Thalidomide metabolites in mice and patients with multiple myeloma.

PURPOSE:This research examines the profile of metabolites of thalidomide that are formed in refractory multiple myeloma patients undergoing thalidomide therapy in comparison with those that are detected in healthy mice. EXPERIMENTAL DESIGN: Urine or plasma samples from patients during thalidomide therapy (100-400 mg daily), or from mice treated i.p. (100 mg/kg) or p.o. with thalidomide (50 mg/kg) were analyzed using liquid chromatography-mass spectrometry. Metabolites in each of the peaks observed in the UV- and mass spectrometry-detected high-performance liquid chromatography traces were identified by comparison of retention times and spectra with those of authentic standards. RESULTS: Plasma and urine samples from mice 4 h after treatment with thalidomide contained eight major metabolites formed by hydroxylation and/or hydrolysis of thalidomide. In contrast, urine samples from seven multiple myeloma patients at steady state levels of thalidomide therapy showed the presence of only three hydrolysis breakdown products and no hydroxylated metabolites. CONCLUSIONS: Our results show that thalidomide metabolite profiles in multiple myeloma patients differ considerably from those in mice. The lack of measurable hydroxylated metabolites in urine and in 1 case plasma of these patients suggests that such metabolites are not responsible for the therapeutic effects of thalidomide in multiple myeloma. We suggest that thalidomide may act directly, down-regulating growth factors essential for multiple myeloma growth.     

Review of Percutaneous Tracheostomy

The purpose of this study is to assess the safety and efficacy of the four known methods of percutaneous tracheostomy. Perioperative, postoperative, and late complication rates were generated for each method after a complete literature review identified 1684 percutaneous tracheostomy patients reported in 40 series. Two methods, the Toye and the guide wire dilator forceps (GWDF) methods, have been the subject of few investigations. Two other methods have been extensively studied. A high perioperative complication rate was calculated for the Rapitrac? method, whereas percutaneous dilational tracheostomy (PDT) has complication rates similar to those reported for standard operative tracheostomy. A retrospective review of 22 patients who underwent PDT at a local community hospital confirmed a “learning curve” for this technique that had been previously suggested. Review of the literature suggests that PDT can be safe and cost-effective for selected patients, but a learning curve for this technique exists that dictates caution, experience, and preparation on the part of any surgeon who wishes to add percutaneous tracheostomy to his or her repertoire.     

Changes in the expression of the type-2 but not the type-1 cyclo-oxygenase enzyme in chorion-decidua with the onset of labour

Objective To determine the relative expression of cyclo-oxygenase (COX)-1 and COX-2 in the chorion-decidual part of human fetal membranes following delivery at term and to identify any changes in expression associated with labour.
Methods Fetal membranes were collected from 12 term pregnancies before labour following elective caesarean section and from 12 spontaneous vaginal deliveries. Expression of COX-1 and COX-2 mRNA was measured using a previously validated quantitative RT-PCR assay.
Results COX-2 expression exceeded that of COX-1 by approximately eight-fold. COX1 expression did not change but COX-2 expression was found to increase four-fold with labour.
Conclusions Chorion-decidua has the capacity to contribute to the increase in prostaglandin synthesis within the uterus associated with labour. As in the amnion, it is COX-2 and not COX-1 which is upregulated with labour. COX-2 selective anti-prostaglandins should therefore be as effective as nonselective drugs in inhibition of fetal membrane prostaglandin synthesis.     

Technical advances in pediatric laparoscopy have had a beneficial impact on splenectomy

PURPOSE: The aim of this study was to demonstrate the effects of recent technical advances on the safety and benefits of pediatric laparoscopic splenectomy. METHODS: A retrospective review was conducted of patients undergoing laparoscopic splenectomy from January 1998 to January 2000. Technical advances utilized during this period included the harmonic scalpel, a specialized flexible hilar retractor, a larger, wire-rimmed specimen bag, and lateral patient positioning. RESULTS: Laparoscopic splenectomy was performed successfully on 18 patients aged 3 to 17 years (median, 9). The indications were hereditary spherocytosis (n = 10), idiopathic thrombocytopenic purpura (n = 5), and other (n = 3). Eight patients had concomitant procedures including cholecystectomy (n = 3), resection of an accessory spleen (n = 3), and other (n = 2). The median operating time, including the concomitant procedures, was 125 minutes (range, 70 to 235). Patients tolerated a regular diet on median postoperative day 1 (range, 1 to 3), and 16 were discharged home on or before postoperative day 2. None of the patients required blood product transfusion or conversion to an open technique. There were no complications, and all patients had returned to usual activity by 2 weeks. CONCLUSION: With recent technological advances, the laparoscopic approach has become easy to perform, safe, and should be considered the procedure of choice for pediatric splenectomy.     

Asymptomatic spondylodiscitis an unusual feature of ankylosing spondylitis

Six patients with ankylosing spondylitis were found to have asymptomatic spondylodiscitis. They have been followed for a mean of 17 years and have been free of symptoms or complications from this lesion. This benign asymptomatic course has not been stressed by previous authors.     

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS)

Background: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS.Objective: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA’s Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing.Methods: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement–only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata.Results: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams.Discussion: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343     

Distinct generation, pharmacology, and distribution of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate in human neural progenitor cells

In vivo and in vitro studies suggest a crucial role for Sphingosine 1-phosphate (S1P) and its receptors in the development of the nervous system. Dihydrosphingosine 1-phosphate (dhS1P), a reduced form of S1P, is an agonist at S1P receptors, but the pharmacology and physiology of dhS1P has not been widely studied. The mycotoxin fumonisin B1 (FB(1)) is a potent inhibitor of ceramide synthases and causes selective accumulation of dihydrosphingosine and dhS1P. Recent studies suggest that maternal exposure to FB(1) correlates with the development of neural tube defects (NTDs) in which the neural epithelial progenitor cell layers of the developing brain fail to fuse. We hypothesize that the altered balance of S1P and dhS1P in neural epithelial cells contributes to the developmental effects of FB(1). The goal of this work was first to define the effect of FB(1) exposure on levels of sphingosine and dh-sphingosine and their receptor-active 1-phosphate metabolites in human embryonic stem cell-derived neural epithelial progenitor (hES-NEP) cells; and second, to define the relative activity of dhS1P and S1P in hES-NEP cells. We found that dhS1P is a more potent stimulator of inhibition of cAMP and Smad phosphorylation than is S1P in neural progenitors, and this difference in apparent potency may be due, in part, to more persistent presence of extracellular dhS1P applied to human neural progenitors rather than a higher activity at S1P receptors. This study establishes hES-NEP cells as a useful human in vitro model system to study the mechanism of FB(1) toxicity and the molecular pharmacology of sphingolipid signaling. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.     

An algorithmic approach to diagnosis of hypoglycemia

An algorithm has been devised to facilitate the diagnostic approach to the causes of hypoglycemia. This systematic approach enables the physician to reach the final diagnosis in a logical way without subjecting the child to unnecessary and possibly hazardous investigations. The algorithm is based on the following measurements as required by each patient: concentrations of blood glucose, lactate, ketone bodies, and glucose-regulating hormones. These measurements are performed with the patient in the fasting state and after loading tests (glycerol and galactose) as needed. If indicated, an enzymatic test is performed to establish the final diagnosis. Eighteen children aged 1 month to 7 years who had persistent or recurrent hypoglycemia have been examined according to this algorithm. The correct diagnosis was arrived at in 17 patients. The diagnosis was not reached in one neonate who had glucose-6-phosphatase deficiency and initially did not have lactic acidosis; once lactic acidosis developed, his illness fitted perfectly into the algorithm.