Long-term toxicity of cisplatin in germ-cell tumor survivors.

CONTEXT: Testicular germ-cell tumors (GCT) are highly curable. A multidisciplinary approach, including cisplatin-based chemotherapy has resulted in cure in the majority of patients with GCT. Thus, the life expectancy of survivors will extend to many decades post-diagnosis. Late treatment toxicities associated with cisplatin-based chemotherapy may impact their future health. OBJECTIVE: To systematically evaluate evidence regarding the long-term toxicity of cisplatin in GCT survivors. EVIDENCE ACQUISITION: We carried out a critical review of PubMed/Medline in February 2017 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) criteria. Eighty-three publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports evaluated long-term toxicities of cisplatin-based chemotherapy in GCT survivors. Studies reporting neuro- and ototoxicity, secondary malignancies, cardiovascular, renal and pulmonary toxicities, hypogonadism and infertility were found. Seven studies (8%) reported genetic underpinnings of long-term toxicities and 3 (4%) and 14 (19%) studies correlated long-term toxicities with circulating platinum levels and cumulative dose of cisplatin, respectively. Significant risks for long-term toxicities associated with cisplatin and platinum-based regimens were reported. The cumulative dose of cisplatin and circulating platinum were reported as risk factors. Several single-nucleotide polymorphisms identified patients susceptible to cisplatin compared with wild-type individuals. CONCLUSIONS: GCT survivors cured with cisplatin-based chemotherapy are at risk for long-term side-effects. Detection of single-nucleotide polymorphisms could be a valuable tool for predicting long-term toxicities. PATIENT SUMMARY: Herein, this article summarizes the available evidence of long-term toxicity of cisplatin-based chemotherapy in GCT survivors and provide insights from Indiana University.

Th1, Th2 and Treg/T17 cytokines in two types of proliferative glomerulonephritis.

IgA nephropathy (IgAN) and focal segmental necrotizing glomerulonephritis (FSNGN) are characterized by proliferation of native glomerular cells and infiltration by inflammatory cells. Several cytokines act as mediators of kidney damage in both diseases. The aim of the present study was to investigate the role of Th1, Th2 and Treg/T17 cytokines in these types of proliferative glomerulonephritis. Simultaneous measurement of Th1 interleukin (IL-2, IL-12, tumor necrosis factor-alpha [TNF-α], interferon-gamma [INF-γ]), Th2 (IL-4, IL-5, IL-6, IL-10, IL-13), Treg/T17 transforming growth factor-beta 1 (TGF-ß1, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-17) cytokines and C-C chemokines Monocyte chemoattractant protein-1 (MCP-1, macrophage inflammatory protein-1 [MIP-1] ß) was performed in first-morning urine samples, at the day of renal biopsy, using a multiplex cytokine assay. Cytokine concentrations were correlated with histological findings and renal function outcome. Urinary excretion of Th1, Th2 and Treg/Th17 cytokines were significantly higher in FSNGN compared to IgAN patients. In IgAN patients (n = 50, M/F: 36/14, M age: 40.7 [17-67] years), Th1, Th2 and T17 cytokines correlated significantly with the presence of endocapillary proliferation, while in FSNGN patients (n = 40, M/F: 24/16, M age: 56.5 [25-80] years), MCP-1 and TGF-ß1 had a positive correlation with severe extracapillary proliferation (P = 0.001 and P = 0.002, respectively). Urinary IL-17 was the only independent parameter associated with endocapillary proliferation in IgAN and with MCP-1 urinary excretion in FSNGN. Response to treatment was mainly predicted by IL-6 in IgAN, and by Th2 (IL-4, IL-6), Treg (GM-CSF) cytokines and MIP-1 ß in FSNGN. Th1, Th2 and T17 cytokines were directly implicated in renal pathology in IgAN and possibly through MCP-1 production in FSNGN. IL-17 and IL-6 seem to have a central role in inflammation and progression of kidney injury.

Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease.

BACKGROUND: Late-onset Alzheimer disease (LOAD) is a common disorder with a substantial genetic component. We postulate that many disease susceptibility variants act by altering gene expression levels. METHODS: We measured messenger RNA (mRNA) expression levels of 12 LOAD candidate genes in the cerebella of 200 subjects with LOAD. Using the genotypes from our LOAD genome-wide association study for the cis-single nucleotide polymorphisms (SNPs) (n = 619) of these 12 LOAD candidate genes, we tested for associations with expression levels as endophenotypes. The strongest expression cis-SNP was tested for AD association in 7 independent case-control series (2,280 AD and 2,396 controls). RESULTS: We identified 3 SNPs that associated significantly with IDE (insulin degrading enzyme) expression levels. A single copy of the minor allele for each significant SNP was associated with approximately twofold higher IDE expression levels. The most significant SNP, rs7910977, is 4.2 kb beyond the 3' end of IDE. The association observed with this SNP was significant even at the genome-wide level (p = 2.7 x 10(-8)). Furthermore, the minor allele of rs7910977 associated significantly (p = 0.0046) with reduced LOAD risk (OR = 0.81 with a 95% CI of 0.70-0.94), as expected biologically from its association with elevated IDE expression. CONCLUSIONS: These results provide strong evidence that IDE is a late-onset Alzheimer disease (LOAD) gene with variants that modify risk of LOAD by influencing IDE expression. They also suggest that the use of expression levels as endophenotypes in genome-wide association studies may provide a powerful approach for the identification of disease susceptibility alleles.

Frequency and nature of recorded childhood immunization-related errors in Greece.

