46 research outputs found
Utilization of multiparametric prostate magnetic resonance imaging in clinical practice and focal therapy: report from a Delphi consensus project
To codify the use of multiparametric magnetic resonance imaging (mpMRI) for the interrogation of prostate neoplasia (PCa) in clinical practice and focal therapy (FT). An international collaborative consensus project was undertaken using the Delphi method among experts in the field of PCa. An online questionnaire was presented in three consecutive rounds and modified each round based on the comments provided by the experts. Subsequently, a face-to-face meeting was held to discuss and finalize the consensus results. mpMRI should be performed in patients with prior negative biopsies if clinical suspicion remains, but not instead of the PSA test, nor as a stand-alone diagnostic tool or mpMRI-targeted biopsies only. It is not recommended to use a 1.5 Tesla MRI scanner without an endorectal or pelvic phased-array coil. mpMRI should be performed following standard biopsy-based PCa diagnosis in both the planning and follow-up of FT. If a lesion is seen, MRI-TRUS fusion biopsies should be performed for FT planning. Systematic biopsies are still required for FT planning in biopsy-naïve patients and for patients with residual PCa after FT. Standard repeat biopsies should be taken during the follow-up of FT. The final decision to perform FT should be based on histopathology. However, these consensus statements may differ for expert centers versus non-expert centers. The mpMRI is an important tool for characterizing and targeting PCa in clinical practice and FT. Standardization of acquisition and reading should be the main priority to guarantee consistent mpMRI quality throughout the urological communit
Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism
Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery
Fetal megacystis: a lot more than LUTO
ABSTRACT
Objective Fetal megacystis presents a challenge in terms
of counseling and management because of its varied
etiology and evolution. The aim of this study was to
present a comprehensive overview of the underlying
etiologies and structural anomalies associated with fetal
megacystis.
Methods This was a retrospective multicenter study of
cases referred to the fetal medicine unit of one of the eight
academic hospitals in The Netherlands with a diagnosis of
fetal megacystis. For each case, data on and measurements
of fetal urinary tract and associated structural anomalies
were collected. All available postmortem examinations
and postnatal investigations were reviewed in order to
establish the final diagnosis. In the first trimester, fetal
megacystis was defined as longitudinal bladder diameter
(LBD) ≥ 7 mm, and in the second and third trimesters as
an enlarged bladder failing to empty during an extended
ultrasound examination lasting at least 40 min.
Results Of the 541 pregnancies with fetal megacystis,
it was isolated (or solely accompanied by other signs
of lower urinary tract obstruction (LUTO)) in 360
(67%) cases and associated with other abnormal
ultrasound findings in 181 (33%) cases. The most
common associated ultrasound anomaly was an increased
nuchal translucency thickness (22%), followed by single
umbilical artery (10%) and cardiac defect (10%). A
final diagnosis was established in 418 cases, including
222 (53%) cases with isolated LUTO and 60 (14%)
infants with normal micturition or minor isolated
urological anomalies. In the remaining 136 (33%) cases,
concomitant developmental or chromosomal abnormality
or genetic syndrome was diagnosed. Overall, 40
chromosomal abnormalities were diagnosed, including
trisomy 18 (n = 24), trisomy 21 (n = 5), Turner syndrome
(n = 5), trisomy 13 (n = 3) and 22q11 deletion (n = 3).
Thirty-two cases presented with anorectal malformations
involving the anus, rectum and urogenital tract. In cases
with confirmed urethral and anal atresia, megacystis
occurred early in pregnancy and the bladder appeared
severely distended (the LBD (in mm) was equal to or
greater than twice the gestational age (in weeks)). Fetal
macrosomia was detected in six cases and an overgrowth
syndrome was detected in four cases, comprising two
infants with Beckwith–Wiedemann syndrome and two
with Sotos syndrome. Megacystis-microcolon-intestinal
hypoperistalsis syndrome was diagnosed in five (1%) cases
and prenatally suspected only in one case.
