Analysis of Wnt/Beta catenin signalling in desmoid tumors

Desmoid tumors are fibromatous lesions occurring both sporadically and in patients with familial adenomatous polyposis (FAP). Because of the association of these tumors with the hereditary colorectal cancer syndrome FAP we set out to define the molecular events driving desmoid tumorigenesis, hypothezising these might be identical to events driving colorectal tumorigenesis. We found that whereas FAP-associated desmoid tumors are caused by germline APC mutations followed by somatic inactivation of the wild-type APC allele, sporadic desmoids are usually characterized by oncogenic mutations in the b-catenin gene, both identical molecular alterations to those found in the vast majority of colorectal cancers. Next we set out to investigate the cellular pathways activated by these mutations, and identified activation of the Wnt signaling pathway in desmoid tumors. Wnt signaling modulates expression of developmental genes and cell fate via beta-catenin, and has been implicated in many cancer types. Currently we are investigating tissue-specific downstream effectors of the Wnt pathway that might be responsible for the behaviour of these invasive fibrous tumors. Our findings also point to a role for this pathway in the regulation of normal myofibroblast proliferation and suggest novel treatments in desmoid tumors and other fibrous proliferative disorders.     

Low body temperature governs the decline of circulating lymphocytes during hibernation through sphingosine-1-phosphate

Hibernation is an energy-conserving behavior consisting of periods of inhibited metabolism ('torpor') with lowered body temperature. Torpor bouts are interspersed by arousal periods, in which metabolism increases and body temperature returns to euthermia. In deep torpor, the body temperature typically decreases to 2-10 °C, and major physiological and immunological changes occur. One of these alterations constitutes an almost complete depletion of circulating lymphocytes that is reversed rapidly upon arousal. Here we show that torpor induces the storage of lymphocytes in secondary lymphoid organs in response to a temperature-dependent drop in plasma levels of sphingosine-1-phosphate (S1P). Regulation of lymphocyte numbers was mediated through the type 1 S1P receptor (S1P(1)), because administration of a specific antagonist (W146) during torpor (in a Syrian hamster at ～8 °C) precluded restoration of lymphocyte numbers upon subsequent arousal. Furthermore, S1P release from erythrocytes via ATP-binding cassette (ABC)-transporters was significantly inhibited at low body temperature (4 °C) but was restored upon rewarming. Reversible lymphopenia also was observed during daily torpor (in a Djungarian hamster at ± 25 °C), during forced hypothermia in anesthetized (summer-active) hamsters (at ± 9 °C), and in a nonhibernator (rat at ～19 °C). Our results demonstrate that lymphopenia during hibernation in small mammals is driven by body temperature, via altered plasma S1P levels. S1P is recognized as an important bioactive lipid involved in regulating several other physiological processes as well and may be an important factor regulating additional physiological processes in hibernation as well as in mediating the effects of therapeutic hypothermia in patients.     

Hypersensitivity pneumonitis in a cluster of sawmill workers: a 10-year follow-up of exposure,symptoms, and lung function

Background:

The long-term prognosis of repeated acute episodes of hypersensitivity pneumonitis (HP) is not well described. We report on a 10-year follow-up of a 10-person cluster from a Norwegian sawmill who had all experienced relapsing episodes of HP.

Objectives:

To evaluate the health symptoms, work-related sick-leave, and lung function of 10 workers exposed to mold in a Norwegian sawmill.

Methods:

Participants were evaluated at baseline and 10 years later at follow-up. A structured interview, measurement of serum IgG antibodies to Rhizopus microsporus (R. microsporus) antigens, lung function tests, high resolution computed tomography (HRCT) of the chest, and personal measurements of exposure to mold spores and dust were completed for each participant.

Results:

At baseline, nearly all workers reported acute episodes of HP more than twice a month. At follow-up, both the frequency and intensity of symptoms had declined. Sick-leave was reduced and gas diffusing capacity improved – paralleling the gradually reduced air levels of mold spores.

Conclusions:

In spite of an initially high occurrence of symptoms, long-term clinical and physiological outcome was good. With reduced exposure to mold spores, symptoms declined and lung function was restored.     

Vaginal and anal human papillomavirus infection and seropositivity among female sex workers in Amsterdam,the Netherlands: Prevalence,concordance and risk factors

Background

We studied prevalence, risk factors and concordance of vaginal and anal HPV infection and L1 seropositivity among female sex workers (FSW) in Amsterdam.

