Happle-Tinschert, Curry-Jones and segmental basal cell naevus syndromes, overlapping disorders caused by somatic mutations in hedgehog signalling genes: the mosaic hedgehog spectrum.

Happle-Tinschert syndrome (HTS) and Curry-Jones syndrome (CJS; OMIM 601707) are rare, sporadic, multisystem disorders characterized by hypo- and hyperpigmented skin patches following Blaschko's lines, plus acral skeletal and other abnormalities. The blaschkoid pattern implies mosaicism, and indeed CJS was found in 2016 to be caused by a recurrent postzygotic mutation in a gene of the hedgehog signalling pathway, namely SMO, c.1234C>T, p.Leu412Phe. More recently the original case of HTS was found to carry the same somatic mutation. Despite this genetic and phenotypic overlap, two significant differences remained between the two syndromes. The histological hallmark of HTS, basaloid follicular hamartomas, is not a feature of CJS. Meanwhile, the severe gastrointestinal manifestations regularly reported in CJS had not been described in HTS. We report a patient whose phenotype was entirely consistent with HTS apart from intractable constipation, and a second patient with classic features of CJS plus early-onset medulloblastoma, a feature of basal cell naevus syndrome (BCNS). Both had the same recurrent SMO mutation. This prompted a literature review that revealed a case with the same somatic mutation, with basaloid follicular hamartomas and other features of both CJS and BCNS. Segmental BCNS can also be caused by a somatic mutation in PTCH1. We thus demonstrate for the first time phenotypic and genetic overlap between HTS, CJS and segmental BCNS. All of these conditions are caused by somatic mutations in genes of the hedgehog signalling pathway and we therefore propose the unifying term 'mosaic hedgehog spectrum'. What's already known about this topic? Happle-Tinschert syndrome (HTS) and Curry-Jones syndrome (CJS) are rare mosaic multisystem disorders with linear skin lesions. CJS is characterized by severe constipation, which has not previously been reported in HTS. HTS is characterized by basaloid follicular hamartomas, which are not a recognized feature of CJS. The recurrent mosaic SMO mutation found in CJS was recently reported in a patient with HTS. What does this study add? We describe a patient with HTS and intractable constipation, and a case of CJS with medulloblastoma. Both patients had the same recurrent somatic SMO mutation also found in a case reported as segmental basal cell naevus syndrome. SMO functions in the hedgehog pathway, explaining phenotypic overlap between HTS, CJS and mosaic basal cell naevus syndrome. We propose the term 'mosaic hedgehog spectrum' for these overlapping conditions.

Palliative care physicians' experiences of end-of-life communication: A focus group study.

The aim of this study was to explore palliative home care physicians' experiences regarding end-of-life breakpoint communication (BPC). This is a qualitative study where focus group interviews were conducted and analysed using qualitative content analysis. The results show that the participants saw themselves as being responsible for accomplishing BPC, and they were convinced that it should be regarded as a process of communication initiated at an early stage, i.e. proactively. However, BPC was often conducted as a reaction to the patient's sudden deterioration or sometimes not at all. The barriers to achieving proactive BPC included physicians' uncertainty regarding the timing of BPC, primarily due to difficulties in prognostication in terms of time of death, and uncertainty as to what BPC should include and how it should best be approached. Furthermore, there was insufficient documentation regarding previous BPC, which impeded proactive BPC. Although our study shows that physicians are ambitious when it comes to the communication of information to patients and families, there is a need for further training in how to conduct BPC and when to initiate the BPC process. Furthermore, there should be documentation that different professionals can access as this would appear to facilitate a proactive BPC process.

Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening.

The inherited palmoplantar keratodermas (PPKs) are a heterogeneous group of genodermatoses, characterized by thickening of the epidermis of the palms and soles. No classification system satisfactorily unites clinical presentation, pathology and molecular pathogenesis. There are four patterns of hyperkeratosis - striate, focal, diffuse and punctate. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate, but also in focal and diffuse PPKs. We report seven unrelated pedigrees with dominantly inherited PPK owing to mutations in the DSG1 gene, with marked phenotypic variation. Genomic DNA from each family was isolated, and individual exons amplified by polymerase chain reaction. Sanger sequencing was employed to identify mutations. Mutation analysis identified novel mutations in five families (p.Tyr126Hisfs*2, p.Ser521Tyrfs*2, p.Trp3*, p.Asp591Phefs*9 and p.Met249Ilefs*6) with striate palmar involvement and varying focal or diffuse plantar disease, and the recurrent mutation c.76C>T, p.Arg26*, in two families with variable PPK patterns. We report one recurrent and five novel DSG1 mutations, causing varying patterns of PPK, highlighting the clinical heterogeneity arising from mutations in this gene.

