Acceptability of self-sampling and human papillomavirus testing among non-attenders of cervical cancer screening programs in El Salvador.

In a cross-sectional study carried out in El Salvador between February 2016 and July 2017, self-sampling and human papillomavirus (HPV) testing was found to be highly acceptable among 2019 women who had not attended a cervical cancer screening in at least 3 years. Within this population, HPV positivity rates differed according to age, marital status, number of children, and lifetime sexual partners. The proportion of women who tested HPV positive or who were diagnosed with cervical intraepithelial neoplasia grade 2 (CIN2) or more severe diagnoses (CIN2+) was similar to the general population of the area. Among the reasons for failing to participate in previous screening programs, non-attending women described logistic concerns, but also erroneous beliefs regarding HPV and cervical cancer, misconceptions regarding the screening procedure, discomfort with male providers, and confidentiality fears. The aim of this study was to identify opportunities and challenges that emerged from the use of self-sampling and HPV testing as part of a public cervical cancer control effort in a low-resource setting.

A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results.

The effective management of women with human papillomavirus (HPV)-positive, cytology-negative results is critical to the introduction of HPV testing into cervical screening. HPV typing has been recommended for colposcopy triage, but it is not clear which combinations of high-risk HPV types provide clinically useful information. This study included 18,810 women with Hybrid Capture 2 (HC2)-positive, cytology-negative results and who were age ≥30 years from Kaiser Permanente Northern California. The median follow-up was 475 days (interquartile range [IQR], 0 to 1,077 days; maximum, 2,217 days). The baseline specimens from 482 cases of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and 3,517 random HC2-positive noncases were genotyped using 2 PCR-based methods. Using the case-control sampling fractions, the 3-year cumulative risks of CIN3+ were calculated for each individual high-risk HPV type. The 3-year cumulative risk of CIN3+ among all women with HC2-positive, cytology-negative results was 4.6%. HPV16 status conferred the greatest type-specific risk stratification; women with HC2-positive/HPV16-positive results had a 10.6% risk of CIN3+, while women with HC-2 positive/HPV16-negative results had a much lower risk of 2.4%. The next most informative HPV types and their risks in HPV-positive women were HPV33 (5.9%) and HPV18 (5.9%). With regard to the etiologic fraction, 20 of 71 cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma in the cohort were positive for HPV18. HPV16 genotyping provides risk stratification useful for guiding clinical management; the risk among HPV16-positive women clearly exceeds the U.S. consensus risk threshold for immediate colposcopy referral. HPV18 is of particular interest because of its association with difficult-to-detect glandular lesions. There is a less clear clinical value of distinguishing the other high-risk HPV types.

Plasma cytokine levels and human papillomavirus infection at the cervix in rural Nigerian women.

INTRODUCTION: We conducted a study to test the hypothesis that systemic dysregulation of Th1/Th2 cytokine levels was associated with detection of carcinogenic or overall human papillomavirus (HPV) at the cervix among 964 women residing in a rural village in Nigeria. METHODS: Levels in plasma were measured for 19 cytokines, including Th1-like cytokines IL-2, IL-12 (p40), TNF-a, IFN-g; Th2-like cytokines IL-4, IL-5, IL-6, IL-10, IL-13; innate/inflammation cytokines IL-1a, IL-1b, IL-8, eotaxin, MCP-1, MIP-1a, and IL-7; and cell development cytokines G-CSF, VEGF, and IL-17. Analysis was restricted to 5 cytokines, TNF-α (Th1), IL-8 (Th2), eotaxin and MCP-1 (innate/inflammation), and G-CSF (cell development), whose levels were detected in 80% or more of the samples measured as well as had a coefficient of variation of <30%. RESULTS: Strong correlations were noted between levels of eotaxin and TNF-α (r=0.75), IL-8 and MCP-1 (r=0.60), eotaxin and G-CSF (r=0.44), and G-CSF and IFN-γ (r=0.43). Detection of carcinogenic or non-carcinogenic HPV DNA was unrelated to cytokine levels, except for levels of eotaxin and TNF-α, which were inversely correlated, albeit weakly, with detection of any carcinogenic HPV (P=0.048 and P=0.067, respectively). In analyses stratified by age group, levels of eotaxin were inversely correlated with detection of any HPV DNA (P=0.026) and carcinogenic HPV (P=0.042) in older, but not younger, women. CONCLUSIONS: Our results do not support the hypothesis of association between systemic cytokine dysregulation and detection of HPV at the cervix in Nigerian women, but subgroup analyses raise questions about inverse associations between eotaxin and TNF-α in older women.

