An observational analysis on the influence of parental allergic rhinitis, asthma and smoking on exhaled nitric oxide in offspring.

BACKGROUND: Parental allergic diseases and smoking influence respiratory disease in the offspring but it is not known whether they influence fractional exhaled nitric oxide (FeNO) in the offspring. We investigated whether parental allergic diseases, parental smoking and FeNO levels in parents were associated with FeNO levels in their offspring. METHODS: We studied 609 offspring aged 16-47 years from the Respiratory Health in Northern Europe, Spain and Australia generation (RHINESSA) study with parental information from the Respiratory Health in Northern Europe (RHINE) III study and the European Community Respiratory Health Survey (ECRHS) III. Linear regression models were used to assess the association between offspring FeNO and parental FeNO, allergic rhinitis, asthma and smoking, while adjusting for potential confounding factors. RESULTS: Parental allergic rhinitis was significantly associated with higher FeNO in the offspring, both on the paternal and maternal side (percent change: 20.3 % [95%CI 5.0-37.7], p = 0.008, and 13.8 % [0.4-28.9], p = 0.043, respectively). Parental allergic rhinitis with asthma in any parent was also significantly associated with higher offspring FeNO (16.2 % [0.9-33.9], p = 0.037). However, parental asthma alone and smoking were not associated with offspring FeNO. Parental FeNO was not associated with offspring FeNO after full adjustments for offspring and parental factors. CONCLUSIONS: Parental allergic rhinitis but not parental asthma was associated with higher levels of FeNO in offspring. These findings suggest that parental allergic rhinitis status should be considered when interpreting FeNO levels in offspring beyond childhood.

Epidemiology and surgical management of 184 obturator hernias: a nationwide registry-based cohort study.

PURPOSE: We aimed describe the patient characteristics, surgical details, postoperative outcomes, and prevalence and incidence of obturator hernias. Obturator hernias are rare with high mortality and no consensus on the best surgical approach. Given their rarity, substantial data is lacking, especially related to postoperative outcomes. METHODS: The study was based on data from the nationwide Danish Hernia Database. All adults who underwent obturator hernia surgery in Denmark during 1998-2023 were included. The primary outcomes were demographic characteristics, surgical details, postoperative outcomes, and the prevalence and incidence of obturator hernias. RESULTS: We included 184 obturator hernias in 167 patients (88% females) with a median age of 77 years. Emergency surgeries constituted 42% of repairs, and 72% were laparoscopic. Mesh was used in 77% of the repairs, with sutures exclusively used in emergency repairs. Concurrent groin hernias were found in 57% of cases. Emergency surgeries had a 30-day mortality of 14%, readmission rate of 21%, and median length of stay of 6 days. Elective surgeries had a 30-day mortality of 0%, readmission rate of 10%, and median length of stay of 0 days. The prevalence of obturator hernias in hernia surgery was 0.084% (95% CI: 0.071%-0.098%), with an incidence of one per 400,000 inhabitants annually. CONCLUSIONS: This was the largest cohort study to date on obturator hernias. They were rare, affected primarily elderly women. The method of repair depends on whether the presentation is acute, and emergency repair is associated with higher mortality.

Impact of comorbidity on renal cell carcinoma prognosis: a nationwide cohort study.