Traumatic dental injury among 12‐year‐old South Brazilian schoolchildren: prevalence,severity, and risk indicators

Abstract – An increasing prevalence of traumatic dental injury (TDI) has been reported in the last few decades. The aim of this study was to assess the prevalence and severity of TDI and its association with socio‐demographics and physical characteristics in the anterior permanent teeth of 12‐year‐old Brazilian schoolchildren. A cross‐sectional study was carried out in a population‐based sample of 1528 subjects attending 33 public and nine private schools (response rate of 83.17%). A single calibrated examiner performed the clinical examinations at the schools and recorded the TDI index (Children’s Dental Health Survey criteria), overjet and lip coverage. Height and weight were measured to calculate the body mass index (BMI). Parents/legal guardians answered a questionnaire containing socio‐demographic questions. The relationships among TDI, socio‐demographic variables and physical characteristics were assessed by survey Poisson regression models. The prevalence of TDI was 34.79% (mild trauma = 24.37%; severe trauma = 10.43%). Male schoolchildren (RR = 1.41, 95% CI = 1.23–1.61, P = 0.002) and schoolchildren from low socioeconomic status (RR = 1.32, 95% CI = 1.07–1.64, P = 0.021) were more likely to present at least one tooth with TDI, whereas students attending 7th grade (advanced students) were less likely to experience TDI (RR = 0.59, 95% CI = 0.43–0.82, P = 0.012). Regarding the severity analysis, students of mid‐high (RR = 1.46, 95% CI = 1.09–1.94, P = 0.022), mid‐low (RR = 1.68, 95% CI = 1.01–2.77, P = 0.045) and low (RR = 1.78, 95% CI = 1.11–2.85, P = 0.027) socioeconomic status were more likely to have mild trauma when compared with schoolchildren of high socioeconomic status. No significant association between severe trauma and socioeconomic status was observed. In conclusion, this study showed a high prevalence of TDI in 12‐year‐old Brazilian schoolchildren. Socio‐demographic data and school achievement were associated with TDI.     

Association of in utero sensitization to Schistosoma haematobium with enhanced cord blood IgE and increased frequencies of CD5- B cells in African newborns

This study investigated in utero priming as a consequence of maternal parasitic infections. Cord blood plasma samples of 63 African newborns were assessed by enzyme-linked immunosorbent assay for their content of total and schistosome-specific or filaria-specific IgE and IgG4. The frequencies of lymphocyte phenotypes in cord blood were also determined by using flow cytometry, and were compared with those of European newborns. We found significantly increased schistosome soluble egg antigen (SEA)-specific IgE in cord plasma of those born to mothers with schistosome infections and correlations between fetal and maternal SEA-specific and filaria antigen-specific IgE. These data are evidence for in utero priming of the fetal immune system to maternal helminth infections. Furthermore, we show significantly enhanced percentages of CD5- B cells in African newborns cord blood compared with Europeans, which is consistent with earlier maturation of the African fetal immune system.     

Diagnosis and pathogenesis of CNS lupus

Summary The central nervous system (CNS) is clinically involved in approximately 40% of all systemic lupus erythematosis (SLE) patients. Minor psychiatric symptoms and abnormalities on neuropsychological testing are being detected with increasing frequency. This review summarizes current thinking concerning the diagnosis and pathogenesis of CNS lupus. The main symptoms of CNS lupus can be diffuse (generalized seizures, psychosis) or focal (stroke, peripheral neuropathies). Neuropsychiatric symptoms often occur in the first year of SLE, but are rarely the presenting symptoms of the disease. In studies on the pathology of CNS lupus, vasculopathy, infarcts and haemorrhages are often observed, whereas vasculitis is rare. Endocardial lesions and mural thrombi have also been reported in 33–50% of CNS lupus patients. In fliagnostic imaging of the CNS, magnetic resonance imaging (MRI) scans often provide evidence for edema or small infarcts, both in focal and diffuse CNS lupus, whereas computerized tomography (CT) scans only show gross abnormalitites. The first reports on position emission tomography (PET) scans in CNS lupus patients show decreased glucose uptake in the brain. The cerebral blood flow decreases during active diffuse and focal CNS lupus. The blood-brain barrier is somewhat more frequently impaired in diffuse CNS lupus. Intrathecal IgG and IgM production is observed in 25–66% of all CNS lupus patient. Various specificities of autoantibodies have been observed in CNS lupus. Of these, anticardiolipin (ACA) antibodies show a well-documented association with focal involvement of the CNS in SLE. These antibodies could cause thrombosis by interfering with the protein C pathway of fibrinolysis. In addition, they are associated with endocardial and valvular heart disease, which is often observed in SLE and which could cause ombolism. The relation between ACA and diffuse CNS lupus is not yet clear. Low-avidity anti-DNA antibodies are also found in CNS lupus, possibly because of their fross-reaction with cardiolipin. Antineuronal antibodies and lymphocytotoxic antibodies have been associated with diffuse CNS lupus and abnormalities on neuropsychological testing. However, the population of these antibodies is rather heterogeneous and it has not been possible to assess a common target antigen. Therefore, it is still obscure whether there is also a second immune-mediated mechanism responsible for the development of the diffuse form of CNS lupus.     

