Toxicokinetics of Organic Solvents: A Review of Modifying Factors

This article reviews, with an emphasis on human experimental data, factors known or suspected to cause changes in the toxicokinetics of organic solvents. Such changes in the toxicokinetic pattern alters the relation between external exposure and target dose and thus may explain some of the observed individual variability in susceptibility to toxic effects. Factors shown to modify the uptake, distribution, biotransformation, or excretion of solvent include physical activity (work load), body composition, age, sex, genetic polymorphism of the biotransformation, ethnicity, diet, smoking, drug treatment, and coexposure to ethanol and other solvents. A better understanding of modifying factors is needed for several reasons. First, it may help in identifying important potential confounders and eliminating negligible ones. Second, the risk assessment process may be improved if different sources of variability between external exposures and target doses can be quantitatively assessed. Third, biological exposure monitoring may be also improved for the same reason.     

Laypeople Blog About Fruit and Vegetables for Self-Expression and Dietary Influence

Private health information websites run by laypeople are more often visited than websites of official agencies. Understanding the role of weblogs in dietetic communication—i.e., sharing personal perceptions on healthy eating—is still lacking. This study aims to describe the nature of noncommercial Swedish blogs with fruits and vegetables (F&V)-related content and to identify different blogger types. A qualitative content analysis with abduction was performed on 50 weblogs. Most bloggers presented themselves as women. Only one-third reported their age (range 17 to over 50 years). The bloggers had either an active or passive influential purpose, and they approached F&V through either lived or mediated experiences. From these two dimensions, four F&V blogger ideal types were identified: the Persuader, the Authority, the Exhibitionist, and the Mediator. Particularly women wrote about their lived experiences close to the personal level, whereas men were more equally distributed across the different ideal types. Self-expression (typical for the Exhibitionist) and purpose to influence others' diets (typical for the Persuader and the Authority) were frequently expressed in these weblogs. The current findings on blogging purposes, approaches, and F&V blogger types may help to improve online dietetic communication, which sets new challenges for media strategies of health and nutritional professionals.     

Soluble transferrin receptor: longitudinal assessment from pregnancy to postlactation

OBJECTIVE: To assess the impact of pregnancy and lactation on iron status and erythropoiesis as measured by the soluble transferrin receptor (sTfR). METHODS: We recruited women in early pregnancy to be followed for 2 years. We determined sTfR and sTfR/serum ferritin (sTfR/Fer) during puerperium (n = 77), lactation (n = 111), and postlactation (n = 57), with comparison to data obtained during pregnancy (n = 224). Data were evaluated using analysis of variance for repeated measures as the women continuing the study were found to be representative of those entering the study. RESULTS: We found that sTfR and sTfR/Fer were significantly higher at all sampling occasions compared with early pregnancy (P <.001). Iron status markers did not regain first-trimester levels postpartum. Postlactation, 20% of the women had depleted iron stores (sTfR/Fer greater than 500), and 10% had tissue iron deficiency (sTfR greater than 8.3 mg/L). Iron status worsened with increasing parity and was significantly correlated to blood loss at delivery. In a subgroup of women with persistent adequate iron stores, first-trimester sTfR was similar to that in the puerperium but significantly lower than that postlactation. Cord sTfR (n = 32) was twice maternal sTfR and not correlated to maternal serum ferritin, gestational age, or other birth variables. CONCLUSION: Our data show decreased erythropoiesis in early gestation and during the first week of the puerperium. To prevent a negative effect of childbearing on iron status, postpartum iron supplementation should be considered in women who bleed excessively at parturition and in those who choose to take a low dose of iron or none at all during pregnancy.     

Clinical aspects of acute intermittent porphyria in northern Sweden: A population-based study

The objective of this study was to update the clinical issues of acute intermittent porphyria (AIP), as they have not been in focus for years, and to be aware of potentially associated disorders and social consequences. A total of 356 gene carriers of AIP from northern Sweden participated in this retrospective population-based study. Eight mutations were found with a predominance of W198X (89%). Clinical manifestations of AIP (manifest AIP) were identified in 42%, 65% were women. Women were more severely stricken by AIP attacks concerning number and duration, hospital admission and early onset. Men reporting most attacks were > 40 years of age. In addition to traditional symptoms during attacks, fatigue was commonly described. Chronic AIP symptoms and disability pension due to AIP were reported in about 20% of subjects. Precipitating factors were reported with evident sex differences. Half of the gene carriers who were on medications used drugs considered not safe (in 1999), mainly antihypertensive drugs. Smoking was associated with high AIP attack frequency. Elevated levels of ALT, bile acids, creatinine, U-ALA and U-PBG and decreased levels of creatinine clearance were associated with manifest AIP. The same was true for hypertension and myalgia in the legs. Hepatoma was strikingly overrepresented. The high prevalence of manifest AIP in this study could be explained by a mutation-dependent penetrance. Our results emphasize the importance of early diagnosis, counselling and treatment of attacks, screening and treatment of associated disorders.     

