Relationship between maternal methadone dosage and neonatal withdrawal

OBJECTIVE: To determine whether maternal methadone dosage affects duration and degree of neonatal narcotic withdrawal. METHODS: This was a retrospective cohort study of pregnant women with opioid addiction who delivered live-born singletons between April 1990 and April 2001. Inpatient detoxification or outpatient methadone maintenance therapy was offered. Women who had a positive drug screen or whose neonate tested positive for opioids were considered to be supplementing. We evaluated indices of neonatal withdrawal according to the maximum daily methadone dosage in the last week of pregnancy. RESULTS: Seventy women with opioid addiction were followed. Median methadone dosage was 20 mg (range 0-150 mg), and 32 infants (46%) were treated for narcotic withdrawal. Among women who received less than 20 mg per day, 20-39 mg per day, and at least 40 mg per day of methadone, treatment for withdrawal occurred in 12%, 44%, and 90% of infants, respectively (P < 0.02). Methadone dosage was also correlated with both duration of neonatal hospitalization and neonatal abstinence score (r(s) =.70 and.73 respectively, both P <.001). Neonates were more likely to experience withdrawal if their mothers were supplementing with heroin, 68% versus 35% (P =.01). Regardless of supplementation, there was a significant relationship between methadone dosage and neonatal withdrawal (P <.05). CONCLUSION: Maternal methadone dosage was associated with duration of neonatal hospitalization, neonatal abstinence score, and treatment for withdrawal. Heroin supplementation did not alter this dose-response relationship. In selected pregnancies, lowering the maternal methadone dosage was associated with both decreased incidence and severity of neonatal withdrawal.     

A phased consent policy for cord blood donation

This article focuses on ethical and policy questions concerning when consent may be sought for the collection and donation of cord blood. It reviews the advantages and disadvantages of alternative times for securing consent, challenges common objections to seeking consent during labor or after collection, and describes a phased consent process--a process that permits consent during early labor to the ex utero collection of cord blood followed by after-consent collection to donation. The phased consent policy attends to the unique characteristics of cord blood collection and donation, respects donors and their families, maximizes the number and diversity of cord blood units collected, preserves the relationship between providers and patients, and preserves public trust in cord blood and other types of tissue banking.     

Common peroneal nerve injuries: results with one-stage nerve repair and tendon transfer

The authors report their experience in the treatment of common peroneal nerve (CPN) injuries using a one-stage procedure of nerve repair and tibialis posterior tendon transfer. A series of 45 patients with traumatic injury and graft repair of the CPN is presented. From 1988 to 1991, the six patients elected for surgery had only nerve repair: five ultimately did not recover, while muscle contraction in the remaining patient was graded M1-2. Since 1991, nerve surgery in our clinic was associated with tendon transfer procedures (39 cases) which were followed by a satisfactory reinnervation rate. Nerve transection and iatrogenic injuries, torsion/dislocation of the knee, complex biosseous fractures of the leg, and gunshot wounds showed excellent to fair results in decreasing order: in nerve sections, muscle recovery scored M3 or M4+ in all the patients, and in nerve ruptures due to severe dislocation of the knee, it was M3 or M4+ in 85% of cases. The association of microsurgical nerve repair and tendon transfer has changed the course of CPN injuries.     

Effects of a saccharin and cyclamate mixture on rat embryos

Sodium saccharin (NaS) and calcium cyclamate (CaC) are artificial sweeteners widely used in food and drink. To evaluate their toxicological effects on preimplantation mammalian embryos, pregnant rats were gavaged with 1.65 mg NaS/kg bw + 3.85 mg CaC/kg bw (DI) or 6.6 mg NaS/kg bw + 15.4 mg CaC/kg bw (D2) on days 1, 2, 3 and 4 of pregnancy (positive vaginal smear = day 1). The female rats were killed on day 5 of the pregnancy (GD 5), maternal organs weighed, and the blastocysts collected, counted and evaluated for gross morphology, cell number and mitotic index. There was no alteration in maternal organ weights, but there was an increase of the cell number/embryo in the dams treated with that NaS + CaC mixtures (D1 = 37.20 +/- 7.96; D2 = 37.26 +/- 10.90) compared to control group (32.24 +/- 6.73). Embryos whose dams were exposed to NaS + CaC may have adapted for implantation into the uterus but more studies are needed to demonstrate this mechanism of action.     

