Hidradenitis suppurativa: a review with a focus on treatment data.

Hidradenitis suppurativa (HS) is a chronic disease of the follicular unit that often leads to marked impairment of quality of life and usually affects the axillary, perineum and inframammary regions resulting in tender subcutaneous nodules, abscesses, fibrosis and sinus tract formation. New updates on HS underscores the role of various genes as well as the innate and adaptive immune response in its pathogenesis. Although every patient requires an individualized approach to treatment, topical therapy and antibiotics are mainly used for mild to moderate disease, whereas various systemic immune modulators and/or surgical approaches play a pivotal role in moderate to severe disease. New treatments using various immune modulators, laser modalities and other novel agents provide clinicians with better ways of managing HS.

If there is an evolutionary selection pressure for the high frequency of MBL2 polymorphisms, what is it?

Either immune selection or stochastic processes may have influenced the frequency of highly polymorphic genes such as mannose-binding lectin 2 (MBL2). This pattern recognition receptor of the innate immune system recognizes and binds to pathogenic microorganisms and apoptotic cells leading to lectin pathway complement killing or clearance. In almost all of a large number of studies in different ethnic groups worldwide there is 20-25% carriage of low MBL2 haplotypes, with 8-10% of each population having no MBL detectable in the blood. The source of this high variability of MBL2 remains cryptic. It arises from six main snps in the prompter and exon regions of the gene that assort into seven common haplotypes under linkage disequilibrium. While global studies of MBL2 show that it is not under immune selection pressure, these results are not the same when the same population genetic tools are used on large national studies. Other analyses point to the silenced MBL1 pseudogene and development of promoter polymorphisms in humans as evidence of selection pressure favouring low-producing haplotypes. While these analyses cannot be reconciled readily, there are two processes by which MBL heterozygosity could have been advantageous in an evolutionary sense; protection against adverse effects of various infectious diseases and lethal manifestations of atherosclerosis - a disease that now seems to have a more ancient history than assumed previously. Ultimately, consideration of the context for possible future therapeutic manipulation of MBL means that this can proceed independently of resolution of the evolutionary forces that have shaped MBL2 polymorphism.

Electrobrasion vs. manual dermabrasion: a randomized, double-blind, comparative effectiveness trial.

BACKGROUND: Electrobrasion, like dermabrasion, is a method of surgical planing that is purported to improve postoperative scarring. Data regarding its benefits and harms relative to dermabrasion are absent. OBJECTIVE: To compare the efficacy and potential harms of electrobrasion and dermabrasion. METHODS: This was a pragmatic, randomized, double-blind, split-scar intervention in patients with suboptimal surgical outcomes. Half of the wound was randomized to treatment with dermabrasion and half to electrobrasion. At 3-month follow-up, both the patient and a blinded investigator evaluated the wound. RESULTS: Electrobrasion and dermabrasion reduced the mean scores of the Manchester Scar Scale 1·6 and 1·3 points from baseline, respectively (P = 0·0003). The difference between treatments was not significant (P = 0·08). Global cosmetic improvement by physician and patient assessment indicated clinical improvement for both procedures but did not demonstrate statistical significance between treatments (P = 0·57, P = 0·32 for physician and patient, respectively). CONCLUSIONS: Both dermabrasion and electrobrasion improved scars, but there was no significant difference between the outcomes of the two procedures on several measures. Procedure time and bleeding time were significantly lower for electrobrasion.

Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE)-an open-labelled pilot randomized controlled trial.

BACKGROUND: Combination antibiotic therapy with an antitoxin agent, such as clindamycin, is included in some guidelines for severe, toxin-mediated Staphylococcus aureus infections. The evidence to support this practice is currently limited to in vitro, animal and observational human case-series data, with no previous randomized controlled trials (RCTs). OBJECTIVES: This pilot RCT aimed to determine the feasibility of conducting a clinical trial to examine if adjunctive clindamycin with standard therapy has greater efficacy than standard therapy alone for S. aureus infections. METHODS: We performed an investigator-initiated, open-label, multicentre, pilot RCT (ACTRN12617001416381p) in adults and children with severe S. aureus infections, randomized to standard antibiotic therapy with or without clindamycin for 7 days. RESULTS: Over 28 months, across nine sites, 127 individuals were screened and 34 randomized, including 11 children (32%). The primary outcome-number of days alive and free of systemic inflammatory response syndrome ≤14 days-was similar between groups: clindamycin (3 days [IQR 1-6]) versus standard therapy (4 days [IQR 0-8]). The 90 day mortality was 0% (0/17) in the clindamycin group versus 24% (4/17) in the standard therapy group. Secondary outcomes-microbiological relapse, treatment failure or diarrhoea-were similar between groups. CONCLUSIONS: As the first clinical trial assessing adjunctive clindamycin for S. aureus infections, this study indicates feasibility and that adults and children can be incorporated into one trial using harmonized endpoints, and there were no safety concerns. The CASSETTE trial will inform the definitive S. aureus Network Adaptive Platform (SNAP) trial, which includes an adjunctive clindamycin domain and participants with non-severe disease.