BACKGROUND: Presence of comorbid diseases at time of cancer diagnosis may affect prognosis. We evaluated the impact of comorbidity on survival of patients diagnosed with renal cell carcinoma (RCC), overall and among younger (<70 years) and older (≥70 years) patients. METHODS: We established a nationwide register-based cohort of 7894 patients aged ≥18 years diagnosed with RCC in Denmark between 2006 and 2017. We computed 1- and 5-year overall survival and hazard ratios (HRs) for death according to the Charlson Comorbidity Index (CCI) score. RESULTS: Survival decreased with increasing CCI score despite an overall increase in survival over time. The 5-year survival rate of patients with no comorbidity increased from 57% among those diagnosed in 2006-2008 to 69% among those diagnosed in 2012-2014. During the same periods, the survival rate increased from 46% to 62% among patients with a CCI score of 1-2 and from 39% to 44% for those with a CCI score of ≥3. Patients with CCI scores of 1-2 and ≥3 had higher mortality rates than patients with no registered comorbidity (HR 1.15, 95% CI 1.06-1.24 and HR 1.56, 95% CI 1.40-1.73). Patterns were similar for older and younger patients. Particularly, diagnoses of liver disease (HR 2.09, 95% CI 1.53-2.84 and HR 4.01, 95% CI 2.44-6.56) and dementia (HR 2.16, 95% CI 1.34-3.48) increased mortality. CONCLUSION: Comorbidity decreased the survival of patients with RCC, irrespective of age, despite an overall increasing survival over time. These results highlight the importance of focusing on comorbidity in this group of patients.

Pattern of mortality after menopausal hormone therapy: long-term follow up in a population-based cohort.

OBJECTIVE: To investigate long-term pattern of mortality in menopausal women according to different modalities of hormone therapy. DESIGN: Population-based prospective cohort study. SETTING: Denmark 1993-2013. POPULATION: A total of 29 243 women aged 50-64 years at entry into the Diet, Cancer and Health Cohort, enrolled 1993-97 and followed through 31 December 2013. METHODS: Cox' proportional hazards models for increasingly longer periods of follow-up time were used to estimate mortality pattern according to baseline hormone use adjusted for relevant potential confounders. MAIN OUTCOME(S): All-cause and cause-specific mortality. Outcome information was obtained from the Danish Register of Causes of Death (linkage 99.6%). RESULTS: A total of 4098 women died during a median follow up of 17.6 years. After adjustment for relevant lifestyle risk factors, hormone use had no impact on all-cause mortality, regardless of modality. Among baseline users, lower cardiovascluar disease mortality was only evident after 5 years [hazard ratio (HR) 0.54; 95% CI 0.32-0.92], but dissipated with additional follow up. Conversely, lower colorectal cancer mortality (HR 0.64; 95% CI 0.46-0.89) and higher breast cancer mortality (HR 1.34; 95% CI 1.05-1.72) only became evident after 15 years of follow up. There were no significant associations for mortality from other types of cancer or from stroke. CONCLUSIONS: In this long-term follow-up study, taking hormones during menopause was not associated with overall mortality among middle-aged women. Investigating cause-specific mortality revealed significant, albeit weak, differential associations according to both causes of death and over time, underlining the importance of carefully considering individual risks and duration of treatment when making decisions on hormone therapy. TWEETABLE ABSTRACT: Long-term follow-up study confirms no association between menopausal hormone therapy and overall mortality.

Relation of intraoperative temperature to postoperative mortality in open colon surgery--an analysis of two randomized controlled trials.

INTRODUCTION: The open surgical wound is exposed to cold and dry ambient air resulting in heat loss mainly through radiation and convection. This cools the wound and promotes local vasoconstriction and hypoxia. Carbon dioxide (CO2) and water vapor are greenhouse gases with a warming effect. The aim was to evaluate if warm humidified CO2 insufflated in surgical wound can affect long-term overall mortality METHODS: This is a retrospective study of two clinical trials, where patients were randomized to warm humidified CO2 (n = 80) or not (n = 78). All patients underwent elective major open colon surgery. Patients in the treatment group received insufflation of warm humidified CO2 into the open wound cavity via a gas diffuser to create a local atmosphere of 100% CO2. Temperature in the wound cavity was measured with a heat-sensitive infrared camera. Core temperature was measured at the tympanic membrane. Median follow-up was 70.9 months. RESULTS: A multivariate analysis adjusted for age (p = 0.001) and cancer (p = 0.165) showed that the larger the temperature difference between final core temperature and wound edge temperature, the lower the overall survival rate (p = 0.050). Patients receiving insufflation of warm humidified CO2 had a tendency to a better overall survival compared with control patients (p = 0.508). End-of-operation wound edge temperature was negatively associated with mortality (OR = 0.80, 95% CI = 0.68-0.95, p = 0.011), whereas mortality was positively associated with age (10-year increase, OR = 1.78, 95% CI = 1.37-2.33, p < 0.001) and cancer (OR = 8.1, 95% CI = 1.95-33.7, p = 0.004). CONCLUSIONS: A small end-of-operation temperature difference between final core and wound edge temperature was positively associated with patient survival in open colon surgery.

