Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

High prevalence of slight and mild hearing loss across mid-life: a cross-sectional national Australian study.

OBJECTIVES: Although presbycusis typically becomes symptomatic only in older age, slight and mild hearing loss may be detectable well before this. We studied current prevalence and characteristics of hearing loss in Australian mid-life adults. STUDY DESIGN: This was a population-derived national cross-sectional study nested within the Longitudinal Study of Australian Children. METHODS: A total of 1485 parents/guardians (87.3% female) aged 30-59 years underwent air-conduction audiometry. Hearing loss was defined in three ways to maximize cross-study comparability: high Fletcher index (mean of 1, 2 and 4 kHz; primary outcome relevant to speech perception), lower frequency (mean of 1 and 2 kHz) and higher frequency (mean of 4 and 8 kHz). Multivariable logistic regression examined how losses vary by age, sex and neighbourhood disadvantage. RESULTS: On high Fletcher index, 27.3% had bilateral and 23.8% unilateral thresholds >15 dB hearing level (HL) (slight or worse), and 4.9% had bilateral and 6.3% unilateral thresholds >25 dB HL (mild or worse). Bilateral higher frequency losses were more common than lower frequency losses for thresholds >15 dB HL (30.9% vs. 26.4%) and >25 dB HL (11.0% vs. 4.6%). Age increased the risk of bilateral speech and higher frequency losses (all P for trend < 0.05), but not lower frequency losses >25 dB HL. Although sex was not associated with speech and lower frequency losses, men were more likely to have bilateral higher frequency losses (e.g. >15 dB HL: odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.5-3.2, P < 0.001). CONCLUSIONS: Both slight and mild hearing loss show high and rising prevalence across mid-life. This offers opportunities to prevent progression to reduce the profound later burden of age-related hearing loss.

In vitro activity of an engineered honey, medical-grade honeys, and antimicrobial wound dressings against biofilm-producing clinical bacterial isolates.

OBJECTIVE: Honey is recognised to be a good topical wound care agent owing to a broad-spectrum of antimicrobial activity combined with healing properties. Surgihoney RO (SH1) is a product based on honey that is engineered to produce enhanced reactive oxygen species (ROS) and has been reported to be highly antimicrobial. The objective was to investigate the ability of the engineered honey and its comparators to prevent biofilm formation in vitro. METHOD: We tested the ability of three medical-grade honeys SH1, Activon manuka honey (MH) and Medihoney manuka honey (Med), alongside five antimicrobial dressings (AMDs) to prevent the formation of biofilms by 16 isolates. Honeys were serially double diluted from 1:3 down to 1:6144 and the lowest dilution achieving a statistically significant reduction in biomass of at least 50%, compared with untreated controls, was recorded. RESULTS: Although all the honeys were antibacterial and were able to prevent the formation of biofilms, SH1 was the most potent, with efficacy at lower dilutions than the medical honeys for five isolates, and equivalent dilutions for a further six. Additionally, SH1 was superior in antibacterial potency to three commercially available AMDs that contain honey. CONCLUSION: SH1 is effective at preventing bioflms from forming and is superior to medical honeys and AMDs in in vitro tests. DECLARATION OF INTEREST: Surgihoney RO was provided free of charge for testing by Matoke Holdings, UK and the hospital pharmacy provided the other honeys and dressings. This paper presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

APC promoter 1B deletion in seven American families with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. Clinical genetic testing fails to identify disease causing mutations in up to 20% of clinically apparent FAP cases. Following the inclusion of multiplex ligation-dependent probe amplification (MLPA) probes specific for APC promoter 1B, seven probands were identified with a deletion of promoter 1B. Using haplotype analysis spanning the APC locus, the seven families appear to be identical by descent from a common founder. The clinical phenotype of 19 mutation carriers is classical FAP with colectomy at an average age of 24. The majority of cases had a large number of duodenal and gastric polyps. Measurements of allele-specific expression of APC mRNA using TaqMan assay confirmed that relative expression in the allele containing the promoter 1B deletion was reduced 42-98%, depending on tissue type. This study confirms the importance of APC promoter deletions as a cause of FAP and identifies a founder mutation in FAP patients from the United States.

