Morphoea presenting histopathologically as mycosis fungoides: an illustrative series of four cases.

AIMS: There have been exceptional reports of morphoea presenting with epidermal changes overlapping histopathologically with cutaneous T cell lymphoma of the mycosis fungoides type (MF). This phenomenon gives rise to an ambiguous clinicopathological scenario in which distinguishing these conditions may be challenging. The aim of this study is to characterise the clinical, histopathological and molecular findings of this phenomenon through a case series. METHODS AND RESULTS: Four patients with classical clinical presentation of morphoea but unusual histopathology displaying typical findings of morphoea, together with intra-epidermal CD8 positive lymphocytes indistinguishable from MF, were identified. The clinical phenotypes of morphoea were varied, and they all presented early in the active phase of the disease. They all exhibited intra-epidermal lymphocytes with tagging and cytological atypia. Pautrier-like microabscesses were also seen. Using molecular analysis, two cases showed clonal TCR gene rearrangement. Follow-up of all cases has been consistent with classical morphoea. CONCLUSION: Early morphoea can seldom present with atypical clonal intra-epidermal lymphocytes indistinguishable from MF. The fact that these changes can occur in several different clinical subtypes of morphoea raises the possibility that this could be a pattern of inflammation in early disease more common than currently appreciated.

Huriez syndrome: Additional pathogenic variants supporting allelism to SMARCAD syndrome.

Huriez syndrome (HRZ, OMIM181600) is a rare genodermatosis characterized by scleroatrophic hands and feet, hypoplastic nails, palmoplantar keratoderma, and predisposition to cutaneous squamous cell carcinoma (cSCC). We report herein three HRZ families from Croatia, the Netherlands, and Germany. Deep sequencing followed by Sanger validation, confirmed the presence of germline causative SMARCAD1 heterozygous pathogenic variants. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed cSCC at 32 years of age. Two novel monoallelic germline mutations were identified which are predicted to disrupt the first exon-intron boundary of the skin-specific SMARCAD1 isoform. On the basis of phenotypic and genotypic convergence with Adermatoglyphia (OMIM136000) and Basan syndrome (OMIM129200), our results lend credence to the notion that these three Mendelian disorders are allelic. We propose adding Huriez syndrome to the previously suggested SMARCAD syndrome designation, which was originally invoked to describe the spectrum of monogenic disorders between Adermatoglyphia and Basan syndrome.

A mycotic aneurysm related to Salmonella Rissen infection: a case report.

BACKGROUND: Salmonella species commonly causes infection in humans and on occasion leads to serious complications, such as mycotic aneurysms. Here, we present the first case reported of a patient with a mycotic aneurysm likely secondary to Salmonella Rissen infection. CASE PRESENTATION: The patient presented with 4 weeks of lower back pain, chills and a single episode of diarrhoea 2 months prior during a 14-day trip to Hong Kong and Taiwan. Magnetic resonance imaging revealed an aneurysmal left internal iliac artery with adjacent left iliacus rim-enhancing collection. A stool culture was positive for Salmonella Rissen ST 469 EBG 66 on whole genome sequencing. The patient underwent an emergency bifurcated graft of his internal iliac aneurysm and was successfully treated with appropriate antibiotics. CONCLUSIONS: This case highlights the importance of considering the diagnosis of a mycotic aneurysm in an unusual presentation of back pain with features of infection.

Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host.

Host adaptation is a key factor contributing to the emergence of new bacterial, viral and parasitic pathogens. Many pathogens are considered promiscuous because they cause disease across a range of host species, while others are host-adapted, infecting particular hosts(1). Host adaptation can potentially progress to host restriction, where the pathogen is strictly limited to a single host species and is frequently associated with more severe symptoms. Host-adapted and host-restricted bacterial clades evolve from within a broader host-promiscuous species and sometimes target different niches within their specialist hosts, such as adapting from a mucosal to a systemic lifestyle. Genome degradation, marked by gene inactivation and deletion, is a key feature of host adaptation, although the triggers initiating genome degradation are not well understood. Here, we show that a chronic systemic non-typhoidal Salmonella infection in an immunocompromised human patient resulted in genome degradation targeting genes that are expendable for a systemic lifestyle. We present a genome-based investigation of a recurrent blood-borne Salmonella enterica serotype Enteritidis (S. Enteritidis) infection covering 15 years in an interleukin-12 ß1 receptor-deficient individual that developed into an asymptomatic chronic infection. The infecting S. Enteritidis harboured a mutation in the mismatch repair gene mutS that accelerated the genomic mutation rate. Phylogenetic analysis and phenotyping of multiple patient isolates provides evidence for a remarkable level of within-host evolution that parallels genome changes present in successful host-restricted bacterial pathogens but never before observed on this timescale. Our analysis identifies common pathways of host adaptation and demonstrates the role that immunocompromised individuals can play in this process.

Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host.

Host adaptation is a key factor contributing to the emergence of new bacterial, viral and parasitic pathogens. Many pathogens are considered promiscuous because they cause disease across a range of host species, while others are host-adapted, infecting particular hosts1. Host adaptation can potentially progress to host restriction where the pathogen is strictly limited to a single host species and is frequently associated with more severe symptoms. Host-adapted and host-restricted bacterial clades evolve from within a broader host-promiscuous species and sometimes target different niches within their specialist hosts, such as adapting from a mucosal to a systemic lifestyle. Genome degradation, marked by gene inactivation and deletion, is a key feature of host adaptation, although the triggers initiating genome degradation are not well understood. Here, we show that a chronic systemic non-typhoidal Salmonella infection in an immunocompromised human patient resulted in genome degradation targeting genes that are expendable for a systemic lifestyle. We present a genome-based investigation of a recurrent blood-borne Salmonella enterica serotype Enteritidis (S. Enteritidis) infection covering 15 years in an interleukin (IL)-12 ß-1 receptor-deficient individual that developed into an asymptomatic chronic infection. The infecting S. Enteritidis harbored a mutation in the mismatch repair gene mutS that accelerated the genomic mutation rate. Phylogenetic analysis and phenotyping of multiple patient isolates provides evidence for a remarkable level of within-host evolution that parallels genome changes present in successful host-restricted bacterial pathogens but never before observed on this timescale. Our analysis identifies common pathways of host adaptation and demonstrates the role that immunocompromised individuals can play in this process.

Regressing Eruptive Disseminated Spitz Nevi.

The eruptive disseminated form of Spitz nevi (EDSN) is the rarest variant, is cosmetically disabling, and has a poorly documented natural history. We report the case of a 4-year-old boy with more than 100 Spitz nevi that have significantly regressed 8 years after onset. There is no satisfactory treatment for EDSN. There have been no reports of supervening malignancy. Our case illustrates the possibility of regression of EDSN, corroborating long-term observation as a safe and acceptable management option.

Successful treatment of refractory Trichomonas vaginalis infection using intravenous metronidazole.

Trichomonas vaginalis is a sexually transmitted protozoan infection resulting in a vulvo-vaginitis and altered vaginal discharge in symptomatic women. Since its introduction in the 1960 s, metronidazole has been the first-line drug for trichomonal infection. Other nitroimidazoles, such as tinidazole, are used as alternative regimens with similar activity but at a greater expense. Treatment failure usually represents patient non-compliance or reinfection, although metronidazole resistance has previously been documented. Sensitivity testing is currently not available in the UK. Patients with disease unresponsive to first-line treatments pose a major challenge, as therapeutic options are limited. This case looks at a patient with refractory disease over an 18-month period, where intravenous infusion of metronidazole resulted in cure after multiple previous therapy failures. There is limited evidence to endorse the use of intravenous metronidazole, and this case report provides further support for its efficacy.

The genome of the sparganosis tapeworm Spirometra erinaceieuropaei isolated from the biopsy of a migrating brain lesion.

BACKGROUND: Sparganosis is an infection with a larval Diphyllobothriidea tapeworm. From a rare cerebral case presented at a clinic in the UK, DNA was recovered from a biopsy sample and used to determine the causative species as Spirometra erinaceieuropaei through sequencing of the cox1 gene. From the same DNA, we have produced a draft genome, the first of its kind for this species, and used it to perform a comparative genomics analysis and to investigate known and potential tapeworm drug targets in this tapeworm. RESULTS: The 1.26 Gb draft genome of S. erinaceieuropaei is currently the largest reported for any flatworm. Through investigation of ß-tubulin genes, we predict that S. erinaceieuropaei larvae are insensitive to the tapeworm drug albendazole. We find that many putative tapeworm drug targets are also present in S. erinaceieuropaei, allowing possible cross application of new drugs. In comparison to other sequenced tapeworm species we observe expansion of protease classes, and of Kuntiz-type protease inhibitors. Expanded gene families in this tapeworm also include those that are involved in processes that add post-translational diversity to the protein landscape, intracellular transport, transcriptional regulation and detoxification. CONCLUSIONS: The S. erinaceieuropaei genome begins to give us insight into an order of tapeworms previously uncharacterized at the genome-wide level. From a single clinical case we have begun to sketch a picture of the characteristics of these organisms. Finally, our work represents a significant technological achievement as we present a draft genome sequence of a rare tapeworm, and from a small amount of starting material.