Quality assurance in diagnostic radiology: practical outcomes

Over the last four years, our Health Physics Department has implemented a quality control programme focusing on the performance of the diagnostic X-ray machines in use at our hospital. The results of the tests performed (X-ray and light field alignment, tube voltage reproducibility and accuracy, ) were used to compare the 1999 and 2002 findings by means of the chi squared and Fischer statistical tests. The comparison has demonstrated that the decrease in the number of non-conformities, also emerging from a simple comparative analysis on the experimental data, was statistically significant with a p<0.05 for all of the X-ray machines examined. This finding confirms that our quality control programme had positive effects on the overall performance of the hospital diagnostic X-ray equipment, and appears to justify the resources employed for its implementation.     

Loss of inhibitor of apoptosis proteins as a determinant of polyamine analog-induced apoptosis in human melanoma cells

We have previously shown that the clinically relevant polyamine analog N1,N11-diethylnorspermine (DENSPM) causes rapid apoptosis in human melanoma SK-MEL-28 cells via a series of events that include mitochondrial release of cytochrome c and activation of the caspase cascade. Upstream to these events, DENSPM downregulates polyamine biosynthesis and potently upregulates polyamine catabolism at the level of spermidine/spermine N1-acetyltransferase (SSAT). In searching for downstream effectors that either contribute to or abrogate the apoptotic response, we observed that DENSPM treatment of SK-MEL-28 cells for 30 h led to cytosolic release of Smac/Diablo, a mitochondrial protein known to bind and inhibit the function of inhibitor of apoptosis proteins (IAPs). Subsequently, we found that DENSPM markedly lowered survivin and ML-IAP protein (but not XIAP) levels by 18 h via an apparently Smac/Diablo-independent pathway. Proteasome inhibitors fully prevented survivin and ML-IAP protein loss as well as apoptosis, suggesting that the proteasome-mediated degradation of survivin and ML-IAP is causally linked to the cellular outcome. We also observed that structural analogs of DENSPM which differentially induced SSAT and apoptosis lowered survivin and ML-IAP levels in a manner that correlated with enzyme activity. The linkage between IAPs and SSAT was more directly established by the finding that selective prevention of SSAT induction by small interfering RNA prevented survivin and ML-IAP loss as well as apoptosis during DENSPM treatment. Among the melanoma cell lines (SK-MEL-28, MALME-3M, A375 and LOX), survivin degradation correlated temporally with the onset of DENSPM induced apoptosis or growth inhibition. By contrast, ML-IAP degradation occurred only during rapid apoptosis seen in SK-MEL-28 cells. These data suggest a sequence of events whereby DENSPM induction of SSAT leads to loss of IAP proteins and a more fulminate apoptotic response. The findings implicate survivin and ML-IAP as important determinants of polyamine analog drug action in melanoma cells.     

A comparison of physical examination and imaging in determining the extent of primary penile carcinoma

OBJECTIVE: To determine the accuracy of physical examination and imaging in assessing the extent of the primary tumour in squamous cell carcinoma of the penis. PATIENTS AND METHODS: A physical examination, ultrasonography and magnetic resonance imaging (MRI) were used before surgery in 33 patients with penile carcinoma. The tumour size, infiltration of the penile structures and infiltration depth were assessed. The results were compared with the histopathological examination of the resected specimen. RESULTS: Tumour size was determined with the highest precision by the physical examination (residual sd of 8.1 mm); ultrasonography and MRI were less precise (residual sd 8.9 mm and 9.3 mm). In assessing infiltration depth, ultrasonography and MRI had comparable precision (residual sd 3.7 mm and 3.8 mm). The positive predictive value of corpus cavernosum infiltration was 6/6 for physical examination, 4/6 for ultrasonography and 6/8 for MRI; the sensitivity was 6/7, 4/7 and 6/6, respectively. CONCLUSION: Physical examination is a reliable method for estimating penile tumour size and predicts corpus cavernosum infiltration with a high positive predictive value. Tumours for which the infiltration of the corpora cannot be determined properly by physical palpation only should be examined by imaging.     

