Candidate susceptibility variants for esophageal squamous cell carcinoma

Esophageal cancer is common worldwide, and often fatal. The major histological subtype is esophageal squamous cell carcinoma (ESCC). ESCC shows familial aggregation and high heritability. Mutations in RHBDF2 cause tylosis, a very rare disorder characterized by high life‐time risk of ESCC, but no other well‐established predisposition genes have been identified. To identify candidate susceptibility variants for ESCC we utilized the Population Information System and the Finnish cancer registry to find study materials by clustering ESCC patients by family name at birth and municipality at birth. We collected archival tissue material and exome sequenced a total of 30 ESCC cases. We prioritized shared, deleterious and rare variants that were significantly enriched in our sample set compared to Finnish and population subset specific controls. Six variants passed filtering, the most frequent being a nonsense mutation in DNAH9 (p.Tyr1573Ter) found in four unrelated patients. DNAH9 has been reported to be frequently lost in ESCC tumors. In this study, one patient's tumor showed loss of the wild type allele of DNAH9 suggesting a tumor suppressive function. A missense variant in GKAP1 was shared by three patients, and missense variants in BAG1, NFX1, FUK, and DDOST by two each. EP300 which has previously been implicated in the genesis of ESCC had a missense variant segregating in three affected individuals in a single family. If validated in independent patient sets, these variants could serve as a tool towards prevention and early diagnosis of ESCC.     

Treatment with Paracetamol Can Interfere with the Intradialytic Optical Estimation in Spent Dialysate of Uric Acid but Not of Indoxyl Sulfate

Optical online methods are used to monitor the haemodialysis treatment efficiency of end stage kidney disease (ESKD) patients. The aim of this study was to analyse the effect of the administration of UV-absorbing drugs, such as paracetamol (Par), on the accuracy of optical monitoring the removal of uremic toxins uric acid (UA) and indoxyl sulfate (IS) during standard haemodialysis (HD) and haemodiafiltration (HDF) treatments. Nine patients received Par in daily dosages 1–4 g for 30 sessions. For 137 sessions, in 36 patients the total daily dosage of UV-absorbing drugs was less than 500 mg, and for 6 sessions 3 patients received additional UV-absorbing drugs. Par administration slightly affected the accuracy of optically assessed removal of UA expressed as bias between optically and laboratory-assessed reduction ratios (RR) during HD but not HDF employing UV absorbance of spent dialysate (p < 0.05) at 295 nm wavelength with the strongest correlation between the concentration of UA and absorbance. Corresponding removal of IS based on fluorescence at Ex280/Em400 nm during HD and HDF was not affected. Administration of UV-absorbing drugs may in some settings influence the accuracy of optical assessments in spent dialysate of the removal of uremic solutes during haemodialysis treatment of ESKD patients.     

Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine

Purpose

Drug delivery to the brain is impeded by the blood-brain barrier (BBB). Here, we attempted to enhance the brain uptake of cationic dopamine by utilizing the large amino acid transporter 1 (LAT1) at the BBB by prodrug approach.

Methods

Three amino acid prodrugs of dopamine were synthesized and their prodrug properties were examined in vitro. Their LAT1-binding and BBB-permeation were studied using the in situ rat brain perfusion technique. The brain uptake after intravenous administration and the dopamine-releasing ability in the rat striatum after intraperitoneal administration were also determined for the most promising prodrug.

Results

All prodrugs underwent adequate cleavage in rat tissue homogenates. The prodrug with phenylalanine derivative as the promoiety had both higher affinity for LAT1 and better brain uptake properties than those with an alkyl amino acid -mimicking promoiety. The phenylalanine prodrug was taken up into the brain after intravenous injection but after intraperitoneal injection the prodrug did not elevate striatal dopamine concentrations above those achieved by corresponding L-dopa treatment.

Conclusions

These results indicate that attachment of phenylalanine to a cationic drug via an amide bond from the meta-position of its aromatic ring could be highly applicable in prodrug design for LAT1-mediated CNS-delivery of not only anionic but also cationic polar drugs.     

Genital warts among 18- to 59-year-olds in the United States, national health and nutrition examination survey, 1999--2004

BACKGROUND: Genital warts are caused by human papillomavirus (HPV); over 90% are due to HPV types 6 and 11. We determined the percentage of persons who reported having been diagnosed with genital warts in the United States from 1999--2004. METHODS: We collected genital wart diagnosis history and sociodemographic and sexual behavior data from 8849 sexually active men and women aged 18 to 59 years as part of the National Health and Nutrition Examination Survey, 1999--2004. RESULTS: Overall, 5.6% of 18-to 59-year olds reported having ever been diagnosed with genital warts. The percentage was higher in women (7.2%, 95% CI, 6.2%-8.4%) than in men (4%, 95% CI, 3.2%-5.0%). History of genital wart diagnosis peaked among 25- to 34-year-old women (10.4%) and 35- to 44-year-old men (6.0%). Sex, age, race/ethnicity, number of lifetime sex partners, and cocaine/street drug use were associated with genital warts in multivariate analysis. CONCLUSIONS: These are the first national data on the burden of genital warts in the United States. The substantial burden of genital warts could be reduced by a prophylactic HPV vaccine to types 6 and 11.     

