How to improve opportunistic screening by using EMRs and other data. The prevalence of undetected diabetes mellitus in target population in Croatia.

OBJECTIVES: Opportunistic screening for type 2 diabetes (T2D) has not been adopted as part of routine practice. The aim of the study was to investigate the yield of opportunistic target screening for T2D in Croatia and to evaluate the process of screening by using data from electronic medical record. STUDY DESIGN: We conducted opportunistic screening in 23 general practitioners (GPs) in a population of 13,344 patients aged 45-70 years. METHODS: First, after excluding patients with T2D, patients with risk factors for T2D were derived from the electronic medical record and GP's assessment during the preconsultation phase. Second, those with data about normoglycemia in past three years were excluded. Remaining patients started the consultation phase during their usual visit, when they were offered capillary fasting plasma glucose testing in the next consultation. RESULTS: Prevalence of T2D was 10.9% (new 1.4%). A total of 5568 (46.1%) patients had risks and 2849 (51.2%) had data about normoglycemia in the last three years. Using those data, number needed to invite to screening (NNI) was reduced to half: from 46.1% to 22.5%. One hundred eighty-four patients were screened positive for T2D in two capillary fasting plasma glucose tests (yield 9.8%). Number needed to screen (NNS) in order to detect one T2D was 10.3 patients. Among risks for T2D, overweight was the best predictive factor for undiagnosed T2D (odds ratio [OR]: 2.11, confidence interval [CI]:1.41-3.15, P < .001). Logistic regression showed that in targeted population, overweight patients with a family history in fold were 2.5 times more likely to have T2D (OR: 2.54, CI 1.78-.61, P < .001). CONCLUSIONS: Total yield in targeted population was 1,4%. By using data about normoglycemia from EMRs, NNI was reduced by half and NNS was 10.3 patients. Our findings suggest the model for improvement in opportunistic screening.

Evaluation of serum Vitamin B12 level and related nutritional status among apparently healthy obese female individuals.

OBJECTIVE: Obesity is a major public health problem and great risk for not only cardiovascular diseases but also cancer, musculoskeletal, and gynecological diseases. This study was aimed to investigate the association between serum Vitamin B12 (vitB12), body mass index (BMI), and nutritional status among obese women. METHODS: This cross-sectional study enrolled consecutive female subjects. The consumptions of red meat, fish, bovine liver, egg, and mushroom were recorded. According to the Dietary Reference Intakes, the patients were categorized as insufficiency and sufficiency. Three cutoff points were defined for vitB12 status: (1) Deficiency if vitB12 is <200 pg/mL; (2) insufficiency if vitB12 is 250-350 pg/mL, and (3) sufficient if vitB12 is ≥350 pg/mL. According to BMI, the patients were assigned to nonobese and obese groups. BMI, serum vitB12 level, consumptions of red meat, fish, bovine liver, egg, and mushroom were evaluated and compared between two groups. RESULTS: Mean level of vitB12 was 247.8 ± 10.4 pg/mL and significantly associated with consumption of egg (P = 0.031), bovine liver (P = 0.004), mushroom (P = 0.040), and red meat (P = 0.003). VitB12 was significantly higher in nonobese than obese group (282.5 ± 106.8 vs. 242.5 ± 107.5 pg/mL, P = 0.001). The ratio of vitB12 deficiency was significantly higher in obese than nonobese group (37.6% vs. 24.7%; P = 0.019). VitB12 level was negatively correlated with BMI (r = -0.155; P< 0.001), but not insulin resistance (r = -0.172; P = 0.062). CONCLUSION: Obesity was associated with low level of vitB12 in obese women, and more likely to be vitB12 deficient. Consumption of certain types of food contributes to increase vitB12 level.

IGF-I sensitivity in Silver-Russell syndrome with IGF2/H19 hypomethylation.

