Improving health outcomes and quality at the subdistrict level: Evaluation of the '3 feet model' in Waterberg District, Limpopo Province, South Africa.

BACKGROUND: There is a gap in understanding of potential roles and actions at the subdistrict level to improve quality of care and health outcomes in South Africa (SA). OBJECTIVES: To report on the evaluation of a subdistrict health system-strengthening initiative that aimed to reduce maternal, newborn and child mortality, referred to as the '3 feet model' in Waterberg District, Limpopo Province, SA. The model is centred on systems of real-time morbidity/mortality surveillance and co-ordinated responses. It was implemented in three of five Waterberg subdistricts over an 18-month period in 2021 and 2022. METHODS: A prospective, process-tracing evaluation was conducted jointly between researchers, intervention partners and subdistrict decision-makers. Data sources combined ~100 hours of researcher participant observation, interviews with 14 health system actors, structured reflections by three subdistrict managers and information from the routine District Health Information System. Sources were triangulated and analysed based on a priori hypotheses on mechanisms of action. RESULTS: Following uptake of the model, the perinatal mortality rate (PMR) improved by 28.8%, 11.5% and 28% in the three subdistricts, respectively, while the PMR worsened in two of four neighbouring subdistricts. Plausible factors in implementation successes were the presence of stable and committed hybrid (clinical-managerial) subdistrict leaders and their ability to overcome entrenched silos between a variety of system actors; new collaborative relationships between primary healthcare facilities, hospitals and emergency medical services; the generation and packaging of information in ways that directed responses ('actionable intelligence'); and support from senior district managers. CONCLUSION: While not advocating for a cut-and-paste approach to improving quality and outcomes, positive experiences in Waterberg District suggest that the principles and mechanisms of action of the 3 feet model have wider relevance for policy and practice, especially as emphasis shifts towards the subdistrict as a core unit of population health and wellbeing in SA.

Strengths and limitations of diagnostic tools for endometriosis and relevance in diagnostic test accuracy research.

Endometriosis is a chronic systemic disease that can cause pain, infertility and reduced quality of life. Diagnosing endometriosis remains challenging, which yields diagnostic delays for patients. Research on diagnostic test accuracy in endometriosis can be difficult due to verification bias, as not all patients with endometriosis undergo definitive diagnostic testing. The purpose of this State-of-the-Art Review is to provide a comprehensive update on the strengths and limitations of the diagnostic modalities used in endometriosis and discuss the relevance of diagnostic test accuracy research pertaining to each. We performed a comprehensive literature review of the following methods: clinical assessment including history and physical examination, biomarkers, diagnostic imaging, surgical diagnosis and histopathology. Our review suggests that, although non-invasive diagnostic methods, such as clinical assessment, ultrasound and magnetic resonance imaging, do not yet qualify formally as replacement tests for surgery in diagnosing all subtypes of endometriosis, they are likely to be appropriate for advanced stages of endometriosis. We also demonstrate in our review that all methods have strengths and limitations, leading to our conclusion that there should not be a single gold-standard diagnostic method for endometriosis, but rather, multiple accepted diagnostic methods appropriate for different circumstances. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Phosphonate Treatment Effects on Phytophthora Root Rot Control, Phosphite Residues and Phytophthora cactorum Inoculum in Young Apple Orchards.

Phytophthora root rot, caused by Phytophthora cactorum, is an economically important disease on young apple trees. Limited information is available on the effect of different phosphonate application methods and dosages on disease control, fruit and root phosphite concentrations, and soil and root pathogen inoculum levels. Evaluation of phosphonate treatments in three apple orchard trials (two in the Grabouw and one in the Koue Bokkeveld region) showed that foliar sprays (ammonium or potassium phosphonate), trunk sprays and trunk paints, were equally effective at increasing trunk diameter in one trial and yield in a second trial over a 25-month period. Foliar ammonium and potassium phosphonate sprays (12 g of phosphorous acid/tree), and two different dosages of the ammonium phosphonate sprays (∼4.8 g or 12 g of phosphorous acid/tree) were all equally effective at improving tree growth. The addition of a bark penetrant (polyether-polymethylsiloxane-copolymer) to trunk sprays did not improve the activity of trunk sprays. The low dosage ammonium phosphonate foliar spray (∼4.8 g a.i./tree) was the only treatment that, in general, yielded significantly lower root phosphite concentrations than the other phosphonate treatments. Root phosphite concentrations were significantly positively correlated (P < 0.0001) with an increase in trunk diameter and negatively (P < 0.0001) with P. cactorum root DNA quantities. Phosphite fruit residues were <31 ppm for all treatments, with the trunk paint treatment (80 g of phosphorous acid/tree applied annually) yielding significantly lower residues than the higher dosage foliar sprays (∼12 g a.i./tree). Twenty-one months posttreatment, most of the phosphonate treatments in all of the trials similarly significantly reduced P. cactorum DNA quantities estimated directly from roots, but not from soil based on soil baiting DNA analysis. Pathogen quantities in fine feeder roots did not differ significantly from those in higher-order roots (<5 mm diameter). P. cactorum DNA quantities estimated using DNA quantification directly from roots were significantly correlated (P < 0.0001) with those obtained through root leaf baiting DNA analysis and, to a lesser extent, with soil leaf baiting DNA quantities (P = 0.025).