Health Risks in Travelers to South Africa: The GeoSentinel Experience and Implications for the 2010 FIFA World Cup

Using the GeoSentinel database, an analysis of ill patients returning from throughout sub-Saharan Africa over a 13-year period was performed. Systemic febrile illness, dermatologic, and acute diarrheal illness were the most common syndromic groupings, whereas spotted fever group rickettsiosis was the most common individual diagnosis for travelers to South Africa. In contrast to the rest of sub-Saharan Africa, only six cases of malaria were documented in South Africa travelers. Vaccine-preventable diseases, typhoid, hepatitis A, and potential rabies exposures were uncommon in South Africa travelers. Pre-travel advice for the travelers to the 2010 World Cup should be individualized according to these findings.In June 2010, South Africa hosts the FIFA World Cup, the largest mass gathering for a single sport. Over 350,000 foreign visitors are expected to travel to one or more World Cup venues. Usually, close to 30% of visitors to South Africa will also travel to other countries on the continent, 77% of whom will visit one of South Africa''s bordering countries or Zambia.¹ Although risk of acquiring malaria and other tropical infections is often perceived to be uniform throughout Africa, comparative data on the spectrum of travel-related illnesses arising from different countries or regions in Africa is lacking. Here, we present a retrospective cohort analysis of selected data collected from ill-returned travelers with defined exposures in South Africa, neighboring countries, and the rest of sub-Saharan Africa (SSA) from 1997 to December 2009, as reported to the GeoSentinel Surveillance Network, the largest existing database of destination-specific travel-related illness. There are no previous studies documenting the range of country-specific illnesses in returning travelers from South Africa. The data here provide an evidence-based approach to guide physicians in advising visitors on the health risks associated with attending the 2010 FIFA World Cup.GeoSentinel sites comprise 50 specialized travel/tropical medicine clinics in 23 countries on six continents, staffed by clinicians experienced in travel and tropical medicine. Diagnostic codes were assigned from a standardized list of over 500 etiologic or 21 general syndromic groups.^2,3Of 114,861 ill patients in the master database, 15,051 had traveled to SSA. Eight hundred twenty-three (823) patients were identified who had acquired their travel-related illness in South Africa as opposed to any other country, (hereafter “South Africa travelers”), i.e., patients who had either traveled only to South Africa, or who had traveled to South Africa and one or more other countries, but had South Africa designated unequivocally as the only possible country of exposure. Similiarly, 768 patients were identified, who acquired an illness from one or more of South Africa''s neighboring countries (hereafter “neighboring country travelers”); Botswana, Lesotho, Mozambique, Namibia, Swaziland, or Zimbabwe, in addition to Zambia, a common add-on destination for visitors to South Africa because of the presence of the Victoria Falls. None of these travelers had visited South Africa. Finally, we identified 13,460 travelers who acquired an illness from countries in SSA, other than South Africa and the neighboring countries (hereafter “SSA travelers”).To eliminate bias, all patients with confirmed (86%) or probable (14%) diagnoses were included in analysis and no site was excluded. The primary variable analyzed was proportionate morbidity, calculated as the number of travelers with a specific diagnosis or group of diagnoses as a proportion of all ill travelers returning from a country or region.²Ninety-five percent (785) of South Africa travelers were seen at a GeoSentinel Clinic in their home country (4 and were more commonly hospitalized.

Table 1

Comparison of characteristics of ill travelers exposed in South Africa vs. its neighboring countries vs. all other sub-Saharan African (SSA) countries

Which domains of thyroid-related quality of life are most relevant? Patients and clinicians provide complementary perspectives.

OBJECTIVE: To identify how thyroid diseases impact the patients' lives and to select the most relevant quality of life (QoL) issues for a thyroid-specific questionnaire. DESIGN: Fifteen thyroid experts and 80 thyroid outpatients (14 with nontoxic goiter, 12 nodular toxic goiter, 21 Graves' disease, 17 thyroid-associated ophthalmopathy, and 16 primary hypothyroidism) were interviewed. METHODS: The relevance of 138 thyroid disease-related issues was rated during interviews. For each issue, three relevance measures were obtained: a diagnosis-specific patient rating, a diagnosis-specific expert rating, and a combined overall patient/expert rating. The 75 most relevant issues overall and the 15 most relevant issues in each patient category were selected. Results: Based on the above, 92 issues were selected, covering a broad range of clinical and QoL domains. Across patient groups, broader QoL domains were most relevant, especially fatigue and emotional susceptibility. However, when focusing on individual patient groups, diagnosis-related physical symptoms were very relevant too. Patients rated issues about psychosocial problems and impact on daily life as more relevant, whereas clinicians focused on thyroid-characteristic issues. CONCLUSIONS: A broad range of QoL issues and physical symptoms are relevant for thyroid patients, particularly fatigue and emotional susceptibility. Patients and clinicians offer complementary perspectives on relevance.