations (transversus muscle release, component separation), Botox application, and robot-assisted repair methods were included. RESULTS: Due to an increase of the number of patients and further development of surgical techniques, repair of primary and secondary abdominal wall hernias attracts increasing interests of many surgeons. Whereas up to three decades ago hernia-related publications did not exceed 20 per year, currently this number is about 10-fold higher. Recent years are characterized by the advent of new techniques-minimal invasive techniques using robotics and laparoscopy, totally extraperitoneal repairs, novel myofascial release techniques for optimal closure of large defects, and Botox for relaxing the abdominal wall. Furthermore, a concomitant rectus diastasis was recognized as a significant risk factor for recurrence. Despite still insufficient evidence with respect to these new techniques it seemed to us necessary to include them in the update to stimulate surgeons to do research in these fields. CONCLUSION: Guidelines are recommendations based on best available evidence intended to help the surgeon to improve the quality of his daily work. However, science is a continuously evolving process, and as such guidelines should be updated about every 3 years. For a comprehensive reference, however, it is suggested to read both the initially guidelines published in 2014 together with the update. Moreover, the presented update includes also techniques which were not known 3 years before.

Evaluation of Enoxaparin Dosing as a Risk Factor for Bleeding in Lung Transplant Recipients.

BACKGROUND: Lung transplant recipients commonly develop complications that lead to anticoagulation. Standard FDA-approved enoxaparin dosing in this population results in a high incidence of above-goal anti-Xa levels, but its association with bleeding remains unclear. OBJECTIVE: To evaluate the association between enoxaparin dosing and bleeding in lung transplant recipients and assess the relationship between dosing and anti-Xa levels. METHODS: We conducted a single-center retrospective cohort study of adult lung transplant recipients who received therapeutic enoxaparin between 2000 and 2012 at a tertiary academic center. We dichotomized enoxaparin dosing regimens into standard dose (FDA-approved doses with a 10% rounding margin) and reduced dose. Clinicians ordered anti-Xa levels as deemed clinically appropriate. The primary outcome was major bleeding or clinically relevant nonmajor bleeding. RESULTS: Of 222 patients treated with enoxaparin, 33 (14.9%) had bleeding events, of which half (17/33) were major. Bleeding occurred in 25/146 (17.1%) patients who received standard-dose enoxaparin versus 8/76 (10.5%) patients who received reduced-dose enoxaparin (P = 0.190). Multiple logistic regression demonstrated an independent association between standard-dose enoxaparin and bleeding, after adjusting for confounders (adjusted odds ratio = 3.04; 95% CI = 1.14-8.10). The median enoxaparin dose in patients with above-goal versus at-goal anti-Xa levels was 0.89 versus 0.76 mg/kg every 12 hours; P = 0.006. However, doses yielding at-goal anti-Xa levels had an interquartile range of 0.67 to 0.90 mg/kg, which overlapped with doses yielding above- and below-goal anti-Xa levels. CONCLUSIONS: Enoxaparin dose reduction and anti-Xa level monitoring can improve drug safety and facilitate individualized dose optimization in lung transplant recipients.

A Randomized Controlled Trial of the Effects of Early Intervention Services On Insight in First Episode Psychosis.

BACKGROUND AND HYPOTHESIS: Impaired insight into one's illness is common in first episode psychosis (FEP), is associated with worse symptoms and functioning, and predicts a worse course of illness. Despite its importance, little research has examined the effects of early intervention services (EIS) on insight. DESIGNS: This paper evaluated the impact of EIS (NAVIGATE) on insight compared to usual community care (CC) in a large cluster randomized controlled trial. Assessments were conducted at baseline and every 6 months for 2 years. RESULTS: A multilevel regression model including all time points showed a significant time by treatment group interaction (P < .001), reflecting greater improvement in insight for NAVIGATE than CC participants. Impaired insight was related to less severe depression but worse other symptoms and functioning at baseline for the total sample. At 6 months, the same pattern was found within each group except insight was no longer associated with depression among NAVIGATE participants. Impaired insight was more strongly associated with worse interpersonal relationships at 6 months in NAVIGATE than in CC, and changes in insight from baseline to 6 months were more strongly correlated with changes in relationships in NAVIGATE than CC. CONCLUSIONS: The NAVIGATE program improved insight significantly more than CC. Although greater awareness of illness has frequently been found to be associated with higher depression in schizophrenia, these findings suggest EIS programs can improve insight without worsening depression in FEP. The increased association between insight and social relationships in NAVIGATE suggests these 2 outcomes may synergistically interact to improve each other in treatment.

