Abstract Background: Reference intervals are crucial tools aiding clinicians when making medical decisions. However, for children such values often are lacking or incomplete. The present study combines data from separate pediatric reference interval studies of Denmark and Sweden in order to increase sample size and to include also pre-school children who were lacking in the Danish study. Methods: Results from two separate studies including 1988 healthy children and adolescents aged 6 months to 18 years of age were merged and recalculated. Eighteen general clinical chemistry components were measured on Abbott and Roche platforms. To facilitate commutability, the NFKK Reference Serum X was used. Results: Age- and gender-specific pediatric reference intervals were defined by calculating 2.5 and 97.5 percentiles. Conclusion: The data generated are primarily applicable to a Nordic population, but could be used by any laboratory if validated for the local patient population.

AimsGenetic heterogeneity can pose a challenge to identifying eligible cases for targeted therapy in the human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 2+ breast carcinoma group. In this study, we characterised this subset of tumours according to clinicopathological parameters.Methods and resultsWe assessed 1000 tumour cells per case and recorded the number of HER2 and chromosome enumeration probe 17 (CEP17) copies using gene–protein assay slides. HER2 status was determined based on ASCO/CAP 2013 guidelines. Tumours with 5–50% of cancer cells with amplification were considered to be heterogeneous, whereas those with >50% were considered to be non‐heterogeneous. In a study cohort of 110 HER2 IHC 2+ carcinomas, 93 (84.5%) were non‐amplified, 12 (10.9%) were amplified and five (4.5%) were ISH‐equivocal. All the HER2‐amplified and two of ISH‐equivocal cases (12.7%) corresponded to non‐heterogeneous tumours, with highly significant differences evident in the average HER2/CEP17 ratio (P = 0.0002) and the proportion of cells with HER2 >6 copies (P < 0.0001) compared with heterogeneous lesions. NST grade 3 and HER2‐amplified carcinomas average HER2/CEP17 ratio correlated with an increased number of cells with HER2/CEP17 ≥2.0 (P < 0.014). Triple‐negative CEP17 polysomic carcinomas showed increased metastatic capacity (P = 0.003) compared with other tumour types.ConclusionNon‐heterogeneous HER2 IHC 2+ tumours tend to be HER2‐amplified. Adding the percentage of cells with HER2 >6 copies to the average HER2/CEP17 ratio may facilitate assessment of amplification status in ISH‐equivocal cases. The proportion of cells with HER2/CEP17 ≥2.0 contributes information concerning the actual average HER2/CEP17 ratio, depending on tumour type.

To determine the volume of tumoral and normal breast tissue containing sufficient DNA (>2 μg/sample) for genetic platforms and biobanking, with a focus on multifocality, tumoral heterogeneity, and factors that critically influence sample acceptability.

Purpose: To evaluate topical treatment with clobetasol propionate and lidocaine in women with urethral pain syndrome (UPS) in a retrospective pilot study. Materials and Methods: Urethral instillations of two ml clobetasol propionate cream and two ml lidocaine gel in 30 Caucasian women age 15-74 years with UPS between 1999 and 2006 were evaluated retrospectively. Instillations were given approximately once a week until the patient improved. Between one and 15 (median three) instillations were given. In substudy I a review was undertaken of the medical records to register the treatment effect at the end of the treatment (the last instillation) and any relapses six months thereafter. Substudy II was a follow-up at least five years after last instillation based on medical records and a written questionnaire. Results: Substudy I (n=30): By the end of the treatment 18 women had no symptoms and 12 were improved. Five patients had relapsed within six months. Substudy II (n=28): Twenty-eight women responded to the questionnaire. Four women remained with no symptoms, 18 remained improved, and six had the same symptoms as before treatment. Twenty women thought the treatment was very effective, five rather effective, and three women reported poor effect. Twenty-six women would ask for retreatment if a relapse occurred, two patients would not. No side effects, except transient pain, were reported. Conclusions: This retrospective study and long-term follow-up suggests that urethral instillation of clobetasol propionate and lidocaine is effective in treating women with UPS. Randomized control studies are warranted.