An exploration of patient-reported symptoms in systemic lupus erythematosus and the relationship to health-related quality of life.

OBJECTIVE: The aim of this study was to explore the most distressing symptoms of systemic lupus erythematosus (SLE) and determine how these relate to health-related quality of life (HRQoL), anxiety/depression, patient demographics, and disease characteristics (duration, activity, organ damage). METHODS: In a cross-sectional study, patients with SLE (n = 324, age 18-84 years) gave written responses regarding which SLE-related symptoms they experienced as most difficult. Their responses were categorized. Within each category, patients reporting a specific symptom were compared with non-reporters and analysed for patient demographics, disease duration, and results from the following questionnaires: the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), the Hospital Anxiety and Depression Scale (HADS), the Systemic Lupus Activity Measure (SLAM), the SLE Disease Activity Index (SLEDAI), and the Systemic Lupus International Collaboration Clinics/American College of Rheumatology (SLICC/ACR) damage index. RESULTS: Twenty-three symptom categories were identified. Fatigue (51%), pain (50%), and musculoskeletal distress (46%) were most frequently reported. Compared with non-reporters, only patients reporting fatigue showed a statistically significant impact on both mental and physical components of HRQoL. Patients with no present symptoms (10%) had higher HRQoL (p < 0.001) and lower levels of depression (p < 0.001), anxiety (p < 0.01), and disease activity (SLAM) (p < 0.001). CONCLUSION: Fatigue, pain, or musculoskeletal distress dominated the reported symptoms in approximately half of the patients. Only patients reporting fatigue scored lower on both mental and physical aspects of HRQoL. Our results emphasize the need for further support and interventions to ease the symptom load and improve HRQoL in patients with SLE. Our findings further indicate that this need is particularly urgent for patients with symptoms of pain or fatigue.

Changing epidemiology of methicillin-resistant Staphylococcus aureus in Alberta, Canada: population-based surveillance, 2005-2008.

SUMMARYIncreasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has been reported in Canada. We report the results of a prospective surveillance of MRSA infections in Alberta over a consecutive 3-year period. A total of 8910 unique clinical MRSA isolates was analysed from July 2005 to June 2008. The incidence of MRSA infection increased over the study period and was highest in males, age group ⩾85 years, and the Calgary Area. CMRSA10 (USA300) and CMRSA2 (USA100/800) were the most common PFGE strain types, representing 53·0% and 27·9% of all isolates, respectively. Significant differences were noted between MRSA strains in the source of infection and antimicrobial susceptibility. The incidence of MRSA infection in Alberta has nearly doubled in the last 3 years; this is attributed to the emergence of CMRSA10 as the predominant strain.

The International Circumpolar Surveillance interlaboratory quality control program for Streptococcus pneumoniae, 1999 to 2008.

The International Circumpolar Surveillance (ICS) Program was initiated in 1999 to conduct population-based surveillance for invasive pneumococcal disease in select regions of the Arctic. An interlaboratory quality control (QC) program for pneumococcal serotyping and antibiotic susceptibility testing was incorporated into ICS by reference laboratories in northern Canada (Laboratoire de Santé Publique du Québec [LSPQ] in Sainte-Anne de Bellevue, Québec; National Centre for Streptococcus [NCS] in Edmonton, Alberta) and Alaska (Arctic Investigations Program [AIP]). The World Health Organization's Collaborating Centre for Reference and Research on Pneumococci at the Statens Serum Institute (SSI) in Copenhagen, Denmark, joined the QC program in 2004. The Iceland Reference Laboratory (IRL) in Reykjavik, Iceland, joined the QC program in 2006, but due to small sample sizes, data from IRL are not included in this report. From 1999 through 2008, 190 isolates were distributed among four laboratories (AIP, NCS, LSPQ, and SSI). The overall serotype concordance was 95.8%, and the overall serogroup concordance was 97.4%. The overall modal MIC concordance for testing by broth microdilution (BMD) and agar dilution was >96% for all the antibiotics except erythromycin (92.1%) and clindamycin (89.5%). MIC comparisons between the Etest and BMD resulted in lower concordance for erythromycin (73.9%), clindamycin (65.5%), and trimethoprim-sulfamethoxazole (80%); however, categorical concordance (susceptible, resistant) remained high at 98.6%, 89.1%, and 90.9%, respectively. Our data demonstrate a high degree of correlation of serotyping and antimicrobial susceptibility testing results between four participating laboratories.

