Hair testing applied to the assessment of in utero exposure to drugs: Critical analysis of 51 cases of the University Hospital of Verona

The work discusses the results of hair and urine testing performed in 51 cases of suspected in utero drug exposure handled at the University Hospital of Verona from 2016 to 2022. On the day of birth or the day after birth, urine from mother and newborn (UM and UN) and hair from mother (HM), newborn (HN) and father (HF), if possible, were collected. Urine underwent immunoassay and GC–MS analysis, whereas hair underwent LC–MS/MS and GC–MS/MS analysis. In 50 out of 51 cases, HM and/or HN were available. In 92% of them, hair testing resulted in a positive, often (>50% cases) for more than one class of substance. The most detected substances were cocaine, opiates, methadone and cannabinoids. Maternal segmental analysis showed a prevalent decreasing concentration trend during pregnancy in case of positivity for one class of substances, whereas, as expected, a neatly prevalent increasing trend in the case of positivity for more than one class of substances. In nine cases, HF was also available, resulting in all being positive, usually for the same classes of substances identified in HM, thus questioning parental responsibility. In 33 cases, urine samples from the mother or newborn were also collected. Of them, 27 cases (82%) tested positive, showing peri-partum drug consumption and then confirming the severity of the addiction. Hair testing showed to be a reliable diagnostic tool to investigate in utero drug exposure because of the possibility of obtaining a complete picture of maternal addictive behaviour and family background, thanks to segmental maternal hair analysis and father hair testing.     

水体中克雷伯菌属的分布及其在水源性急性肠道感染中的价值

俄罗斯不同气候地区不同功能水体中克雷伯菌属广泛分布。克雷伯菌属可见于遭受生物、化学污染的集中供水的地表水源,无防护的地下蓄水层,缺乏有效清洁、消毒系统的饮用水。研究表明,水体中的克雷伯菌属具有致病性和毒性,对现代药物和消毒剂(氯、紫外线)具有抗性,很容易穿透进入地下蓄水层。克雷伯菌属细菌有很强的致病性(粘附力、侵袭力、磷酸酯酶、卵磷脂酶、脱氧核糖核酸酶、溶血活性),含有致病性遗传标记cnf-1。克雷伯菌属(100 CFU/dm³)可引起急性肠道感染。在不检测总大肠菌群的情况下,检测水体尤其是饮用水中的克雷伯菌属,可以评估所用水的流行病学危险。     

Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors: Part I--discovery of two binding modes

Through a de novo design approach, hydroxamates derived from trans-cyclopropyl dicarboxylate were examined as potential TNF-alpha converting enzyme (TACE) inhibitors. Two distinctive series of inhibitors (A and B) were identified and shown to have different structure-activity relationship trends and selectivity profiles against other matrix metalloproteases despite their close structural similarities. X-ray crystallography of the inhibitors binding to the TACE enzyme demonstrates that each series derives its activity from the opposite enantiomer of the cyclopropyl scaffolds, which display almost superimposable hydroxamate groups that coordinate to the zinc at the catalytic site. Mode A inhibitors occupy the S1'-S3' binding pockets, whereas mode B resides in the nonprime binding sites.     

MHB4 Comparison of Standard Gamble, Time Trade-Off, and Visual Analog Scale Scores for Hypothetical Stroke Health States Using a Computer-Based Program

The most frequently used techniques for conducting utility assessments are the Standard Gamble (SG), the Time Trade-Off (TTO), and the Visual Analog Scale (VAS).
OBJECTIVES: The objectives of this study were to compare scores obtained on the SG, TTO, and VAS for hypothetical stroke health states; to determine the effect of age and gender on utility scores; to identify any ceiling or floor effects, and to determine the presence of interviewer effects.
METHODS: Forty-nine PharmD students from the College of Pharmacy at the University of Iowa were selected as the sample, and utility assessments were conducted by two interviewers, for hypothetical stroke scenarios adapted from the Glasgow Outcomes Sale. The health states evaluated were Good Recovery, Moderate Disability, Severe Disability, and a Vegetative State. Two rounds of interviews were separated by a period of 4 months. Regresion analysis was used to identify the factors influencing utility scores.
RESULTS: Mean SG scores for the four health states were 82.2, 62.7, 26.3, and 3.3, respectively. TTO scores for the four health states were 79.9, 57.3, 24.6, and 2.9, respectively. However, VAS scores were found to be higher than both TTO and SG scores. Neither age nor gender were found to be statistically significant determinants of reported utility scores. Interviewer effects were found for one out of 12 assessments in round 1, while none were observed in round 2. Floor effects were observed for all three techniques for the vegetative state.
CONCLUSION: Further research using larger, more representative samples from the general population is required to establish the validity of computer-based programs for utility assessments.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

Mutagenic perylenequinone metabolites of Alternaria alternata: altertoxins I, II, and III

The mold genus Alternaria is a widely distributed plant pathogen. Some of these species, e.g., A. alternata, are common decay organisms of fruits and vegetables. Two novel perylene oxide metabolites, altertoxins II and III, have been identified in extracts of A. alternata isolates that exhibit mutagenic responses in the Ames Salmonella typhimurium assay. These identifications were based on mass, optical rotational, and 1H- and 13C-nmr spectral studies. Previous reports of related perylene dione mycotoxins have been clarified.     