Trace element concentration and speciation in selected urban soils in New York City.

A long history of urbanization and industrialization has affected trace elements in New York City (NYC) soils. Selected NYC pedons were analyzed by aqua regia microwave digestion and sequential chemical extraction as follows: water soluble (WS); exchangeable (EX); specifically sorbed/carbonate bound (SS/CAR); oxide-bound (OX); organic/sulfide bound (OM/S). Soils showed a range in properties (e.g., pH 3.9 to 7.4). Sum of total extractable (SUMTE) trace elements was higher in NYC parks compared to Bronx River watershed sites. NYC surface horizons showed higher total extractable (TE) levels compared to US non-anthropogenic soils. TE levels increased over 10 year in some of the relatively undisturbed and mostly wooded park sites. Surface horizons of park sites with long-term anthropogenic inputs showed elevated TE levels vs. subsurface horizons. Conversely, some Bronx River watershed soils showed increased concentrations with depth, reflective of their formation in a thick mantle of construction debris increasing with depth and intermingled with anthrotransported soil materials. Short-range variability was evident in primary pedons and satellite samples (e.g., Pb 253 ± 143 mg/kg). Long-range variability was indicated by PbTE (348 versus 156 mg/kg) and HgTE (1 versus 0.3 mg/kg) concentrations varying several-fold in the same soil but in different geographic locations. Relative predominance of fractions: RES (37 %) > SS/CAR (22 %) > OX (20 %) > OM/S (10 %) > EX (7 %) > WS (4 %). WS and EX fractions were greatest for Hg (7 %) and Cd (14 %), respectively. RES was predominant fraction for Co, Cr, Ni, and Zn (41 to 51 %); SS/CAR for Cd and Pb (40 and 63 %); OM/S for Cu and Hg (36 and 37 %); and OX for As (59 %).

Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps.

Most inherited mutant alleles of the adenomatosis polyposis coli gene (APC) cause the appearance of large numbers of colon polyps, the familial polyposis syndrome. (These mutant alleles are designated APCp alleles.) A subset of APC mutations, the attenuated or APC(AP) alleles, predispose to only a few colon polyps. This leads to the hypothesis that if mutation of the inherited normal allele is rate limiting in polyp development, the increased number of polyps associated with the APCp allele indicates that the frequency of mutations that can lead to polyp formation is higher among APCp carriers than among APC(AP) carriers. We have previously suggested that the APC protein might modulate the frequency of mutations, such as loss of heterozygosity (LOH), necessary for colon polyp formation. We thus reasoned that tumours from patients who carry an APC(AP) allele might show a reduced frequency of LOH compared with tumours from patients who carry an APCp allele. Loss of AAPC mutant alleles is designated as LOH(AP). Screening of tumours from APC(AP) carriers revealed a reduction of LOH compared with that of an unselected group of polyposis patients. In fact, no loss of the inherited APC(N) allele was observed, although sequencing showed that the inherited APC(N) allele had frequently undergone point mutations and small deletions in the tumours. A low frequency loss of the inherited APC(AP) allele was seen. These findings support the suggestion that the APC(AP) allele has residual gene activity and that this activity modulates the spectrum and frequency of mutations that lead to adenoma formation.

Safety, cost-effectiveness and feasibility of daycase paracentesis in the management of malignant ascites with a focus on ovarian cancer.