Morphine-induced spinal cholinergic activation: in vivo imaging with positron emission tomography.

Positron emission tomography (PET) imaging of spinal cord in monkeys with a cholinergic tracer demonstrates increased spinal cholinergic activity in response to an analgesic dose of morphine, and this PET result correlates with measurement of acetylcholine spillover into spinal cord extracellular space induced by morphine, as measured by microdialysis. Previous studies in rats, mice, and sheep demonstrate activation of spinal cholinergic neurons by systemic opioid administration, and participation of this cholinergic activity in opioid-induced analgesia. Testing the relevance of this observation in humans has been limited to measurement of acetylcholine spillover into lumbar cerebrospinal fluid. The purpose of this study was to apply a recently developed method to image spinal cholinergic terminals non-invasively via PET and to test the hypothesis that the tracer utilized would reflect changes in local cholinergic activity. Following Animal Care and Use Committee approval, seven adult male rhesus monkeys were anesthetized on three separate occasions. On two of the occasions PET scans were performed using [(18)F] (+)-4-fluorobenzyltrozamicol ([(18)F]FBT), which selectively binds to the vesicular acetylcholine (ACh) transporter in the presynaptic cholinergic terminals. PET scans were preceded by injection of either saline or an analgesic dose of IV morphine (10 mg/kg). On the third occasion, microdialysis catheters were inserted in the spinal cord dorsal horn and acetylcholine concentrations in dialysates determined before and after IV morphine injection. Morphine increased cholinergic activity in the spinal cord, as determined by blood flow corrected distribution volume of [(18)F]FBT in the cervical cord compared to the cerebellum. Morphine also increased acetylcholine concentrations in microdialysates from the cervical cord dorsal horn. The one animal which did not show increased spinal cholinergic activity by PET from this dose of morphine also did not show increased acetylcholine from this morphine dose in the microdialysis experiment. These data confirm the ability to use PET to image spinal cholinergic terminals in the monkey spinal cord and suggest that acute changes in cholinergic activity can be imaged with this non-invasive technique. Following preclinical screening, PET scanning with [(18)F]FBT may be useful to investigate mechanisms of analgesic action in normal humans and in those with pain.

Breath concentration as an index of the health risk from benzene. Studies on the accumulation and clearance of inhaled benzene.

Human subjects were exposed to known concentrations of benzene in air for single and repeated daily periods. The breath concentrations measured repeated exposures approached a maximum after 3 d, and this phenomenon indicated that the tissues were approaching saturation under the experimental conditions. The breath concentrations measured after exposure indicated an initial rapid clearance of benzene with a half-time of 2.6 h, followed by a slower phase with a half-time of 24 h. The decay in breath concentration after prolonged occupational exposure appeared to be slower; the difference between the laboratory and industrial studies was, however, not significant. The hygienic significance of these results was discussed, and it was recommended that control measures be employed when a morning breath concentration exceeds 10 ppb.

The action of paraquat and diquat on the respiration of liver cell fractions.

