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Introduction The ultrasound-guided interpectoral-pectoserratus plane block is a fascial plane block for superficial surgery of the anterolateral chest wall. This technique involves injecting a relatively large volume of local anesthetics (typically 30 mL of 0.25%-0.50%, ie, 75-150 mg ropivacaine) underneath the major and minor pectoral muscles of the anterior thoracic wall. There is a potential risk of toxic serum concentrations of local anesthetics due to systemic absorption. Methods 22 patients scheduled for elective unilateral breast cancer surgery were included in this study. All surgery was performed with general anesthesia and an ultrasound-guided interpectoral-pectoserratus plane block with 2.5 mg/kg ropivacaine. Ten venous blood samples were collected at 0 (two samples) 10, 20, 30, 45, 60, 90 and 120 min and at 4 hours after performing the block. Free and total ropivacaine levels were measured at each time point. Albumin and alpha-1-acid-glycoprotein were measured to monitor shifts between the free and bound fraction of ropivacaine. Results Samples of 20 patients were analyzed. The mean dose of ropivacaine was 172.8 (22.5) mg. In 50% of the patients, the potentially toxic threshold of 0.15 µg/mL free ropivacaine concentration was exceeded. Mean peak serum concentration occurred at 20 min postinjection. Conclusions This pharmacokinetic study demonstrated that a 2.5 mg/kg ropivacaine interpectoral-pectoserratus plane block may result in exceeding the threshold for local anesthetic systemic toxicity. [ABSTRACT FROM AUTHOR]

The effect of trade policy on the South African soybean industry is analyzed by using 4 digits Standard International Trade Classification of soybean (1201) data of 1996–2011. The Revealed comparative advantage (RCA), Hirschman index, Major export category, Effective rate of protection (ERP) and Nominal rate of protection (NRP) were calculated. The RCA of the soybean industry in South Africa has shown a revealed comparative disadvantage from 1996–2011. Hirschman index indicates that the soybean industry shows lower concentration throughout 16 years. Lower concentration reduces the impact of international trade risk due to the possibility of price fluctuation of the soybean product. MEC measurement also indicates that South Africa does not rely its international trade from the soybean industry. ERP and NRP were also calculated, using an enterprise budget for soybean production. The result shows that the ERP is negative, which indicates that the weighted input tariffs on soybean inputs amount are more than the output tariffs; that is an indication producers of soybean would be better off, everything else being equal, by not being protected through tariffs. The NRP is higher than the ERP which implies that the tariff applied on the output is higher than the tariff applied on inputs. The structure of the tariff schedule may have an important bearing on efficiency. Thus, the study recommended that an extremely dispersed and ill-chosen tariff structure implies that protection remains uneven and gains from openness may still be confined.

Introduction: Total CO2, or bicarbonate, is a parameter in clinical chemistry often applied to assess the metabolic status of a patient. This article discusses the observations and interventions during an episode of assay instability on an Abbott Architect routine chemistry analyser. Results: The Levey–Jennings plot of QC data showed a circadian pattern, having an overestimation of total CO2 during periods of high personnel attendance. A qualitative analysis revealed a correlation between atmospheric CO2 in the lab environment and the acquired total CO2 value in a quality control sample. Assessment of total CO2 is hence influenced by the equilibrium between atmospheric CO2, dissolved CO2 and bicarbonate. The effect is more pronounced on samples containing low concentrations of total CO2. The bias related to environmental CO2 is also noticeable on patient samples, patient means between periods with high and low atmospheric CO2 levels differed by 2 mmol/L. Discussion: Passive ventilation of the laboratory environment is proven insufficient during weather conditions in which the lab is not exposed to wind. Consistent reduction of atmospheric CO2 could only be guaranteed with an active ventilation infrastructure. Systematic closure of analyser lids also reduced analyser variance. Conclusion: The lab environment is an important source of parameter variance. Both environmental and infrastructural aspects must be considered when assessing the potential cause of the instability. [ABSTRACT FROM AUTHOR]

The long-term effectiveness of crop insurance products to provide cost effective and constant cover for maize producers against a production risk under stochastic yields and prices was evaluated. Hail occurrence in low and high risk areas was considered as the production risk, with Short-term Crop Hail Insurance (SCHI) and a Contingency Policy (Self-insurance) in the Alternative Risk Transfer (ART) market as insurance options. A financial simulation model was built to simulate the cash flow of a maize enterprise and to calculate the producer’s annual margin after interest and tax. Stochastic Efficiency with Respect to a Function (SERF) was used to rank Net Present Value (NPV) of the margin after interest and tax for different scenarios of Certainty Equivalents (CE’s) and to calculate the Utility Weighted Risk Premium (UWRP) of each scenario. The model could evaluate the effectiveness of crop insurance products. The SCHI was the preferred option in Mpumalanga (high hail risk area) and ART in North West (low hail risk area) based on the cost effectiveness of the options. The ART, however, was not able to provide constant cover at all times and the long term efficiency thereof should be carefully considered before it is applied as the sole hail risk mitigation strategy. [ABSTRACT FROM PUBLISHER]