Computer-assisted analysis of abrasive transepithelial brush biopsies increases the effectiveness of esophageal screening: a multicenter prospective clinical trial by the EndoCDx Collaborative Group.

BACKGROUND: The sensitivity of screening for Barrett's esophagus (BE) and esophageal dysplasia (ED) is hampered by the limited amount of tissue that can be sampled by forceps biopsy (FB). AIM: The aim of this study was to evaluate computer assisted analysis of an abrasive, transepithelial brush biopsy as an adjunct to FB to increase detection of BE and ED. METHODS: This was a multicenter prospective trial of patients being screened for BE and ED. Each patient had two brush biopsies (BB) and then random four-quadrant FB every 1-2 cm of the esophagus. All BB were examined with computer assistance by pathologists at CDx Laboratories (Suffern, NY), and all FB were examined by the investigators' local pathologists. RESULTS: Of 1,266 patients enrolled, 363 were diagnosed with BE by FB alone and 146 additional cases of BE were identified by adding BB. The addition of BB to FB increased the overall detection of BE by 39.8% (95% CI 32-48%). This added detection of BE in 11.5% of all patients tested with the BB (146/1266) resulted in a number of patients needed to test (NNT) to obtain each additional positive finding of Barrett's esophagus of 8.7. Among a subset of 848 patients with gastroesophageal reflux disease and no prior history of BE, the addition of BB to FB identified an additional 105 patients with BE increasing the overall detection of BE by 70.5% (95% CI 54-90%). Dysplasia was diagnosed in 16 patients by FB alone, with an additional 14 cases detected by adding BB. The addition of BB to FB thus increased the detection of ED by 87.5%. CONCLUSION: These results suggest that adjunctive computer-assisted analysis of an abrasive brush biopsy has the potential to substantially improve the detection of Barrett's esophagus and dysplasia in screening populations.

Hospitalisation for lower respiratory tract infection is associated with an increased incidence of acute myocardial infarction and stroke in tropical Northern Australia.

Acute respiratory infections appear to precipitate vascular events. Acute myocardial infarction (AMI) and stroke are the leading cause of death and disability globally. This study was based on a cohort of patients admitted to Townsville University Hospital between January 2006 and December 2016. Using a self-controlled case series design, we investigated the risk of AMI or ischaemic stroke after an episode of pneumonia. We defined the 'risk interval' as the first 14 days after hospitalisation for pneumonia and the 'control interval' as one year before and one year after the risk interval. Among a population (N = 4557) with a median age of over 70, a total of 128 AMI and 27 stroke cases were identified within 1 year of an episode of pneumonia in this study. Ten and two admissions occurred during the risk interval, while 118 and 25 admissions occurred during the control period. The relative incidence ratios (RIR) of AMI increased after an episode of pneumonia (RIR=4.85, 95% confidence interval (CI) 2.44-9.67). The risk for stroke after the exposure period of 14 days was 4.94 (95% CI 1.12-21.78) considering only the first stroke incidence. The RIR results for AMI and stroke were not altered by adjusting for age, sex or Indigenous status. The risk of AMI and stroke were significantly higher two weeks after an episode of pneumonia.

Association between severe pandemic 2009 influenza A (H1N1) virus infection and immunoglobulin G(2) subclass deficiency.