1. Paraquat and diquat produce only a slight increase in the oxygen uptake of rat liver mitochondria, and it is likely that they do not penetrate the mitochondrial membrane. 2. In mitochondrial fragments inhibited by antimycin A or by Amytal, both substances stimulate oxygen uptake with NADH or beta-hydroxybutyrate as substrate but not with succinate. The NADH dehydrogenase of the respiratory chain appears to be involved, at a site only partially inhibited by Amytal. 3. An NADPH oxidase activity is stimulated in rat liver microsomes by diquat, and to a smaller extent by paraquat; diquat also causes an NADH oxidase activity to develop. The effect is not inhibited by carbon monoxide or p-chloromercuribenzoate, and it is probable that a flavoprotein is involved by a mechanism not requiring thiol groups. 4. One molecule of oxygen can oxidize two molecules of NADPH in the stimulated microsomal system, the hydrogen peroxide produced being broken down by a catalase activity in the microsomes. 5. Diquat can stimulate NADH oxidase and NADPH oxidase activity in the postmicrosomal soluble fraction; the enzyme involved may be DT-diaphorase. 6. The mechanism of these reactions and their significance in relation to the toxicity of the dipyridilium compounds are discussed.

Pathogenesis of ethanol-induced hydronephrosis and hydroureter as demonstrated following in vivo exposure of mouse embryos.

Urinary tract abnormalities have been noted to occur in 10-27% of individuals diagnosed as having Fetal Alcohol Syndrome. Among a wide range of functional and structural abnormalities, renal agenesis/hypoplasia, hydronephrosis, and ureteropelvic obstruction feature most prominently. This study was designed to examine the pathogenesis of ethanol-induced urinary tract abnormalities in a mouse model. C57Bl/6J mice were acutely exposed to two doses of ethanol (2.9 g/kg IP) administered 4 hours apart beginning on gestational day (GD) 9, hour 4. This resulted in an incidence of 40.7% urinary tract anomalies among GD18 fetuses. With the exception of duplicate ureter, urinary tract abnormalities consisted exclusively of hydroureter/hydronephrosis. Examination of GD13-17 fetuses revealed that the first grossly detectable differences in the urinary tracts of control vs. affected specimens occurred on GD16 and initially only involved ureteral changes. Hydronephrosis was first detected on GD17. A contributing factor to the development of hydronephrosis appears to be the abnormal location of the ureterovesicle junction which commonly involves duplicate ureteral lumens with resultant functional obstruction to urine flow at the distal end of the ureter. Study of the early pathogenetic changes which appear to result in the urinary tract malformations observed involved utilization of scanning electron microscopy, vital dye (Nile blue sulphate) staining of whole embryos, and analysis of histological sections. These studies revealed that 12 hours following initial maternal ethanol exposure, embryos have excessive amounts of cell death localized in the region of the developing mesonephric duct just proximal to the cloaca. Also affected were premigratory neural crest cells located just proximal to the posterior neuropore. We conclude that excessive amounts of ethanol-induced cell death in these selectively vulnerable populations could account for the subsequently observed urinary tract malformations.

The metabolism of 3,5-di-tert.-butyl-4-hydroxytoluene in the rat and in man.

1. The major metabolites of 3,5-di-tert.-butyl-4-hydroxytoluene (BHT) in the rat are 3,5-di-tert.-butyl-4-hydroxybenzoic acid (BHT-acid), both free (9% of the dose) and as a glucuronide (15%), and S-(3,5-di-tert.-butyl-4-hydroxybenzyl)-N-acetylcysteine. 2. The mercapturic acid does not appear to derive from the usually accepted enzyme mechanism, and may involve a non-enzymic reaction between BHT free radical and cysteine. 3. The ester glucuronide and mercapturic acid found in rat urine are also the major metabolites in rat bile and must be responsible for the enterohepatic circulation. 4. Free BHT-acid is the main component in rat faeces. 5. In man, BHT-acid, free and conjugated, is a minor component in urine, and the mercapturic acid is virtually absent. The bulk of the radioactivity is excreted as the ether-insoluble glucuronide of a metabolite in which the ring methyl group and one tert.-butyl methyl group are oxidized to carboxyl groups, and a methyl group on the other tert.-butyl group is also oxidized, probably to an aldehyde group. 6. These differences in metabolism by the rat and by man are sufficient to account for the difference in excretion by the two species.

The metabolism of methoxyethylmercury salts.

