Transcranial focused ultrasound, pulsed at 40 Hz, activates microglia acutely and reduces Aß load chronically, as demonstrated in vivo.

OBJECTIVE: Iaccarino et al. (2016) [1] exposed 1 h of light flickering at 40 Hz to awake 5XFAD Alzheimer's Disease (AD) mouse models, generating action potentials at 40 Hz, activating ∼54% of microglia to colocalize with Aß plaque, acutely, and clearing âˆ¼ 50% of Aß plaque after seven days, but only in the visual cortex. HYPOTHESIS: Transcranially delivered, focused ultrasound (tFUS) can replicate the results of Iaccarino et al. (2016) [1] but throughout its area of application. METHODS: We exposed sedated 5XFAD mice to tFUS (2.0 MHz carrier frequency, 40 Hz pulse repetition frequency, 400 µs-long pulses, spatial peak pulse average value of 190 W/cm2). Acute studies targeted tFUS into one hemisphere of brain centered on its hippocampus for 1 h. Chronic studies targeted comparable brain in each hemisphere for 1 h/day for five days. RESULTS: Acute application of tFUS activated more microglia that colocalized with Aß plaque relative to sham ultrasound (36.0 ± 4.6% versus 14.2 ± 2.6% [mean ± standard error], z = 2.45, p < 0.014) and relative to the contralateral hemisphere of treated brain (36.0 ± 4.6% versus 14.3 ± 4.0%, z = 2.61, p < 0.009). Chronic application over five days reduced their Aß plaque burden by nearly half relative to paired sham animals (47.4 ± 5.8%, z = - 2.79, p < 0.005). CONCLUSION: Our results compare to those of Iaccarino et al. (2016) [1] but throughout the area of ultrasound-exposed brain. Our results also compare to those achieved by medications that target Aß, but over a substantially shorter period of time. The proximity of our ultrasound protocol to those shown safe for non-human primates and humans may motivate its rapid translation to human studies.

Mycobacterium chimaera infection following cardiac surgery in the United Kingdom: clinical features and outcome of the first 30 cases.

OBJECTIVES: Mycobacterium chimaera infection following cardiac surgery, due to contaminated cardiopulmonary bypass heater-cooler units, has been reported worldwide. However, the spectrum of clinical disease remains poorly understood. To address this, we report the clinical and laboratory features, treatment and outcome of the first 30 UK cases. METHODS: Case note review was performed for cases identified retrospectively through outbreak investigations and prospectively through ongoing surveillance. Case definition was Mycobacterium chimaera detected in any clinical specimen, history of cardiothoracic surgery with cardiopulmonary bypass, and compatible clinical presentation. RESULTS: Thirty patients were identified (28 with prosthetic material) exhibiting a spectrum of disease including prosthetic valve endocarditis (14/30), sternal wound infection (2/30), aortic graft infection (4/30) and disseminated (non-cardiac) disease (10/30). Patients presented a median of 14 months post surgery (maximum 5 years) most commonly complaining of fever and weight loss. Investigations frequently revealed lymphopenia, thrombocytopenia, liver cholestasis and non-necrotizing granulomatous inflammation. Diagnostic sensitivity for a single mycobacterial blood culture was 68% but increased if multiple samples were sent. In all, 27 patients started macrolide-based combination treatment and 14 had further surgery. To date, 18 patients have died (60%) a median of 30 months (interquartile range 20-39 months) after initial surgery. Survival analysis identified younger age, mitral valve surgery, mechanical valve replacement, higher serum sodium concentration and lower C-reactive protein as factors associated with better survival. CONCLUSIONS: Mycobacterium chimaera infection following cardiac surgery is associated with a wide spectrum of disease. The diagnosis should be considered in all patients who develop an unexplained illness following cardiac surgery.

Resource impact of managing suspected Middle East respiratory syndrome patients in a UK teaching hospital.

Clinical challenges exist in the management of hospitalized patients returning to the UK with potential Middle East respiratory syndrome coronavirus (MERS-CoV) infection, particularly with its clinical overlap with influenza, as demonstrated in this case-series and cost-analysis review of returning Hajj pilgrims. These patients were hospitalized with acute febrile respiratory illness, initially managed as potential MERS-CoV infections, but were eventually diagnosed with influenza. Additional costs were small, yet enhanced infection prevention measures created significant burdens on isolation rooms and staff time. Planning for predictable events such as Hajj is important for resource management. Here, in-house MERS-CoV diagnostic testing would have facilitated earlier diagnosis and discharge.

Cutaneous Mycobacterium abscessus infection following hair transplant.

