Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients.

BACKGROUND: Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. PATIENTS AND METHODS: This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI Cmin) and 3-month PSA response. RESULTS: From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50-78]). In univariate analysis, ABI Cmin was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4-15.6) versus 8.0 ng/mL (CI 95% 5.8-11.6; P = 0.0015). In multivariate analysis, only ABI Cmin was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01-1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI Cmin was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI Cmin above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31-0.99], 12.2 [CI 95% 9.2-19.5] versus 7.4 [CI 95% 5.5-14.7] months otherwise, P = 0.044). CONCLUSIONS: We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients.

Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients.

BACKGROUND: Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib. METHODS: Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation. RESULTS: Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)<25 kg m(-2). Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25 kg m(-2) experienced more DLTs (P=0.01; odds ratio=4.1; 95% CI: (1.3-13.3)), more cumulative grade 2 or 3 toxicities (P=0.008), more grade 3 toxicities (P=0.04) and more acute vascular toxicities (P=0.009). CONCLUSION: Patients with sarcopenia and a BMI<25 kg m(-2) experienced significantly more DLTs during the first cycle of treatment.

Assessment of real-time PCR for quantification of Legionella spp. in spa water.

AIMS: Legionella bacteria ubiquitously colonize natural freshwater and are responsible for legionellosis in humans. Several cases of legionellosis have been associated in particular with the use of whirlpool spas. The objective of this study was to verify whether real-time PCR is applicable for the quantification of Legionella spp. in spa water. METHODS AND RESULTS: The study compared concentrations obtained by real-time PCR vs that obtained by conventional culture for 101 spa water samples. For the culture method, Legionella spp. were detected and quantified in 14 of 101 samples with measured concentrations ranging from 250 to 3.5 × 10(5) CFU l(-1). With the real-time PCR method, Legionella spp. were detected and quantified in 42 of 101 samples with concentrations ranging from 1000 to 6.1 × 10(7) GU l(-1). Results revealed a significant but weak correlation (r(2) = 0.1867) between the two methods. The positive predictive value (35%) of the PCR method compared to conventional culture herein was low. In contrast, the negative predictive value was excellent, reaching 93%. CONCLUSIONS: Real-time PCR could be used as a screening tool to rapidly ascertain the absence of Legionella spp. in spa water. However, a positive result involves the need to resort to conventional culture. SIGNIFICANCE AND IMPACT OF THE STUDY: Data of this study highlighted the pros and cons of quantification of Legionella spp. in spa water with real-time PCR using a commercial quantitative PCR kit in a routine laboratory, when compared to conventional culture.

A history of biological disasters of animal origin in North America.

This paper examines past occurrences in North America relevant to the possibility of biological disasters with animal origins. With respect to naturally occurring animal disease outbreaks, North America, while not as adversely affected by epizootics as other regions, has had its fair share of such outbreaks of both 'traditional' and emerging animal diseases. The traditional category includes such diseases as anthrax, classical swine fever, bluetongue, brucellosis, foot and mouth disease, and the family of equine encephalomyelitis viruses. The emerging diseases include relatively more recent culprits such as postweaning multisystemic wasting syndrome, poultry enteritis mortality syndrome, and newly discovered examples of the transmissible spongiform encephalopathies. Additionally, several serious diseases of human beings that involve animal vectors or reservoirs occur naturally in North America or have emerged in recent decades; these include plague, hantavirus, monkeypox, West Nile virus and avian-derived influenza. At the same time, there have been very few intentional attacks on livestock using biological agents and no recorded cases in North America of animals intentionally being used to transmit disease to humans. According to the historical record, therefore, naturally occurring emerging zoonoses probably constitute the greatest threat in terms of biological disasters with animal origins. However, some of the general trends in terrorist activity, such as the intensification of activities by animal rights extremists against facilities undertaking animal research, mean that the possibility of intentional animal-related biological disasters should not be discounted.

Two cases of systemic Candida glabrata infection following in vitro fertilization and embryo transfer.

