Plasmodium vivax: a cause of malnutrition in young children

We studied the aetiology of malnutrition in a cohort of 1511 children < 10 years old in Espiritu Santo, Vanuatu. Malnutrition was categorized using standard anthropometric criteria as: underweight [weight-for-age (WA) Z score < -2], wasting [weight-for-height (WH) Z < -2], or stunting [height-for-age (HA) Z < -2]. On multiple logistic regression analysis, the only factors significantly associated with wasting were age < 5 years [OR (95% CI) 1.8 (1.2-2.9), p = 0.01] and having suffered one or more episodes of clinical P. vivax malaria in the 6 months preceding nutritional assessment [OR 2.4 (1.3-4.4), p = 0.006]. The incidence of P. vivax infection was significantly higher during the 6 months preceding assessment in underweight vs. non-underweight children [incidence rate ratio (IRR) 2.6 (1.5-4.4), p < or = 0.0001). These groups had similar incidences of clinical P. falciparum infection during the same period [IRR 1.1 (0.57-2.1) p = 0.8] and of either species during the 6 months following assessment [IRR P. vivax 1.3 (0.9- 2.0) p = 0.2; IRR P. falciparum 1.3 (0.9-1.9) p = 0.2]. In these children, P. vivax malaria was a major predictor of acute malnutrition; P. falciparum was not. Wasting neither predisposed to nor protected against malaria of either species. Although P. vivax malaria is generally regarded as benign, it may produce considerable global mortality through malnutrition.      

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.     

Expression of IL-23, VEGF and TLR2/TLR4 on mononuclear cells after exposure to Pseudomonas aeruginosa

Pseudomonas aeruginosa is a Gram-negative, aerobic bacillus causing infections of the respiratory and other organ systems in susceptible hosts. Although it does not cause pulmonary infections in immunocompetent individuals, P. aeruginosa causes chronic lung infection in individuals with cystic fibrosis and nosocomial pneumonia resulting in significant morbidity and mortality. Exogenous administration of an important P. aeruginosa virulence factor, lipase, present in P. aeruginosa culture supernatant, induces potent mononuclear cell activation leading to the production of numerous proinflammatory cytokines. In particular, P. aeruginosa culture supernatant stimulated increased proliferation of THP-1 cells and monocytes (MN). The addition of culture supernatant to THP-1 cells and MN also induced Interleukin (IL)-23 and vascular endothelial growth factor (VEGF) release in a time-dependent manner. To investigate whether any compounds present in the supernatant lipase contributed to releasing IL-23 and VEGF, the culture supernatant from P. aeruginosa containing lipase was treated with hexadecylsulfonylfluoride (AMSF). The AMSF-treated culture supernatant (CS) did not show any induction on the IL-23 and VEGF release compared to the cells treated with CS without AMSF. We also showed that Toll-like receptors (TLR)2/TLR4 are expressed in THP-1 cells and MN treated with P. aeruginosa CS in a time-dependent fashion. Flow cytometry analysis revealed a higher TLR4 and a lower TLR2 expression at 48 and 72 h of treatment. The treatment of cells with TLR4 neutralizing antibody, and to a lesser extent with TLR2 neutralizing antibody, resulted in a decrease in P. aeruginosa CS-induced IL-23 and VEGF production.     

Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11

We report a patient with a clinical and molecular diagnosis of LEOPARD syndrome (LS) associated with multiple granular cell tumors (MGCT). Bidirectional sequencing of exons 7, 12, and 13 of the PTPN11 gene revealed the T468M missense mutation in exon 12. This mutation has been previously reported in patients with LS. To our knowledge, this is the first report of MGCT associated with molecularly characterized LS and provides the first molecular evidence linking granular cell tumors (GCT) to the Ras/mitogen-activated protein (MAP) kinase pathway. We propose that MGCT can be associated with LS. Analysis of GCT from this case tested negatively for loss of heterozygosity (LOH) at the PTPN11 and NF1 loci and did not show deletions of the PTEN gene. The absence of LOH of PTPN11 supports published functional data that T468M is a dominant-negative mutation.     

Algorithm of the major and minor diagnostic criteria for active myopic choroidal neovascularization

Graefe's Archive for Clinical and Experimental Ophthalmology - To propose an algorithm of the major and minor diagnostic criteria for macular myopic choroidal neovascularization (mCNV). This...     

Partial synthesis of (3R,6'R)-alpha-cryptoxanthin and (3R)-beta-cryptoxanthin from (3R,3'R,6'R)-lutein

(3R,3'R,6'R)-Lutein (1), (3R,3'R)-zeaxanthin (2), (3R,6'R)-alpha-cryptoxanthin (3), and (3R)-beta-cryptoxanthin (4) are among dietary hydroxycarotenoids that have been identified in human serum, milk, and ocular tissues. While 1 containing 6% of 2 is commercially available, industrial production of optically active 3 and 4 has not yet been accomplished. Several processes have been developed that transform 1 into 3, 4, and minor quantities of (3R,5'RS,6'R)-3',4'-didehydro-5',6'-dihydro-beta,beta-caroten-3-ol (5) (a regioisomer of 3). In one process, lutein (1) was cleanly deoxygenated to 3 in the presence of trifluoroacetic acid (TFA) and Me3N.BH3 in CH2Cl2 at ambient temperature in nearly 90% yield. Reaction of lutein (1) with a Lewis acid (AlCl3, ZnBr2, ZnI2) and a hydride donor (Me3N.BH3, Na[BH3(OCOCF3)], NaCNBH3) in solvents such as CH2Cl2, THF, and TBME produced similar results. In a two-step process, high-temperature acid-catalyzed dehydration of 1 (propanol/water/acid, 90 degrees C) gave a mixture of anhydroluteins 6, 7, and 8 in 86% yield. In the second step, these dehydration products underwent ionic hydrogenation with TFA/Me3N.BH3 in CH2Cl2 to afford a mixture of 3 and 4 in nearly 80% yield that contained only 1% of 5.     

Bilateral axillary artery inflow in the treatment of a rare case of pseudocoarctation of the aortic arch

The axillary artery is the preferred site for arterial cannulation in operations for ascending aorta and aortic arch replacement in order to reduce perfusion-related morbidity in acute dissection and to prevent cerebral embolism in atherosclerotic aneurysm. We present the case of a patient with a chronic dissection presenting as pseudocoarctation of the aortic arch in which bilateral axillary artery inflow was necessary to perfuse both ascending and descending aorta.     

Can Hernia Sac to Abdominal Cavity Volume Ratio Predict Fascial Closure Rate for Large Ventral Hernia? Reliability of the Tanaka Score

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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.