Magnetic resonance imaging flowmetry demonstrates portal vein dilatation subsequent to oxaliplatin therapy in patients with colorectal liver metastasis

Objectives

Sinusoidal injury (SI) after oxaliplatin-based therapies for colorectal liver metastasis (CRLM) can increase postoperative morbidity. Preoperative methods to estimate SI are lacking. The aim of this study was to identify SI by evaluating portal vein haemodynamics.

Methods

Magnetic resonance imaging flowmetry (MRIF) was used to estimate portal vein haemodynamics in 29 patients with CRLM before liver surgery. Sinusoidal injury was evaluated from resected non-tumorous liver parenchyma according to the combined vascular injury (CVI) score of ≥3.

Results

All patients with SI (six of 29) received oxaliplatin; however, a significant association could not be proven (P= 0.148). Oxaliplatin-treated patients showed portal vein dilatation in both the SI and non-SI groups compared with patients who had not received oxaliplatin (Bonferroni corrected P= 0.003 and P= 0.039, respectively). Mean portal velocity tended to be lower in patients with SI compared with oxaliplatin-treated patients without SI (Bonferroni corrected P= 0.087). A mean portal velocity of ≤14.35 cm/s together with a cross-section area of ≥1.55 cm² was found to predict SI with sensitivity of 100% and specificity of 78%.

Conclusions

Oxaliplatin treatment was associated with portal vein dilatation. Patients with SI showed a tendency towards decreased mean portal flow velocity. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma. Portal vein haemodynamic variables estimated by MRIF can identify patients without SI non-invasively.     

DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

We have previously shown that macaques vaccinated with DNA vectors expressing SIVmac239 antigens developed potent immune responses able to reduce viremia upon high-dose SIVmac251 challenge. To further improve vaccine-induced immunity and protection, we combined the SIVmac239 DNA vaccine with protein immunization using inactivated SIVmac239 viral particles as protein source. Twenty-six weeks after the last vaccination, the animals were challenged intrarectally at weekly intervals with a titrated dose of the heterologous SIVsmE660. Two of DNA-protein coimmunized macaques did not become infected after 14 challenges, but all controls were infected by 11 challenges. Vaccinated macaques showed modest protection from SIVsmE660 acquisition compared with naïve controls (P = 0.050; stratified for TRIM5α genotype). Vaccinees had significantly lower peak (1.6 log, P = 0.0048) and chronic phase viremia (P = 0.044), with 73% of the vaccinees suppressing viral replication to levels below assay detection during the 40-wk follow-up. Vaccine-induced immune responses associated significantly with virus control: binding antibody titers and the presence of rectal IgG to SIVsmE660 Env correlated with delayed SIVsmE660 acquisition; SIV-specific cytotoxic T cells, prechallenge CD4⁺ effector memory, and postchallenge CD8⁺ transitional memory cells correlated with control of viremia. Thus, SIVmac239 DNA and protein-based vaccine protocols were able to achieve high, persistent, broad, and effective cellular and humoral immune responses able to delay heterologous SIVsmE660 infection and to provide long-term control of viremia. These studies support a role of DNA and protein-based vaccines for development of an efficacious HIV/AIDS vaccine.     

Exposure to methyl isobutyl ketone: toxicokinetics and occurrence of irritative and CNS symptoms in man

The toxicokinetics as well as irritative effects and CNS symptoms of methyl isobutyl ketone (MIBK) were studied in human volunteers during inhalation exposure. The volunteers were exposed (2h, 50 W) in an exposure chamber on four different occasions to about 10, 100 and 200 mg/m3 MIBK and to a combination of about 100 mg/m3 MIBK and 150 mg/m3 toluene. The relative pulmonary uptake of MIBK was about 60% and the total uptake increased linearly with increasing exposure concentration. The concentration of MIBK in blood rose rapidly after the onset of exposure and no plateau level was reached during exposure. No tendency for saturation kinetics could be observed within the dose interval and the apparent blood clearance was 1.61/h/kg at all exposure levels. The concentration of unchanged MIBK in the urine after exposure was proportional with the total uptake. Only 0.04% of the total MIBK dose was eliminated unchanged via the kidneys within 3 h post exposure. The concentrations of the metabolites 4-hydroxy-4-methyl-2-pentanone and 4-methyl-2-pentanol were below the detection limit (5 nmol/l). Irritative and CNS symptoms occurred during exposure. The degree of both irritative and CNS symptoms increased during exposure to 100 and 200 mg/m3 compared with 10 mg/m3, but combination exposure with toluene exhibited the most pronounced effect. There were no significant effects from exposure on the performance of a simple reaction time task or a test of mental arithmetic.