Structural analysis of a set of proteins resulting from a bacterial genomics project.

The targets of the Structural GenomiX (SGX) bacterial genomics project were proteins conserved in multiple prokaryotic organisms with no obvious sequence homolog in the Protein Data Bank of known structures. The outcome of this work was 80 structures, covering 60 unique sequences and 49 different genes. Experimental phase determination from proteins incorporating Se-Met was carried out for 45 structures with most of the remainder solved by molecular replacement using members of the experimentally phased set as search models. An automated tool was developed to deposit these structures in the Protein Data Bank, along with the associated X-ray diffraction data (including refined experimental phases) and experimentally confirmed sequences. BLAST comparisons of the SGX structures with structures that had appeared in the Protein Data Bank over the intervening 3.5 years since the SGX target list had been compiled identified homologs for 49 of the 60 unique sequences represented by the SGX structures. This result indicates that, for bacterial structures that are relatively easy to express, purify, and crystallize, the structural coverage of gene space is proceeding rapidly. More distant sequence-structure relationships between the SGX and PDB structures were investigated using PDB-BLAST and Combinatorial Extension (CE). Only one structure, SufD, has a truly unique topology compared to all folds in the PDB.

An analysis of relative costs and potential benefits of different policies for antenatal screening for beta thalassaemia trait and variant haemoglobins.

AIMS: To investigate the costs and potential benefits of different policies for antenatal screening for haemoglobinopathies in two multiethnic London communities. METHODS: 1000 consecutive antenatal patient samples referred to each of two London teaching hospital laboratories for haemoglobinopathy testing were investigated using the standard procedures of the laboratory in question. When the standard procedures did not include high performance liquid chromatography (HPLC), this technique was added, in order to assess its diagnostic value and cost-effectiveness. A comparison was made between the costs and potential benefits of universal testing for variant haemoglobins and beta thalassaemia trait using HPLC and the costs and potential benefits of universal testing for variant haemoglobins and selective testing for beta thalassaemia trait using the mean cell haemoglobin (MCH) as a screening test and less automated techniques than HPLC for definitive diagnosis. RESULTS: The costs of the two policies were found to be comparable, as the higher reagent/instrument costs of HPLC were offset by the lower labour costs. Universal testing of 2000 consecutive samples did not disclose any extra cases of beta thalassaemia trait which would not have been detected by universal screening and selective testing. However, six patients were found to have a haemoglobin A2 variant which can interfere with the diagnosis of beta thalassaemia trait. CONCLUSIONS: The introduction of universal testing by HPLC into British laboratories could be cost neutral and has potential benefits. If a higher cost is accepted then the greater degree of automation could be used to release skilled staff for other tasks within the laboratory.

Longitudinal study of neuropsychological functioning in patients on chronic hemodialysis: a preliminary report.

This study is part of a five-year project to investigate the long term effect of chronic hemodialysis on patients with end-stage renal failure. Previous research has associated hemodialysis with progressive dialysis encephalopathy (PDE), which is characterized by speech disturbances, cognitive impairment, myoclonus and behavioral changes. Little is known about the cause or the course of this syndrome except that it begins 14-36 months after treatment onset and usually culminates in death. The purpose of this study was to investigate neuropsychological (cognitive and behavioral) functioning in dialysis patients over a period of years. To date, 34 patients have been studied for 22 months utilizing a cross-sectional method comparing patients at different stages of treatment combined with a longitudinal method of repeated evaluations over time. Current findings show improved cognitive functioning during at least the first year of treatment and no evidence of cognitive deterioration in patients on dialysis for more than one year (M = 4.3). These findings offer strong evidence that PDE is not necessarily a general phenomenon among patients on chronic hemodialysis.

Acute antibody-mediated rejection after lung transplantation.

