The role of glucose, insulin and NEFA in regulating tissue triglyceride accumulation: Substrate cooperation in adipose tissue versus substrate competition in skeletal muscle.

BACKGROUND AND AIMS: Metabolic factors initiating adipose tissue expansion and ectopic triglyceride accumulation are not completely understood. We aimed to investigate the independent role of circulating glucose, NEFA and insulin on glucose and NEFA uptake, and lipogenesis in skeletal muscle and subcutaneous adipose tissue (SCAT). METHODS AND RESULTS: Twenty-two pigs were stratified according to four protocols: 1) and 2) low NEFA + high insulin ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia-euglycaemia), 3) high NEFA + low insulin (fasting), 4) low NEFA + low insulin (nicotinic acid). Positron emission tomography with [18F]fluoro-2-deoxyglucose and [11C]acetate, was combined with [14C]acetate and [U-13C]palmitate enrichment techniques to assess glucose and lipid metabolism. Hyperinsulinaemia increased glucose extraction, whilst hyperglycaemia enhanced glucose uptake in skeletal muscle and SCAT. In SCAT, during hyperglycaemia, elevated glucose uptake was accompanied by greater [U-13C]palmitate-TG enrichment compared to the other groups, and by a 39% increase in de novo lipogenesis (DNL) compared to baseline, consistent with a 70% increment in plasma lipogenic index. Conversely, in skeletal muscle, [U-13C]palmitate-TG enrichment was higher after prolonged fasting. CONCLUSIONS: Our data show the necessary role of hyperglycaemia-hyperinsulinaemia vs euglycaemia-hyperinsulinaemia in promoting expansion of TG stores in SCAT, by the consensual elevation in plasma NEFA and glucose uptake and DNL. In contrast, skeletal muscle NEFA uptake for TG synthesis is primarily driven by circulating NEFA levels. These results suggest that a) prolonged fasting or dietary regimens enhancing lipolysis might promote muscle steatosis, and b) the control of glucose levels, in association with adequate energy balance, might contribute to weight loss.

Seasonal variation in the month of birth in patients with skin cancer.

BACKGROUND: Month of birth influences the risk of developing several diseases. We investigated the influence of date of birth on melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC) incidence. METHODS: Enhanced cancer registry data were analysed including 1751 MSC and 15 200 NMSC. RESULTS: People born in February to April showed significantly elevated risks of NMSC compared with those born in summertime. CONCLUSIONS: We demonstrated seasonality by date of birth for skin cancer incidence. Neonatal UV exposure may explain this finding.

Multiple primary cancers in women with gynaecological malignancies: a cancer registry-based study in Umbria region of Italy.

To investigate the risk of developing multiple primary cancers (MPCs) in patients with previous gynaecological malignancies (cervical, uterine, and ovarian). The study's subjects included all the women on the Umbrian Cancer Registry who were first diagnosed with gynaecological cancer between 1994 and 2009. MPCs were defined according to the rules defined by International Association of Cancer Registries (IACR) and International Agency for Research on Cancer (IARC). Standardized incidence ratios (SIRs) of observed to expected cases were used as the measure of relative risk; its significance and 95% confidence intervals were determined assuming a Pois- son distribution. During the analysed period, the authors observed a total of 346 cases of MPCs in women with cervix (54 cases), corpus of uterus (196 cases), and ovarian (96 cases) malignancies. Significant SIRs were found in all of them, considering all sites combined: 2.43 (95% CI: 1.87-3.14) for cervix, 1.75 (95% CI: 1.52-2.01) for corpus of uterus, and 2.32 (95% CI: 1.90-2.84) for ovary malignancies, with different site-specific risks. Current data confirmed an excess risk of MPCs among women with gynaecological malignancies compared to the general population. The observed site-specific associations are useful to investigate shared risk factors and set up specific follow-up patients.

Epidemiology of HPV-related female cancers in the Umbria region of Italy: pre-vaccination period.

The authors describe the incidence and mortality rates of human papillomavirus (HPV)-related female cancers in Umbria (Italy) in the pre-vaccination period from 1978-2008. Joinpoint regression was applied on age-adjusted incidence and mortality rates to evaluate temporal trends. Mouth and pharynx cancers incidence and mortality trends decreased about three percent per year. For anus and anal canal cancer, incidence and mortality trends presented a non-significant decrease. For malignant neoplasm of vulva, a significant change was found in incidence trend: the annual percentage change decreased from 2001 (- 1.8%). Mortality trend showed a non-significant decrease. Incidence and mortality rates from vaginal cancer were non-significantly decreased. For malignant neoplasm of cervix uteri, incidence rates showed a significant decrease by 2.1% per year. Mortality rates decreased as well, although non-significantly. HPV-related cancers consistently decreased in Umbria. This trend may be a consequence of safer sexual behavior. For cervical cancer, a combination of opportunistic and programmed screening led to a much-reduced disease burden. It is expected that the implementation of vaccination in the future will lead to a further decrease of HPV-related cancer incidence and mortality.

Risk of multiple primary cancers following melanoma and non-melanoma skin cancer.

BACKGROUND: The relationship between cutaneous malignancies and successive primary cancers has been studied since several years, but it still remains controversial. OBJECTIVE: The aim of this study was to evaluate the excess risk of multiple primary cancer among the population of Umbria, Italy, that survived a skin cancer. METHODS: The data registered in the Umbrian Population Cancer Registry from 1994 to 2006 were collected, recorded, and analysed in accordance to the standard methods recommended for cancer registries. Among skin cancer patients, those with multiple cutaneous and non-cutaneous cancers were selected. Only sites with a frequency of more than five cases were considered. The expected number of cases was obtained from indirect standardization with regional incidence rates in several sites that incurred in the overall period. The significance of the observed/expected ratios and the corresponding 95% CI were based on the Poisson distribution. RESULTS: In men, a significant standardized incidence ratio (SIR) was found for melanoma (2.21), non-melanoma skin cancers (1.86), Hodgkin's (4.95) and non-Hodgkin lymphoma (1.82), and tongue/mouth cancer (2.47). In women, melanoma, non-melanoma skin and breast cancer showed a significant high SIRs (4.13, 1.55 and 1.28 respectively). All other cancers showed a non-significant SIR. Considering all sites combined and all sites except skin cancers, the analysis showed a significant excess in men, whereas a significant risk was observed in women only when also skin cancers were considered. CONCLUSIONS: Data from the whole of Umbrian population revealed that skin cancer patients experience marked excess risk of further primary cancers. The main risk in both genders is skin melanoma and other skin cancers. The excess of lymphomas and tongue/mouth cancers is also significant in men, and breast cancer in women. These observations prompt us to include a screening for these cancers in the follow-up of our patients surviving a skin malignancy.

The failure of a major histocompatibility antigen to stimulate a thyroid allograft reaction after culture in oxygen.

The lymphocytic infiltration found in multiple cultured BALB/c thyroids placed in the same C57BL/6 recipient was found to be highly correlated and the high variability between animals was not influenced by the number of lobes. It was concluded that the variable infiltration was largely due to host factors. Because a similar correlation was found between BALB/c and C3H grafts, the response to a minor antigen common to these two strains was suggested as a cause of the infiltration. When the response of C57BL/6 mice to cultured B6.C (H-2d) and BALB.B (H-2b) grafts was compared, a synergism between major and minor antigens was suggested. However, when the time of culture was increased from 48 to 60 h and the response of BALB/c and C57BL/6 mice were compared with identically cultured B6.C (H-2d) grafts, a striking difference between major and minor antigens was observed. None of 10 such grafts in C57BL/6 recipients (major antigens only) showed any infiltration, whereas 8 out of the 9 grafts in BALB/c recipients (minor antigens only) were infiltrated.

Recent trends in incidence, mortality and survival after cancer of the female breast and reproductive organs. Umbria, Italy: 1978-2005.

This study analyzed the incidence, mortality and survival after cancer of the female breast and reproductive organs in the Umbria region of Italy with the aim of generating hypotheses to explain trends. Mortality data were supplied by ISTAT (1978-1993) and ReNCaM (1994-2005) and incidence (1994-2005) and survival (at 12/31/2007) data by RTUP. Joinpoint regression was applied to evaluate temporal trends of the age-adjusted incidence and mortality rates. Mortality, incidence and relative survival rates were compared with national and international data. The incidence of breast cancer increased up to 2001 and afterwards significantly decreased; mortality rates significantly decreased after 1994. Uterine corpus incidence was practically stable, and decreased over the study period; mortality from all uterine subsites significantly decreased from 1978 onwards. Trends in ovarian cancer incidence and mortality (after 1985) were constant. Trends in occurrence of breast and cervical cancer were linked to population screening of Umbrian women, noting a low compliance by younger females with cervical cancer screening and emphasizing the opportunity of starting breast cancer screening at a younger age. Trends in the incidence of cancer of the uterus and ovary, though unsteady, were probably related to modifications in risk factor exposure. Survival was better for breast and cervical cancers than in the 1978-1982 period and might be due to early diagnosis and progress in therapy.

White Matter Disease and Outcomes of Mechanical Thrombectomy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The increased severity of white matter disease is associated with worse outcomes and an increased rate of intracerebral hemorrhage in patients with ischemic stroke undergoing thrombolytic treatment. However, whether white matter disease is associated with outcomes in patients undergoing endovascular treatment remains unclear. MATERIALS AND METHODS: In this prespecified exploratory analysis of our prospective multi-institutional study that enrolled consecutive adult patients with anterior circulation ischemic stroke undergoing endovascular treatment from November 2017 to September 2018, we compared the following outcomes between patients with none-to-minimal (van Swieten score, 0-2) and moderate-to-severe (van Swieten score, 3-4) white matter disease using logistic regression: 90-day mRS 3-6, death, intracerebral hemorrhage, successful recanalization, and early neurologic recovery. RESULTS: Of the 485 patients enrolled in the Blood Pressure after Endovascular Stroke Therapy (BEST) study, 389 had white matter disease graded (50% women; median age, 68 years; range, 58-79 years). A van Swieten score of 3-4 (n = 74/389, 19%) was associated with a higher rate of 90-day mRS of 3-6 (45% versus 18%; adjusted OR, 2.73; 95% CI, 1.34-5.93; P = .008). Although the death rate was higher in patients with van Swieten scores of 3-4 (26% versus 15%), the adjusted likelihood was not significantly different (adjusted OR, 1.14; 95% CI, 0.56-2.26; P = .710). Ordered regression revealed a shift toward worse mRS scores with increasing van Swieten scores (adjusted common OR, 3.04; 95% CI, 1.93-4.84; P < .001). No associations between white matter disease severity and intracerebral hemorrhage, successful recanalization, and early neurologic recovery were observed. CONCLUSIONS: Moderate-to-severe white matter disease is associated with worse outcomes in patients undergoing endovascular treatment without a significant increase in hemorrhagic complications. Studies comparing patients with and without endovascular treatment are necessary to determine whether the benefit of endovascular treatment is attenuated with greater white matter disease.

Incidence of multiple primary malignancies in women diagnosed with breast cancer.

Using data from the Umbrian Population Cancer Registry (RTUP) we tested the hypothesis of relationships between several subsequent cancer sites in women who had had breast cancer. New patients (7,840) were collected from the RTUP between 01/01/1994 and 31/12/2006; 24 DCO cases were excluded; 332 successive multiple cancers in 320 patients were recorded. Including all second cancers, metachronous contralateral breast cancer, the observed/expected ratio (SIR) was non-significant. Excluding these cases, SIR was significantly lower whether with or without second skin carcinomas. SIR of all second metachronous contralateral cancers, excluding skin carcinomas, was non-significant. Significantly lower risk involved the colorectum, stomach, pancreas and metachronous breast with different histology. A significant excess was found of melanoma and total second breast cancers, including the contralateral. The excessive skin melanoma in breast cancer survivors was attributed to the relationship with BRCA2 and CDKN2A mutation-positive patients. The excess risk due to the CDKN2A mutation should also include pancreatic cancer which, in the present study, presented a significantly lower risk.

Regional indices of socio-economic and health inequalities: a tool for public health programming.

OBJECTIVES: The aim was to provide an affordable method of computing socio-economic (SE) deprivation indices at the regional level, in order to reveal the specific aspects of the relationship between SE inequalities and health outcomes. The Umbria Region Socio-Health Index (USHI) was computed and compared with the Italian National Deprivation Index at the Umbria regional level (NDI-U). METHODS: The USHI was computed by applying factor analysis to census tract SE variables correlated with general mortality and validated through comparison with the NDI-U. RESULTS: Overall mortality presented linear positive trends in USHI, while trends in NDI-U proved non-linear or non-significant. Similar results were obtained with regard to specific causes of death according to deprivation groups, gender and age. CONCLUSIONS: The USHI better describes a local population in terms of health-related SE status. Policy-makers could therefore adopt this method in order to obtain a better picture of SE-associated health conditions in regional populations and to target strategies for reducing health inequalities.

Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis.

Individuals with one aerodigestive tract malignancy have a high incidence of second primary aerodigestive tumors. The mechanism for this field effect has not been determined. We studied an individual with widespread dysplastic changes in the respiratory epithelium but no overt carcinoma. The entire tracheobronchial tree obtained at autopsy was embedded in paraffin, and bronchial epithelial cells were isolated by microdissection. DNA extracted from the microdissected cells was analyzed for point mutations in the p53 tumor suppressor gene. A single, identical point mutation consisting of a G:C to T:A transversion in codon 245 was identified in bronchial epithelium from 7 of 10 sites in both lungs. Epithelium at sites containing the p53 mutation was morphologically abnormal, exhibiting squamous metaplasia and mild to moderate atypia. No invasive tumor was found in the tracheobronchial tree or any other location. Cells from peripheral blood, kidney, liver, and lymph node exhibited no abnormality in the p53 gene. The widespread presence of a single somatic p53 point mutation in the bronchi of a smoker suggests that a single progenitor bronchial epithelial clone may expand to populate broad areas of the bronchial mucosa-a novel mechanism for field carcinogenesis in the respiratory epithelium that may be of importance in assessing individuals for risk of a second primary tumor as well as in devising effective strategies for chemoprevention of lung cancer.

Differential regulation of the c-myc oncogene promoter by the NF-kappa B rel family of transcription factors.

The murine c-myc gene contains two elements responsive to the rel-oncogene-related family of NF-kappa B factors. Previously we have shown that factor binding to these two NF-kappa B elements mediates induction of transcription of the c-myc promoter upon interleukin-1 treatment of human dermal fibroblasts and human T-cell leukemia virus type I tax gene expression in T cells (D. J. Kessler, M. P. Duyao, D. B. Spicer, and G. E. Sonenshein, J. Exp. Med. 176:787-792, 1992; M. P. Duyao, D. J. Kessler, D. B. Spicer, C. Bartholomew, J. L. Cleveland, M. Siekevitz, and G. E. Sonenshein, J. Biol. Chem. 267:16288-16291, 1992). To begin to delineate the specific roles of the individual members of the NF-kappa B family, here we have tested their effects on activation of a c-myc promoter/exon 1-CAT construct in NIH 3T3 cells. Classical NF-kappa B (p65/p50) was a potent transcriptional activator of the c-myc promoter. Cotransfection with either p65 alone or p65 in combination with p50 mediated significant induction. In contrast, expression of either v-rel or chicken c-rel failed to transactivate, while murine c-rel induced c-myc promoter activity only slightly. Furthermore, induction by classical NF-kappa B was inhibited by coexpression of either v-rel or chicken c-rel. Thus, individual members of the rel family have differential effects of the c-myc promoter, which can modulate overall transcriptional activity and allow for precise regulation of this oncogene under diverse physiologic conditions.

Epidemiological overview on the effectiveness of mass screening for female cancer in Umbria, Italy.

Using incidence, survival and mortality we tried to verify the effectiveness of mass-screening interventions for cervical uterine, breast, and colorectal cancer in females. Mortality data concern the period from 1978-2002. Incident cases derived from an ad hoc survey for 1978-1982 data and from the RTUP from 01/01/1994 to 31/12/2002. Relative survival rates were calculated for 1978-1982, 1994-1997 and 1998-2002 time intervals. All standardized mortality figures showed a steady trend. Incidence rates concerning cervical uterine cancer showed a decrease starting from the 1978-1982 period, whereas those for breast cancer had a constant increasing trend, and those for colorectal cancer increased up to 1997-1999 and later remained constant. For breast cancer the 5-year survival rate increased about 15% compared to the first period, for colon cancer there was less of an increase and the increase for cervical uterine cancer survival was only for the 1998-2002 period compared to the former ones. With constant incidence rates, improvement in survival from cervical uterine cancer may be due to a high number of cancer cases detected at an early stage. The effect of breast cancer screening on incidence is evident, though differences still did not influence mortality and survival. Colorectal cancer epidemiology can be considered as a prescreening pattern. Mortality, incidence and survival data allow a good overview for the effectiveness of screening procedures.

Urban-rural differences in gynaecological cancer occurrence in a central region of Italy: 1978-1982 and 1998-2002.

Differences in gynaecological cancer incidence and mortality in the urban and rural areas of the Umbria region (central Italy) were investigated. All women with primary invasive breast cancers, uterine cervix and uterine corpus, and ovarian cancers diagnosed during the periods 1978-1982 and 1998-2002 were identified and analysed according to place of residence (either urban or rural). Mortality data were supplied by the National Institute of Statistics (ISTAT) for the period 1978 to 1982, whereas for the 1994-2002 period they were supplied by the Regional Nominative Causes of Death Registry (ReNCaM). Incident cases considered were taken from an ad hoc survey for the first period and from the Umbrian Population Cancer Registry database for the second one. For each site the age-adjusted incidence (AAIR) and mortality (AADR) rates were calculated. The expected number of rural cases was obtained from indirect standardisation with urban incidence and mortality rates of several sites. The significance of the observed expected ratios (SIRs for incidence and SMRs for mortality) and the corresponding 95% confidence intervals were based on the Poisson distribution. Urbanisation levels were established following the classification of the Italian Institute of Statistics. For all sites, excluding the ovary during the most recent period, the SIR relative to rural areas was below 1, but the rates were statistically significant only for breast cancer in both periods (SIR 0.81, 95% CI 0.74-0.88 and SIR 0.82, 95% CI 0.77-0.88, respectively) and for cervix uteri in the first period (SIR 0.77, 95% CI 0.59-0.94). The lower breast cancer incidence in the rural area could also be due to lesser compliance with screening procedures which, up until 2002, were not provided in the form of mass-screenings throughout the region by the Regional Health Department. These results underscore the need for continued efforts to provide preventive health services to medically underserved women throughout Umbria, including rural communities. Underutilisation of preventive healthcare services may result in failure to identify healthcare problems that might be successfully managed with medication or lifestyle changes, as well as missed opportunities to prevent potentially life-threatening diseases.

Age, Sex, and Racial Differences in Neuroimaging Use in Acute Stroke: A Population-Based Study.

BACKGROUND AND PURPOSE: Limited information is available regarding differences in neuroimaging use for acute stroke work-up. Our objective was to assess whether race, sex, or age differences exist in neuroimaging use and whether these differences depend on the care center type in a population-based study. MATERIALS AND METHODS: Patients with stroke (ischemic and hemorrhagic) and transient ischemic attack were identified in a metropolitan, biracial population using the Greater Cincinnati/Northern Kentucky Stroke Study in 2005 and 2010. Multivariable regression was used to determine the odds of advanced imaging use (CT angiography/MR imaging/MR angiography) for race, sex, and age. RESULTS: In 2005 and 2010, there were 3471 and 3431 stroke/TIA events, respectively. If one adjusted for covariates, the odds of advanced imaging were higher for younger (55 years or younger) compared with older patients, blacks compared with whites, and patients presenting to an academic center and those seen by a stroke team or neurologist. The observed association between race and advanced imaging depended on age; in the older age group, blacks had higher odds of advanced imaging compared with whites (odds ratio, 1.34; 95% CI, 1.12-1.61; P < .01), and in the younger group, the association between race and advanced imaging was not statistically significant. Age by race interaction persisted in the academic center subgroup (P < .01), but not in the nonacademic center subgroup (P = .58). No significant association was found between sex and advanced imaging. CONCLUSIONS: Within a large, biracial stroke/TIA population, there is variation in the use of advanced neuroimaging by age and race, depending on the care center type.

Linking surgical specimen length and examined lymph nodes in colorectal cancer patients.

AIM: The number of examined lymph nodes (NLN) was associated with survival of stages II and III colorectal cancer (CRC) patients. Guidelines recommend examining at least 12 lymph nodes. This study investigated the influence of surgical specimen length on lymph node harvest and compliance with international guidelines. MATERIALS AND METHODS: This population-based study included 4,724 cases of surgically treated CRC that were diagnosed from 2002 to 2008. Multivariate analyses were performed for the main study variables (age, gender, diagnosis at screening or in symptomatic patients, cancer site, staging, grading, number of positive nodes, neo-adjuvant treatment for rectal cancer, hospital were surgery was performed). Fractional polynomial models investigated the relationship between continuous variables and outcomes. RESULTS: The NLN increased over time reaching ≥12 NLN in 64% of cases at the end of the study period. More NLN were associated with young age, right colon cancer, pT3-T4 disease, stages II and III and high grade. Fewer NLN were associated with short surgical specimen length and neo-adjuvant treatment in rectal cancer patients. Use of laparoscopy increased sharply over time. CONCLUSIONS: NLN increased over time in accordance with international guidelines. Surgical specimen length correlated with NLN which may determine therapeutic choices, particularly in stage II colon cancer. When harvested lymph nodes are under 10 in number and all are negative, chemotherapy is always recommended. As specimen lengths <20 cm were associated with a high risk of inadequate NLN counts, patients are at risk of over-treatment.

Post-rotavirus vaccine intussusception in identical twins: A case report.

The intussusception is one of the most frequent causes of occlusive syndrome in infants and in children. (1) The mesenteric lymphadenopathy, wich is very rare post rotavirus vaccination, can cause intussusception, (2-5) especially in genetically predisposed individuals. (6) There is an association between intussusception and some classes of genotype. (7-9) Two infants aged 3 months, vaccinated against rotavirus. After about a week, one of the 2 identical infants presented inconsolable crying, vomiting, loose stools mixed with blood, and was diagnosed with bowel obstruction with intussusception. He was operated in urgency. After a few hours, his brother presented vomiting, and was admitted to our Hospital for suspected intussusception. The controls carried out have confirmed the presence of intussusception that was treated early, before the onset of severe symptoms. The incidence of post rotavirus vaccine intussusception is very low. The determining factor hypothetically might be linked to the presence of a genotype that exposes infants to a greater risk of developing mesenteric lymphadenitis and intussusception. In our case, the diagnosis of intussusception occurred in a twin, which allowed us to recognize early symptoms which accused the brother and schedule the surgery with less urgency. Our experience may want to sensitize families and pediatricians to report cases of intussusception given a theoretical familiar association. The study of the genotype could be decisive for or not to exclude the presence of a risk of invagination, thus avoiding vaccination.