Background Physical activity is of benefit for primary prevention of cardiovascular diseases, but it appears to increase the risk for atrial fibrillation. We aimed to study a cohort of patients following a first stroke in individuals with previous high physical activity, compare them to the general population with respect to recurrent stroke and death, and relate these to atrial fibrillation. Methods and Results From the participants of the Vasaloppet, the world's largest ski‐race, and matched individuals from the general population (n=708 604), we identified 5964 patients hospitalized with a first‐time stroke between 1994 and 2010. Individuals with severe diseases were excluded. One half percent of skiers and 1% of nonskiers were hospitalized due to stroke. The incidence rate was 8.3 per 100 person‐years among skiers and 11.1 among nonskiers. The hazard ratio ( HR ) for recurrent stroke or death between the 2 groups was 0.76 (95% CI 0.67 to 0.86). The result was consistent in subgroups. The HR for death was 0.66 (95% CI 0.56 to 0.78) and for recurrent stroke 0.82 (95% CI 0.70 to 0.96). After adjustment for smoking and socioeconomic factors, the HR for death was consistent at 0.70 (95% CI 0.56 to 0.87) while the HR for recurrent stroke was not statistically significant. Outcomes for skiers with atrial fibrillation tended to show a lower risk than for nonskiers. Conclusions This large cohort study supports the hypothesis that patients with a stroke and with prior regular physical activity have a lower risk of death, while their risk for recurrent stroke is similar to that of nonskiers. The skiers had a higher incidence of atrial fibrillation, but still no increased risk of recurring stroke.

OBJECTIVEEpidemiological studies of the prevalence of periodontitis over an extended time using the same methodology to investigate and classify periodontitis are sparse in the literature. Smoking and socio-economic factors have been proven to increase the risk for periodontal disease. The objective of this study was to investigate 30-year time trends, using the same methodology to classify the prevalence and severity in alveolar bone loss (ABL) and to investigate the influence of tobacco and socio-economic factors.METHODSFour cross-sectional epidemiological studies in an adult population were performed in the county of Dalarna, Sweden, in 1983, 2003, 2008 and 2013. Random samples of 787-1133 individuals aged 35-85 who answered a questionnaire about tobacco use and socio-economic factors were radiographically and clinically examined. A number of teeth, ABL and calculus visible on radiographs were registered. The severity of ABL as detected on radiographs was classified into no bone loss, moderate or severe.RESULTSThe prevalence of moderate ABL decreased from 45% in 1983 to 16% in 2008, but increased to 33% in 2013 (P < 0.05). The prevalence of severe ABL remained the same from 1983 (7%) to 2013 (6%). Calculus visible on radiographs increased from 22% in 2008 to 32% in 2013 (P < 0.05). Socio-economic factors had limited impact on the severity of ABL.CONCLUSIONModerate ABL and calculus visible on radiographs significantly increased between 2008 and 2013. Smoking was the strongest factor associated with ABL overall.

Aims To study whether a high level of physical activity prior to myocardial infarction (MI) also protects against recurrent MI (re-MI) or death.Methods and Results A longitudinal study of a primary cohort consisting of 204,038 skiers with a proved substantially high level of physical activity in the world's largest long-distance ski race, Vasaloppet, and 499,543 non-skiers selected from the Swedish population. Individuals with severe diseases at baseline were excluded. In the nationwide clinical register, Swedeheart, we identified 7092 individuals with a first MI incident between 1989 and 2010. Of these, 1039 (0.5%) were skiers and 6053 (1.2%) were non-skiers. One hundred and sixty-three (15.7%) skiers and 1352 (22.3%) non-skiers suffered a re-MI or died during follow-up (median 4.44 years), corresponding to an incidence rate of 38.9 (95% confidence interval (CI) 33.2-45.4)/1000 person-years and 55.6 (95% CI 52.7-58.7)/1000 person-years, respectively. Severity of MI in both groups was the same. For skiers compared to non-skiers the unadjusted hazard ratio (HR) for re-MI was 0.66 (95% CI 0.52-0.82). For death or re-MI, HR was 0.70 (95% CI 0.59-0.82) with consistent results in subgroups based on race year, age, gender, education level, marital status. After adjustment for also smoking, diabetes, hypertension and cardiovascular medication, HR was 0.80 (95% CI 0.67-0.97).Conclusions This large cohort study supports the hypothesis that patients with MI and with prior physical activity and healthy lifestyle, as evidenced by their participation in a long-distance ski race, have a lower risk of subsequent re-MI or death.