A 28-year-old man presented with a 10-day history of scalp nodules. He had undergone hair transplantation 2 months previously. Incision and drainage of one of the nodules yielded gelatinous material, which was sent for microscopy and culture, including low-temperature culture. After 2 weeks of incubation, culture of the nodule yielded acid- and alcohol-fast bacilli, which were identified as Mycobacterium abscessus, a rapidly growing, nontuberculous mycobacterium, which has been reported to cause cutaneous, soft tissue and respiratory infections following trauma, surgery or injection with nonsterile needles. A high index of suspicion is therefore needed in patients who present with cutaneous infections after cosmetic dermatological procedures, including hair transplantation.

Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Vulval intraepithelial neoplasia and periungual Bowen's disease concordant for mucosal (HPV-34) and epidermodysplasia verruciformis (HPV-21) human papillomavirus types.

Human papillomavirus (HPV) infection is associated with genital malignancy and specific cutaneous malignancies. We report a case of an HPV-associated concurrent vulval intraepithelial neoplasia and periungual Bowen's disease in a young immunocompetent Afro-Caribbean woman with no known risk factors for either disease. HPV genotyping studies detected multiple alpha and beta papillomaviruses with concordance for HPV-34 [a high-risk (HR) mucosal type], and HPV-21 [an epidermodyslasia verruciformis (EV) type] in both vulval and finger tissue. Although the HR-mucosal viruses detected are likely to have a pathogenic role in vulval intraepithelial neoplasia, this is the first report of concordance for EV HPV types in both genital and nongenital skin premalignancies. This case, in the context of accumulating epidemiological and experimental data in cutaneous SCC, raises the question of whether EV HPV may contribute to vulval malignancy, and further study is merited.

A unique presentation of immuno-osseous dysplasia.

The immuno-osseous dysplasias are a rare group of conditions in which short-limbed dwarfism is associated with an immune defect. The best known of these is cartilage hair hypoplasia. However, several reports of other distinct conditions exist, which have been arbitrarily classified on the basis of the immune defect. We present a child with a previously unreported combination of immune and skeletal abnormalities in whom there was an unusual and distinctive skin appearance associated with defective cutaneous elastic fibers. These cutaneous features suggest a unifying link with other immuno-osseous dysplasia but the combination of immune and skeletal defects exposes weaknesses in the current method of classification.

Sequential analysis of kidney stone formation in the Aprt knockout mouse.

BACKGROUND: We have previously shown that, as in human adenine phosphoribosyltransferase (APRT) deficiency, Aprt knockout mice form 2,8-dihydroxyadenine (DHA) renal stones. The disease develops earlier and is more severe in male than in female mice. To examine the biological bases for these differences, the area occupied by DHA crystals was quantified in kidney sections from male and female mice (strain 129) aged one day to eight months and this parameter was correlated with changes in renal histopathology. Aprt heterozygous and wild-type mice were used as controls. METHODS: Following anesthesia, the left kidney was removed and immediately frozen in dry ice. Unstained cryosections were examined by polarized light to determine total area of birefringent particles. The right kidney was perfused and embedded in plastic, and stained sections were viewed by light microscopy to examine the histopathology and to determine the location of the birefringent particles. A pathological score was assigned to the histological findings. The scores from the right kidney were compared with crystal/particle area in the left kidney, and the data were analyzed using two-way analysis of variance. The chemical composition of the particles was determined by x-ray diffraction analysis. Several stone fragments from the bladder were also examined by scanning electron microscopy (SEM). RESULTS: Crystals were detected in kidney sections from one- to two-day-old Aprt knockout mice. The crystal burden remained low in both sexes throughout the study except in males at the 120- to 240-day period. Furthermore, there was a substantial degree of renal pathology, primarily seen as interstitial fibrosis, in those males with a very high level of stone formation. The crystalline material was identified as 6-amino-2,8(3,9)-purine dione, a tautomeric form of DHA. SEM indicated that the crystals were spherical, with a diameter of 10 to 20 microm. Tissue staining and fixation procedures dramatically reduced the amount of birefringent material in kidney sections. Aprt heterozygotes of both sexes had low levels of crystalline material in the kidneys and no pathology. Birefringent material or pathological changes were not seen in kidneys from wild-type mice. CONCLUSIONS: Both male and female Aprt knockout mice accumulate DHA. However, the area occupied by DHA crystals was significantly greater in 120- to 240-day-old males compared with the females of similar age. Also, substantial renal pathology was detected in kidneys of male mice that had very high levels of stone material.

2,8-Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT.