The inevitable switch from standard molecular methods to next-generation sequencing for the molecular profiling of tumors is challenging for most diagnostic laboratories. However, fixed validation criteria for diagnostic accreditation are not in place because of the great variability in methods and aims. Here, we describe the validation of a custom panel of hotspots in 24 genes for the detection of somatic mutations in non-small cell lung carcinoma, colorectal carcinoma and malignant melanoma starting from FFPE sections, using 14, 36 and 5 cases, respectively. The targeted hotspots were selected for their present or future clinical relevance in solid tumor types. The target regions were enriched with the TruSeq approach starting from limited amounts of DNA. Cost effective sequencing of 12 pooled libraries was done using a micro flow cell on the MiSeq and subsequent data analysis with MiSeqReporter and VariantStudio. The entire workflow was diagnostically validated showing a robust performance with maximal sensitivity and specificity using as thresholds a variant allele frequency >5% and a minimal amplicon coverage of 300. We implemented this method through the analysis of 150 routine diagnostic samples and identified clinically relevant mutations in 16 genes including KRAS (32%), TP53 (32%), BRAF (12%), APC (11%), EGFR (8%) and NRAS (5%). Importantly, the highest success rate was obtained when using also the low quality DNA samples. In conclusion, we provide a workflow for the validation of targeted NGS by a custom-designed pan-solid tumor panel in a molecular diagnostic lab and demonstrate its robustness in a clinical setting. [ABSTRACT FROM AUTHOR]

The objective of this article is to estimate the maximum value of crop hail insurance according to the financial extent of hail risk's impact on the enterprise in two regions, North West (low hail risk area) and Mpumalanga (high hail risk area). The difference in the cumulative probability distributions of the Net Present Value (NPV) of the margin after interest and tax in the event of hail and in the event of no hail will provide a graphic indication of the financial impact of hail. To determine if the decision maker is willing to pay in order to remove the impact of hail on the enterprise, the utility weighted risk premium (UWRP) must be calculated with the use of stochastic efficiency with respect to a function (SERF) analysis. The calculated maximum benefit (or UWRP) that the decision maker will receive through the elimination of hail will set the upper limit for the cost of crop hail insurance. The results indicate that hail does have a negative impact on the financial position of the farms in North West and Mpumalanga. The effect of hail risk in Mpumalanga is, however, more severe. The calculated maximum benefit (UWRP) from the elimination of hail damage in two regions is R83.50/hectare in North West and R708.70/hectare in Mpumalanga. The conclusion can thus be made that decision makers in both regions will be willing to pay for crop hail insurance, but much more so in Mpumalanga than in North West. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with hereditary emphysema are treated with α1-antitrypsin (α1-proteinase inhibitor [A1PI]) concentrates. High-resolution isoelectric focusing (IEF) analysis of A1PI shows that commercial A1PI products have different glycoisoform band patterns predominantly caused by varying degrees of C-terminal Lys truncation at position 394 from the A1PI molecule. Basic carboxypeptidases (CPs) are a group of enzymes that specifically cleave C-terminal basic amino acids (Arg or Lys) from peptides and proteins. STUDY DESIGN AND METHODS: In this study, whether A1PI is a substrate for basic CPs was investigated. CPN and CPU, two CPs present in plasma, and CPM, a GPI-anchored membrane protein highly expressed in lung tissues, were included. RESULTS: Basic CPs are able to mediate the C-terminal Lys truncation of A1PI although with a very low efficiency. However, presence of ethanol, for example, during Cohn fractionation, renders A1PI highly susceptible to cleavage by CP with the extent of Lys truncation depending on the ethanol concentration. This ethanol concentration dependence elegantly explains the varying amounts of des-Lys A1PI present in commercial preparations purified from different Cohn fractions. CONCLUSIONS: The cause of C-terminal truncation of A1PI present in products used for augmentation therapy has been identified, and it has been shown that A1PI becomes a substrate for CPs, specifically CPN, because of the presence of ethanol during Cohn fractionation. [ABSTRACT FROM AUTHOR]