Hip subluxation associated with Pipkin II fracture: an injury to look for before reduction

Fractures of the femoral head are rare. They usually occur in association with a posterior hip dislocation secondary to a high-energy trauma (motor vehicle accident). We report a case of Pipkin II fracture associated with an irreducible hip subluxation. Clinical signs are poor unlike in posterior hip subluxation. CT scan is important to evaluate the traumatism. The Hardinge approach is relevant in this context of irreducible hip subluxation. The clinical, diagnostic, and therapeutic particularities of this lesion type are discussed.     

An algorithm to improve outcomes of radial forearm flap donor site

Background: Due to the high rate of donor site complications the Radial Forearm Flap (RFF) has lost ground in favor of the Antero-lateral tight flap (ALT) and other flaps. We have designed a reconstruction algorithm for reconstruction of its donor site. The goal of this study was to retrospectively evaluate the impact of this algorithm on RFF donor site complication rates.

Methods: The authors analyzed retrospectively 31 patients who underwent free radial forearm flap reconstruction between November 2009 and May 2013. Donor site complications were compared with data from patients treated before introdutction of the algorithm. Within the group were compared patients in which the flap was harvested suprafascial with those in which the flap was harvested as subfascial.

Results: Before application of the algorithm, there was a 23.3% complication rate at the RFF donor site, in our experience. After introduction of the algorithm, complication rate has dropped to 3.2%, consisting in a partial skin graft necrosis treated by local wound-care and healed without further intervention.

Conclusions: Application of the algorithm described has led to a significant reduction in RFF donor site complication rates. This demonstrates that if flap donor sites are analyzed and tailor treated in the same way as primary defects are, instead of being given secondary importance and just grafted, outcomes improve.     

GSTP1 and ABCB1 Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel‐Based Chemotherapy in Ovarian Cancer

Variation in drug disposition genes might contribute to susceptibility to toxicities and interindividual differences in clinical management on chemotherapy for epithelial ovarian cancer (EOC). This study was designed to explore the association of GST and ABCB1 genetic variation with hematologic and neurologic toxicity, changes in chemotherapy, and disease prognosis in Brazilian women with EOC. A total of 112 women with a confirmed histological diagnosis of EOC treated with carboplatin/paclitaxel were enrolled (2014–2019). The samples were analyzed by multiplex polymerase chain reaction (PCR) for the deletion of GSTM1 and GSTT1 genes. GSTP1 (c.313A>G/rs1695) and ABCB1 (c.1236C>T/rs1128503; c.3435C>T/rs1045642; c.2677G>T>A/rs2032582) single nucleotide polymorphisms (SNPs) were detected by real‐time PCR. Subjects with the GSTP1 c.313A>G had reduced risk of anemia (odds ratio (OR): 0.17, 95% confidence interval (CI): 0.04–0.69, P = 0.01, dominant model) and for thrombocytopenia (OR: 0.27, 95% CI: 0.12–0.64, P < 0.01; OR 0.18, 95% CI 0.03–0.85, P = 0.03, either dominant or recessive model), respectively. The GSTP1 c.313A>G AG genotype was associated with a lower risk of dose delay (OR: 0.35, 95% CI: 0.13–0.90, P = 0.03). The ABCB1 c.1236C>T was associated with increased risk of thrombocytopenia (OR: 0.15, 95% CI: 0.03–0.82, P = 0.03), whereas ABCB1 c.3435C>T had increased risk of grade 2 and 3 neurotoxicity (OR: 3.61, 95% CI: 1.08–121.01, P = 0.03) in recessive model (CC + CT vs. TT). This study suggests that GSTP1 c.313A>G, ABCB1 c.1236C>T, and c.3435C>T SNP detection is a potential predictor of hematological toxicity and neurotoxicity and could help predict the clinical management of women with EOC.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Variation in drug disposition genes encoding drug‐metabolizing enzymes and transporters might contribute to susceptibility to toxicities and interindividual differences in clinical management such as the need to delay, reduce, or discontinue treatment.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We studied the association of GST and ABCB1 genetic variation with hematologic and neurologic toxicity, clinical management, and disease prognosis in Brazilian women with epithelial ovarian carcinoma (EOC) who undergo carboplatin and paclitaxel‐based chemotherapy.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

