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.

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).

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.

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.

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.

MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines.

A candidate tumor suppressor gene, MMAC1/PTEN, located in human chromosome band 10q23, was recently identified based on sequence alterations observed in several glioma, breast, prostate, and kidney tumor specimens or cell lines. To further investigate the mutational profile of this gene in human cancers, we examined a large set of human tumor specimens and cancer cell lines of many types for 10q23 allelic losses and MMAC1 sequence alterations. Loss of heterozygosity (LOH) at the MMAC1 locus was observed in approximately one-half of the samples examined, consistent with the high frequency of 10q allelic loss reported for many cancers. Of 124 tumor specimens exhibiting LOH that have been screened for MMAC1 alterations to date, we have detected variants in 13 (approximately 10%) of these primary tumors; the highest frequency of variants was found in glioblastoma specimens (approximately 23%). Novel alterations identified in this gene include a missense variant in a melanoma sample and a splicing variant and a nonsense mutation in pediatric glioblastomas. Of 76 tumor cell lines prescreened for probable LOH, microsequence alterations of MMAC1 were detected in 12 (approximately 16%) of the lines, including those derived from astrocytoma, leukemia, and melanoma tumors, as well as bladder, breast, lung, prostate, submaxillary gland, and testis carcinomas. In addition, in this set of tumor cell lines, we detected 11 (approximately 14%) homozygous deletions that eliminated coding portions of MMAC1, a class of abnormality not detected by our methods in primary tumors. These data support the occurrence of inactivating MMAC1 alterations in multiple human cancer types. In addition, we report the discovery of a putative pseudogene of MMAC1 localized on chromosome 9.

[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.

[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.

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.

Microsatellite deletion mapping on chromosome 10q and mutation analysis of MMAC1, FAS, and MXI1 in human glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an end-stage brain tumor of glial origin. Allelic deletions encompassing all or part of chromosome 10q occur frequently in GBMs, indicating that loss of one or more tumor suppressor genes on 10q plays a role in GBM formation. One of these genes is MMAC1 (PTEN), a gene on 10q23 which encodes a dual-specificity protein phosphatase. We carried out a loss of heterozygosity (LOH) analysis of 66 GBM patients using microsatellite markers for 27 loci on 10q. Overall, LOH was detected in 70% of cases, most showing LOH with every informative marker. Eleven patients showed partial 10q deletions, the smallest spanning a 35 cM region distal to D10S187. Sequence analysis of the MMAC1 gene in 45 of these tumors revealed mutations in eleven cases (24%), all with LOH on 10q. None of these mutations was present in normal DNA from the same patients. In addition, we utilized SSCP analysis to test two other candidate genes on 10q: FAS, a cell surface receptor which transduces an apoptotic, cell death signal and MXI1, a transcriptional repressor. The absence of mutations in these genes suggested that FAS and MXI1 are not likely to be tumor suppressor genes physiologically relevant to GBM. These data do support a significant role for MMAC1 in GBM.

Percutaneous ethanol sclerotherapy of autonomous thyroid nodules: preliminary results.

Percutaneous ethanol sclerotherapy was applied to 20 patients (17 women and 3 men, aged 30 to 77 yrs) with autonomous thyroid nodules. The patients either were contraindicated because of hazardous concomitant diseases or refused surgical or 131I treatment. Ethanol (95 alc%) was injected in 4 to 6 sessions at a mean dose of 0.63 ml/cc nodular tissue. Physical examination, T3, T4 and TSH assays, thyroid scintigraphy, sonography, and fine needle aspiration biopsy were used to evaluate the treatment results within a 12-month follow-up. Two months after ethanol injection all patients showed an improvement; in six patients the symptoms recurred in the 6th month. Two of them underwent a second cycle of ethanol injection. 12 months later an euthyroid state was maintained in 16 (80%) patients, while 4 (20%) did not respond to the treatment. The treatment results were markedly determined by the nodule size as no effect was achieved in nodules larger than 15-20 ml in volume. This method appears to be an appropriate and harmless alternative to the surgical and 131I treatment of autonomous thyroid nodules less than 15-20 ml in volume, especially in patients with grave concomitant diseases.

[The European Council and health: the added value of a pan-European approach]. / Le Conseil de l'Europe et la santé: la valeur ajoutée d'une approche paneuropéenne.

The Council of Europe, from its creation in 1949, has been involved in establishing regulations in various field of skills. A group of conventions and actions shows the creation of status objectives. In the field of health, the Council's actions were to improve the economic and social progress in Europe. The European Committee of Health founded in 1954, is particularly in charge of health in order to establish recommendations for the members-states such as the implementation of experts groups and the preparation of precious reports. This article exposes the main decisions.

[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.

[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.

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.