Conclusions Although the main cause of fetal megacystis
is LUTO, an enlarged fetal bladder can also be present
as a concomitant finding of miscellaneous genetic syndromes, developmental disturbances and chromosomal
abnormalities. We provide an overview of the structural anomalies and congenital disorders associated with fetal
megacystis and propose a practical guide for the differential diagnosis of genetic syndromes and chromosomal
and developmental abnormalities in pregnancies presenting with fetal megacystis, focusing on the morphological
examination of the fetus
Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei
A non-targeted metabolomics-based approach is presented that enables the study of pathways in response to drug action with the aim of defining the mode of action of trypanocides. Eflornithine, a polyamine pathway inhibitor, and nifurtimox, whose mode of action involves its metabolic activation, are currently used in combination as first line treatment against stage 2, CNS-involved, human African trypanosomiasis (HAT). Drug action was assessed using an LC-MS based non-targeted metabolomics approach. Eflornithine revealed the expected changes to the polyamine pathway as well as several unexpected changes that point to pathways and metabolites not previously described in bloodstream form trypanosomes, including a lack of arginase activity and N-acetylated ornithine and putrescine. Nifurtimox was shown to be converted to a trinitrile metabolite indicative of metabolic activation, as well as inducing changes in levels of metabolites involved in carbohydrate and nucleotide metabolism. However, eflornithine and nifurtimox failed to synergise anti-trypanosomal activity in vitro, and the metabolomic changes associated with the combination are the sum of those found in each monotherapy with no indication of additional effects. The study reveals how untargeted metabolomics can yield rapid information on drug targets that could be adapted to any pharmacological situation
Advances in structure elucidation of small molecules using mass spectrometry
The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules
Persistent fetal sinus bradycardia associated with maternal anti-SSA/Ro and anti-SSB/La antibodies
To study the clinical course and outcome of fetal sinus bradycardia (SB) due to maternal antibody-induced sinus node dysfunction. We reviewed the maternal, prenatal, and postnatal findings of fetuses with SB associated with elevated maternal anti-SSA/Ro and anti-SSB/La antibodies. Of the 6 cases diagnosed prenatally, 3 had isolated SB persisting after birth and had a good prognosis. Three fetuses with SB and severe myocardial involvement (congenital complete heart block and/or endocardial fibroelastosis) succumbed in utero in spite of treatment. Postmortem histopathology in 1 fetus showed inflammatory destruction of the sinus and atrioventricular nodes. SB was detected incidentally in a 7-year-old girl. She had intermittent heart block with progressive sinus arrest requiring permanent pacemaker. Fetal SB associated with maternal autoantibodies may persist in childhood, with a good prognosis in the absence of widespread cardiac involvemen
Outcome of isolated gastroschisis; an international study, systematic review and meta-analysis
To determine outcome of children born with isolated gastroschisis (no extra-gastrointestinal congenital abnormalities). International cohort study and meta-analysis. time to full enteral feeding (TFEF); secondary outcomes: Duration of mechanical ventilation, length of stay (LOS), mortality and differences in outcome between simple and complex gastroschisis (complex; born with bowel atresia, volvulus, perforation or necrosis). To compare the cohort study results with literature three databases were searched. Studies were eligible for inclusion if cases were born in developed countries with isolated gastroschisis after 1990, number of cases >20 and TFEF was reported. The cohort study included 204 liveborn cases of isolated gastroschisis. The TFEF, median duration of ventilation and LOS was, 26days (range 6-515), 2days (range 0-90) and 33days (range 11-515), respectively. Overall mortality was 10.8%. TFEF and LOS were significantly longer (P <0.0001) and mortality was fourfold higher in the complex group. Seventeen studies, amongst the current study, were included for further meta-analysis comprising a total of 1652 patients. Mean TFEF was 35.3±4.4days, length of ventilation was 5.5±2.0days, LOS was 46.4±5.2days and mortality risk was 0.06 [0.04-0.07 95%CI]. Outcome of simple and complex gastroschisis was described in five studies. TFEF, ventilation time, LOS were significant longer and mortality rate was 3.64 [1.95-6.83 95%CI] times higher in complex cases. These results give a good indication of the expected TFEF, ventilation time and LOS and mortality risk in children born with isolated gastroschisis, although ranges remain wide. This study shows the importance of dividing gastroschisis into simple and complex for the prediction of outcom