Ancient host shifts followed by host conservatism in a group of ant parasitoids.

While ant colonies serve as host to a diverse array of myrmecophiles, few parasitoids are able to exploit this vast resource. A notable exception is the wasp family Eucharitidae, which is the only family of insects known to exclusively parasitize ants. Worldwide, approximately 700 Eucharitidae species attack five subfamilies across the ant phylogeny. Our goal is to uncover the pattern of eucharitid diversification, including timing of key evolutionary events, biogeographic patterns and potential cophylogeny with ant hosts. We present the most comprehensive molecular phylogeny of Eucharitidae to date, including 44 of the 53 genera and fossil-calibrated estimates of divergence dates. Eucharitidae arose approximately 50 Ma after their hosts, during the time when the major ant lineages were already established and diversifying. We incorporate host association data to test for congruence between eucharitid and ant phylogenies and find that their evolutionary histories are more similar than expected at random. After a series of initial host shifts, clades within Eucharitidae maintained their host affinity. Even after multiple dispersal events to the New World and extensive speciation within biogeographic regions, eucharitids remain parasitic on the same ant subfamilies as their Old World relatives, suggesting host conservatism despite access to a diverse novel ant fauna.

A multinational outbreak of histoplasmosis following a biology field trip in the Ugandan rainforest.

BACKGROUND: Outbreaks of histoplasmosis have been increasingly reported in association with travel to endemic areas. Multiple outbreaks have been reported following travel to the Americas, but reports of pulmonary histoplasmosis in short-term immunocompetent travelers to Africa are rare. METHODS: A biology student was referred to our unit with suspected pulmonary histoplasmosis following her return from a field trip in the Ugandan rainforest. The patient informed us that several of her multinational student colleagues on the same expedition had developed a similar illness. Using an alert in ProMED-mail and a questionnaire forwarded to each of the symptomatic students, we accumulated data on the other cases involved in this apparent outbreak of pulmonary histoplasmosis. RESULTS: Thirteen of 24 students developed respiratory symptoms following the expedition. Chest X-ray appearances were often suggestive of miliary tuberculosis but in most cases a final diagnosis of histoplasmosis was made (confirmed with serology in five cases, clinically diagnosed in six, and retrospectively suspected in two). Detailed questioning indicated that the likely source was a large hollow bat-infested tree within the rainforest. CONCLUSIONS: This is an unusual outbreak of histoplasmosis following short-term travel to Africa. Pulmonary histoplasmosis should always be considered in the differential diagnosis of an acute febrile respiratory illness in travelers returning from endemic areas or reporting activities suggesting exposure.

Mortality in Clostridium difficile infection: a prospective analysis of risk predictors.

OBJECTIVES: To date, the vast majority of studies investigating risk factors for mortality in Clostridium difficile infection (CDI) have been based on retrospective, routinely collected data, and have not specifically tested the capacity of risk factors to predict outcome. We aimed to prospectively evaluate predictors of mortality in patients with CDI, utilizing established metrics of risk prediction to assess their ability to prognosticate. PATIENTS AND METHODS: We collected a cohort of all patients diagnosed with CDI at Addenbrooke's Hospital in 2010. Univariate associations between several parameters and all-cause 30-day in-hospital mortality were assessed, with statistically significant parameters entered into a Cox regression model. A backwards selection procedure was used to derive a final multivariate model. RESULTS: The cohort consisted of 131 patients. From the univariate analyses white blood cell count (WBC)>15×10/l, serum albumin <25 g/l, serum creatinine >200 µmol/l and C-reactive protein >100 nmol/l met criteria for entry into the multivariate model. WBC>15×10/l (hazard ratio 5.3, 95% confidence interval 1.7-16.8) and serum albumin level <25 g/l (hazard ratio 9.5, 95% confidence interval 1.2-74.5), were significantly associated with mortality in the final multivariate model. The model containing these variables had a C-index of 0.79, D-statistic of 2.1 and RD measure of 0.52. CONCLUSION: We have demonstrated in a prospective cohort of patients diagnosed with CDI that WBC and serum albumin, when used together, offer good risk predictive ability for mortality. Our results support the inclusion of these parameters in a clinically useful risk prediction model.