Presented here are two cases of systemic Candida glabrata infection diagnosed in two expectant mothers and their fetuses at 34 and 22 weeks' gestation. The underlying risk factors in case 1 were in vitro fertilization and embryo transfer, recurrent yeast vaginitis and two intravenous injections of betamethasone. The risk factors in case 2 were in vitro fertilization and embryo transfer, recurrent yeast vaginitis, antibiotics for treatment of a urinary tract infection due to Morganella morganii and amniocentesis. In both cases, vaginal fluid yielded growth of a yeast that was not identified. Candida glabrata was isolated from samples obtained from the mothers and their babies. Since Candida glabrata lacks hyphae, membranitis and infection of the fetuses were demonstrated only on slides stained with Gomori Grocott and periodic acid-Schiff. Both cases suggest that for such pregnancies the follow-up of vaginal fluid should include the identification of any yeasts grown on selective Candida medium. In case of premature rupture of membranes, systematic sampling of mothers and their infants or fetuses should be associated with microscopic study of placentas, membranes and stillborn fetuses with Gomori Grocott and periodic acid-Schiff staining techniques.

Expression of wild-type pinB sequence in transgenic wheat complements a hard phenotype.

Wheat grain hardness is a major factor in the wheat end-product quality. Grain hardness in wheat affects such parameters as milling yield, starch damage and baking properties. A single locus determines whether wheat is hard or soft textured. This locus, termed Hardness ( Ha), resides on the short arm of chromosome 5D. Sequence alterations in the tryptophan-rich proteins puroindoline a and b (PINA and PINB) are inseparably linked to hard textured grain, but their role in endosperm texture has been controversial. Here, we show that the pinB-D1b alteration, common in hard textured wheats, can be complemented by the expression of wild-type pinB-D1a in transformed plants. Transgenic wheat seeds expressing wild-type pinB were soft in phenotype, having greatly increased friabilin levels, and greatly decreased kernel hardness and damaged starch. These results indicate that the pinB-D1b alteration is most likely the causative Ha mutation in the majority of hard wheats.

Low national breast and cervical cancer-screening rates in American Indian and Alaska Native women with diabetes.

BACKGROUND: The cervical cancer mortality rate for American Indian and Alaska Native women is twice that of all races in the United States. To date the only published national breast and cervical cancer-screening rates for American Indian and Alaska Native women are based on self-reported data. When the Indian Health Service (IHS) conducts an annual audit on patients with diabetes, it includes cancer screening. This observational study presents national breast and cervical cancer-screening rates for American Indian and Alaska Native women with diabetes. METHODS: Cancer-screening rates were extracted from the 1995 diabetic audit for the 12 IHS areas. These rates were compared with rates for women without diabetes of the same age, 50 to 69 years, by chart review, at four IHS hospitals in the Aberdeen IHS area. RESULTS: Screening rates for women with diabetes in the 12 areas varied: mammogram (ever) 35% to 78%; clinical breast examination (last year) 28% to 70%, and Papanicolaou smear (last year) 26% to 69%. The Aberdeen IHS area women with diabetes had 51% more clinic visits per year than women without diabetes, but the groups had similar screening rates. CONCLUSION: Cancer-screening rates for American Indian and Alaska Native women vary by region. In the Aberdeen IHS area, women with diabetes had more visits (missed opportunities) but similar screening rates as women without diabetes. The diabetic audit could be used to monitor national IHS cancer-screening trends for women with diabetes and in the Aberdeen IHS area for all women aged 50 to 69 years.

Fetal distress increases interleukin-6 and interleukin-8 and decreases tumour necrosis factor-alpha cord blood levels in noninfected full-term neonates.

OBJECTIVE: To assess the influence of fetal distress on interleukin-1beta, interleukin-6, interleukin-8 and on tumour necrosis factor-alpha blood levels in noninfected full-term neonates. STUDY DESIGN: In a multicentre prospective study, cord blood samples were obtained at time of delivery from 234 noninfected full-term neonates for the purposes of measuring serum levels of interleukin-1beta, interleukin-6, interleukin-8 and tumour necrosis factor-alpha using immunoassays. Women were classified into four groups according to the mode of delivery (vaginal delivery or caesarean section) and the presence or absence of fetal distress. The role of labour was also investigated. RESULTS: No significant relationship was found between cytokine cord blood levels and the mode of delivery. Fetal distress was associated with an increase in interleukin-6 (P = 0.01) and interleukin-8 (P < 0.001) levels, and a decrease in tumour necrosis factor-alpha (P < 0.001). Labour was also associated with a significant increase in interleukin-6 and interleukin-8 cord blood levels (P = 0.01 and P < 0.001, respectively). CONCLUSION: Fetal distress and labour were each associated with elevated interleukin-6 and interleukin-8 cord blood levels in noninfected full term neonates while only fetal distress was associated with decreased tumour necrosis factor-alpha levels.