BACKGROUND: Silver-Russell syndrome (SRS) is characterized by intrauterine and postnatal growth retardation, typical facial appearance and body asymmetry. The mechanism of growth retardation is unclear. 50% of the patients have a paternal chromosome 11 epimutation-DNA hypomethylation of the imprinting center region 1 (ICR1) of the insulin-like growth factor 2 (IGF2)/H19 locus. SRS children who carry such an epimutation have increased levels of IGF-I and IGFBP-3 in relation to their stature and body weight, suggesting IGF-I resistance. No IGF-I receptor (IGF-1R) defect has been discovered. Therefore, another mechanism, probably an IGF-I post-receptor signaling defect, might be present. OBJECTIVE: The aim of this in-vitro study was to examine: 1) if IGF-I- and IGF-II-induced fibroblast growth is different in SRS children with IGF2/H19 hypomethylation compared to controls; and 2) whether there is IGF-I insensitivity in this subgroup of SRS children due to IGF-I post-receptor signaling defects. DESIGN: Four SRS patients (two males, two females; 9.2 to 16.6 years of age) with an IGF2/H19 hypomethylation defect and three age-matched healthy controls were included in the in-vitro study. Cultivated skin fibroblasts from the patients and the healthy controls were used for the experiments. Proliferation rates of fibroblasts were measured in the presence or absence of recombinant human IGF-I and IGF-II using the commercially available 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test. PI3K (phosphoinositide 3-kinase) assay and NF-κB transcription factor assay were performed using ELISA in order to estimate the IGF-I-stimulated Akt phosphorylation and IκB phosphorylation, respectively. RESULTS: Fibroblasts from SRS patients and fibroblasts from control individuals showed a comparable potential to proliferate in serum-free medium when stimulated with IGFs. No significant differences were found between both groups concerning Akt phosphorylation and IκB phosphorylation rates. CONCLUSIONS: The results of the in-vitro study do not support the hypothesis that IGF-I/IGF-II resistance is a major pathogenetic mechanism responsible for the growth failure in the subgroup of SRS children with IGF2/H19 hypomethylation.

Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.

BACKGROUND: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). METHODS: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. RESULTS: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects. CONCLUSION: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.

Catch-up growth in autosomal dominant isolated growth hormone deficiency (IGHD type II).

OBJECTIVE: Data on the GH-induced catch-up growth of severely GH-deficient children affected by monogenetic defects are missing. PATIENTS: Catch-up growth of 21 prepubertal children (6 females, 15 males) affected with IGHD type II was analyzed in a retrospective chart review. At start of therapy, mean age was 6.2 years (range, 1.6-15.0), mean height SDS was -4.7 (-7.6 to -2.2), mean IGF-I SDS was -6.2 (-10.1 to -2.2). GH was substituted using a mean dose of 30.5microg/kg*d. RESULTS: Catch-up growth was characterized by a mean height gain of +0.92, +0.82, and +0.61 SDS after 1, 2, and 3 years of GH therapy, respectively. Mean height velocities were 10.7, 9.2 and 7.7cm/year during the first three years. Mean duration of complete catch-up growth was 6 years (3-9). Mean height SDS reached was -0.97 (-2.3 to +1.1), which was within the range of the estimated target height of -0.60 SDS (-1.20 to -0.15). The younger and shorter the children were at start of therapy the better they grew during the first year independent of the dose. Mean bone age was delayed at start by 2.1 years and progressed by 2.5 years during the first two years of therapy. Incomplete catch-up growth was caused by late initiation or irregular administration of GH in four cases. CONCLUSIONS: Our data suggest that GH-treated children with severe IGHD show a sustained catch-up growth over 6 years (mean) and reach their target height range. This response to GH is considered to be characteristic for young children with severe growth retardation due to IGHD.

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis.

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203 269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7 Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P=0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.

[Pregnancy after treatment of primary sterility with zoladex in patient with essential thrombocytopenia].

We have a patient with essential /idiopathic/ thrombocitopeny and primary sterility, who becomes pregnant after medical and operative treatment. With the beginning of the menarche her menstrual cycle goes irregular with menstrual bleeding duration from 8 to 20 days, cystic ovaries, non-ovulation cycles, trombocytopeny and anemia. A laparotomy was performed twice, because of the existence of hemoperitoneum, caused by a rupture of the corpus luteum. After achieving a amenorrhoea with Zoladex treatment, a splenectomia was performed. As a result we observe a physiological recovery of the menstrual cycle, the ovulation cycle and the pregnancy. The patient's hematology and hemostaseology statuses went back to normal.

Transcriptional analysis of LPS-stimulated activation of trout (Oncorhynchus mykiss) monocyte/macrophage cells in primary culture treated with cortisol.