BACKGROUND: Antibody-mediated rejection (AMR) after lung transplantation remains enigmatic, and there is no consensus on the characteristic clinical, immunologic and histologic features. METHODS: We performed a retrospective, single-center cohort study and identified cases of acute AMR based on the presence of circulating donor-specific human leukocyte antigen (HLA) antibodies (DSA), histologic evidence of acute lung injury, C4d deposition and clinical allograft dysfunction. RESULTS: We identified 21 recipients with acute AMR based on the aforementioned criteria. AMR occurred a median 258 days after transplantation; 7 recipients developed AMR within 45 days of transplantation. All patients had clinical allograft dysfunction, DSA, histology of acute lung injury and capillary endothelial C4d deposition. Fifteen recipients improved clinically and survived to hospital discharge, but 6 died of refractory AMR. One survivor had bronchiolitis obliterans syndrome at the time of AMR diagnosis; 13 of the 14 remaining survivors developed chronic lung allograft dysfunction (CLAD) during follow-up. Overall, 15 recipients died during the study period, and the median survival after the diagnosis of AMR was 593 days. CONCLUSIONS: Acute AMR can be a fulminant form of lung rejection, and survivors are at increased risk of developing CLAD. The constellation of acute lung injury, DSA and capillary endothelial C4d deposition is compelling for acute AMR in recipients with allograft dysfunction. This clinicopathologic definition requires validation in a multicenter cohort, but may serve as a foundation for future studies to further characterize AMR.

Linezolid for the treatment of resistant gram-positive cocci.

OBJECTIVE: To provide a comprehensive review of linezolid, the first of a new class of antibiotics, the oxazolidinones. Therapeutic issues regarding the emergence of multidrug-resistant bacteria and a brief history of the oxazolidinones are also discussed. DATA SOURCES: A MEDLINE search (1966-March 2001) was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Unpublished clinical data, adverse effects, and dosing information were abstracted from product labeling. STUDY SELECTION: Clinical efficacy data were extracted from clinical trials, case reports, and abstracts that mentioned linezolid. Additional information concerning antibiotic resistance, the oxazolidinones, in vitro susceptibility and the pharmacokinetic profile of linezolid also was reviewed. DATA SYNTHESIS: Linezolid exhibits activity against many gram-positive organisms, including vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae. Linezolid inhibits bacterial protein synthesis at an early step in translation and is rapidly and completely absorbed from the gastrointestinal tract following oral administration. Efficacy has been demonstrated in a number of unpublished clinical trials in adults with pneumonia, skin and skin structure infections, and vancomycin-resistant E. faecium infections. The adverse effect profile is similar to that of comparator agents (beta-lactams, clarithrornycin, vancomycin). CONCLUSIONS: Linezolid is the first oral antimicrobial agent approved for the treatment of vancomycin-resistant enterococci. Since the oxazoildinones have a unique mechanism of action and expanded spectrum of activity against virulent and highly resistant gram positive pathogens, linezolid is a valuable alternative to currently available treatment options. Clinical trials evaluating linezolid and other oxazolidinones for antibiotic-resistant gram-positive infections, as well as comparator studies comparing linezolid with other candidate drugs, such as quinupristin/dalfopristin and choramphenicol, will further define the role of linezolid.

Cognitive outcome after emergent treatment of acute herpes simplex encephalitis with acyclovir.

Longitudinally designed case studies, reporting cognitive and psychosocial outcome of herpes simplex virus encephalitis (HSVE), were conducted prior to current antiviral medication usage and primarily in persons with either left hemispheric or bilateral temporal lobe involvement. The current study demonstrated relatively better outcome (cognitive recovery and functional independence for activities of daily life) in an individual treated with IV Acyclovir within hours of initial symptoms and whose CT scans showed right hemispheric involvement. In contrast with earlier case reports, no semantic specific categories of memory impairment were noted on serial assessment. The time from first symptoms to antiviral medical treatment appears to be the best predictor of outcome from HSVE. Historical case studies with relatively poorer outcome and differing deficits suggest survivors of HSVE are a heterogenous group. Variability in anatomic lesions and time to treatment contribute to outcome.

Non-organic visual loss in children.

BACKGROUND: Patients with non-organic visual loss (NOVL) can take up a disproportionate amount of clinic time and clinicians often resort to expensive and prolonged investigations to ensure the correct diagnosis. This is especially the case in children. METHODS: The case notes of 30 children (18 girls, 12 boys) were retrospectively reviewed following presentation with a primary complaint of visual impairment and a diagnosis of non-organic visual loss. This figure represents 1% of new paediatric referrals to our unit. Associated symptoms included headache, periorbital pain, diplopia, photopsia and photophobia. Visual field defects were present in 5 patients and spasm of the near reflex in 1 child. RESULTS: Treatment consisted of reassurance and was associated with recovery of normal visual function in all cases. Three children were referred to other health care professionals. All psychophysical, electrophysiological and neuroradiological investigations were negative. CONCLUSION: Our study shows that non-organic visual loss is relatively common in pre-pubertal children and that this condition can be safely diagnosed using standard clinical tests in the majority of cases. Prompt diagnosis prevents unnecessary investigations and prolonged 'disease' course. Coexisting social conflict was common and may be a contributory factor. Careful explanation and reassurance to both the child and parents remains the mainstay of management.

The phenotype of lymphocytes in a thymoma as studied with monoclonal antibodies.

In a thymoma, with lymphocytic predominance, we characterized the lymphocytes using a battery of monoclonal antibodies. The T lymphocytes had a phenotype most characteristic of cortical thymocytes (T3+, T4+, T6+, T8+, T11+, TdT+, PNA+).

Immunophenotypic profile of CNS lymphoma: a review of eighteen cases.

The cell surface antigenic phenotype of 18 cases of central nervous system (CNS) large-cell lymphoma (14 primary, four secondary) was examined by an immunoperoxidase technique using antibodies that identify B cell restricted and associated antigens. All cases were shown to be of B cell origin by virtue of the expression of monotypic immunoglobulin (Ig) (16 IgM, two IgG) and the pan B cell antigen B1 (CD20). A panel of monoclonal antibodies directed against B cell restricted and associated activation antigens including B5, Blast-1, Blast-2 (CD23), BB1, interleukin 2 receptor (IL2R, CD25), T9 (transferrin receptor) and TNK-TAR (4F2) was used on 12 of the cases. The majority expressed T9 and TNK-TAR. Blast-1 was expressed by less than half the cases and Blast-2 and B5 by one of 12 cases each. This is in contrast to 10 non-CNS diffuse large cell lymphomas where B5 and Blast-1 were present on all cases. This study confirms previous observations that primary CNS large cell lymphomas are of B cell derivation. Moreover, the differences in expression of B cell activation antigens on CNS large cell lymphomas as compared to non-CNS lymphomas raise the possibility that a subset of neoplastic B cells may have unique tropism for the CNS.

The effect of topical 20% benzocaine on pain during loop electrosurgical excision of the cervix.

OBJECTIVE: Our purpose was to evaluate the effect of cervical application of 20% benzocaine on the pain associated with subsequent cervical injection of local anesthetic and tissue excision during the loop electrosurgical excision procedure of the cervix. STUDY DESIGN: Fifty consecutive women scheduled for loop electrosurgical excision were randomized by use of computer-generated numbers to receive cervical application of either 20% benzocaine or placebo gel in a double-blinded fashion. A visual analog scale was used to measure the pain associated with both cervical injection of local anesthetic and tissue excision. RESULTS: Lower mean pain scores were associated with the use of benzocaine gel for both anesthetic injection and tissue excision, but these scores did not reach statistical significance in either group. CONCLUSION: Preoperative cervical application of 20% benzocaine does not appear to reduce the pain associated with either subsequent local anesthetic injection or tissue excision during the loop electrosurgical excision procedure of the cervix.

Decisions on breast-feeding or formula feeding and trends in infant-feeding practices.

To develop programs that effectively promote breast-feeding in the United States, information is needed on when mothers decide to breast-feed or formula feed and on trends in infant-feeding practices. Our surveys showed that 85% to 92% of mothers decided on a feeding method before the end of the second trimester of pregnancy, that only 5% to 7% were undecided in the third trimester, and that 96% to 97% fed their infants as previously planned. Surveys of mothers of young infants from 1976 to 1980 showed changes in infant-feeding practices to 6 months of age as follows: increase in incidence and duration of breast-feeding, decrease in newborn infants receiving formula, increase in use of formula rather than cows' milk when breast-feeding is discontinued early, and later introduction of supplementary foods for both breast-fed and formula-fed infants.

Separation and isolation of rat natural killer (NK) cells from T cells with monoclonal antibodies.

It has been difficult to clearly differentiate rat NK cells from cytotoxic T cells. In this study we have shown that rat NK cells do not express the T cell protein defined by the OX 19 antibody. By using the FACS we have isolated the OX 19- OX 8+ lymphocyte subset that contains virtually all the NK activity. The simultaneous use of the OX 19 and OX 8 antibodies allows the separation of NK cells from T cells.