Push or pull? Relationships between lung cancer patients' perceptions of quality of care and use of complementary and alternative medicine.

UNLABELLED: Little is known about relationships between quality of care (QoC) and use of complementary and alternative medicine (CAM) among patients with lung cancer (LC). PURPOSE: This study examines CAM-use among patients with LC in Sweden, associations between QoC and CAM-use among these patients, and reported aspects of LC-care perceived as particularly positive and negative by patients, as well as suggestions for improving QoC. METHODS: Survey data from 94 patient members of the Swedish LC patient organization about CAM-use and QoC as measured by the instrument "Quality from the patient's perspective" were analyzed. RESULTS: Fifty (53%) LC-patients used CAM, with 40 of the CAM-users reporting that CAM helped them. The most common CAMs used were dietary supplements and natural remedies, followed by prayer. Significantly more patients reported using prayer and meditation for cure than was the case for other types of CAM used. Less than half the CAM-users reported having spoken with staff from the biomedical health care system about their CAM-use. Patients provided numerous suggestions for improving LC-care in a variety of areas, aiming at a more effective and cohesive care trajectory. No differences in QoC were found between CAM-users and non-CAM-users, but differences in CAM-use i.e. type of CAM, reasons for using CAM, and CAM-provider consulted could be associated with different experiences of care. CONCLUSIONS: It is important to recognize that CAM-users are not a homogeneous group but might seek different types of CAMs and CAM-providers in different situations depending on experiences of care.

Evolution of Streptococcus pneumoniae serotypes and penicillin susceptibility in Latin America, Sireva-Vigía Group, 1993 to 1999. PAHO Sireva-Vigía Study Group. Pan American Health Organization.

BACKGROUND: Since 1993 the Pan American Health Organization has coordinated a surveillance network with the National Reference Laboratories of Argentina, Brazil, Chile, Colombia, Mexico and Uruguay aimed at monitoring capsular types and antimicrobial susceptibility of Streptococcus pneumoniae causing invasive disease in children <6 years of age. METHODS: The surveillance system included children 6 years of age and younger with invasive disease caused by S. pneumoniae. The identification, capsular typing and susceptibility to penicillin of the isolates were conducted using a common protocol, based on standard methodologies. RESULTS: By June, 1999, 4,105 invasive pneumococcal isolates had been collected mainly from pneumonia (44.1%) and meningitis (41.1%) cases. Thirteen capsular types accounting for 86.1% of the isolates (14, 6A/6B, 5, 1, 23F, 19F, 18C, 19A, 9V, 7F, 3, 9N and 4) remained the most common types during the surveillance period. Diminished susceptibility to penicillin was detected in 28.6% of the isolates, 17.3% with intermediate and 11.3% with high level resistance. Resistance varied among countries and increased during this period in Argentina, Colombia and Uruguay. Serotypes 14 and 23F accounted for 66.6% of the resistance. CONCLUSION: These surveillance data clearly demonstrate the potential impact of the introduction of a conjugate vaccine on pneumococcal disease and the need for more judicious use of antibiotics to slow or reverse the development of antimicrobial resistance.

Reduced susceptibility to penicillin among pneumococci causing invasive infection in children - Canada, 1991 to 1998.

OBJECTIVE: To determine, over time, the rate and serotypes of pneumococci with reduced penicillin susceptibility obtained from children with invasive infection. DESIGN: Active, hospital-based, multicentre surveillance spanning from 1991 to 1998. SETTING: Eleven Canadian tertiary care paediatric facilities located from coast to coast. POPULATION STUDIED: 1847 children with invasive pneumococcal infection whose isolates (from a normally sterile site) were available for serotyping and standardized testing for penicillin susceptibility at the National Centre for Streptococcus. MAIN RESULTS: The prevalence of reduced penicillin susceptibility increased from 2.5% of 197 cases in 1991 to 13.0% of 276 cases in 1998. In the latter year, 8.7% of isolates had intermediate level resistance, and 4.3% had high level resistance. Since they were first detected in 1992, strains with high level resistance have been encountered only sporadically at most centres, but by 1998, all centres but two had encountered examples. Of 40 isolates with high level resistance and 101 isolates with intermediate level resistance, serotypes matched those included in new seven-valent conjugate vaccines for children in 97.5% and 79.2% of cases, respectively. CONCLUSIONS: Pneumococci with reduced susceptibility to penicillin are increasing in frequency across Canada among children with invasive infection. The Immunization Monitoring Program, Active data indicate that new conjugate vaccines could help to curb infections due to pneumococci with reduced susceptibility to penicillin but are unlikely to control completely the problem of antibiotic resistance.