Magnetocardiographic indices of left ventricular hypertrophy

OBJECTIVE: We tested the hypothesis that multichannel magnetocardiographic (MCG) mapping can detect and quantify the degree of left ventricular hypertrophy (LVH). DESIGN: A cross-sectional study. SETTING: Helsinki University Central Hospital, a tertiary referral center. PARTICIPANTS: Forty-two patients with pressure overload induced LVH by gender-specific echocardiographic criteria (LVH group), and 12 healthy middle-aged controls. MAIN OUTCOME MEASURES: MCG QRS-T area integrals and QRS-T angle in magnetic field maps in relation to echocardiographic LVH as well as left ventricular (LV) mass and structure. Conventional 12-lead electrocardiographic (ECG) LVH indices (Sokolow-Lyon voltage, Cornell voltage, Cornell voltage duration product) were assessed for comparison. RESULTS: MCG QRS- and T-wave integrals provided complementary information of echocardiographic LV mass. Their combination, the QRS-T integral, and the QRS-T angle were increased in patients with LVH and, in those patients, correlated significantly with LV mass indexed to body surface area (r = 0.455;P = 0.002 and r= 0.379; P= 0.013, respectively). A QRS-T integral 16000 fT.s had identical sensitivity of 62% at 92% specificity as the gender-adjusted Cornell voltage duration product of 240 micro V.s for the detection of LVH. CONCLUSIONS: The MCG method can detect patients with LVH and also quantify the degree of LVH in patients with increased LV mass.     

Violence perpetration across peer and partner relationships: co-occurrence and longitudinal patterns among adolescents.

PURPOSE: To examine the co-occurrence and consistency over time of peer violence, sexual aggression, and dating violence among European American and Mexican-American adolescent boys and girls. METHODS: One-hundred-twelve girls and 135 boys who were either European American or Mexican-American were recruited from a large health maintenance organization. They were interviewed by telephone at baseline (at ages 16 to 20 years) and at one-year follow-up. Variable-centered and person-centered analyses examined the co-occurrence of violent behavior across domains, and whether adolescents who engaged in violent behavior at baseline also engaged in violent behavior during the following year. RESULTS: Results indicated that adolescent boys who engaged in violence in one domain were more likely to engage in violence in other domains during the same time period. Results for girls were less consistent. For boys but not girls, perpetration of either sexual aggression or peer violence was a significant predictor of the same behavior at follow-up. Person-centered analyses indicated that boys who perpetrated both peer violence and sexual aggression at baseline were most likely to perpetrate later violence. CONCLUSIONS: These results suggest that adolescent boys who engage in peer violence are also at risk for perpetrating sexual aggression or dating violence. Boys who perpetrate peer violence and sexual aggression are at high risk for later violence. Interventions with a dual focus on peer and partner violence may be valuable.     

Hemoglobin adducts of benzo[a]pyrene diolepoxide in newspaper vendors: association with traffic exhaust

Benzo[a]pyrene diol epoxide adducts with hemoglobin (Hb) weremeasured to detect human exposure to environmental benzo[a]pyrenefrom traffic exhaust. Benzo[a]pyrene tetrahydrotetrols (BPTs)released from Hb after acid hydrolysis were quantitated by gaschromatography-mass spectrometry after immunoaffinity chromatography.Fifty three newspaper vendors were enrolled. The median adductconcentration was 0.3 fmol BPTs/mg Hb in high density traffic-exposedvendors and     

Aryl hydrocarbon hydroxylase in lymphocytes and lung tissue from lung cancer patients and controls

The inducibility of aryl hydrocarbon hydroxylase (AHH) activity in peripheral mitogen-treated lymphocytes, and of AHH and other monoxygenase activities in lung samples, was studied in 41 patients--34 with pulmonary carcinoma, 4 with a benign lung tumour and 3 with chronic obstructive pulmonary disease. Lymphocyte AHH induction alone was studied in 43 non-smoking and 37 smoking surgical patients. Absolute induced and non-induced AHH activities were at about the same level in the lymphocytes from the lung cancer patients as in those from the non-smoking controls, whereas the activities in smoking controls were about 100% higher. The mean inducibility ratios were very similar in all groups, ranging from 4.4 in the benign tumour patients to 5.4 in both control groups. Thymidine incorporation was on average about 40% lower in the lymphocytes from the lung cancer patients. AHH activity was detectable in all the peripheral lung samples, both normal or tumorous tissue, and its inter-individual variation was more than 67-fold. ECDE activity was also detectable in all the samples studied and its correlation with AHH activity was statistically significant (r = 0.888), suggesting that the same enzyme metabolizes both substrates. ERDE was detectable only in the samples with the highest AHH and ECDE activities. There was no correlation between basal or induced lymphocyte AHH activities and lung tissue AHH activity, but there were statistically significant correlations between lung AHH activity and the inducibility ratio with (r = 0.618) or without correction by thymidine incorporation (r = 0.442). These correlations suggest that there are common regulatory factors for AHH inducibility in different tissues. No significant difference in any drug metabolism parameter measured was observed between the lung cancer patients and the controls.     

Extraperitoneal approach for repair of inflammatory abdominal aortic aneurysm

Inflammatory abdominal aortic aneurysms are characterized by dense perianeurysmal fibrosis involving the adjacent organs. Attempts to isolate the aneurysm can lead to operative injuries of these structures, thus increasing the rates of complications and mortality. In the last 12 years 45 patients with inflammatory abdominal aortic aneurysms underwent aneurysm resection at the Department of Vascular Surgery of the University of Rome. The aneurysm was resected through a standard, midline transperitoneal approach in 39 patients, through a thoracophrenolaparotomy in two patients, and through a left-flank extraperitoneal approach in the last four patients. The extraperitoneal approach simplified aneurysm dissection and aortic clamping with no cases of postoperative morbidity or death. In addition, we reviewed the CT scan findings of 12 patients surgically treated for inflammatory abdominal aortic aneurysm. The amount of fibrosis in the anterior wall of the aneurysm was greater than in the left posterolateral aspect (p = 0.008). We conclude that the left-flank extraperitoneal approach is the most anatomically advantageous route for repair of inflammatory abdominal aortic aneurysm.