We have examined the mutational basis of adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency (MIM 102600) in a patient of Polish origin who has been passing 2,8-dihydroxyadenine (DHA) stones since birth, but has considerable residual enzyme activity in lymphocyte extracts. The five exons and flanking regions of APRT were amplified by PCR and then sequenced. A single T insertion was identified at the intron 4 splice donor site (TGgtaa to TGgttaa:IVS4+2insT) in one allele from the proband, his mother, and brother. A G-to-T transversion in exon 5 (GTC-to-TTC:c.448G>T, V150F) was identified in the other allele, and this mutation was also present in one allele from the father and the paternal grandmother. Tru91 and AvaII digestions of PCR products spanning exons 4 and 5, respectively, confirmed the mutations. The mother was heterozygous for an intragenic TaqI site, but all other family members were homozygous for the presence of this site. IVS4+2insT, located on the allele containing the TaqI site, has been identified previously in several families from Europe, suggesting a founder effect, but the substitution in exon 5 is a novel mutation. IVS4+2insT is known to result in complete loss of enzyme activity, and our results suggest that V150F produces an enzyme that is nonfunctional in vivo but has considerable residual activity in vitro.

Altered gene expression in kidneys of mice with 2,8-dihydroxyadenine nephrolithiasis.

BACKGROUND: We have developed a knockout mouse model for adenine phosphoribosyltransferase (APRT) deficiency, a condition that often leads to 2,8-dihydroxyadenine (DHA) nephrolithiasis in humans. Aprt knockout male mice develop severe renal damage by three months of age, but this is strain specific. Renal damage in female mice is less pronounced than in males. The gene level changes that promote renal injury in APRT-deficient mice are not known. METHODS: We used mRNA differential display polymerase chain reaction (DD-PCR) to analyze renal gene expression changes in APRT-deficient male and female mice (strain C3H) compared with age- and sex-matched Aprt heterozygote controls. The differentially amplified bands were reamplified, cloned, sequenced, and queried against the National Center for Biotechnology Information nonredundant databases using the Basic Alignment Search Tool. Relative quantitative reverse transcription-polymerase chain reaction was used to confirm the results of DD-PCR for a selected number of genes in one-, three-, and six-month-old male and female mice. RESULTS: Sixty-three differentially amplified bands were identified, including 21 for known genes, and 8 of these were examined further. In three-month-old APRT-deficient male mice, the expression of C10 was increased tenfold, and there was a fourfold to sevenfold increase in the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1), MGP (matrix Gla protein), and lysyl oxidase (LOX). The expression of cholecystokinin-A receptor (CCKAR), imprinted multimembrane-spanning polyspecific transporter-like gene 1 (IMPT-1), and kidney androgen-regulated protein (KAP) was diminished twofold to fourfold, but there was little or no change in the expression of organic anion transporter (OATP). Except for a more than tenfold increase in C10 expression and up to tenfold decrease in KAP expression, APRT-deficient female mice did not show significant changes in gene expression compared with controls. CONCLUSIONS: These findings suggest that (1) there are sex-related differences in gene expression in DHA lithiasis, possibly caused by increased deposition of DHA crystals in male compared with female kidneys; and (2) the expression of certain genes (for example, C10) may simply be an indication of nonspecific cellular stimulation and may not be related to renal injury.

Microchimerism and rejection: a meta-analysis.

AIMS: To study the relationship between graft rejection and microchimerism with and without donor bone marrow infusion in recipients of kidney, liver, heart and lung transplants. Selection of manuscripts. Thirty-seven manuscripts presenting clinical data on microchimerism and rejection, published between 1991 and 1997, were identified. Of these, 16 were excluded due to duplication or insufficient data. Inclusion criteria were data on microchimerism, bone marrow infusion and rejection episodes. STATISTICAL TESTS: A mixed effect logistic model was used to test for homogeneity of transplant centers. The centers were found to be homogeneous for rejection rates controlling for microchimerism and bone marrow infusion. Using rejection episodes at 3, 6, and 12 months post-transplant as the outcome, we evaluated logistic regression models to derive odds ratios for rejection with microchimerism and with bone marrow infusion for each organ. RESULTS: Microchimerism was generally associated with a higher incidence of acute rejection for heart, lung, and kidney transplants and a lower incidence for liver transplants, especially at 12 months and above. Bone marrow infusion decreased the risk of acute rejection for heart transplants and increased the risk for lung and, to a lesser extent, for liver transplants. No consistent effect was seen in kidney transplants. At 12 months and longer, microchimerism was associated with a decreased incidence of chronic rejection in recipients of lung transplants, but there were insufficient data to determine this outcome for other organs. CONCLUSIONS: (i) Microchimerism was detected in the majority of patients. (ii) The effect of microchimerism and bone marrow infusion on rejection episodes varied with the organ and, for a given organ, it was time-dependent. (iii) These findings demonstrate the need for more extensive studies on microchimerism and donor-specific hyporesponsiveness.