Brain-derived neurotrophic factor (BDNF) expression and function in the mammalian reproductive Tract.

BACKGROUND: Neurotrophins of the nerve growth factor family are soluble polypeptides that are best known for their role in nerve growth, survival and differentiation in the central nervous system. A growing body of literature shows that neurotrophins and their receptors are also expressed throughout the reproductive tract. OBJECTIVE AND RATIONALE: Neurotrophins are key regulatory proteins in reproductive physiology during development and throughout adult life. Of the neurotrophins, the literature describing the expression and function of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, neurotrophin receptor kinase-2 (NTRK2), has been expanding rapidly. We therefore conducted a systematic inductive qualitative review of the literature to better define the role of the BDNF in the reproductive tract. We postulate that BDNF and NTRK2 are central regulatory proteins throughout the reproductive system. SEARCH METHODS: An electronic search of Medline (PubMed) and Web of Science for articles relating to BDNF and the reproductive system was carried out between January 2018 and February 2019. OUTCOMES: In the ovary, BDNF expression and levels have been linked with follicle organisation during ovarian development, follicle recruitment and growth and oocyte maturation. In the endometrium, BDNF is involved in cell proliferation and neurogenesis. In contrast, literature describing the role of BDNF in other reproductive tissues is sparse and BDNF-NTRK2 signalling in the male reproductive tract has been largely overlooked. Whilst estradiol appears to be the primary regulator of BDNF expression, we also identified reports describing binding sites for glucocorticoid and myocyte enhancer factor-2, a calcium-response element through activation of an N-methyl-D-aspartate (NMDA) receptor, and aryl hydrocarbon receptor nuclear transporter protein-4 (ARNT) response elements in promoter regions of the BDNF gene. Expression is also regulated by multiple microRNAs and post-translational processing of precursor proteins and intracellular shuttling. BDNF-NTRK2 signalling is modulated through tissue specific receptor expression of either the full-length or truncated NTRK2 receptor; however, the functional importance remains to be elucidated. Dysregulation of BDNF expression and circulating concentrations have been implicated in several reproductive disorders including premature ovarian failure, endometriosis, pre-eclampsia, intra-uterine growth restriction (IUGR) and several reproductive cancers. WIDER IMPLICATIONS: We conclude that BDNF and its receptors are key regulatory proteins central to gonadal development, ovarian regulation and uterine physiology, as well as embryo and placenta development. Furthermore, dysregulation of BDNF-NTRK2 in reproductive diseases suggests their potential role as candidate clinical markers of disease and potential therapeutic targets.

Determining Mancozeb Deposition Benchmark Values on Apple Leaves for the Management of Venturia inaequalis.

Apple scab, caused by Venturia inaequalis, is the most common fruit and foliar disease in commercial apple production worldwide. Early in the production season, preventative contact fungicide sprays are essential for protecting highly susceptible continuously unfolding and expanding young leaves. In South Africa, mancozeb is a key contact fungicide used for controlling apple scab early in the season. The current study developed deposition benchmarks indicative of the biological efficacy of mancozeb against apple scab, using a laboratory-based apple seedling model system. The model system employed a yellow fluorescent pigment that is known to be an effective tracer of mancozeb deposition. A concentration range of mancozeb (0.15 to 1 times the registered dosage) and fluorescent pigment concentrations was sprayed onto seedling leaves, which yielded various fluorescent particle coverage (FPC%) levels. Modeling of the FPC% values versus percent disease control yielded different benchmark values when disease quantification was conducted using two different methods. Thermal infrared imaging (TIRI) disease quantification resulted in a benchmark model where 0.40%, 0.79%, and 1.35 FPC% yielded 50, 75, and 90% apple scab control, respectively. These FPC% values were higher than the benchmarks (0.10, 0.20, and 0.34 FPC%, respectively) obtained with quantitative real-time PCR (qPCR) disease quantification. The qPCR benchmark model is recommended as a guideline for evaluating the efficacy of mancozeb sprays on leaves in apple orchards since the TIRI benchmark model underestimated disease control. The TIRI benchmark model yielded 68% disease control at the lowest mancozeb dosage, yet no visible lesion developed at this dosage. Both benchmark models showed that mancozeb yielded high levels of disease control at very low concentrations; for the qPCR benchmark model the FPC% value of the FPC90 (90% control) corresponded to 0.15 times that of the registered mancozeb concentration in South Africa, i.e., 85% lower than the registered dosage.