Incidence of chronic bronchitis: a prospective study in a large general population.

SETTING: A county in western Sweden. OBJECTIVE: To prospectively investigate the incidence rate of chronic bronchitis (CB) in relation to smoking, age, sex, atopy and asthma in a large sample of the general population. DESIGN: Subjects from a county in western Sweden born between 1943 and 1973, who had participated in our previous study in 1993, were mailed a new questionnaire in 2003. Altogether 11 463 (72%) answered the questionnaire, which comprised items about smoking, atopy, respiratory symptoms and age at onset of CB symptoms. CB was defined as chronic productive cough for at least 3 months per year for 2 consecutive years. RESULTS: There were 98 new cases of CB during 1993-2003 in the study population aged 30-60 years at follow-up. The incidence rate was 0.9/1000 person-years (py); there was no significant difference between women and men or different age groups. However, CB incidence was higher in women in relation to smoking (incidence rate ratio 3.6, 95%CI 1.9-7.3) and in those with ever asthma (hazard ratio 5.6, 95%CI 3.5-9.0). CONCLUSION: This prospective general population-based study shows an incidence rate of CB of 0.9/1000 py. Smoking and asthma were both associated with an increased risk of CB.

Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial.

This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a transfusion need of 4 units over 8 weeks were included. Aza 75 mg m(-2) d(-1), 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza+Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n=3) and DNMT3A (n=4) were only observed in non-responders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations.

Lifestyle factors correlate with the risk of late pelvic symptoms after prostatic radiotherapy.

AIMS: Although technological improvements are reducing the risks of late side-effects of radiotherapy for prostate cancer, the influence of lifestyle has been less well examined. The aim of this study was to correlate the effects of exercise, body mass index and smoking on the incidence and severity of late pelvic symptoms after radical radiotherapy for prostate cancer. MATERIALS AND METHODS: In total, 440 men completed a questionnaire consisting of the Vaizey rectal symptoms score, the National Cancer Institute common symptoms scores for rectal bleeding, erectile function and urinary incontinence, the General Practice Physical Activity Questionnaire and questions regarding smoking, height and weight. The effect of each lifestyle factor on pelvic symptoms was investigated using a non-parametric multivariate ANOVA (Kruskal-Wallis) test and the chi-squared test. RESULTS: At the time of the survey, 63.3% of men were overweight or obese (body mass index > 25 kg/m(2)) and 71% were inactive or moderately inactive. Active men had significantly lower rectal symptoms scores (P < 0.001) and better erectile (P < 0.001) and urinary function (P < 0.01). Men smoking more than five a day had higher rectal symptoms scores (P < 0.001), as did overweight men (P < 0.05). CONCLUSION: The data show lower late pelvic symptoms after radiotherapy among non-smokers and physically active individuals with a body mass index <25. Although these results would ideally require confirmation in a prospective study, we now include advice on lifestyle in our pre-radiotherapy information pack. The high percentage of obesity and inactivity among this cohort of prostate cancer survivors revealed in this study has prompted the development of an exercise/weight reduction programme in our unit.

Incidence and prevalence of chronic bronchitis: impact of smoking and welding. The RHINE study.