Primary immune responses to pathogen invasion are mediated by the innate immune system in which tissue macrophages play a key role. During infectious processes glucocorticoids generally may function to dampen inflammatory responses. In this study, the ability of cortisol to directly modulate the transcriptional response of rainbow trout macrophages to the cellular activator lipopolysaccharide (LPS) was investigated. The results indicate that cortisol significantly inhibits the well-described LPS-dependent induction of the expression of TNF-alpha2, a pro-inflammatory cytokine. In order to further characterize the molecular effects of LPS and the immunomodulatory role of cortisol, the in vitro macrophage response to LPS in the absence or presence of 12-h cortisol exposure was analyzed utilizing a salmonid-specific microarray platform. Genes that were stimulated or inhibited with LPS plus cortisol fell into several major functional groups. The first, a general "response" group comprising genes within ontology classes including the response to external stimuli, stress, humoral immunity and apoptosis, exhibited a significant increase after LPS stimulation, whereas suppression of this response was observed in the presence of cortisol. LPS stimulated other genes in a second group involved in cell signalling and also genes in a third group involved in the activation of transcription. Categories activated with cortisol were mainly related to various aspects of metabolism (including protein biosynthesis, binding and transport of ions) and structural proteins (mainly cytoskeleton and microtubules). The immunomodulatory action of cortisol on LPS-stimulated macrophages therefore appears more complex than simply the antagonism of LPS-induced transcriptional responses.

[Repair of episiotomies with synthetic suture material].

PURPOSE: The aim of the current study is to investigate possibilities for episiorrhaphy with synthetic sutures and patients follow up for complains and physical status. MATERIALS AND METHODS: The present study is prospective and it includes 180 patients. We used for episiorrhaphy: synthetic sutures Polyglycolic acid (1st group), Polyglactin 910 (2nd group) and plain cat gut and silk (3rd group). Vaginal walls, perineum and skin, in the former two groups of patients, had been sutured only with synthetic suture materials. In the third group we used plain cat gut for vaginal walls and perineum sutures and silk sutures for the skin. We used classical surgical and anesthesiological technics. We followed up anatomical repair, presence ofperineal pain, doctors opinion and patients' attitude. We took into account 5th day post partum results. RESULTS AND DISCUSSION: Anatomical repair of the episiorrhaphy doesn't differ significantly depending on the type of suture material (n.s.-P>0.05). All episiorrhaphies had been healed primary. In the groups were Polyglycolic acid or Polyglactin 910 had been used, local injury reaction (erythema, edema) had been developed more slightly compared with plain cat gut - silk group. Functional results as perineal pain are significantly less expressed in Polyglycolic acid and Polyglactin 910 groups. These patients had pain less frequently and with lesser degree (s.-P<0.05). In these groups patients didn't suffer from fear of sutures removal and sutures were both functional and cosmetic.

Dominant transmission of prepubertal gynecomastia due to serum estrone excess: hormonal, biochemical, and genetic analysis in a large kindred.

Increased extraglandular aromatization has been reported to cause the rare entity of familial gynecomastia. Recently heterozygous inversions at the p450 aromatase gene promotor locus were detected in two different families with this syndrome. We studied a family in which seven affected males over three generations had inherited prepubertal gynecomastia in an autosomal dominant manner. The proband developed gynecomastia at 11.5 yr, entered puberty at 12.5 yr, but was incompletely virilized at 19 yr. A similar development was observed in his affected stepbrother and one first-degree cousin. All three boys had acceleration of prepubertal growth and bone age. The older two had a diminished pubertal growth spurt and precocious growth arrest, but their final heights were within the range of their target height. In addition, the maternal grandfather and three maternal uncles were affected, who all had been mastectomized. The mother of the proband had normal age at menarche and no macromastia. Estrone levels of the proband and the other affected boys were elevated, 17beta-estradiol levels were high-normal, and testosterone levels were low. Hormonal analyses of the affected adults, who had all fathered children, revealed pathologically low serum testosterone levels but normal to high-normal levels of estradiol and estrone. The mother of the proband had elevated estrone levels. Treatment of the proband was more effective with anastrozole than with testolactone and increased the initially reduced testes volume to normal size, promoted virilization, and normalized serum estrone and testosterone levels. Neither preadipocytes from breast fat tissue of the affected stepbrother nor peripheral lymphocytes of the affected boys exhibited increased aromatase activity in culture. Therefore, these cells can be excluded from being the source of estrone excess. In addition, serum of the proband and his stepbrother did not contain factors promoting aromatase activity as assayed using preadipocytes from control individuals.A repeat polymorphism of the p450 aromatase gene cosegregated with the disease phenotype in the family, making a mutation of the p450 aromatase gene likely. Single-strand conformational polymorphism analysis of the known alternative untranslated exons and all coding exons of the p450 aromatase gene did not indicate any mutation. In addition, fluorescent in situ hybridization analysis using four probes covering the promotor region did not reveal the presence of any major inversion at this locus. In conclusion, preadipocytes and blood cells were excluded as the cell source of increased aromatization. Fluorescent in situ hybridization and single-strand conformational polymorphism analyses did not reveal any mutation of the p450 aromatase gene, but an intragenic polymorphic marker cosegregated with the disease phenotype. Excess of serum estrone in the presence of normal 17beta-estradiol levels may be the only indicative serum parameter of this mild manifestation of aromatase excess syndrome, which includes prepubertal gynecomastia and moderate hypogonadism in men but not necessarily short stature. In women, this mode of aromatase excess may remain clinically inapparent.