Gemella species endocarditis in a child.

Organisms of the genus Gemella can, on occasion, cause serious systemic illness. The present paper reports a successfully treated case of endocarditis in a 12-year-old girl with congenital heart disease caused by species of Gemella. The child presented with cough, fatigue and decreased appetite without fever. Echocardiogram demonstrated marked mitral insufficiency with flail posterior mitral valve leaflet, mitral valve vegetations, and an enlarged left atrium and ventricle. While being treated with vancomycin, the child initially had persistent bacteremia, which resolved after the addition of gentamycin; the course of therapy was completed with penicillin G and gentamycin once antimicrobial susceptibilities were available. Attempts to identify the species of Gemella were unsuccessful in the local laboratory, and at reference laboratories in Canada and the United States. The isolate is undergoing further evaluation to determine its taxonomic status.

Antibiotic resistance in Streptococcus pneumoniae in six Latin American countries: 1993-1999 surveillance.

The impact of invasive pneumococcal invasive disease is increased by the emergence of antibiotic resistance. We report regional and temporal variations in antibiotic resistance for 4,105 invasive Streptococcus pneumoniae isolates collected from Latin American children <5 years, between 1993 and 1999. Reduced susceptibility to penicillin was detected in 1,182 isolates (28.8%); 36% of these were resistant (> or = 2 microg/ml), including 12.6% with MIC > or = 4 microg/ml, occurring primarily in serotypes 14 and 23F. Reduced susceptibility to third-generation cephalosporins was detected in 12.1% of the collection. Mexico had the highest proportion of reduced susceptibility to penicillin (51.6%) and to third-generation cephalosporins (22%), whereas Brazil had the lowest at 20.9% and 0.7%, respectively. Isolates cultured from patients with pneumonia were more likely to have reduced susceptibility to third-generation cephalosporins than isolates from patients with meningitis (p < 0.0001). Susceptibility to trimethoprim-sulfamethoxazole, chloramphenicol, erythromycin, and vancomycin was tested by disk diffusion for 2.899 isolates. Reduced susceptibility was observed for 45.6%, 11.5%, 6.9%, and 0%, respectively. Thirty-one percent of the strains were resistant to > or = 2 drugs. High levels of antibiotic resistance in Latin America emphasize the need for the development of and adherence to rational antibiotic use guidelines. On-going surveillance will monitor the impact of these programs.

Invasive disease due to group B streptococcal infection in adults: results from a Canadian, population-based, active laboratory surveillance study--1996. Sentinel Health Unit Surveillance System Site Coordinators.

In 1996, a population-based surveillance program for invasive adult group B streptococcal (GBS) diseases in Canada was undertaken, to define the epidemiologic and microbiologic characteristics of the disease. Nine public health units across Canada, representing 9.6% of the population, participated in the program. In total, 106 culture-positive cases of invasive adult GBS disease were reported, which represented an incidence rate 4.6 per 100,000 adults (41/100, 000 for pregnant and 4.1/100,000 for nonpregnant adults). Sixty-two (58.5%) of the 106 cases occurred in females, and, of these, 15 (14. 2%) were associated with pregnancy. Serotype V was the most common, accounting for 31% of the 90 GBS isolates typed (26.7% of nonpregnant and 4.4% of pregnant cases). This was followed by serotypes III (19%), Ia (17%), Ib (10%), II (9%), and VII (1%). Thirteen percent were nontypeable. All isolates were susceptible to penicillin, ampicillin, and vancomycin. Resistance to erythromycin and clindamycin was 6.7% and 4.4%, respectively.

Fatal group A Streptococcal toxic shock-like syndrome in a child with varicella: report of the first well documented case with detection of the genetic sequences that code for exotoxins spe A and B, in São Paulo, Brazil.