BACKGROUND: . Severe pandemic 2009 influenza A virus (H1N1) infection is associated with risk factors that include pregnancy, obesity, and immunosuppression. After identification of immunoglobulin G(2) (IgG(2)) deficiency in 1 severe case, we assessed IgG subclass levels in a cohort of patients with H1N1 infection. METHODS: Patient features, including levels of serum IgG and IgG subclasses, were assessed in patients with acute severe H1N1 infection (defined as infection requiring respiratory support in an intensive care unit), patients with moderate H1N1 infection (defined as inpatients not hospitalized in an intensive care unit), and a random sample of healthy pregnant women. RESULTS: Among the 39 patients with H1N1 infection (19 with severe infection, 7 of whom were pregnant; 20 with moderate infection, 2 of whom were pregnant), hypoabuminemia (P < .001), anemia (P < .001), and low levels of total IgG (P= .01), IgG(1) (P= .022), and IgG(2) (15 of 19 vs 5 of 20; P= .001; mean value +/- standard deviation [SD], 1.8 +/- 1.7 g/L vs 3.4 +/- 1.4 g/L; P= .003) were all statistically significantly associated with severe H1N1 infection, but only hypoalbuminemia (P= .02) and low mean IgG(2) levels (P= .043) remained significant after multivariate analysis. Follow-up of 15 (79%) surviving IgG(2)-deficient patients at a mean (+/- SD) of 90 +/- 23 days (R, 38-126) after the initial acute specimen was obtained found that hypoalbuminemia had resolved in most cases, but 11 (73%) of 15 patients remained IgG(2) deficient. Among 17 healthy pregnant control subjects, mildly low IgG(1) and/or IgG(2) levels were noted in 10, but pregnant patients with H1N1 infection had significantly lower levels of IgG(2) (P= .001). CONCLUSIONS: Severe H1N1 infection is associated with IgG(2) deficiency, which appears to persist in a majority of patients. Pregnancy-related reductions in IgG(2) level may explain the increased severity of H1N1 infection in some but not all pregnant patients. The role of IgG(2) deficiency in the pathogenesis of H1N1 infection requires further investigation, because it may have therapeutic implications.

Mannose-binding lectin and susceptibility to tuberculosis: a meta-analysis.

It has been proposed that mannose-binding lectin (MBL) levels may impact upon host susceptibility to tuberculosis (TB) infection; however, evidence to date has been conflicting. We performed a literature review and meta-analysis of 17 human trials considering the effect of MBL2 genotype and/or MBL levels and TB infection. No significant association was demonstrated between MBL2 genotype and pulmonary TB infection. However, the majority of studies did not report MBL2 haplotype inclusive of promoter polymorphisms. Serum MBL levels were shown to be consistently elevated in the setting of TB infection. While this may indicate that high MBL levels protect against infection with TB, the increase was also of a degree consistent with the acute-phase reaction. This analysis suggests that the relatively poorly characterized MBL2 genotypes reported are not associated significantly with susceptibility to pulmonary TB infection, but high MBL serum levels may be.

Portable video media for presenting informed consent and wound care instructions for skin biopsies: a randomized controlled trial.

BACKGROUND: In fast-paced dermatology clinics, the process of obtaining informed consents for biopsies and providing postprocedure instructions may be incomplete and inconsistent. OBJECTIVES: To compare effectiveness of video-based education with that of verbal education for giving informed consent and providing postprocedure wound care instructions in patients undergoing skin biopsies. METHODS: In this randomized controlled trial, participants were randomized to receive either video education on portable video devices or conventional verbal instructions regarding skin biopsies. Participants completed a skin-biopsy knowledge assessment, patient satisfaction assessment and evaluation of educational medium. Main outcome measures were differences in the changes in the prestudy and poststudy knowledge assessment scores, patient satisfaction and evaluation of the educational medium. RESULTS: Eight-four patients undergoing skin biopsies at the University of California Davis dermatology clinic participated in the study. Participants in the control group had a nonstatistically significant increase in knowledge score (mean ± SD 1·12 ± 1·74), whereas those in the video group had a statistically significant increase in knowledge score (mean ± SD 1·55 ± 1·71). The difference in knowledge scores between the video and verbal groups was not statistically significant. Participants in both groups were highly satisfied with the biopsy education. On a 10-point scale, the mean ± SD usefulness and appeal of the videos were 9·01 ± 1·5 and 9·01 ± 1·66, respectively. CONCLUSIONS: Our study demonstrated a significant increase in knowledge score following video education, but not following oral education. Although between-group comparisons did not achieve statistical significance, portable video media for presenting informed consent and wound care instructions for skin biopsies appear to be more effective and result in higher satisfaction than traditional oral education.

IgM in human immunity to Plasmodium falciparum malaria.

Most studies on human immunity to malaria have focused on the roles of immunoglobulin G (IgG), whereas the roles of IgM remain undefined. Analyzing multiple human cohorts to assess the dynamics of malaria-specific IgM during experimentally induced and naturally acquired malaria, we identified IgM activity against blood-stage parasites. We found that merozoite-specific IgM appears rapidly in Plasmodium falciparum infection and is prominent during malaria in children and adults with lifetime exposure, together with IgG. Unexpectedly, IgM persisted for extended periods of time; we found no difference in decay of merozoite-specific IgM over time compared to that of IgG. IgM blocked merozoite invasion of red blood cells in a complement-dependent manner. IgM was also associated with significantly reduced risk of clinical malaria in a longitudinal cohort of children. These findings suggest that merozoite-specific IgM is an important functional and long-lived antibody response targeting blood-stage malaria parasites that contributes to malaria immunity.