The metabolism of methoxy[(14)C]ethylmercury chloride in the rat has been investigated. After a single subcutaneous dose a small proportion is excreted unchanged in urine and a larger amount in bile with some resorption from the gut. The greater part of the dose is rapidly broken down in the tissues with a half-time of about 1 day to yield ethylene and inorganic mercury. Ethylene is exhaled in the breath and the mercury migrates to the kidney and is excreted in urine. A small proportion of the dose appears as carbon dioxide in the breath and about 12% in urine as a mercury-free metabolite. It is possible that the breakdown of methoxyethylmercurychloride to ethylene and inorganic mercury is not catalysed by an enzyme system.

The metabolism of phenylmercury by the rat.

The metabolism of [U-(14)C]phenylmercury acetate was studied in the rat. After a single subcutaneous dose a small proportion is excreted unchanged in urine, and a larger amount in bile with some resorption from the gut. The greater part of the dose is broken down in the tissues to yield inorganic mercury which is excreted mainly in faeces, and conjugates of phenol and quinol are excreted in urine. In experiments in vitro phenylmercury is broken down by liver homogenates to release inorganic mercury and benzene; this reaction is effected by the soluble, but not the microsomal, fraction and does not require NADPH or NADH. No elemental mercury is formed under these conditions. It is probable that this reaction occurs in vivo and the benzene produced is rapidly converted into phenol and quinol by microsomal enzymes.

Does dextrose affect analgesia or the side effects of intrathecal sufentanil?

UNLABELLED: Intrathecal (i.t.) sufentanil provides rapid effective pain relief for early labor, but it also produces undesirable side effects, which may be primarily related to cephalad spread. Although the combination of dextrose and positioning the patient head-up limits the spread of other spinally administered drugs, these factors have not been examined in laboring women receiving i.t. sufentanil. We hypothesized that the addition of dextrose to i.t. sufentanil injected with women in the sitting position would limit cephalad spread and side effects. Sixty-six healthy nulliparous parturients in early labor were randomized to receive 2-mL i.t. injections of sufentanil 10 micrograms plus saline with patients in either the lateral decubitus or sitting position, sufentanil 10 micrograms plus dextrose 7.5% with patients in either the lateral decubitus or sitting positions, or plain dextrose 7.5%. Pain scores using a 10-cm visual analog pain scale, sensory block height, and side effects were recorded. Dextrose 7.5% did not affect cephalad spread, as measured by block height to pin testing, but it did significantly reduce the duration of analgesia and the incidence of pruritus from i.t. sufentanil administered to patients in the sitting position compared with patients in the lateral position. In contrast, patient position had no effect on analgesia or side effects in patients receiving i.t. sufentanil in saline. I.t. dextrose alone had no effect. IMPLICATIONS: The authors conclude that the addition of dextrose to intrathecal sufentanil injected into patients in the sitting position reduces the duration of analgesia without significantly reducing side effects with the exception of pruritus, and therefore does not improve the clinical utility of intrathecal sufentanil.

In vivo imaging of the spinal cord cholinergic system with PET.

PURPOSE: Our goal was to demonstrate the feasibility of an in vivo noninvasive method for imaging spinal cord cholinergic terminals using (+)-4-[18F]fluorobenzyltrozamicol ([18F]FBT) and PET. METHOD: In vitro and in vivo experiments in rats were conducted to demonstrate the specific binding characteristics, localization, and time course of [3H]FBT binding in the spinal cord. PET imaging was then performed on seven rhesus monkeys. RESULTS: The rat studies demonstrate high specific binding in the spinal cord with a distribution coinciding with the known distribution of cholinergic terminals. In vivo tracer concentrations in the spinal cord and basal ganglia were of the same magnitude. With use of [18F]FBT and PET in the rhesus monkey, the spinal cord was clearly visualized, with tracer concentration in the spinal cord being approximately one-fourth of that seen in the basal ganglia. CONCLUSION: This work demonstrates the feasibility of imaging cholinergic terminals in vivo in the spinal cord using [18F]FBT and PET.