Clinical and pharmacogenetic influences on response to hydroxychloroquine in discoid lupus erythematosus: a retrospective cohort study.

The recommended systemic therapy of choice for discoid lupus erythematosus (DLE) is the 4-aminoquinolone antimalarial hydroxychloroquine. There is limited published information on the likelihood of clinical response and, in particular, what factors influence outcome. We conducted a multicenter observational and pharmacogenetic study of 200 patients with DLE treated with hydroxychloroquine. The primary outcome was clinical response to hydroxychloroquine. We investigated the effects of disease attributes and metabolizing cytochrome P450 (CYP) polymorphisms on clinical outcome. Although the majority of patients responded to hydroxychloroquine, a significant proportion (39%) either failed to respond or was intolerant of the drug. Cigarette smoking and CYP genotype did not have any significant influence on response to hydroxychloroquine. Moreover, multivariate analysis indicated that disseminated disease (odds ratio (OR): 0.21; 95% confidence interval (CI): 0.08-0.52; P<0.001) and concomitant systemic lupus erythematosus (SLE; OR: 0.06; 95% CI: 0.01-0.49; P = 0.009) were significantly associated with lack of response to hydroxychloroquine. These findings suggest that baseline lupus severity and SLE are predictors of response to hydroxychloroquine. A prospective study is now required to further investigate the relationship between disease activity and response to hydroxychloroquine. This will have the potential to further inform the clinical management of this disfiguring photosensitive disease.

STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis.

BACKGROUND: Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown. METHODS: We evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations. RESULTS: The mononuclear cells from the affected patients were characterized by poor production of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these patients. CONCLUSIONS: Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).

Effect of organic and conventional crop rotation, fertilization, and crop protection practices on metal contents in wheat (Triticum aestivum).

The effects of organic versus conventional crop management practices (crop rotation, crop protection, and fertility management strategies) on wheat yields and grain metal (Al, Cd, Cu, Ni, Pb, and Zn) concentrations were investigated in a long-term field trial. The interactions between crop management practices and the season that the crop was grown were investigated using univariate and redundancy analysis approaches. Grain yields were highest where conventional fertility management and crop protection practices were used, but growing wheat after a previous crop of grass/clover was shown to partially compensate for yield reductions due to the use of organic fertility management. All metals except for Pb were significantly affected by crop management practices and the year that the wheat was grown. Grain Cd and Cu levels were higher on average when conventional fertility management practices were used. Al and Cu were higher on average when conventional crop protection practices were used. The results demonstrate that there is potential to manage metal concentrations in the diet by adopting specific crop management practices shown to affect crop uptake of metals.

Impaired T(H)17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

BACKGROUND: Accumulating evidence implicates T(H)17 cytokines in protection against Candida species infections, but the clinical relevance is not clear. Chronic mucocutaneous candidiasis (CMC) is a heterogeneous syndrome with the unifying feature of selective susceptibility to chronic candidiasis. Different subgroups with distinct clinical features are recognized, including autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), CMC with hypothyroidism, and isolated CMC. Understanding immune defects in patients with CMC will define cellular and molecular mechanisms crucial for protection against Candida species in human subjects. OBJECTIVES: We sought to determine whether impaired T(H)17 responses underlie susceptibility to Candida species infections and whether the same defect is present in different CMC subgroups. METHODS: We assessed T(H)17 responses of PBMCs to Candida and non-Candida species stimuli by measuring IL-17, IL-22, IL-21, IL-6, IL-23, and IFN-γ cytokine production using cytokine arrays and intracellular cytokine-producing cell numbers and proliferation with flow cytometry. PBMCs from healthy subjects and unaffected family members served as controls. RESULTS: In patients with CMC with hypothyroidism, T(H)17 cells demonstrated decreased proliferation and IL-17 production in response to Candida species. In contrast, in patients with APECED, T(H)17 cell proliferation and IL-17 production were normal unless exposed to APECED plasma, which inhibited both functions in both APECED and normal PBMCs. Candida species-stimulated IL-22 production was impaired in all patients with CMC, whereas IL-6 and IL-23 responses were unaltered. CONCLUSION: An impaired T(H)17 response to Candida species, although mediated by different mechanisms, was present in all CMC subgroups studied and might be a common factor predisposing to chronic candidiasis.