BACKGROUND/AIM:Histopathological and clinical scores to predict prognosis in cervical cancer have been of limited value. In the present study a tumor marker expression score was evaluated for prognostication in early-stage cervical cancer.MATERIALS AND METHODS:The entire study population included 128 women with invasive squamous cell cervical cancer followed-up for at least 10 years.RESULTS:Expression of 12 tumor markers (epidermal growth factor receptor (EGFR), Ki-67, c-MYC, p53, p27, E-cadherin, CD44, vascular endothelial growth factor receptor (VEGF), cyclooxygenase-2 (COX2), CD4, and leucine-rich immunoglobulin-like repeats-1 (LRIG1) and LRIG2, considered relevant for cervical cancer prognostication was evaluated by immunohistochemistry. Expression of five markers, LRIG1, LRIG2, p53, COX2 and c-MYC were useful to make a prognostication score, ranging from 0 to 5. Score 0-1 correlated to less than 5% 10-year mortality, while the mortality rate of those with score 4-5 approached 70%; those with score 2 formed an intermediate group. Using different models, a high sensitivity, specificity, positive predictive value and negative predictive value was attained.CONCLUSION:Tumor marker scoring could be an adjunct to histopathological and clinical parameters in prognostication of early-stage cervical cancer.

The novel biomarker LRIG3 is a member of the LRIG family (LRIG1-3). While LRIG1 has been associated with favorable prognosis and LRIG2 with poor prognosis in invasive cervical cancer, little is known about the role of LRIG3. The aim of this study was to investigate the expression of LRIG3 in invasive cancer and cervical intraepithelial neoplasia (CIN) for possible correlation with other tumor markers, to hormones and smoking, as a diagnostic adjunct in CIN, and prognostic value in invasive cancer. Cervical biopsies from 129 patients with invasive squamous cell carcinoma and 170 biopsies showing low grade and high grade CIN, or normal epithelium were stained for LRIG3 and 17 additional tumor markers. Among other variables the following were included: smoking habits, hormonal contraceptive use, serum progesterone, serum estradiol, high-risk HPV-infection, menopausal status and ten-year survival. In CIN, high expression of the tumor suppressors retinoblastoma protein, p53, and p16, and E-cadherin (cell-cell interaction), or low expression of CK10, correlated to LRIG3 expression. In addition, progestogenic contraceptive use correlated to high expression of LRIG3. In invasive cancer there was a correlation between expression of the major tumor promoter c-myc and high LRIG3 expression. High LRIG3 expression correlated significantly to presence of high-risk HPV infection in patients with normal epithelium and CIN. There was no correlation between LRIG3 expression and 10-year survival in patients with invasive cell cervical cancer. LRIG3 expression is associated with a number of molecular events in CIN. Expression also correlates to hormonal contraceptive use. The results on expression of other tumor markers suggest that LRIG3 is influenced by or influences a pattern of tumor markers in cancer and precancerous cells. Further studies are needed to elucidate if LRIG3 expression might be clinically useful.

Very few high-quality studies on paediatric reference intervals for general clinical chemistry and haematology analytes have been performed. Three recent prospective community-based projects utilising blood samples from healthy children in Sweden, Denmark and Canada have substantially improved the situation. The present review summarises current reference interval studies for common clinical chemistry and haematology analyses.

Very few high-quality studies on paediatric reference intervals for general clinical chemistry and haematology analytes have been performed. Three recent prospective community-based projects utilising blood samples from healthy children in Sweden, Denmark and Canada have substantially improved the situation.ConclusionThe present review summarises current reference interval studies for common clinical chemistry and haematology analyses.

BACKGROUND:Transient hyperphosphatasemia (TH) is an often unnoticed benign entity, primarily affecting children below 5 years of age. However, the prevalence among healthy children is unknown. We used data from a Swedish pediatric reference interval project to estimate the prevalence of high alkaline phosphatase (ALP) among healthy children and to calculate pediatric reference intervals.METHODS:Blood was collected from 699 subjectively healthy children aged 6 months to 18 years. After exclusion of subjects with high ALP, age- and gender-specific reference intervals were calculated.RESULTS:Six children had ALP levels >16.7 µkat/l (>1,000 U/l), including 4 females and 2 males aged 7-22 months. The prevalence in the age group from 6 months to 2 years was 6.2% (6/97). None of the older children had levels of ALP >16.7 µkat/l. The study did not include the follow-up of these apparently healthy children. Consequently, conditions others than TH explaining the elevated ALP could not be excluded. However, general chemistry analyses, such as liver enzymes, calcium, intact PTH and vitamin D, were essentially normal in these children.CONCLUSIONS:The prevalence of high ALP among subjectively healthy children was approximately 2.4% below 5 years of age and 6.2% below 2 years. Reference intervals vary with age and gender.