Acid-active neuraminidases in the growth media from cultures of pathogenic Naegleria fowleri and in sonicates of rabbit alveolar macrophages.

Using bovine mucin and isolated human myelin as sources of sialic acid, we demonstrate the presence of neuraminidase activities in the growth media of pathogenic, but not nonpathogenic, Naegleria sp. and in sonicates of rabbit alveolar macrophages. Neuraminidase activity was maximal at pH 4.5 and 5.0, and the specific activity for sialic acid release was up to 13-fold greater with mucin than with human myelin. Activity in the growth media from cultures of pathogenic Naegleria fowleri was ion-independent, while that of macrophage sonicates required divalent cation; optimal activity was noted with 2.5 mM Zn2+, while Mg2+ and Mn2+ supported activity to a lesser extent. Such acid-active neuraminidases may contribute to the reported glycolipid alterations associated with demyelinating diseases.

Inhibition of lysosomal phospholipases C and A in rabbit alveolar macrophages, polymorphonuclear leukocytes and rat liver by sodium bisulfite.

Phospholipase C activity was measured in disrupted rat liver lysosomes, Bacillus Calmette Guérin-induced rabbit alveolar macrophages and glycogen-induced rabbit polymorphonuclear leukocytes, using [N-methyl-14C]sphingomyelin and the phospholipids of human myelin. Phospholipase C activity with both substrates was maximal at pH 4.5 and was unaffected by monovalent or divalent cations or EDTA. The enzyme(s) had little or no substrate specificity, since most of the phospholipids of human myelin were degraded to the same extent. Solutions of gentamycin and tobramycin which contained preservatives inhibited activity, whereas similar preparations of streptomycin had no effect. On the other hand, preservative-free solutions of gentamycin and tobramycin were not inhibitory. Sodium bisulfite, an antioxidant, used in commercial preparations of gentamycin, tobramycin, streptomycin and other drugs, produced dose-dependent, reversible inhibition of the sphingomyelinase and myelin-degrading phospholipase C. Moreover, bisulfite-antibiotic interactions protected enzymatic activity from inactivation by the antioxidant. Other preservatives in commercial aminoglycosides, methyl- and propylparaben, phenol and EDTA had no effect on enzymic activity. Sodium bisulfite also inhibited acid-active phospholipase(s) A in rat liver lysosomes and alveolar macrophages, but had no effect on neutral-active, calcium-dependent phospholipases A2 from various cell types. Equimolar concentrations of streptomycin instantaneously relieved most of the inhibition by bisulfite, whereas molar ratios of gentamycin/bisulfite of 10 restored only 50% of the activity.

HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection.

OBJECTIVE: To describe two cases of cryptococcal meningitis and one re-exacerbation of Cryptococcus-associated meningitis occurring in temporal association with commencement of highly active antiretroviral therapy (HAART) in patients with advanced HIV infection (CD4 cells < 50 x 10(6)/l), which suggests that partial immune restitution can facilitate development of clinically apparent meningitis in response to Cryptococcus or its antigen. DESIGN: All HIV-infected patients with culture-proven cryptococcal meningitis diagnosed at a tertiary referral centre specialist infectious diseases unit from 1 January 1996 to 31 December 1996 were reviewed to examine the clinical and immunological parameters prior to and after commencing antiretroviral therapy. RESULTS: Three patients were diagnosed with clinically apparent meningitis within 7-39 days of changing or altering antiretroviral combination therapy consisting of zidovudine or stavudine, in combination with lamivudine and saquinavir. All patients had CD4 cell counts below 50 x 10(6)/l at initiation of therapy. Following institution of HAART, evidence of immune restitution was suggested by the following: (i) significant increases (3.7-14-fold) in numbers of CD4 cells (all three patients), (ii) significantly reduced (> 2-4 log10 reduction) HIV viral loads (two out of three patients), and (iii) prominent inflammatory changes in cerebrospinal fluid (white blood cells > 10 x 10(6)/l) at diagnosis (two out of three patients). CONCLUSIONS: Our report suggests that in patients with advanced HIV infection, partial immune restitution induced by HAART can precipitate onset of clinically apparent meningitis in those patients with latent cryptococcal central nervous system infection or with residual cryptococcal antigen present in the cerebrospinal fluid.