BACKGROUND: Paracentesis for malignant ascites is usually performed as an in-patient procedure, with a median length of stay (LoS) of 3-5 days, with intermittent clamping of the drain due to a perceived risk of hypotension. In this study, we assessed the safety of free drainage and the feasibility and cost-effectiveness of daycase paracentesis. METHOD: Ovarian cancer admissions at Hammersmith Hospital between July and October 2009 were audited (Stage 1). A total of 21 patients (Stage 2) subsequently underwent paracentesis with free drainage of ascites without intermittent clamping (October 2010-January 2011). Finally, 13 patients (19 paracenteses, Stage 3), were drained as a daycase (May-December 2011). RESULTS: Of 67 patients (Stage 1), 22% of admissions and 18% of bed-days were for paracentesis, with a median LoS of 4 days. In all, 81% of patients (Stage 2) drained completely without hypotension. Of four patients with hypotension, none was tachycardic or symptomatic. Daycase paracentesis achieved complete ascites drainage without complications, or the need for in-patient admission in 94.7% of cases (Stage 3), and cost £954 compared with £1473 for in-patient drainage. CONCLUSIONS: Free drainage of malignant ascites is safe. Daycase paracentesis is feasible, cost-effective and reduces hospital admissions, and potentially represents the standard of care for patients with malignant ascites.

Laryngeal transplantation in minipigs: early immunological outcomes.

Despite recent tissue-engineering advances, there is no effective way of replacing all the functions of the larynx in those requiring laryngectomy. A recent clinical transplant was a success. Using quantitative immunofluorescence targeted at immunologically relevant molecules, we have studied the early (48 h and 1 week) immunological responses within larynxes transplantated between seven pairs of National Institutes of Health (NIH) minipigs fully homozygous at the major histocompatibility complex (MHC) locus. There were only small changes in expression of some molecules (relative to interindividual variation) and these were clearest in samples from the subglottic region, where the areas of co-expression of CD25(+) CD45RC(-) CD8(-) and of CD163(+) CD172(+) MHC-II(-) increased at 1 week after transplant. In one case, infiltration by recipient T cells was analysed by T cell receptor (TCR) Vß spectratype analysis; this suggested that changes in the T cell repertoire occur in the donor subglottis mucosal tissues from day 0 to day 7, but that the donor and recipient mucosal Vß repertoires remain distinct. The observed lack of strong immunological responses to the trauma of surgery and ischaemia provides encouraging evidence to support clinical trials of laryngeal transplantation, and a basis on which to interpret future studies involving mismatches.

Neutral metallated and meso-substituted porphyrins as antimicrobial agents against gram-positive pathogens.

Staphylococcus aureus is a bacterial pathogen that causes severe infections among humans. The increasing emergence of antibiotic resistance necessitates the development of new strategies to combat the spread of disease. One approach is photodynamic inactivation using porphyrin photosensitizers, which generate superoxide and other radicals in the presence of light, causing cell death via the oxidation of proteins and lipids. In this study, we analyzed a novel library of meso-substituted and metallated porphyrins for activity against multidrug-resistant S. aureus. From a library of 251 compounds, 51 showed antimicrobial activity, in three discrete classes of activity: those that functioned only in light, those that had toxicity only in darkness, and those that displayed activity regardless of illumination. We further demonstrated the broad-spectrum activity of these compounds against a variety of pathogens, including Bacillus anthracis, Enterococcus faecalis, and Escherichia coli. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) analyses of lead compounds (XPZ-263 and XPZ-271) revealed strong activity and killing towards methicillin-resistant S. aureus (MRSA) strains. An analysis of mutation frequencies revealed low incidences of resistance to lead compounds by E. coli and MRSA. Finally, an exploration of the underlying mechanism of action suggests that these compounds do not depend solely upon light-induced radical generation for toxicity, highlighting their potential for clinical applications.

Indigenous Health: ACTION on Prevention - 50th annual Australian Society for Medical Research National Scientific Conference.

The 50th annual National Scientific Conference of the Australian Society for Medical Research was held in Cairns, Queensland, 13-16 November 2011. The theme, 'Indigenous Health: ACTION on Prevention' highlighted the direct action being undertaken by health and medical researchers, as well as allied health professionals, to improve long-term health outcomes for Indigenous Australians.