BACKGROUND: While routine immunizations are very safe, their administration to healthy children requires minimization of immunization programmatic errors. In order to estimate the incidence and ascertain the nature of reported immunization errors in the Greek childhood population, we have undertaken a study using data from the National Poison Information Center in Greece, which also has the responsibility to address medication-induced errors. METHODS: All immunization errors concerning children and reported to the National Poison Information Center during the 2-yr period 1999-2000 were retrieved and the conditions of their occurrence were examined. The incidence of reported errors was calculated under the assumption that during each year 100,000 children are born in Greece, and during their childhood they receive a total of about 20 immunization doses of all childhood immunizations. RESULTS: There were 40 immunization errors reported, corresponding to a reported incidence of about 11 per million immunization doses. Of these errors, 20 concerned OPV, 13 DTP, 5 MMR, 1 Haemophilus influenza and 1 Hepatitis B immunizations. In 12 instances an erroneous route was used (out of which 11 concerned OPV), whereas overdose was documented in 13 instances (out of which 8 concerned OPV). The third most common error was administration of DTP instead of the recommended Td vaccine. No adverse patient outcomes were reported. CONCLUSIONS: In Greece, reported errors in immunization practice are relatively rare. Packaging modifications (about one in three errors in this study) of the OPV and DTP could further reduce their incidence.

Relative and population attributable risk of traffic injuries in relation to blood-alcohol levels in a Mediterranean country.

Blood samples were taken from, and interviews were conducted with, 76 persons injured in motor vehicle crashes, and from 126 controls with a home and leisure injury. The analysis was undertaken by modelling the data through conditional logistic regression, controlling for gender- and age-matched variables and other potentially confounding variables, including education and visual acuity. Detectable alcohol levels were associated with a 4.9 relative risk (95% confidence intervals 1.4 to 16.8). The population attributable fraction was about 10% with wide confidence intervals. There was no evidence for a safe threshold in these data. The increased injury risk associated with detectable blood-alcohol levels was disproportionally, albeit non-significantly, elevated among occasional drinkers in comparison to regular drinkers. We conclude that alcohol intake is an important cause of road traffic injuries even in the context of the Mediterranean countries where alcohol is taken in moderation and mainly in the form of wine during meals.

Unintentional childhood poisoning in athens: a mirror of consumerism?

OBJECTIVE: To estimate the incidence of unintentional childhood injuries resulting from accidental poisonings in the Greater Athens area and to ascertain what fraction of this incidence could be linked to specified conditions, amenable to preventive interventions. METHODS: Prospective study over 12 months of 670 children hospitalized 224 hours for accidental poisoning. Site: Two pediatric hospitals and three smaller units in Greater Athens admitting children < or = 15 years old. Information was recorded in a semistructured questionnaire and the data were analyzed through simple stratification by one or more variables. Results Accidental poisoning requiring hospitalization > or = 24 hours was 50% higher among boys than among girls, peaked towards the end of the second year, and declined sharply after the fourth year of life with an estimated incidence of 500 cases per 100,000 among children > or = 5 years old. Cigarettes were the most common agent among infants, whereas medicinal products dominated all other childhood periods. Detergents, petroleum products, and pesticides each contributed about 10% of all poisonings with detergents peaking during the second year of life, petroleum products during the third year, and pesticides remaining constant, in proportional terms, throughout childhood. During the working hours of the day the incidence of poisonings was 80% higher than during the late afternoon and evening hours or the weekends, the times when both parents are usually at home; the excess was statistically significant. The presence of both parents at home in the afternoon hours was associated with an almost 50% reduction of hospitalized poisoning. The accessibility of products with poisoning potential was of major importance. Some specific conditions that led to the incident included storage of potentially poisoning products in the refrigerator, storage of such products in containers of innocuous products, without proper labeling, and parental errors in medication. CONCLUSIONS: Unintentional childhood poisoning further reflects an interaction between inappropriate storage of consumer products and suboptimal supervision during the housekeeping hours of the day.

Risk factors for childhood poisoning: a case-control study in Greece.

OBJECTIVES: To identify child or family related risk factors for unintentional childhood poisoning in Greece and to explore whether product specific poisonings might have special features that make them amenable to preventive interventions. SETTING: A case-control study was undertaken in Athens, Greece in 1995. Cases were 100 consecutive children brought with poisoning to the emergency clinics of the two university affiliated children's hospitals. For every case two age, gender, and hospital matched controls were chosen from among children brought to the outpatient clinics of these hospitals on the same date. METHODS: All children and their guardians were interviewed by the same person using a standard questionnaire that covered demographic, socioeconomic, behavioral, and past injury characteristics. Information was also obtained concerning type and conditions of poisoning for cases. Statistical analysis was undertaken by modeling the data using conditional logistic regression. RESULTS: Socioeconomic factors were not important risk indicators in these data but children living with other than both parents were at increased risk (odds ratio (OR) = 4.7, p = 0.08), as were children with a history of previous poisoning that required medical care (OR = 5.1, p = 0.05). Unintentional poisonings caused by chewing or swallowing cigarettes were concentrated in families where both parents were smokers. CONCLUSIONS: Absence of a parent appears to be associated with increased likelihood of childhood poisoning. The importance of product accessibility is underlined by the concentration of tobacco poisoning among children of parents who were both smokers. In the cultural context of this study, sociodemographic factors do not appear to represent demonstrable risk factors. Instead, control of childhood poisoning should be concentrated on safe packaging, storage, and disposal of potentially hazardous products.