Development and validation of a HPLC electrochemical detection method to measure COMT activity as a tool in drug development.

The determination of catechol-O-methyltransferase (COMT) activity is considered valuable for various pharmaceutical and biomedical research projects. A specific high performance liquid chromatography-coulometric electrochemical detection method, for the assay of COMT activity was developed by measuring the formation of normetanephrine from norepinephrine. The chromatographic separation was achieved on a C18 reversed phase column with a mobile phase consisting of 10 mM sodium dihydrogen phosphate buffer, 4 mM sodium 1-octanesulfonate, 0.17 mM ethylenediaminetetra-acetic acid disodium salt, 6 % methanol and 4 % acetonitrile (pH ± 4.0). The detection of normetanephrine was achieved through electrochemical detection, with a coulometric cell potential setting of +450 mV. The flow rate was at 1 ml/min and the total run time was 45 min. The method was validated according to validation guidelines (Shabir 2006; European Medicines Agency 2011; US FDA 2018). The method was found to be linear (R² > 0.99) over the analytical range (100 to 2500 ng/ml) for all the analytes. All the other validation parameters (sensitivity, precision, accuracy, recovery and stability) were acceptable and within range. The method was applied for the determination of COMT activity in rat liver homogenate test samples. The known selective COMT inhibitor entacapone was used as test inhibitor. The results confirmed the ability of entacapone to inhibit COMT activity by decreasing the production of all the metabolites of norepinephrine.

An HPLC-DAD validated method for the detection and quantification of cortisol, corticosterone and melatonin in plasma samples of two different animal species.

The monitoring of endogenous hormone plasma levels could be valuable in biomedical, veterinary and pharmaceutical research. A specific high performance liquid chromatography method with diode array detection, for the assay of cortisol, corticosterone and melatonin in animal plasma was developed and validated. The chromatographic separation was achieved on a C8 reversed phase column with a mobile phase consisting of HPLC-grade water and 35% v/v acetonitrile (pH ± 3.36). The detection was achieved through diode array detection, with two set wavelengths; 245 and 275 nm. The flow rate was at 1 ml/min and the total run time was 50 min. The method was validated according to validation guidelines (Shabir, 2006; US FDA, 2013). The method was found to be linear (R² > 0.99) over the analytical range (10 to 500 ng/ml) for all three analytes. All the other validation parameters were acceptable and within range. The method was applied to plasma samples from Sprague-Dawley rats and white rhinoceros.

The Efficacy of Semiselective Chemicals and Chloropicrin/1,3-Dichloropropene-Containing Fumigants in Managing Apple Replant Disease in South Africa.

Apple replant disease (ARD) is a biological phenomenon that is encountered when old apple orchards are replanted, resulting in tree growth and yield reductions in young trees. Three ARD orchard trials were conducted, which showed that semiselective chemicals (fenamiphos, metalaxyl, imidacloprid, and phosphonates) used independently, two fumigant formulations (33.3% chloropicrin and 60.8% 1,3-dichloropropene [Pic33-1,3D] and 57.% chloropicrin and 38% 1,3 dichloropropene [Pic57-1,3D]), and semiselective chemicals combined with Pic33-1,3D or Pic57-1,3D all contributed to significant increases in tree growth (trunk diameter and shoot length) relative to the untreated control 3 to 4 years postplanting. The treatments did not differ significantly from each other in improving tree growth. Yield was more indicative of treatment efficacy, but this varied between the three orchards. The Pic33-1,3D fumigant in combination with semiselective chemistries was the most consistent in significantly increasing cumulative yields. The Pic57-1,3D treatment was superior in increasing yields relative to the Pic33-1,3D treatment, because (i) it significantly increased cumulative yields in comparison with the Pic33-1,3D treatment in one orchard and (ii) in another orchard, a significant increase in yield was obtained with Pic57-1,3D relative to the control treatment but not with the Pic33-1,3D treatment. The quantification of ARD causative agents 20 months postplant showed that Phytophthora cactorum contributed to disease development in all three orchards; significant negative correlations existed between the quantity of P. cactorum DNA detected in tree roots and tree growth and less often, yield. In two orchards, only some of the treatments that significantly reduced the quantity of P. cactorum DNA in tree roots relative to the control also resulted in a significant increase in tree growth. Some of the aforementioned trends were also evident for Pratylenchus spp. root densities in two of the orchards. There was a significant positive correlation between P. cactorum root DNA quantities and Pratylenchus spp. root densities. Pythium spp. and "Cylindrocarpon"-like DNA quantities detected in tree roots typically were not indicative of treatment efficacy. However, a significant positive correlation existed between these two pathogen groups, suggesting complex interactions not associated with pathogen quantities per se.