Constitutional mismatch repair-deficiency syndrome presenting as colonic adenomatous polyposis: clues from the skin.

Constitutional mismatch repair-deficiency (CMMR-D) syndrome is an autosomal recessive condition characterized by hematologic malignancies, brain tumors, Lynch syndrome-associated cancers and skin manifestations reminiscent of neurofibromatosis type 1 (NF1). In contrast to Lynch syndrome, CMMR-D syndrome is exceptionally rare, onset typically occurs in infancy or early childhood and, as described in this report, may also present with colonic polyposis suggestive of attenuated familial adenomatous polyposis (AFAP) or MUTYH associated polyposis (MAP). Here we describe two sisters with CMMR-D syndrome due to germline bi-allelic MSH6 mutations. Both sisters are without cancer, are older than typical for this condition, have NF1 associated features and a colonic phenotype suspicious for an attenuated polyposis syndrome. This report highlights the role of skin examinations in leading to an underlying genetic diagnosis in individuals with colonic adenomatous polyposis, but without mutations associated with AFAP or MAP.

Laryngeal transplantation in minipigs: vascular, myologic and functional outcomes.

There is no effective way of replacing all the functions of the larynx in those requiring laryngectomy. Regenerative medicine offers promise, but cannot presently deliver implants with functioning neuromuscular units. A single well-documented laryngeal transplant in man was a qualified success, but more information is required before clinical trials may be proposed. We studied the early response of the larynx to laryngeal transplantation between 17 pairs of NIH minipigs full matched at the MHC2 locus. Following iterative technical improvements, pigs had good swallowing and a patent airway at 1 week. No significant changes in mucosal blood flux were observed compared with pre-operative measurements. Changes in muscle morphology and fibre phenotype were observed in transplant muscles retrieved after 7 days: the levels of fast and slow myosin heavy chain (MyHC) protein were reduced and embryonic MyHC was up regulated consistent with denervation induced atrophy. At 1 week laryngeal transplantation can result in good swallowing, and is not associated with clinical evidence of ischemia-reperfusion injury in MHC-matched pigs.

Antibodies against merozoite surface protein (MSP)-1(19) are a major component of the invasion-inhibitory response in individuals immune to malaria.

Antibodies that bind to antigens expressed on the merozoite form of the malaria parasite can inhibit parasite growth by preventing merozoite invasion of red blood cells. Inhibitory antibodies are found in the sera of malaria-immune individuals, however, the specificity of those that are important to this process is not known. In this paper, we have used allelic replacement to construct a Plasmodium falciparum parasite line that expresses the complete COOH-terminal fragment of merozoite surface protein (MSP)-1(19) from the divergent rodent malaria P. chabaudi. By comparing this transfected line with parental parasites that differ only in MSP-1(19), we show that antibodies specific for this domain are a major component of the inhibitory response in P. falciparum-immune humans and P. chabaudi-immune mice. In some individual human sera, MSP-1(19) antibodies dominated the inhibitory activity. The finding that antibodies to a small region of a single protein play a major role in this process has important implications for malaria immunity and is strongly supportive of further understanding and development of MSP-1(19)-based vaccines.

The gene for familial polyposis coli maps to the long arm of chromosome 5.

The inherited genetic defect in adenomatous polyposis has been localized to a small region on the long arm of chromosome 5. Sixteen DNA marker loci were used to construct a linkage map of the chromosome. When five kindreds segregating a gene for adenomatous polyposis coli were characterized with a number of the markers, significant linkage was found between one marker and the disease gene. Linkage analysis determined the location of the defective gene within a primary genetic map of chromosome 5.

Development of perioperative care for pigs undergoing laryngeal transplantation: a case series.