GSTP1 c.313A>G is a potential predictor of anemia and thrombocytopenia and associated with a lower risk of dose delay during chemotherapy. In addition, ABCB1 c.1236C>T and c.3435C>T is associated with a higher risk of thrombocytopenia and neurotoxicity.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The polymorphism detection could be a strategy to careful monitoring of patients at increased risk of toxicity and appropriate supportive therapy could decrease the need for changes in treatment, thus improving the likelihood of a beneficial treatment response in women with EOC.

Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer death, largely due to the advanced stage of the disease at the time of diagnosis. ¹ Standard first‐line treatment is cytoreductive surgery and subsequent chemotherapy using a combination of carboplatin and paclitaxel or neoadjuvant chemotherapy and residual tumor resection. ² Despite a high response rate to chemotherapy, ~ 70% of the women have a relapse within the subsequent 3 years. ³ Platinum and taxane‐based chemotherapy are often associated with severe hematological toxicities, such as anemia, neutropenia, leukopenia, and thrombocytopenia. ⁴ In addition, neuropathy is a dose‐limiting side effect of paclitaxel. ⁵ , ⁶ Interindividual differences in carboplatin and paclitaxel toxicity may be associated with polymorphisms in genes encoding drug‐metabolizing enzymes and transporters, including GSTs and ATP‐binding cassette (ABC) efflux transporters like ABCB1. ⁴ , ⁷ , ⁸ , ⁹ The GSTs are a family of phase II enzymes involved in detoxification of xenobiotics by conjugation reactions between glutathione and endogenous and exogenous electrophilic compounds, such as chemotherapeutic drugs, including the platinum agents. The GST family consists of several gene subfamilies of which GSTM1, GSTT1, and GSTP1 are the most relevant for drug metabolism. ¹⁰ , ¹¹ Functional GSTM1 and GSTT1 enzymes are directly related with the presence of the intact genes, because the absence of activity is the result of a 15 kb and 54 kb deletions that span the entire GSTM1 and GSTT1 genes (GSTM1‐null and GSTT1‐null genotypes), respectively. Consequently, individuals homozygous for the GSTM1 or GSTT1‐null allele have a complete absence of GSTM1 and GSTT1 activity, whereas individuals with two copies of the GSTM1 or GSTT1 genes have reference protein levels. ¹² , ¹³ There is some evidence that these deletion genotypes may play a role in toxicity, response to treatment, and survival in some cancers, ¹⁴ , ¹⁵ , ¹⁶ including cancer of the ovary. ⁸ In contrast to the commonly studied GSTM1 and GSTT1 genotypes, the GSTP1 c.313A>G (rs1695) is an exonic single nucleotide polymorphism (SNP) that causes an amino acid substitution and results in an isoleucine to valine (Ile > Val) change at codon 105 of the enzyme. The highest level of GSTP1 activity is seen in individuals with the AA genotype (Ile/Ile) and is associated with increased toxicity in different carcinomas, but there are discordant results regarding the effect of GSTP1 c.313A>G on treatment outcomes. ⁹ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ Polymorphisms in ABCB1 or multidrug resistance 1 may affect the function of P‐glycoprotein, a critical transporter for efflux of paclitaxel from cells. ²¹ , ²² Three SNPs in the coding region of ABCB1 (c.1236C>T, rs1128503; c.3435C>T, rs1045642; and c.2677G>T>A, rs2032582) have been extensively studied. ²³ , ²⁴ These common ABCB1 SNPs have been associated with toxicity during carboplatin and paclitaxel‐based chemotherapy, including increased risk of anemia in carriers of the c.1236C>T SNP, a more pronounced neutrophil decrease in patients carrying the c.3435C>T and c.2677G>T>A SNPs and increased risk of peripheral neuropathy associated with the c.3435C>T SNP. ¹⁸ , ²⁵ , ²⁶ Similar to studies of GST polymorphisms, the associations of ABCB1 genetic variation with treatment outcomes is inconsistent across studies. ²⁷ , ²⁸ Patients developing severe toxicities often require dose reduction, dose delay, or treatment interruption that require clinical interventions and may affect the disease prognosis. ⁴ However, no study has been found so far focus on regarding the utility of polymorphisms in the management of chemotherapy and toxicities for ovarian cancer. The current study was designed to examine the association of GST and ABCB1 genetic variants with hematologic and neurologic toxicities, clinical management on chemotherapy, and disease prognosis in Brazilian women with EOC.