Background. Many previous studies on reference intervals are hampered by the inclusion of only hospital-based populations of children and adolescents. Methods. This study included 694 children, evenly distributed from 6 months to 18 years of age. They were recruited as volunteers at child care units and schools. All subjects were apparently healthy. A questionnaire on diseases and medications was filled out by parents and by the older children. Results. Alanine aminotransferase (ALT), albumin, aspartate aminotransferase (AST), bilirubin, conjugated bilirubin, C-reactive protein (CRP), creatine kinase (CK), Gamma-glutamyltransferase (GGT), HbA1c (mono S and IFCC calibrations), lactate dehydrogenase (LD), myoglobin and panceratic amylase were analyzed on Abbott Architect ci8200, and for HbA1c on Tosoh G7 and a mono S-system. Age- and gender-related 2.5th and 97.5th percentiles were estimated. For some analytes the differences to comparable studies were substantial. Conclusion. The study gives age- and gender-specific pediatric reference intervals, measured with modern methods for a number of important analytes. The results emphasize the importance to evaluate pediatric reference intervals in different populations and ethnic groups including only healthy subjects.

AIM:To evaluate the natural course, onset, diagnostics and long-term follow-up masturbation in infant girls, which up to now has only been described in case reports.METHODS:Nineteen consecutive healthy, masturbating girls, diagnosed in early infancy between three and 15 months, were followed up for an average of 8 years. All were diagnosed in the same Swedish hospital between May 1996 and June 2010. Ten girls were videotaped and/or directly observed while masturbating.RESULTS:Mean age at onset of masturbation was 10.4 months. The diagnosis was based on history taking and clinical observation. Parents reported that masturbation ranged from a few times a week to two-to-fifty episodes a day. Twelve girls had stopped masturbating when this study was written, after a mean duration of 66 months. Their symptoms and diagnostics are described in detail.CONCLUSION:This is the first follow-up study of girls who started masturbating in early infancy, with a mean duration of five-and-a-half years. Diagnosis may be difficult, but with awareness and knowledge of the condition, a normal physical and neurological examination, a detailed history from the parents and, in particular, video documentation, it can be settled without extensive investigations and the parents reassured.

BACKGROUNDMultiple synchronous, ipsilateral, invasive foci of breast carcinomas are frequent and are associated with a poorer prognosis. Few studies have investigated the prognostic and therapeutic implications of heterogeneity of such foci.METHODSThe authors reviewed the tumor type, grade, and size of all invasive foci in a series of 110 multifocal breast carcinomas documented on large‐format slides. Molecular phenotype was determined by immunohistochemistry in tissue microarray blocks using 3 classification systems. The survival of patients who had tumors with microscopic (tumor type and/or grade) heterogeneity and of those who had tumors with phenotypic heterogeneity was compared with the survival of patients who had multifocal homogeneous tumors using Kaplan‐Meier curves. The hazard ratio of dying from breast cancer was also calculated.RESULTSIntertumoral heterogeneity in tumor type and grade was detected in 16 of 110 tumors (14.6%) and in 6 of 110 tumors (5.5%), respectively. The molecular phenotype of invasive tumor foci within the same breast differed in 10% to 12.7% of patients (11‐14 of 110 tumors), depending on the classification system used. Patients who had phenotypically heterogeneous, multifocal cancers had a greater risk of dying from disease (HR=2.879; 95%CI=1.084−7.649; P = .034) and had significantly shorter survival (P = .016). Phenotypic differences were most common in patients who had tumors that were homogeneous in terms of tumor type (11 of 18 tumors) and histology grade (14 of 18 tumors). Phenotyping additional tumor foci had the potential to influence the therapeutic decisions in up to 8 patients.CONCLUSIONSPhenotyping more than 1 invasive focus of multifocal breast carcinomas only if the individual foci deviate microscopically appears to be insufficient, because phenotypic intertumoral heterogeneity may be observed in microscopically identical foci and has potential prognostic and therapeutic consequences. Cancer 2014;120:26–34. © 2013 American Cancer Society.

Kreatininvarden bor kompletteras med GFR-berakningar : [Creatinine values ​​should be complemented with GFR estimates]