Pigs are ideal animal models for airway surgical research, facilitating the successful translation of science into clinical practice. Despite their ubiquitous use, there is a paucity of information on the perioperative care of pigs, especially for major procedures. In a series of experiments to investigate laryngeal transplantation, we combined veterinary and medical experience to develop protocols for perioperative management of pigs, including high dependency care. Novel airway management methods were developed. A pain scoring system was used to direct analgesia use. Fluid balance and electrolytes were monitored closely. Recent animals received a central venous line via the femoral vein two days prior to transplantation to facilitate blood sampling and drug delivery. Intensive monitoring and airway management were required to ensure a successful outcome. Methods for optimal perioperative care are proposed. These results will help future groups wishing to use pigs in airway research, will reduce numbers of animals used and improve animal welfare.

The residency mess at the Royal Infirmary of Edinburgh: history and traditions.

For almost 250 years the Edinburgh Royal Infirmary was staffed with resident physicians and surgeons.This paper traces the history and the traditions of the Residency Mess, its inhabitants' lives, duties and leisure activities and how these have changed over the years.

Autologous non-myeloablative haematopoietic stem cell transplantation for refractory systemic vasculitis.

OBJECTIVE: For patients with systemic vasculitis (SV) refractory to conventional therapy, new treatment strategies aimed at aggressive induction of remission and relapse prevention are being sought. We herein report our single-centre experience in treating four patients with refractory SV employing non-myeloablative autologous haematopoietic stem cell transplantation (HSCT). METHODS: Four patients with refractory SV (two with neurovascular Behcet disease, one with neurovascular Sjögren syndrome, and one with Wegener granulomatosis) were involved in an Institutional Review Board (IRB) and US Food and Drug Administration (FDA) approved phase I clinical trial of high dose chemotherapy and autologous HSCT. Peripheral blood stem cells were mobilised with cyclophosphamide (Cy) and granulocyte-colony stimulating factor (G-CSF). Conditioning regimen consisted of Cy 200 mg/kg and rabbit anti-thymocyte globulin 5.5 mg/kg intravenously (iv). RESULTS: All four patients tolerated HSCT well without transplant related mortality or any significant toxicity. At median follow-up of 28 (range 22-36) months all patients were alive. Three patients (one with Behcet disease, one with Sjögren syndrome, and one with Wegener granulomatosis) entered a sustained remission at 6, 6 and 24 months, respectively, after transplant. They had significant decrease in disease activity and disease or treatment related damage, as measured by the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, respectively. All three patients who achieved remission discontinued immunosuppressive therapy at the time of transplant and have not required treatment since. One patient with Behcet disease and positive for human leukocyte antigen (HLA)-B51 has not improved after HSCT. CONCLUSION: We suggest non-myeloablative autologous HSCT is an alternative therapy for select patients with SV refractory to conventional immunosuppressive therapies.

Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis.

Autologous hematopoietic stem cell transplantation (HSCT) utilizing a myeloablative regimen containing total body irradiation has been performed in patients with systemic sclerosis (SSc), but with substantial toxicity. We, therefore, conducted a phase I non-myeloablative autologous HSCT study in 10 patients with SSc and poor prognostic features. PBSC were mobilized with CY and G-CSF. The PBSC graft was cryopreserved without manipulation and re-infused after the patient was treated with a non-myeloablative conditioning regimen of 200 mg/kg CY and 7.5 mg/kg rabbit antithymocyte globulin. There was a statistically significant improvement of modified Rodnan skin score whereas cardiac (ejection fraction, pulmonary arterial pressure), pulmonary function (DLCO) and renal function (creatinine) remained stable without significant change. One patient with advanced disease died 2 years after the transplant from progressive disease. After median follow-up of 25.5 months, the overall and progression-free survival rates are 90 and 70% respectively. Autologous HSCT utilizing a non-myeloablative conditioning regimen appears to result in improved skin flexibility similar to a myeloablative TBI containing regimen, but without the toxicity and risks associated with TBI.