Vesicle-bound EBV-BART13-3p miRNA in circulation distinguishes nasopharyngeal from other head and neck cancer and asymptomatic EBV-infections

Cell-free microRNA (miRNA) in biofluids released by tumors in either protein or vesicle-bound form, represent promising minimally-invasive cancer biomarkers. However, a highly abundant non-tumor background in human plasma and serum complicates the discovery and detection of tumor-selective circulating miRNAs. We performed small RNA sequencing on serum and plasma RNA from Nasopharyngeal Carcinoma (NPC) patients. Collectively, Epstein Barr virus-encoded miRNAs, more so than endogenous miRNAs, signify presence of NPC. However, RNAseq-based EBV miRNA profiles differ between NPC patients, suggesting inter-tumor heterogeneity or divergent secretory characteristics. We determined with sensitive qRT-PCR assays that EBV miRNAs BART7-3p, BART9-3p and BART13-3p are actively secreted by C666.1 NPC cells bound to extracellular vesicles (EVs) and soluble ribonucleoprotein complexes. Importantly, these miRNAs are expressed in all primary NPC tumor biopsies and readily detected in nasopharyngeal brushings from both early and late-stage NPC patients. Increased levels of BART7-3p, BART9-3p and particularly BART13-3p, distinguish NPC patient sera from healthy controls. Receiver operating characteristic curve analysis using sera from endemic NPC patients, other head and neck cancers and individuals with asymptomatic EBV-infections reveals a superior diagnostic performance of EBV miRNAs over anti-EBNA1 IgA serology and EBV-DNA load (AUC 0.87–0.96 vs 0.86 and 0.66 respectively). The high specificity of circulating EBV-BART13-3p (97%) for NPC detection is in agreement with active secretion from NPC tumor cells. We conclude EV-bound BART13-3p in circulation is a promising, NPC-selective, biomarker that should be considered as part of a screening strategy to identify NPC in endemic regions.     

Global correlation of genome and transcriptome changes in classical Hodgkin lymphoma

To identify genes involved in the pathogenesis of classical Hodgkin lymphoma (cHL), we performed serial analysis of gene expression (SAGE) and array-based comparative genomic hybridization (aCGH). Comparison of SAGE libraries of cHL cell lines L428 and L1236 with that of germinal centre B cells revealed consistent overexpression of only 14 genes. In contrast, 141 genes were downregulated in both cHL cell lines, including many B cell and HLA genes. aCGH revealed gain of 2p, 7p, 9p, 11q and Xq and loss of 4q and 11q. Eighteen percent of the differentially expressed genes mapped to regions with loss or gain and a good correlation was observed between underexpression and loss or overexpression and gain of DNA. Remarkably, gain of 2p and 9p did not correlate with increased expression of the proposed target genes c-REL and JAK2. Downregulation of many genes within the HLA region also did not correlate with loss of DNA. FSCN1 and IRAK1 mapping at genomic loci (7p and Xq) that frequently showed gain were overexpressed in cHL cell lines and might be involved in the pathogenesis of cHL.     

Circulating immunogenic cell death biomarkers HMGB1 and RAGE in breast cancer patients during neoadjuvant chemotherapy

Neoadjuvant chemotherapy in breast cancer patients aims at preoperative reduction of tumor volume for better resection results and prognosis. As not all patients respond to neoadjuvant therapy, predictive biomarkers are needed for more efficient individual management. In prospectively collected sera of 51 consecutive locally confined breast cancer (LBC) patients receiving preoperative, neoadjuvant chemotherapy, value level kinetics of soluble high mobility group box 1 (HMGB1), soluble receptor for advanced glycation end products (sRAGE) as well as the established breast cancer biomarkers CA 15–3 and carcinoembryonic antigen (CEA) were investigated and correlated with therapy response objectified by pathological staging at surgery. In addition, biomarkers were measured in sera of 30 healthy controls (HC), 13 patients with benign breast diseases, and 28 metastatic breast cancer (MBC) patients. Pretherapeutic levels of soluble HMGB1 were decreased in MBC, while sRAGE was already decreased in LBC. In contrast, CA 15–3 and CEA were strongly elevated in MBC, but not in LBC. Combination of sRAGE and CA 15–3 enabled best discrimination of LBC from HC (AUC 78.2 %; sens 58 % at 95 % spec), while CA15-3 and CEA discriminated best between MBC and all controls (AUC 90.9 %; sens 70 % at 95 % spec). In LBC patients undergoing neoadjuvant chemotherapy, nine patients achieved complete remission (CR), 29 achieved partial remission (PR), while 13 had no change of disease (NC). NC patients tended to have higher HMGB1 and lower sRAGE levels before therapy onset (p?=?0.056 and p?=?0.054), while CA 15–3 and CEA did not predict therapeutic outcome. Furthermore, kinetics of HMGB1 during therapy correlated with efficacy of the treatment (p?=?0.053). Markers of immunogenic cell death are valuable for the diagnosis of MBC and early estimation of response to neoadjuvant therapy in LBC patients.