Abstract: The influence of the P1 amino acid on the substrate selectivity, the catalytic parameters K m and k cat, of carboxypeptidase M (CPM) (E.C. 3.4.17.12) was systematically studied using a series of benzoyl-Xaa–Arg substrates. CPM had the highest catalytic efficiency (k cat/K m) for substrates with Met, Ala and aromatic amino acids in the penultimate position and the lowest with amino acids with branched side-chains. Substrates with Pro in P1 were not cleaved in similar conditions. The P1 substrate preference of CPM differed from that of two other members of the carboxypeptidase family, CPN (CPN/CPE subfamily) and CPB (CPA/CPB subfamily). Aromatic P1 residues discriminated most between CPM and CPN. The type of P2 residue also influenced the k cat and K m of CPM. Extending the substrate up to P7 had little effect on the catalytic parameters. The substrates were modelled in the active site of CPM. The results indicate that P1-S1 interactions play a role in substrate binding and turn-over. [Copyright &y& Elsevier]

Since its discovery more than 20 years ago, a lot has been revealed about the biochemistry and physiological behaviour of carboxypeptidase U (CPU). Recent advances in CPU research include the unravelling of the crystal structure of proCPU and revealing the molecular mechanisms for the marked instability of the active enzyme, CPU. The recent development of two highly sensitive assays has cleared the path toward the direct measurement of CPU in circulation or the determination of CPU generation, rather than the measurement of total proCPU concentration in plasma. Finally, since CPU is known to have a prominent bridging function between coagulation and fibrinolysis, the development of CPU inhibitors as profibrinolytic agents is an attractive new concept and has gained a lot of interest from several research groups and from the pharmaceutical industry. These recent advances in CPU research are reviewed in this literature update.

Although the maintenance of precise balance between coagulation and fibrinolysis is of utmost importance for normal haemostasis, until recently these two systems were considered as completely separate mechanisms involved in the process of formation and dissolution of blood clot. Thrombin activatable fibrinolysis inhibitor (TAFI) is a recently described attenuator of the fibrinolytic rate and is considered to be the molecular link between coagulation and fibrinolysis. TAFI circulates in plasma as an inactive precursor and its conversion in active enzyme (TAFIa) occurs by the action of thrombin or plasmin, but most efficiently by thrombin in the presence of its cofactor thrombomodulin. Once generated, TAFI down-regulates fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin; thereby preventing the upregulation of plasminogen binding and activation. Because TAFI is activated by thrombin on one side, and acts as the attenuator of fibrinolysis on another side, it enables fine synchronization between these two systems. The antifibrinolytic function of TAFI mostly depends on TAFI concentration, the rate of its activation and the half-life of TAFIa in plasma. Changes in thrombin generation can have a profound effect on the rate of TAFI activation, and consequently on the rate of fibrinolysis. Therefore, it has been hypothesized that increased thrombin generation seen in thrombophilia patients may enhance TAFI activation, leading to a hypofibrinolytic state, which may further contribute to the thrombotic tendency. However, the results of several studies, in which relation between TAFI level and the occurrence of thromboembolic complications in carriers of hereditary thrombophilia have been investigated, were not consistent.

The maintenance of the equilibrium between coagulation and fibrinolysis is crucial for normal haemostasis. In contrast, pathologic consequences of imbalance manifest tendencies of bleeding or thrombosis. Procarboxypeptidase U (proCPU, TAFI) is recognized as an important link between the coagulation system and fibrinolysis. Following activation by thrombin (IIa), carboxypeptidase U (CPU) exerts an antifibrinolytic effect by abolishing the cofactor function of partially degraded fibrin in plasminogen (Pg) activation. This review article focuses on the role of the proCPU/CPU system in the balance between fibrin deposition and removal. How a disturbed system can lead to a higher thrombotic tendency is discussed, while CPU inhibition as a new drug target for fibrinolytic therapy is extensively reviewed.

Background: The importance of carboxypeptidase U (CPU) as a novel regulator of the fibrinolytic rate has attracted much interest during recent years. CPU circulates in plasma as a zymogen, proCPU, that can be activated by thrombin, thrombin-thrombomodulin (T-Tm), or plasmin. Given that the proCPU concentration in plasma is far below its K(m) for activation by the T-Tm complex, the formation of CPU will be directly proportional to the proCPU concentration. A low or high proCPU plasma concentration might therefore tip the balance between profibrinolytic and antifibrinolytic pathways and thereby cause a predisposition to bleeding or thrombosis., Content: To measure plasma proCPU concentrations, different methods have been developed based on 2 different principles: antigen determination and measurement of CPU activity after quantitative conversion of the proenzyme to its active form by addition of T-Tm. The major drawbacks that should be kept in mind when analyzing clinical samples by both principles are reviewed., Conclusions: proCPU is a potential prothrombotic risk factor. Evaluation of its relationship with thrombosis requires accurate assays. Many assays used in different clinical settings are inadequately validated, forcing reconsideration of conclusions made in these reports.