Characterization of a highly inducible novel CC chemokine from differentiated rainbow trout (Oncorhynchus mykiss) macrophages.

A full-length cDNA clone encoding a novel trout CC chemokine was identified in expressed sequence tags generated from lipopolysaccharide (LPS)-stimulated in vitro differentiated macrophages isolated from the head kidney of the rainbow trout (Oncorhynchus mykiss). The putative 101-amino-acid protein is 38% similar to Macaca mulatta CCL4 (macrophage inflammatory protein 1beta) but is also similar to several other related mammalian CC chemokines, including human Act-2. Real-time PCR and conventional RT-PCR revealed significant up-regulation of transcript levels of the trout CCL4-like mRNA in LPS-stimulated in vitro differentiated macrophages. In unstimulated trout, CCL4-like mRNA expression was detected at different levels in all tissues tested, whereas in LPS-challenged animals (6 mg/kg), CCL4-like mRNA increased in intestine, ovary and spleen at both 24 h and 72 h post-injection. In gills, CCL4-like mRNA expression was inhibited after LPS administration. Based on the highly regulated expression pattern exhibited by the trout CCL4-like mRNA, it is likely that this chemokine plays an important regulatory role in the immune response of trout.

[Endometriosis during postmenopausal period--probable causes for its origin and development]. / Endometrioza v postmenopauzalnata vuzrast--veroiatni prichini za vuznikvane i razvitie na zaboliavaneto.

A very rare--casuistic--case of endometriosis is presented, which appeared ten years after surgical menopause (hysterectomy and ovariectomy) without concomitant use of hormone replacement therapy or phytoestrogens. The possibilities of endogenous production and exogenous supply of estrogens in the female organism are discussed as well as the possible causes of proliferation of endometrial lesions during postmenopausal period. When menopause is induced by surgery (a stress for the organism) without exogenous supply of estrogens (HRT, phytoestrogens, xenoestrogens) the production of suprarenal hormones, including androgens, increases. The peripheral conversion of androgens into estrogens in fat tissue is increased and implanted during hysterectomy endometrial lesions in vagina walls are stimulated.

Mixed gonadal dysgenesis and precocious puberty.

A girl aged 5 years and 6 months presented with premature thelarche in our outpatient clinic. During long-term observation, we recorded growth acceleration, advanced bone age, and elevated oestradiol levels which together were taken to confirm the diagnosis of precocious puberty. The patient was successfully treated with a gonadotropin-releasing hormone agonist, but in view of the poor growth prognosis, recombinant human growth hormone was administered concurrently. At the age of 9 years and 6 months a mild clitoris enlargement and conspicuous muscle development without any further signs of virilization were noticed. Laboratory findings showed high values for testosterone and normal basal values for 17-hydroxyprogesterone and dehydroepinadrosterone sulphate. Explorative laparotomy revealed a gonadoblastoma arising from testicular structures on the left, a female streak gonad on the right side, and normal uterus and fallopian tubes. The karyotype was 46,XY/45,X. These findings confirmed the diagnosis of mixed gonadal dysgenesis with testosterone-producing gonadoblastoma.

[Diagnosis of eczema. Can you recognize what your patient's symptom?]. / Ekzemdiagnostik. Erkennen Sie, woran Ihr Patient leidet?