Changes in cerebrospinal fluid monoamine metabolites, tryptophan, and gamma-aminobutyric acid during the 1st year of life in normal infants. comparison with victims of sudden infant death syndrome.

Cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, homovanillic acid, tryptophan, and gamma-aminobutyric acid were measured using high-performance liquid chromatography in 102 infants during the 1st year of life (preterm and term neonates included). CSF levels are expressed versus corrected age (postnatal days - preterm days) which reflects the stage of maturity of the central nervous system. These results are compared to those obtained in CSF of 53 victims of sudden infant death syndrome (SIDS). All components were significantly higher in SIDS than in the age-matched control group. This increase does not seem to be an artefact related to death. Indeed, under the same conditions concerning postmortem time interval before CSF sampling and analysis, the levels are not significantly higher in infants who died from a known pathology than in living infants. Moreover, in living infants as regards a pathology such as asphyxia or hypoventilation in comparison with SIDS, similar profiles are observed in some neurotransmitters or metabolites. Other studies are necessary to explore further neurotransmission systems in SIDS.

Phonological skills of children with specific expressive language impairment (SLI-E): outcome at age 3.

Naturalistic speech samples of 29 3-year-olds diagnosed with specific expressive language delay (SU-E) were compared to those produced by 19 age-matched normally developing peers in order to determine their improvement in phonological skills since age 2, when Rescorla and Ratner (1996) studied them. Specifically, the groups were compared with regard to vocalization rate, verbalizations, fully intelligible utterances, phonetic inventories, percentages of consonants correct (PCC), phonological processes, and mean length of utterance (MLU). Results revealed that there was no significant difference between the groups in their numbers of vocalizations (as there had been at age 2), although there continued to be differences in their phonetic inventories, PCC scores, and overall intelligibility. These findings suggest that at age 2 the children with SU-E were not only less phonologically skilled but less talkative, whereas by age 3 they were equally vocal. Analysis of the phonetic inventories of the children demonstrated that for most consonants, the SLI-E group followed the some pattern of development as the comparison children, but more of the normally developing group had productive control of each consonant, consistent with findings of Rescorla and Ratner. There continued to be differences in intelligibility as measured by rates of verbalization (those utterances with at least one intelligible word) and fully intelligible utterances. Using these measures, we found that approximately half the SU-E children had caught up with their normally developing peers in terms of articulation, whereas half of them continued to be significantly delayed. Finally, although some of the late-bloomer group had caught up to the comparison children in language skills, as measured by MLU, many had not, suggesting that there was a tendency for the children to catch up in some articulation skills before catching up in language abilities.

Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes.

Erythrokeratodermias are a clinically heterogeneous group of rare autosomal dominant disorders of cornification with overlapping features including hyperkeratosis and erythema. We ascertained five extended pedigrees with different phenotypes for a linkage study. Three families presented with localized erythrokeratodermia variabilis, and one with erythrokeratodermia and ataxia. Another family had Greither disease associated with variable hyperkeratotic plaques. Despite their phenotypic differences, both erythrokeratodermia variabilis and erythrokeratodermia with ataxia map to a common region in 1p34-p35. Multipoint linkage and haplotype analyses place erythrokeratodermia variabilis between the marker D1S496 and D1S186 with a maximum LOD score of 12.88. Our linkage results provide compelling evidence for genetic homogeneity among families of mixed European and French-Canadian origin. In contrast, results excluded Greither's disease from the established erythrokeratodermia variabilis gene region indicating genetic heterogeneity of erythrokeratodermias. Based on recombinations, two genes assigned to 1p34-p35 were excluded: cartilage matrix protein and avian myelocytosis viral oncogene. Connexin-37 (GJA4), a member of the connexin gene family, maps within the erythrokeratodermia variabilis region and is an attractive candidate gene. Direct sequencing of the coding region of GJA4 in four patients revealed several variations, including a novel polymorphism within the 5' cytoplasmic domain, but no pathogenic mutations were found, thus excluding Connexin-37 as a candidate. There is evidence, however, that other epidermally expressed connexins cluster in this region, and one may yet be determined to play a role in the pathogenesis of erythrokeratodermia variabilis.

Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial.

BACKGROUND: Onychomycosis is an increasing problem with limited therapeutic options. OBJECTIVE: We evaluated the safety and efficacy, of oral terbinafine, a new fungicidal antimycotic, in patients with toenail onychomycosis. METHODS: A North American multicenter, double-blind, placebo-controlled study evaluated the mycologic and clinical efficacy of oral terbinafine 250 mg/day for 12 or 24 weeks in 358 patients with toenail onychomycosis. RESULTS: A total of 74% of patients treated with 12 or 24 weeks of terbinafine achieved a successful clinical outcome. Approximately 11% of terbinafine responders showed evidence of relapse 18 of 21 months after cessation of treatment. Terbinafine was well tolerated; most adverse events were transient and mild to moderate in severity. CONCLUSION: The results of this study confirm that oral terbinafine is a safe and effective therapy for the treatment of onychomycosis.

[Neonatal detection of central hypothyroidism]. / Hypothyroïdie centrale de découverte néonatale.

BACKGROUND: Congenital hypothyroidism is very rare compared to primary hypothyroidism. Its early diagnosis may escape neonatal mass screening using TSH assay. CASE REPORT: Anthony was born at 37 weeks, weighing 3,060 g. He presented with hypotony, jaundice, tongue protrusion evoking congenital hypothyroidism. Thyroid function tests favored hypothyroidism central in origin, while the systematic neonatal screening was normal. CONCLUSION: Clinical signs of congenital hypothyroidism must lead to more specific tests when neonatal screening is normal.

[Transitory hyperinsulinism with hypoglycemia in asphyxia neonatorum]. / Hyperinsulinisme transitoire avec hypoglycémie par asphyxie néonatale.

BACKGROUND: Hypoglycemia is a well-known complication in neonates small for gestational age and in those with diabetic mothers. Birth asphyxiated infants can develop severe hypoglycemia due to reduced glycogen stores. CASE REPORTS: The first patient was born at 41 weeks, weighing 3,780 g by emergency cesarean section because of fetal distress. He developed a pneumothorax and hypoglycemia. He was given glucose infusion (at day 4: 20 mg/kg/d). Hyperinsulinism was confirmed: blood levels at 18.3 mU/L on day 1 and 11.7 mU/L on day 2. The infusion rate was gradually decreased. The second patient was born at 39 weeks, weighing 2,780 g by emergency cesarean section because of fetal distress. She needed glucose infusion (24 g/kg/d) because of hypoglycemia with hyperinsulinism (12.8 mU/L on day 2 and 11.7 mU/L on day 3). After 5 days, the infusion of glucose was replaced by oral feeding only. CONCLUSION: Transient hypoglycemia in asphyxiated newborn infants with hyperinsulinism must be considered even when hypoglycemia may be difficult to prove.

[The CHARGE association]. / L'association CHARGE.

The CHARGE association is a polymalformative disease associating coloboma, heart disease, atresia of choanae, retarded growth and development, genital hypoplasia and ear anomalies, CHARGE being an acronym based on these different malformations. The diagnosis requires at least four of these malformations including necessarily coloboma and/or atresia of choanae. The various clinical aspects, the genetics and the therapeutics implications are described.

[Neonatal diabetes mellitus associated with an autoimmune disease]. / Diabète néonatal vrai associé à une maladie auto-immune.

BACKGROUND: Insulin-dependent diabetes mellitus can be associated to an auto-immune disease. A similar association may be seen in the neonate. CASE REPORT: A one-day-old boy was admitted for ketoacidosis due to diabetes mellitus. Investigation showed that he also suffered from an auto-immune enteropathy with several types of autoantibodies, particularly anti-enterocytes antibodies. Immunotherapy was ineffective. Multi-organ lesions developed subsequently, particularly a pulmonary disease responsible for the death at the age of 2 years. CONCLUSION: Physiopathology of this association remains unclear and the report of further cases should help improve our knowledge.