Cytokine polymorphism and its possible impact on cancer

Human cancer is an unpredictable disease as is its response to therapy. The intrinsic genetic heterogeneity and instability of cancer cells could in part explain such behavior. However, it is possible that, individual variation in the genetic make-up of humans may affect the relationship between host and cancer cells and, therefore, be, at least in part responsible for this extraordinary variation. Human gene polymorphism has been shown indeed to play a role in immune responses; among the immune-related genes, cytokines are often polymorphic. Some polymorphisms of cytokine and cytokine receptor may have direct functional significance by altering directly and indirectly the level of gene expression and/or its function; other may only demarcate a genetic linkage to a particular haplotype associated with a given clinical condition. The majority of polymorphisms found in cytokines or their receptors are located in the promoter, intronic and 3′ untranslated regions. These sequence variations can still affect gene expression and function. In this review will we summarize the current knowledge about the role of cytokine polymorphism in disease and more specifically in cancer.     

Partial protective effect of CCR5-Delta 32 heterozygosity in a cohort of heterosexual Italian HIV-1 exposed uninfected individuals

Despite multiple sexual exposure to HIV-1 virus, some individuals remain HIV-1 seronegative (exposed seronegative, ESN). The mechanisms underlying this resistance remain still unclear, although a multifactorial pathogenesis can be hypothesised. Although several genetic factors have been related to HIV-1 resistance, the homozigosity for a mutation in CCR5 gene (the 32 bp deletion, i.e. CCR5-Delta32 allele) is presently considered the most relevant one. In the present study we analysed the genotype at CCR5 locus of 30 Italian ESN individuals (case group) who referred multiple unprotected heterosexual intercourse with HIV-1 seropositive partner(s), for at least two years. One hundred and twenty HIV-1 infected patients and 120 individuals representative of the general population were included as control groups. Twenty percent of ESN individuals had heterozygous CCR5-Delta 32 genotype, compared to 7.5% of HIV-1 seropositive and 10% of individuals from the general population, respectively. None of the analysed individuals had CCR5-Delta 32 homozygous genotype. Sequence analysis of the entire open reading frame of CCR5 was performed in all ESN subjects and no polymorphisms or mutations were identified. Moreover, we determined the distribution of C77G variant in CD45 gene, which has been previously related to HIV-1 infection susceptibility. The frequency of the C77G variant showed no significant difference between ESN subjects and the two control groups.     

Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women

The transdermal and oral administration of estrogens for one year were compared with respect to the effects on lipid metabolism. Eighty-one postmenopausal women (1.5-3 years after menopause) were randomly divided into three groups. The first two groups received sequential estrogen treatment with either transdermal estradiol (Estraderm TTS, Ciba Geigy; 50 μg/day; 24 women) or 0.625 mg/day conjugated estrogens (Premarin, Wyeth; 20 subjects), respectively. In both groups medroxyprogesterone (10 mg/day per os) was added for 12 days of each cycle. Thirty-five subjects served as control group without therapy. No significant changes in the lipid profile was observed in control subjects after 1 year of follow-up. Serum triglycerides decreased significantly (-10.9 ± 26% S.D.; P < 0.05) in transdermal treated women, whereas it slightly rose in oral estrogen group. Comparable significant decreases in total and low density lipoprotein (LDL) cholesterol (mean range -6.5/-18.0%) were observed in women on estrogen replacement therapy. High density lipoprotein (HDL) cholesterol significantly diminished in transdermal estradiol group, but it rose slightly in the oral estrogen group. Thus the fraction of HDL cholesterol over LDL cholesterol did not change in the transdermal group whereas it significantly rose in subjects treated with oral estrogens. It remains to be established to what extent these differences on lipid metabolism are relevant for the prevention of cardiovascular diseases.     

Distribution of acid alpha-naphthyl acetate esterase among human T lymphocyte subsets

Human T lymphocyte subsets, identified by means of OKT3, 4 and 8 monoclonal antibodies, were isolated by a fluorescence activated cell sorter (FACS IV) and analyzed for distribution of alpha-naphthyl acetate esterase (ANAE) activity. As compared to OKT8⁺ lymphocytes a higher proportion of OKT4⁺ lymphocytes was ANAE-positive exibiting a spot or dot-like pattern in the cytoplasm. OKT8 and 4 positive subsets showed a similar ANAE distribution in diffuse granular form. Although OKT4 and OKT8 populations presented a different ANAE dot-like reactivity, this marker did not allow as clear a distinction between them as that reported for T_G and T_M lymphocytes.     