OBJECTIVE: To investigate the prevalence and incidence rate of chronic bronchitis (CB) in relation to smoking habits and exposure to welding fumes in a general population sample. METHODS: Subjects from Northern Europe born between 1945 and 1971 who participated in Stage 1 (1989-1994) of the European Community Respiratory Health Survey were mailed a respiratory questionnaire in 1999-2001 (the RHINE study); 15,909 answered the questionnaire and gave complete data on smoking. CB was defined as chronic productive cough of at least 3 months a year for 2 consecutive years. The questionnaire comprised an item about age when CB started and items about exposure to welding fumes. The incidence of CB was retrospectively assessed for the observation period 1980-2001. RESULTS: CB had a prevalence of 5.4%, and was associated with current smoking and welding exposure. The incidence rate of CB was 1.9 per 1000 person-years, and was increased in relation to welding exposure (low exposure HR 1.4, 95%CI 1.1-1.8; high exposure HR 2.0, 95%CI 1.6-2.7) and in relation to smoking (HR 2.1, 95%CI 1.8-2.5). CONCLUSION: Smoking and occupational exposure to welding fumes are both associated with an increased risk of CB.

Remission of asthma: a prospective longitudinal study from northern Europe (RHINE study).

The aim of the present study was to investigate the remission rate of adult asthma in a general population sample in relation to age, sex, asthma symptoms, allergic rhinitis and smoking. A follow-up of the random population samples from the European Community Respiratory Health Survey in Northern Europe was conducted from 1999-2001 on 1,153 individuals (aged 26-53 yrs) with reported asthma. Remission was defined as no asthmatic symptoms in two consecutive years and no current use of asthma medication. Remission rates per 1,000 person-yrs were calculated and Cox regression models, adjusting for confounders, were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). An average remission rate of 20.2 per 1,000 person-yrs was found. There was no significant difference according to sex; the remission rates were 21.7 and 17.8 per 1,000 person-yrs in females and males, respectively. An increased remission rate was observed among subjects who quit smoking during the observation period. Subjects not reporting any asthma symptom at baseline had an increased remission rate. In the Cox regression model, ex-smoking (HR 1.65, 95% CI 1.01-2.71) was associated with increased remission rate, and reporting any asthma symptom at baseline was associated with decreased remission rate (HR 0.7, 95% CI 0.40-0.90). In conclusion, the present prospective longitudinal study showed that quitting smoking and the presence of mild disease appeared to favour remission.

Modulation of chemokine gene expression in CD133+ cord blood-derived human mast cells by cyclosporin A and dexamethasone.

We have recently developed a protocol for generating huge numbers of mature and functional mast cells from in vitro differentiated umbilical cord blood cells. Using CD133 as a positive selection marker to isolate haematopoietic progenitors we routinely expand the number of recovered cells at least 150-fold, which vastly exceeds the yields of conventional protocols using CD34+ cells as a source of progenitors. Taking advantage of the large quantities of in vitro differentiated mast cells, here we assess at the levels of transcription and translation the kinetics of chemokine gene induction following receptor mediated mast cell activation or following pharmacological activation of specific signal transduction cascades that become activated upon classical FcepsilonRI receptor crosslinking. We demonstrate that chemokine genes encoding IL-8, MCP-1, MIP-1alpha, and MIP-1beta are induced with different kinetics and with different amplitudes in a receptor activation dependent manner, and that these events can be mimicked using pharmacological agents which activate distinct signal transduction pathways. These findings were corroborated by adding immunomodulators such as cyclosporin A and dexamethasone prior to mast cell activation. Finally, we demonstrate that the same modulators added after mast cell activation can differentially quench ongoing chemokine gene induction. Thus, considering the vast yields of mast cells, our protocol is valuable not only for studying regulation of gene expression in mast cells in general, but also as an experimental tool to develop better and more balanced treatments of mast cell related disorders.

ESPEN Guidelines on Enteral Nutrition: Non-surgical oncology.

Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility of increasing or ensuring nutrient intake in cases where normal food intake is inadequate. These guidelines are intended to give evidence-based recommendations for the use of ONS and TF in cancer patients. They were developed by an interdisciplinary expert group in accordance with officially accepted standards, are based on all relevant publications since 1985 and were discussed and accepted in a consensus conference. Undernutrition and cachexia occur frequently in cancer patients and are indicators of poor prognosis. EN should be started if undernutrition already exists or if food intake is markedly reduced for more than 7-10 days. Standard formulae are recommended for EN. Nutritional needs generally are comparable to non-cancer subjects. In cachectic patients metabolic modulators such as progestins, steroids and possibly eicosapentaenoic acid may help to improve nutritional status. EN is indicated preoperatively for 5-7 days in cancer patients undergoing major abdominal surgery. During radiotherapy of head/neck and gastrointestinal regions dietary counselling and ONS prevent weight loss and interruption of radiotherapy. Routine EN is not indicated during (high-dose) chemotherapy.

Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis.

Insulin-like factor 3 (INSL3) serum levels were measured in 135 andrologically well-characterized normal men and 85 patients with testicular disorders to investigate how the hormone, which is a major secretory product of human Leydig cells, is related to testosterone (T), LH, and semen quality. INSL3 was measured by using a newly developed fluorescence immunoassay. Median (2.5-97.5 percentiles) INSL3 serum levels were as follows: normal men (n = 135), 0.99 (0.55-1.73) ng/ml; infertile men (n = 23), 1.11 (0.60-2.07) ng/ml; anorchid men (n = 21), nondetectable (ND); patients with 47, XXY, Klinefelter syndrome (n = 21), 0.12 (ND-0.78) ng/ml; men with hypogonadotropic hypogonadism and T substitution (n = 11), ND; and men with hypogonadotropic hypogonadism and human chorionic gonadotropin (hCG) treatment (n = 5), 0.36 (0.13-0.73) ng/ml. Before testicular biopsy, two infertile men had blood samples drawn directly from vena spermatica. Here, the serum INSL3 levels were 15-fold higher than in serum from peripheral blood samples (13.84 and 14.00 ng/ml, respectively). In two unilaterally orchiectomized former testis cancer patients, who underwent hCG stimulation test, INSL3 serum levels were unchanged 72 and 96 h after hCG stimulation. In conclusion, we provide a normal range for INSL3 serum levels in adult men and show that the majority, if not all, circulating INSL3 derives from the testes. Furthermore, our data strongly indicate that INSL3 secretion is dependent on the differentiating effect of LH on Leydig cells but independent of the steroidogenic LH-mediated action. Thus, even though T and INSL3 are both dependent on LH, these two Leydig cell hormones are regulated differently.

Cytogenetic and molecular analysis of a family with three brothers afflicted with germ-cell cancer.

A thorough cytogenetic investigation and an analysis of detailed questionnaires were performed in a family with three brothers afflicted with germ-cell tumors (GCTs), in an attempt to detect a congenital factor related either to a hereditary genetic background or an environmental/lifestyle influence. One brother had an intracranial tumor in the pineal region and the two others had testicular tumors. Peripheral blood was studied by traditional karyotyping, multicolor-FISH, high-resolution comparative genomic hybridization (HR-CGH), and molecular analysis of selected loci on sex chromosomes (Yq11 region, TSPY, and the androgen receptor gene); however, no abnormalities were detected. The HR-CGH analysis of microdissected histological components of the overt tumors and the adjacent carcinoma in situ demonstrated a pattern of genomic imbalances characteristic for sporadic GCTs, including gain of 12p. The questionnaire and interview revealed a history of different cancers in the extended family, and a possible in utero and/or infantile exposure of the three brothers with GCTs to compounds suspected of endocrine-disrupting properties. Although no genetic aberration was detected in this family, we suspect the presence of a recessive hereditary factor pre-disposing to cancer, which probably was manifested as GCTs in the three brothers because of an adverse effect of an environmental factor on the early germ-cell differentiation.