The term eczema is applied to specific non-infectious inflammatory reactions of the skin, and covers a number of etiologically highly heterogeneous conditions which, however, demonstrate common features in terms of clinical presentation and pathogenesis. Eczematous disorders account for approximately 20% of the dermatological disturbances. They include allergic, contact and irritant contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular-microbial and dyshidrotic eczema, and stasis eczema. They have a high individual and socio-economic impact, and are dependent on individual predisposition.

[Dermatological local therapy. How to control eczema]. / Dermatologische Lokaltherapie. Wie Sie Ekzemen auf die Pelle rücken.

The success of a topical treatment of eczema depends not only on the active agent employed, but also to a large extent on the choice of a suitable base. In the overview, therefore, not only the physical effects of the various galenic preparations (solution, shaking mixture, cream, etc.) are considered, but also the pharmacological and clinical effects of the topical corticoids and alternatives, such as, for example, bufexamac, dyes, coal tar, capsaicin, as also radiation treatment with UV-A in combination with psoralens.

A candidate prostate cancer susceptibility gene at chromosome 17p.

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines.

Human BRG1 is a component of the evolutionarily conserved SWI-SNF chromatin remodeling complex. BRG1 has been implicated in growth control through its interaction with the tumor suppressor pRb and may consequently serve as a negative regulator of proliferation. Postulating that BRG1 may itself be a tumor suppressor gene, we screened a panel of tumor cell lines to determine whether the gene is targeted for mutation. We report that the COOH-terminal region of BRG1 is homozygously deleted in two carcinoma cell lines, prostate TSU-Pr1 and lung A-427. In addition, biallelic inactivations of BRG1 were observed in four other cell lines derived from carcinomas of the breast, lung, pancreas, and prostate; their mutations in BRG1 included three frameshift lesions and one nonsense lesion. Point mutations were also discovered in a number of other cell lines, however in most cases any effect of these mutations on BRG1 function remains to be established. A variety of different mutations within BRG1, in several cell lines, suggest that BRG1 may be targeted for disruption in human tumors. Significantly, reintroduction of BRG1 into cells lacking BRG1 expression was sufficient to reverse their transformed phenotype inducing growth arrest and a flattened morphology. These data strongly support the model that BRG1 may function as a tumor suppressor and strengthen the hypothesis that the regulation of gene expression through chromatin remodeling is critical for cancer progression. It will be important to confirm these observations in primary tumors.

Hand eczema in metalworker trainees--an analysis of risk factors.

The present study, as part of PROMETES (Swiss Prospective Metal Worker Eczema Study), was performed to examine risk factors for the development of occupational hand dermatitis in metal-worker trainees. Since this disease is very common, a high standard of preventive measures is necessary, especially for persons with an endogenous disposition for the development of eczema, e.g., atopics. Within the cohort of 201 healthy young men, 47 (23%) showed at least mild signs of hand eczema at 1 point of the 2.5 year observation period. Various occupational and domestic exposures, skin protection behaviour, regeneration time, and smoking habits, as well as atopic disposition, were studied with regard to their influence on the skin condition of the metalworker trainees. By multivariate analysis, we determined 3 important risk factors for the development of hand eczema in the cohort. (i) We showed once more the important influence of an atopic disposition as a major risk factor for occupational contact dermatitis. (ii) Furthermore, the results suggest that, apart from chemical irritants, mechanical factors should not be underestimated in their role as irritants to the epidermal barrier. (iii) Additionally, an insufficient amount of skin recovery time seems to support a cumulative sub-irritant effect on the skin, which may lead to irritant contact dermatitis.

Transient pseudohypoaldosteronism with complex malformation of internal genitalia. A case report.

At the age of 3 weeks, a girl presenting with acute dehydration was admitted to our hospital. Clinical and laboratory findings revealed malformations of the genitourinary tract, an acute urinary infection and electrolyte disturbances (severe hyponatremia at 115 mmol/l and mild hyperkalemia at 5.6 mmol/l). According to anamnestic data, the child was born to healthy, nonconsanguineous parents. Vaccum extraction was done in the 38th gestational week due to pathological cardiotocography (CTG) findings. Auxological parameters were within the normal range for gestational age. Normal values for 17-OH progesterone and ACTH ruled out congenital adrenal hyperplasia (CAH). Pathologically high aldosterone and plasma renin activity (PRA) confirmed the diagnosis of pseudohypoaldosteronism with salt-wasting crisis which proved to be transient.