A high frequency of the A30, B18, DR3, DRw52, DQw2 extended haplotype in Sardinian celiac disease patients: Further evidence that disease susceptibility is conferred by DQ A1*0501, B1*0201

This study characterizes by serological and molecular methods the HLA class I and class II alleles in a group of celiac disease children, their parents and a control group of Sardinian descent. We found the DR3-DQw2 haplotype in all patients which was, in almost all cases (84%), associated with the HLA-A30, B18, DR3, DRw52, DQw2 extended haplotype named "Sardinian haplotype" because of its frequency (12-15%) in this Caucasian population. This is the first time that this DQw2-linked haplotype has been reported with such a high frequency in CD. However, no different distribution of "Sardinian haplotype" was found comparing CD patients with 91 haplotyped DQw2-positive controls. This finding indicates that the DQw2 antigen in Sardinians is almost always associated with the A30, B18, DR3, DRw52, DQw2 extended haplotype. The DQA1 and DQB1 second exon sequence analysis of the B18,DR3 and B8,DR3 haplotypes showed the DQA1*0501 and DQB1*0201 alleles which shared the already published sequences. DPB1 subtyping showed the DPB1*0301 allele more frequently (p less than 0.005) in CD patients but this difference was no longer significant when patients and controls, both heterozygous for the DR3-DQw2 haplotype, were compared. We suggest that the divergent HLA extended haplotypes and DP allele associated with CD, described in different Caucasian populations, can be explained by the particular DQw2 linkage disequilibrium in each population.     

Emilin genes are duplicated and dynamically expressed during zebrafish embryonic development.

Emilins are a family of extracellular matrix proteins with common structural organization and containing a characteristic N-terminal cysteine-rich domain. The prototype of this family, Emilin-1, is found in human and murine organs in association with elastic fibers, and other emilins were recently isolated in mammals. To gain insight into these proteins in lower vertebrates, we investigated the expression of emilins in the fish Danio rerio. Using sequence similarity tools, we identified eight members of this family in zebrafish. Each emilin gene has two paralogs in zebrafish, showing conserved structure with the human ortholog. In situ hybridization revealed that expression of zebrafish emilin genes is regulated in a spatiotemporal manner during embryonic development, with overlapping and site-specific patterns mostly including mesenchymal structures. Expression of certain emilin genes in peculiar areas, such as the central nervous system or the posterior notochord, suggests that they may play a role in key morphogenetic processes.     

The ultrasonic detection of insulinomas during surgical exploration of the pancreas

The sensitivity of preoperative imaging was evaluated for the localization of insulinomas in 2 series of 54 and 17 patients, respectively. In the first series, diagnosis was obtained with ultrasonography (US) in 14.8%, with computed tomographic (CT) scan in 60%, and with arteriography and/or angio CT scan in 75% of patients. In the second series, US, CT scan, and arteriography were performed preoperatively showing a sensitivity of 53% of one or more of the imaging techniques. The last 17 patients all underwent intraoperative pancreatosonography, and the insulinoma was localized in each. Considering the high reliability of intraoperative ultrasonography, and the high costs and low benefits of other current diagnostic techniques, a new management plan is suggested for patients with a definite laboratory diagnosis of insulinoma.

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Resumen La sensibilidad de la imagenología preoperatoria para la localización de insulinomas fue evaluada en 2 series de 54 y 17 pacientes respectivamente. En la primera serie, el diagnóstico fue logrado con ultrasonografía en 14.8%, con escanografía computadorizada en 60%, y con arteriografía y/o angiografía con escanografía computadorizada en 75% de los casos. En la segunda serie, la ultrasonografía, la escanografía computadorizada, y la arteriografía fueron realizadas preoperatoriamente demostrando una sensibilidad de 53% en una o más de las técnicas de imagenología. En los últimos 17 pacientes se realizó pancreatosonografía, la cual permitió la localización del tumor en 100% de los casos.En consideración a la elevada confiabilidad de la ultrasonografía intraoperatoria, y los altos costos y bajo rendimiento de las técnicas corrientes de diagnóstico, se sugiere un nuevo plan de manejo para pacientes con un diagnóstico de laboratorio certero de insulinoma. Se fundamenta en la localización ultrasonográfica intraoperatoria del tumor, la cual puede ser aplicada en los más comprensivos centras médicos.

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Résumé La sensibilité de l'imagerie pré-opératoire permettant la localisation des insulinomes a été étudiée dans 2 séries de 54 et 17 sujects. Dans la première série le diagnostic fut posé par l'échographie dans 14.8% des cas, par la tomodensitométrie dans 60% des cas, par l'artériographie et/ou l'angiotomodensitométrie dans 75% des cas. Dans la seconde série, l'échographie, la tomodensitométrie et l'artériographie furent pratiquées avant l'intervention avec une sensibilité de 53% pour l'une ou pour plusieurs techniques. Chez les 17 derniers malades l'échographie opératoire fut systématiquement pratiquée et permit la localisation de la tumeur dans 100% des cas.Considérant la haute fiabilité de l'échographie opératoire, le coût élevé et les faibles résultats des autres techniques de diagnostic, un nouveau plan d'investigation est proposé pour explorer les malades qui présentèrent certains signes biologiques d'insulinome. Il repose sur la localisation per-opératoire de la tumeur par l'échographie, méthode qui peut être pratiquée dans des centres spécialisés.

     

Adequacy and support of physiological functions in the acutely ill cirrhotic patient

The cirrhotic condition is characterized by a series of changes in physiological functions and of subclinical alterations that imply an abnormal and fragile adaptive pattern with reduced resistance to superimposed distress. In the care of the critically ill cirrhotic patient, the supportive measures aimed at maintaining physiological stability through the control of such debilitating factors have a key role and are not secondary in importance to the more obvious measures needed to treat clinically evident and specific alterations or complications. The relationship between hepatic malfunction and the development of these physiological abnormalities is not fully understood. Our knowledge of the problem, however, has been recently improved and the need for supportive measures motivated by a series of notions on cardiorespiratory and metabolic abnormalities and interactions in hepatic decompensation.

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Resumen La condición cirrótica se caracteriza por una serie de cambios en las funciones fisiológicas y por alteraciones subclinicas que implican un patrón de adaptación anormal y fragil de resistencia reducida al estrés. Estas incluyen disfunción respiratoria con tendencia a la hipoxemia arterial en presencia de elevados indices cardiacos, una situatión crónica de hiperdinamismo cardiovascular pero con precaria eficacia miocárdica y latente riesgo de falla de alto débito, y cambios metabólicos que se traducen en un estado de fallas multisistémicas interrelacionadas características del cirrótico. En el cuidado del paciente cirrótico en estado crítico, las medidas de soporte orientadas al mantenimiento de la estabilidad fisiológica mediante el control de tales factores debilitantes tienen una importancia capital y no son secundarias frente a aquellas muy obvias que se requieren para tratar alteraciones o complicaciones específicas y clínicamente evidentes. La relación entre la disfunción hepática y el desarrollo de las mencionadas anormalidades fisiológicas no está totalmente aclarada, sin embargo, el estado de nuestro conocimiento sobre el problema ha sido enriquecido recientemente y se ha fortalecido la necesidad de establecer medidas de soporte por una serie de nociones relativas a las anormalidades e interacciones cardiorrespiratorias y metabólicas de la descompensación hepática.

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Résumé La cirrhose est caractérisée par des séries de variations des fonctions physiologiques et de modifications cliniques qui impliquent des modalités d'adaptation anormale et fragile se traduisant par une résistance réduite à l'état de détresse ou peut se trouver le cirrhotique. Des mesures appropriées pour maintenir la stabilité physiologique ont un rôle principal en présence de ces facteurs défavorables. Elles ne doivent pas être considérées comme moins importantes que les mesures essentielles qui sont nécessaires pour traiter les complications et les modifications cliniques spécifiques. La relation entre l'altération des fonctions du foie et le développement des anomalies physiologiques précitées n'est pas parfaitement élucidée, cependant, nos connaissances de ce problème ont été récemment améliorées et le besoin de mesures adéquates de soutien est devenu manifeste en raison de séries acquises de notions concernant les anomalies cardio-respiratoires et métaboliques ainsi que les interactions de la décompensation hépatique.

     

Sarcopenia Risk Evaluation in a Sample of Hospitalized Elderly Men and Women: Combined Use of the Mini Sarcopenia Risk Assessment (MSRA) and the SARC-F

Background: SARC-F and Mini Sarcopenia Risk Assessment (MSRA) questionnaires have been proposed as screening tools to identify patients at risk of sarcopenia. The aim of this study is to test the use of SARC-F and MSRA, alone and combined, as a pre-screening tool for sarcopenia in geriatric inpatients. Methods: 152 subjects, 94 men and 58 women, aged 70 to 94, underwent muscle mass evaluation by dual energy X-ray absorptiometry (DXA), muscle strength evaluation by handgrip, and completed the MSRA, SARC-F and Activity of daily living (ADL) questionnaires. Results: 66 subjects (43.4%) were classified as sarcopenic according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. The 7-item SARC-F and MRSA and 5-item MSRA showed an area under the curve (AUC) of 0.666 (95% confidence interval (CI): 0.542–0.789), 0.730 (95% CI: 0.617–0.842) and 0.710 (95% CI: 0.593–0.827), respectively. The optimal cut-off points for sarcopenia detection were determined for each questionnaire using the Youden index method. The newly calculated cut-off points were ≤25 and ≤40 for MSRA 7- and 5-items, respectively. The ideal cut-off for the SARC-F was a score ≥3. Applying this new cut-off in our study population, sensitivity and specificity of the 7-item MSRA were 0.757 and 0.651, and 0.688 and 0.679 for the 5-item MSRA, respectively. Sensitivity and specificity of SARC-F were 0.524 and 0.765, respectively. The combined use of the 7-item SARC-F and MSRA improved the accuracy in sarcopenia diagnosis, with a specificity and sensitivity of 1.00 and 0.636. Conclusion: 7-item SARC-F and MSRA may be co-administered in hospital wards as an easy, feasible, first-line tool to identify sarcopenic subjects.