Correction: Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome

In table 3, the correlation coefficient between peak plasma cortisol and mRS at 3 months (column 4, row 5), should read 0.48, not 0 [1]

Saskatchewan Northern Health Authorities, Saskatchewan Correspondence and reprints: Dr James Irvine, Population Health Unit, Athabasca Health Authority, Keewatin Yatthé Health Region and Mamawetan Churchill River Health Region, Box 6000, LaRonge, Saskatch

A 51-year-old Aboriginal woman from northern Saskatchewan presented to a local family medical clinic in early October 2006 with a three-day history of left knee pain. Her vital signs included a blood pressure of 114/70 mmHg, a heart rate of 100 beats/min and a respiratory rate of 20 breaths/min. Her temperature was not documented. On examination, her knee was warm and painful, and an effusion was noted. Approximately six weeks prior, she had fallen on her right knee while walking. This injury was complicated by hemarthrosis and effusion, requiring needle drainage on two occasions. In addition, she had a history of pain, swelling and erythema involving her shoulder joint. Her past history was significant for alcohol abuse and unstable social and housing conditions. The laboratory results showed the followingwhite blood cell (WBC) count 9.8×10 9 /L (normal 0.2×10 9 /L to 10×10 9 /L); granulocyte count 8.8×10 9 /L (normal 2×10 9 /L to 7.8×10 9 /L); hemoglobin (Hb) level 102 g/L (normal 120 g/L to 180 g/L) and platelet count 68×10 9 /L (normal 150×10 9 /L to 450×10 9 /L). A presumptive diagnosis of inflammatory arthritis was made, and she was given indomethacin 50 mg three times a day for her symptoms. Two days later, the patient became progressively more confused, disoriented and unresponsive to questions. She was brought by ambulance to the local emergency department where her temperature was 38.8°C, pulse 98 beats/min, blood pressure 140/83 mmHg and respiratory rate 32 breaths/min. Her Glasgow coma scale score was 6. She was unresponsive to verbal commands but responsive to painful stimuli. Bruising was noted on both legs, and a large area of erythema was noted around the left knee. Her respiratory examination was unremarkable. Laboratory results showed the following -WBC count 3. 135 U/L) and creatine kinase isoenzyme -MB level 28 U/L (normal 0 U/L to 16 U/L). An evolving neurological condition was thought to be the primary diagnosis. Initial management included intravenous fluid (200 mL/h), cefotaxime 2 g administered intravenously, and blood cultures. She was transferred by air to the Royal University Hospital in Saskatoon, Saskatchewan. During the 1 h flight to Saskatoon, the area of erythema on her left leg tripled in size, and 3 L of intravenous fluids and dopamine were required to stabilize her blood pressure. On arrival, she was noted to be diffusely rigid with no response to painful stimuli. Her temperature was 39°C. She had rigors, peripheral mottling, absence of peripheral pulses, bronchial breath sounds over the right middle lobe, and erythema and target-like lesions over her left knee. Laboratory evaluation on admission showed the following -WBC count 3.

Mass Antibiotic Treatment for Group A Streptococcus Outbreaks in Two Long-Term Care Facilities1

Outbreaks of invasive infections caused by group A β-hemolytic streptococcus (GAS) may occur in long-term care settings and are associated with a high case-fatality rate in debilitated adults. Targeted antibiotic treatment only to residents and staff known to be at specific risk of GAS may be an ineffective outbreak control measure. We describe two institutional outbreaks in which mass antibiotic treatment was used as a control measure. In the first instance, mass treatment was used after targeted antibiotic treatment was not successful. In the second instance, mass treatment was used to control a rapidly evolving outbreak with a high case-fatality rate. Although no further clinical cases were seen after the introduction of mass antibiotic treatment, persistence of the outbreak strain was documented in one institution >1 year after cases had ceased. Strain persistence was associated with the presence of a chronically colonized resident and poor infection control practices

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Research Article Genomic Analysis of a Serotype 5 Streptococcus pneumoniae Outbreak in British Columbia

Background. Streptococcus pneumoniae can cause a wide spectrum of disease, including invasive pneumococcal disease (IPD). From 2005 to 2009 an outbreak of IPD occurred in Western Canada, caused by a S. pneumoniae strain with multilocus sequence type (MLST) 289 and serotype 5. We sought to investigate the incidence of IPD due to this S. pneumoniae strain and to characterize the outbreak in British Columbia using whole-genome sequencing. Methods. IPD was defined according to Public Health Agency of Canada guidelines. Two isolates representing the beginning and end of the outbreak were whole-genome sequenced. The sequences were analyzed for single nucleotide variants (SNVs) and putative genomic islands. Results. The peak of the outbreak in British Columbia was in 2006, when 57% of invasive S. pneumoniae isolates were serotype 5. Comparison of two whole-genome sequenced strains showed only 10 SNVs between them. A 15.5 kb genomic island was identified in outbreak strains, allowing the design of a PCR assay to track the spread of the outbreak strain. Discussion. We show that the serotype 5 MLST 289 strain contains a distinguishing genomic island, which remained genetically consistent over time. Whole-genome sequencing holds great promise for real-time characterization of outbreaks in the future and may allow responses tailored to characteristics identified in the genome

Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome

BACKGROUND: Cerebral ischaemia initiates an inflammatory response in the brain and periphery. We assessed the relationship between peak values of plasma interleukin-6 (IL-6) in the first week after ischaemic stroke, with measures of stroke severity and outcome. METHODS: Thirty-seven patients with ischaemic stroke were prospectively recruited. Plasma IL-6, and other markers of peripheral inflammation, were measured at pre-determined timepoints in the first week after stroke onset. Primary analyses were the association between peak plasma IL-6 concentration with both modified Rankin score (mRS) at 3 months and computed tomography (CT) brain infarct volume. RESULTS: Peak plasma IL-6 concentration correlated significantly (p < 0.001) with CT brain infarct volume (r = 0.75) and mRS at 3 months (r = 0.72). It correlated similarly with clinical outcome at 12 months or stroke severity. Strong associations were also noted between either peak plasma C-reactive protein (CRP) concentration or white blood cell (WBC) count, and all outcome measures. CONCLUSIONS: These data provide evidence that the magnitude of the peripheral inflammatory response is related to the severity of acute ischaemic stroke, and clinical outcome

Population-Based Surveillance for Invasive Pneumococcal Disease in Homeless Adults in Toronto

BACKGROUND: Identification of high-risk populations for serious infection due to S. pneumoniae will permit appropriately targeted prevention programs. METHODS: We conducted prospective, population-based surveillance for invasive pneumococcal disease and laboratory confirmed pneumococcal pneumonia in homeless adults in Toronto, a Canadian city with a total population of 2.5 M, from January 1, 2002 to December 31, 2006. RESULTS: We identified 69 cases of invasive pneumococcal disease and 27 cases of laboratory confirmed pneumococcal pneumonia in an estimated population of 5050 homeless adults. The incidence of invasive pneumococcal disease in homeless adults was 273 infections per 100,000 persons per year, compared to 9 per 100,000 persons per year in the general adult population. Homeless persons with invasive pneumococcal disease were younger than other adults (median age 46 years vs 67 years, P<.001), and more likely than other adults to be smokers (95% vs. 31%, P<.001), to abuse alcohol (62% vs 15%, P<.001), and to use intravenous drugs (42% vs 4%, P<.001). Relative to age matched controls, they were more likely to have underlying lung disease (12/69, 17% vs 17/272, 6%, P = .006), but not more likely to be HIV infected (17/69, 25% vs 58/282, 21%, P = .73). The proportion of patients with recurrent disease was five fold higher for homeless than other adults (7/58, 12% vs. 24/943, 2.5%, P<.001). In homeless adults, 28 (32%) of pneumococcal isolates were of serotypes included in the 7-valent conjugate vaccine, 42 (48%) of serotypes included in the 13-valent conjugate vaccine, and 72 (83%) of serotypes included in the 23-valent polysaccharide vaccine. Although no outbreaks of disease were identified in shelters, there was evidence of clustering of serotypes suggestive of transmission of pathogenic strains within the homeless population. CONCLUSIONS: Homeless persons are at high risk of serious pneumococcal infection. Vaccination, physical structure changes or other program to reduce transmission in shelters, harm reduction programs to reduce rates of smoking, alcohol abuse and infection with bloodborne pathogens, and improved treatment programs for HIV infection may all be effective in reducing the risk

Sensitivity of MRI Tumor Biomarkers to VEGFR Inhibitor Therapy in an Orthotopic Mouse Glioma Model

MRI biomarkers of tumor edema, vascular permeability, blood volume, and average vessel caliber are increasingly being employed to assess the efficacy of tumor therapies. However, the dependence of these biomarkers on a number of physiological factors can compromise their sensitivity and complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI) and a slight decrease in the water apparent diffusion coefficient (ADC) were observed for both control and cediranib treated animals. This contrasts with a clinical study that observed a significant decrease in tumor rVCI, ADC and volume with cediranib therapy. While the lack of a difference between control and cediranib treated animals in these biomarker responses might suggest that cediranib has no therapeutic benefit, cediranib treated mice had a significantly increased survival. The increased survival benefit of cediranib treated animals is consistent with the significant decrease observed for cediranib treated animals in the relative cerebral blood volume (rCBV), relative microvascular blood volume (rMBV), transverse relaxation time (T2), blood vessel permeability (Ktrans), and extravascular-extracellular space (νe). The differential response of pre-clinical and clinical tumors to cediranib therapy, along with the lack of a positive response for some biomarkers, indicates the importance of evaluating the whole spectrum of different tumor biomarkers to properly assess the therapeutic response and identify and interpret the therapy-induced changes in the tumor physiology

Partial Deletion of Chromosome 8 β-defensin Cluster Confers Sperm Dysfunction and Infertility in Male Mice

β-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine β-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that β-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility