Risk factors for early and late mortality in hospitalized older patients: the continuing importance of functional status

BACKGROUND: Prognostic information collected at hospital admission may be useful in defining care objectives and in deciding on therapy for older people. The aim of our study was to identify admission risk factors for in-hospital and postdischarge mortality. METHODS: The study included 987 patients aged 70 years and older admitted to the geriatric ward of San Giovanni Battista Hospital in Torino during 1995 and 1996. Demographic, clinical, and functional variables were collected on admission to hospital and examined as potential risk factors for mortality during hospitalization and at 5 years of follow-up. RESULTS: During their hospital stay, 147 patients (14.9%) died. Risk factors independently associated with in-hospital mortality included functional impairment (Activities of Daily Living [ADL]) (OR [odds ratio] 1.73, CI [confidence interval] 95% 1.02-2.95), dependence related to medical conditions (OR 2.18, CI 95% 1.39-3.42), cerebrovascular disease (OR 3.23, CI 95% 1.64-6.37), cancer (OR 4.52, CI 95% 1.99-10.24), albumin 3.0-3.4 g/dl (OR 4.51, CI 95% 2.76-7.35), albumin <3.0 g/dl (OR 6.83, CI 95% 3.59-13.0), creatinine 1.5-3 mg/dl (OR 2.23, CI 95% 1.36-3.65), creatinine >3 mg/dl (OR 2.55, CI 95% 1.10-5.93), and fibrinogen >/=452 mg/dl (OR 1.91, CI 95% 1.26-2.89). During the 5-year follow-up, 553 patients (67.7%) died. Variables independently associated with mortality in multivariate analysis were age 75-84 years (HR [hazard ratio] 1.40, CI 95% 1.10-1.78), >/=85 years (HR 2.08, CI 95% 1.59-2.72), male sex (HR 1.50, CI 95% 1.24-1.81), ADL dependency (HR 1.24, CI 95% 1.01-1.52), >/=5 errors on Short Portable Mental Status Questionnaire (HR 1.34, CI 95% 1.10-1.63), dependence on Dependence Medical Index (HR 1.36, CI 95% 1.10-1.67), presence of cancer (HR 2.58, CI 95% 1.80-3.71), hemoglobin /=2 (HR 1.49, CI 95% 1.14-1.95). CONCLUSIONS: A complete functional and clinical evaluation at hospital admission permits identification of patients at higher risk of early and long-term mortality.     

Differential 3,5,3'-triiodothyronine-mediated regulation of uncoupling protein 3 transcription: role of Fatty acids

T(3) regulates energy metabolism by stimulating metabolic rate and decreasing metabolic efficiency. The discovery of mitochondrial uncoupling protein 3 (UCP3), its homology to UCP1, and regulation by T(3) rendered it a possible molecular determinant of the action of T(3) on energy metabolism, but data are controversial. This controversy may in part be attributable to discrepancies observed between the regulation by T(3) of UCP3 expression in rats, humans, and mice. To clarify this issue, we studied 1) the induction kinetics of the UCP3 gene by T(3) in rat skeletal muscle, 2) the influence of fatty acids, and 3) the structure and regulation of the various UCP3 promoters by T(3). Within 8 h of single-dose T(3) administration, hypothyroid rats showed a rise in serum fatty acid levels concomitant with a rapid increase in UCP3 expression in gastrocnemius muscle, followed by inductions of peroxisome proliferator activated receptor delta (PPARdelta) (within 24 h) and PPAR target gene expression (after 24 h). This T(3)-induced early UCP3 expression depended on fatty acid-PPAR signaling because depleting serum fatty acid levels abolished its expression, restorable by administration of the PPARdelta agonist L165,041 (4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid). In transfected rat L6 myoblasts, only the rat UCP3 promoter positively responded to T(3) and L165,041 together in the presence of MyoD, thyroid hormone receptor beta1 (TRbeta1), PPARdelta, or PPARdelta plus the TR dimerization partner retinoid X receptor alpha. All promoters share a response element common to TR and PPAR (TRE 1), but the observed species differences may be attributable to different localizations of the MyoD response element, which in the rat maps to exon 1.     

Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.     

Gram-negative osteomyelitis: clinical and microbiological profile

IntroductionDespite the growing interest in the study of Gram-negative bacilli (GNB) infections, very little information on osteomyelitis caused by GNB is available in the medical literature.Objectives and methods: To assess clinical and microbiological features of 101 cases of osteomyelitis caused by GNB alone, between January 2007 and January 2009, in a reference center for the treatment of high complexity traumas in the city of São Paulo.ResultsMost patients were men (63%), with median age of 42 years, affected by chronic osteomyelitis (43%) or acute osteomyelitis associated to open fractures (32%), the majority on the lower limbs (71%). The patients were treated with antibiotics as inpatients for 40 days (median) and for 99 days (median) in outpatient settings. After 6 months follow-up, the clinical remission rate was around 60%, relapse 19%, amputation 7%, and death 5%. Nine percent of cases were lost to follow-up. A total of 121 GNB was isolated from 101 clinical samples. The most frequently isolated pathogens were Enterobacter sp. (25%), Acinetobacter baumannii (21%) e Pseudomonas aeruginosa (20%). Susceptibility to carbapenems was about 100% for Enterobacter sp., 75% for Pseudomonas aeruginosa and 60% for Acinetobacter baumannii.ConclusionOsteomyelitis caused by GNB remains a serious therapeutic challenge, especially when associated to nonfermenting bacteria. We emphasize the need to consider these agents in diagnosed cases of osteomyelitis, so that an ideal antimicrobial treatment can be administered since the very beginning of the therapy.     

Assessment of prenatal exposure to ethanol by meconium analysis: results of an Italian multicenter study

Background: This study estimated in 7 Italian cities the prevalence of prenatal exposure to ethanol by determining fatty acid ethyl esters (FAEEs; palmitic, palmitoleic, stearic, oleic, linoleic, linolenic, and arachidonic esters) and ethyl glucuronide (EtG) in neonatal meconium samples. Methods: A total of 607 meconium samples were obtained from neonatal wards of 7 public hospitals: Verona and San Daniele del Friuli in the northeast of the country, Reggio Emilia in the middle east, Florence and Rome in the center, and Naples and Crotone in the southwest of the peninsula. Meconium biomarkers were assessed by a validated methodology using liquid chromatography–tandem mass spectrometry and the results categorized using the accepted cutoff of 2 nmol/g total amount of 7 FAEEs and 2 nmol/g EtG, to differentiate between heavy maternal ethanol use during pregnancy and occasional or no use at all. Results: On the basis of the above‐reported cutoffs, the overall prevalence of newborns prenatally exposed to maternal ethanol was 7.9%: 0% in Verona, 4.0% in San Daniele del Friuli, 4.9% in Naples, 5.0% in Florence, 6.2% in Crotone, up to 10.6% in Reggio Emilia, and 29.4% in Rome. Low maternal education level and younger maternal age were associated with biomarker scores over the cutoff. There was also a significant correlation between the highest percentage of prenatal exposure in the capital and certain maternal sociodemographic characteristics. Conclusions: These results indicate considerable variability in the prevalence of fetal exposure to ethanol in different Italian cities, as determined by the objective measurement of biomarkers in meconium. These data, together with previous ones obtained in Barcelona, Spain, indicate that gestational ethanol exposure is widespread, at least in parts of Europe.     

Lesiones detectadas en el programa de cribado de cáncer colorrectal en el País Vasco: primera ronda 2009-2011

Colorectal cancer (CRC) is a major public health problem due to its incidence and mortality. In May 2008, the Basque Country approved the implementation of a population-based colorectal cancer screening program, using the immunochemical fecal occult blood test (FOBT), in persons aged 50-69 years. Patients with a positive result were invited to undergo colonoscopy with sedation.     

Identification of novel genetic variants in the mutational hotspot region 14 kb upstream of the LCT gene in a Mexican population

Several polymorphic loci linked to lactase persistence (LP) have been described, all located in a small mutational hotspot region far upstream (～14?kb) of the lactase (LCT) gene. One is typically found in Europeans, LCT –13910C?>?T, several others are found in East Africans and Arabs, e.g. LCT –13907C?>?G and LCT –13915T?>?G. The possibility of similar loci, specific to populations in South and Central America, has not received much attention so far. To identify possible novel polymorphisms in the mutational hotspot region, we sampled 158 subjects from a rural area in South-Central Mexico. DNA was isolated from serum, and Sanger sequencing of a 501?bp region spanning the LCT –13910C?>?T hotspot was successfully performed in 150 samples. The frequency of the European-type LCT –13910?T-allele was q?=?0.202, and 35% of the population was thus lactase-persistent (CT or TT). Sixteen novel genetic variants were found amongst 11 of the subjects, all were heterozygotes: seven of the subjects were also carriers of at least one LCT –13910?T-allele. Thus, the mutational hotspot region is also a hotspot in the rural Mexican population: 11/150 subjects carried a total of 16 previously unknown private mutations but no novel polymorphism was found. The relationship between such novel genetic variants in Mexicans and lactase persistence is worthy of more investigation.     

Resistance to multikinase inhibitor actions mediated by insulin like growth factor-1

Background

Blood platelet numbers are correlated with growth and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). We previously found that platelet lysates (hPLs) both stimulated HCC cell growth and migration, and antagonized the growth-inhibitory and apoptotic effects of Regorafenib, multikinase growth inhibitor, on HCC cell lines. We evaluated the effects of human insulin-like growth factor-1 (IGF1), a mitogen contained in platelets, on the Regorafenib-mediated growth inhibition.

Methods

An Elisa kit was used to evaluate hPL IGF1 concentrations. The effects of IGF1 on cell proliferation were assessed with MTT assay and analysis of cell cycle progression. Apoptosis assays, scratch assay and Transwell assay were performed to measure apoptosis, cell migration and invasion respectively. Western blots were performed by standard protocols.

Results

IGF1 antagonized growth inhibition exerted by Regorafenib on HCC cell lines. Moreover the mitogen blocked Regorafenib-induced apoptosis and decreased the rate of cell migration and invasion. The IGF1 effects were in turn antagonized by actions of a potent IGF1 receptor inhibitor, GSK1838705A, showing that the IGF1 receptor was involved in the mechanisms of IGF1-mediated blocking of Regorafenib action. GSK1838705A also partially blocked the effects of hPLs in antagonizing Regorafenib-mediated growth inhibition, showing that IGF1 was an important component of hPL actions.

Conclusions

These results show that IGF1 antagonized Regorafenib-mediated growth, migration and invasion inhibition, as well as the drug-mediated induction of apoptosis in HCC cells and reinforce the idea that microenvironmental factors can influence cancer drug actions.