EHEC outbreak among staff at a children's hospital--use of PCR for verocytotoxin detection and PFGE for epidemiological investigation.

This is the first report of a major foodborne outbreak of enterohaemorrhagic Escherichia coli (EHEC) in Sweden. It occurred among the nursing staff at a children's hospital with approximately 1600 employees. Contaminated lettuce was the most likely source of infection. Nine persons were culture-positive for Escherichia coli (E. coli) O157 and verocytotoxin-positive by PCR and a further two were verocytotoxin-positive by PCR only. All 11 EHEC-positive individuals had attended a party for approximately 250 staff members, which was held at the hospital. In a questionnaire 37 persons stated that they had symptoms consistent with EHEC infection during the weeks after the party. There was no evidence of secondary transmission from staff to patients. The value of PCR as a sensitive and fast method for diagnosis is discussed in this paper. Pulsed-field gel electrophoresis (PFGE) was used to ascertain that staff members were infected by the same clone, and that two patients with E. coli O157 infection were not.

PEBP2 and c-myb sites crucial for lambda5 core enhancer activity in pre-B cells.

The lambda5 gene is expressed exclusively in precursor (pre-) B cells where its gene product, as part of the pre-B cell receptor, is crucial for the proliferation of these cells. Several DNA regions regulate the activity and expression pattern of the lambda5 gene. Amongst these is an enhancer, B(lambda5), located 5' of the gene. Here we analyze the lambda5 enhancer core, b(lambda5), which in earlier experiments was demonstrated to retain 50% of the enhancer activity, and show that this activity is restricted to pre-B cells. We identify a DNA element within b(lambda5), PEBP2(lambda5), which is essential for enhancer activity: mutation within this site dramatically reduces core enhancer activity in pre-B cells. The PEBP2(lambda5) site binds bacterially produced polyoma enhancer binding proteins (PEBP) (Runx/AML/CBFA). Furthermore, PEBP2 proteins present in nuclear extracts from murine pre-B cells bind to the PEBP2(lambda5) element. PEBP2 proteins in mature B cells also bind to the PEBP2(lambda5 )element, implying that if PEBP2 proteins are responsible for the stage-specific expression, they have to be non-activating or inhibiting in mature B cells. We also demonstrate that a described partner of PEBP2, c-myb, binds to a sequence termed myb(lambda5) located just upstream of the PEBP2(lambda5) site in the core enhancer. The myb(lambda5) element is also crucial for enhancer activity, since mutating the myb site reduces core enhancer activity to the same extent as mutating the PEBP2 site. Earlier reports have shown that c-myb is expressed at high levels in pre-B cell lines whereas its expression is down-regulated in more mature B cell lines. Thus, c-myb may be involved in determining the stage-specific expression of the lambda5 gene.

Identification of a structural motif that confers specific interaction with the WD40 repeat domain of Arabidopsis COP1.

Arabidopsis COP1 is a photomorphogenesis repressor capable of directly interacting with the photomorphogenesis-promoting factor HY5. This interaction between HY5 and COP1 results in targeted deg radation of HY5 by the 26S proteasome. Here we characterized the WD40 repeat domain-mediated interactions of COP1 with HY5 and two new proteins. Mutational analysis of those interactive partners revealed a conserved motif responsible for the interaction with the WD40 domain. This novel motif, with the core sequence V-P-E/D-φ-G (φ = hydrophobic residue) in conjunction with an upstream stretch of 4-5 negatively charged residues, interacts with a defined surface area of the ss-propeller assembly of the COP1 WD40 repeat domain through both hydrophobic and ionic interactions. Several residues in the COP1 WD40 domain that are critical for the interaction with this motif have been revealed. The fact that point mutations either in the COP1 WD40 domain or in the HY5 motif that abolish the interaction between COP1 and HY5 in yeast result in a dramatic reduction of HY5 degradation in transgenic plants validates the biological significance of this defined interaction.