A previously healthy seven-year-old boy was admitted to the intensive care unit because of toxaemia associated with varicella. He rapidly developed shock and multisystem organ failure associated with the appearance of a deep-seated soft tissue infection and, despite aggressive treatment, died on hospital day 4. An M-non-typable, spe A and spe B positive Group A Streptococcus was cultured from a deep soft tissue aspirate. The criteria for defining Streptococcal toxic shock-like syndrome were fulfilled. The authors discuss the clinical and pathophysiological aspects of this disease as well as some unusual clinical findings related to this case.

First confirmed case of a vancomycin-resistant Enterococcus faecium with vanA phenotype from Brazil: isolation from a meningitis case in São Paulo.

The importance of enterococci as a nosocomial etiologic agent is well documented; however, enterococci are also capable of causing a variety of community-acquired infections. Vancomycin resistance in a clinical Enterococcus isolate was first reported in 1986, and since then vancomycin-resistant enterococci (VRE) have been reported world-wide. This report describes a case of E. faecium with the VanA phenotype, isolated from meningitis in Sao Paulo, Brazil. Two E. faecium strains were isolated. One strain showed VanA phenotype, and the molecular characterization of the VanA gene was confirmed by polymerase chain reaction. The other strain was susceptible to vancomycin and teicoplanin. The authors would like to call the attention of the scientific community to this first identification of a VRE case in Sao Paulo, Brazil.

Molecular epidemiological survey of penicillin-resistant Streptococcus pneumoniae from Asia, Europe, and North America.

One hundred penicillin-resistant Streptococcus pneumoniae (PRSP) strains from Asia, Europe, and North America were analyzed using pulsed-field gel electrophoresis; fingerprinting of penicillin binding protein (pbp) genes; and BOX PCR. Results show that six PFGE patterns (three patterns comprising > or = 2 serotypes) were found widespread and accounted for 64 of the 100 PRSP strains.

Group A Streptococcus carriage among close contacts of patients with invasive infections.

During the past few years, the incidence of invasive group A Streptococcus (GAS) infection has been increasing. However, there are presently no clear recommendations regarding antibiotic prophylaxis for close contacts of index patients. The aims of this study were 1) to determine the prevalence of carriage of the same GAS strain as the patient's among contacts of patients with invasive infections and 2) to assess the importance of exposure duration. From March 1995 to March 1996, the authors prospectively included in the study all patients with invasive GAS infection, as defined by the Working Group on Severe Streptococcal Infections, who came to Hôpital Maisonneuve-Rosemont in Montreal, Quebec, Canada. An epidemiologic investigation was systematically carried out for each index case. Contacts were divided into two groups: those who had spent 24 hours or more with the index patient during the week preceding the beginning of his or her illness and those who had spent 12-24 hours with the index patient during that week. Strains of GAS were examined by serotyping (proteins M and T and the presence or absence of the serum opacity factor) and by characterization of streptococcal pyrogenic exotoxins (exotoxins A, B, and C). One hundred and two contacts of 17 index cases with invasive GAS infection were systematically screened. Contacts were considered positive if they carried the same strain of the bacterium and the same streptococcal pyrogenic exotoxin as the index case. Among the contacts who had spent at least 24 hours per week with their respective index cases, 13 out of 48 (27%) were found to be harboring the same serotype of GAS as the index patient (95% confidence interval 14.5-39.5). By comparison, only one of the 54 contacts in the 12- to 24-hour group (1.8%) was found to be carrying the same strain of the bacterium (95% confidence interval 0-5.3). This difference between the two groups was statistically significant (p<0.001). The median age of the positive carriers (10 years) was significantly lower than the median age of the noncarriers (39 years) (p< or =0.0005). This study showed that close contacts who had spent 12-24 hours with the index patient were rarely colonized with GAS. If antibiotic prophylaxis against GAS is recommended, it should probably target contacts who spent at least 24 hours with an infected patient during the week preceding illness onset.

emm typing and validation of provisional M types for group A streptococci.

This report discusses the following issues related to typing of group A streptococci (GAS): The development and use of the 5' emm variable region sequencing (emm typing) in relation to the existing serologic typing system; the designation of emm types in relation to M types; a system for validation of new emm types; criteria for validation of provisional M types to new M-types; a list of reference type cultures for each of the M-type or emm-type strains of GAS; the results of the first culture exchange program for a quality control testing system among the national and World Health Organization collaborating centers for streptococci; and dissemination of new approaches to typing of GAS to the international streptococcal community.