Retinoic acid receptor gene expression in human skin.

Human skin exhibits a characteristic, pleiotypic response to topical retinoic acid. In attempting to understand this response at the molecular level, we have used fast protein liquid chromatography (FPLC) and RNA blot hybridization to characterize the expression of the nuclear retinoic acid receptor (RAR) alpha, beta, and gamma genes in adult human epidermis. Size exclusion FPLC of 0.6 M NaCl nuclear extracts prepared from keratome biopsies revealed two peaks of specific [3H] retinoic acid (RA) binding at Mr 45 and 18 kDa, in agreement with the expected sizes of RAR and cellular RA binding protein. Blot hybridization analysis of total RNA extracted from keratome biopsies revealed that RAR-gamma was the predominant RAR species expressed in human epidermis, as RAR-alpha transcripts were detectable only at low levels and RAR-beta transcripts were undetectable. RAR transcripts were not induced by topical treatment with 0.1% RA cream under occlusion for 4 h or 4 d. Moreover, there was no significant difference in RAR-gamma transcript levels in normal and psoriatic epidermis. RAR-gamma transcripts were constitutively expressed not only in cultured human keratinocytes, but also in human dermal and lung fibroblasts. RAR-beta was induced by RA in dermal fibroblasts, but not in keratinocytes. RA induced IL-1 beta transcripts in keratinocytes rapidly (2 to 4 h) and at low concentrations (3 x 10(-10) M), consistent with activation of the IL-1 beta gene via RAR. These results demonstrate constitutive expression of RAR-gamma in human epidermis, and suggest that RAR-gamma is a molecular target of RA action in adult human skin.

Alternatives to conventional vaccines--mediators of innate immunity.

Vaccines have been described as "weapons of mass protection". The eradication of many diseases is testament to their utility and effectiveness. Nevertheless, many vaccine preventable diseases remain prevalent because of political and economic barriers. Additionally, the effects of immaturity and old age, therapies that incapacitate the adaptive immune system and the multitude of strategies evolved by pathogens to evade immediate or sustained recognition by the mammalian immune system are barriers to the effectiveness of existing vaccines or development of new vaccines. In the front line of defence against the pervasiness of infection are the elements of the innate immune system. Innate immunity is under studied and poorly appreciated. However, in the first days after entry of a pathogen into the body, our entire protective response is dependant upon the various elements of our innate immune repertoire. In spite of its place as our initial defence against infection, attention is only now turning to strategies which enhance or supplement innate immunity. This review examines the need for and potential of innate immune therapies.

Clinical utility of oral valacyclovir compared with oral acyclovir for the prevention of herpes simplex virus mucositis following autologous bone marrow transplantation or stem cell rescue therapy.

Oral acyclovir has been demonstrated to prevent reactivation of herpes simplex virus (HSV) infections when administered prophylactically to autologous bone marrow transplant (BMT) recipients or patients undergoing stem cell rescue therapy. Oral valacyclovir, which is converted in the body to acyclovir, has greater oral bioavailability than oral acyclovir and compared with oral acyclovir yields similar acyclovir plasma concentrations with less frequent (twice-daily) dosing. This study compared the efficacy of oral valacyclovir with that of oral acyclovir at preventing HSV mucositis in BMT recipients. A total of 60 HSV-1-positive patients scheduled for BMT or stem cell rescue therapy were treated prophylactically with valacyclovir 500 mg twice daily until resolution of neutropenia. Data from these patients were compared with those of a historical control group of 60 patients who had received acyclovir 600 mg every 6 h until resolution of neutropenia or acyclovir 125 mg/m(2) intravenously every 6 h. The results show that none of the patients developed oral or oropharyngeal HSV infection while receiving either treatment. Of the 60 patients receiving valacyclovir, 38 (63%) completed treatment without the need for intravenous acyclovir compared with 12 of 60 (20%) patients in the acyclovir group. Additionally, the total number of doses of drug administered to the valacyclovir group was significantly less than the number received by patients in the acyclovir group. No serious adverse events occurred in either group of patients. This study demonstrates that oral valacyclovir and acyclovir are comparably effective and safe in preventing reactivation of HSV infections in autologous BMT and stem cell recipients. The less frequent dosing schedule with valacyclovir compared with acyclovir offers a potential advantage for patients undergoing BMT who frequently suffer with severe mucositis and have difficulty taking oral medications.