The impact of health programmes to prevent vertical transmission of HIV. Advances, emerging health challenges and research priorities for children exposed to or living with HIV: Perspectives from South Africa.

Over the past three decades, tremendous global progress in preventing and treating paediatric HIV infection has been achieved. This paper highlights the emerging health challenges of HIV-exposed uninfected (HEU) children and the ageing population of children living with HIV (CLHIV), summarises programmatic opportunities for care, and highlights currently conducted research and remaining research priorities in high HIV-prevalence settings such as South Africa. Emerging health challenges amongst HEU children and CLHIV include preterm delivery, suboptimal growth, neurodevelopmental delay, mental health challenges, infectious disease morbidity and mortality, and acute and chronic respiratory illnesses including tuberculosis, pneumonia, bronchiectasis and lymphocytic interstitial pneumonitis. CLHIV and HEU children require three different categories of care: (i) optimal routine child health services applicable to all children; (ii) routine care currently provided to all HEU children and CLHIV, such as HIV testing or viral load monitoring, respectively, and (iii) additional care for CLHIV and HEU children who may have growth, neurodevelopmental, behavioural, cognitive or other deficits such as chronic lung disease, and require varying degrees of specialised care. However, the translation thereof into practice has been hampered by various systemic challenges, including shortages of trained healthcare staff, suboptimal use of the patient-held child's Road to Health book for screening and referral purposes, inadequate numbers and distribution of therapeutic staff, and shortages of assistive/diagnostic devices, where required. Additionally, in low-middle-income high HIV-prevalence settings, there is a lack of evidence-based solutions/models of care to optimise health amongst HEU and CLHIV. Current research priorities include understanding the mechanisms of preterm birth in women living with HIV to optimise preventive interventions; establishing pregnancy pharmacovigilance systems to understand the short-, medium- and long-term impact of in utero ART and HIV exposure; understanding the role of preconception maternal ART on HEU child infectious morbidity and long-term growth and neurodevelopmental trajectories in HEU children and CLHIV, understanding mental health outcomes and support required in HEU children and CLHIV through childhood and adolescence; monitoring HEU child morbidity and mortality compared with HIV-unexposed children; monitoring outcomes of CLHIV who initiated ART very early in life, sometimes with suboptimal ART regimens owing to medication formulation and registration issues; and testing sustainable models of care for HEU children and CLHIV including later reproductive care and support.

HPLC electrochemical detection and quantification of monoamines and their metabolites in rat brain tissue samples.

The monitoring of monoamines and their metabolites in CNS samples can be very valuable in pharmaceutical and biomedical research. A specific high performance liquid chromatography, coupled to a coulometric electrochemical detection method, for the assay of monoamines (dopamine, norepinephrine, epinephrine and serotonin) and their metabolites in rat brain tissue samples was developed. The chromatographic separation was achieved on a C8 reversed phase column with a mobile phase consisting of 0.1 M sodium formate buffer, 5 mM sodium 1-heptanesulfonate, 0.17 mM ethylenediaminetetraacetic acid disodium salt and 5% v/v acetonitrile (pH ±4.0). The detection was achieved through electrochemical detection, with a coulometric cell potential setting of +650 mV. The flow-rate was at 1 ml/min and the total run time was 50 min. The method was validated according to validation guidelines. The method was found to be linear (R2 > 0.99) over the analytical range (5 to 200 ng/ml) for all monoamines and their metabolites. All the other validation parameters were acceptable and within range. The method was applied to three rat brain areas (pre-frontal cortex, hippocampus and striatum), where the monoamines (except for epinephrine) and their metabolites were easily detected.

Nutritional supplements for people being treated for active tuberculosis: A technical summary.

Tuberculosis and nutrition are intrinsically linked in a complex relationship. Altered metabolism and loss of appetite associated with tuberculosis may result in undernutrition, which in turn may worsen the disease or delay recovery. We highlight an updated Cochrane review assessing the effects of oral nutritional supplements in people with active tuberculosis who are receiving antituberculosis drug therapy. The review authors conducted a comprehensive search (February 2016) for all randomised controlled trials comparing any oral nutritional supplement, given for at least 4 weeks, with no nutritional intervention, placebo or dietary advice only in people receiving antituberculosis treatment. Of the 35 trials (N=8 283 participants) included, seven assessed the provision of free food or high-energy supplements, six assessed multi-micronutrient supplementation, and 21 assessed single- or dual-micronutrient supplementation. There is currently insufficient evidence to indicate whether routinely providing free food or high-energy supplements improves antituberculosis treatment outcomes (i.e. reduced death and increased cure rates at 6 and 12 months), but it probably improves weight gain in some settings. Plasma levels of zinc, vitamin D, vitamin E and selenium probably improve with supplementation, but currently no reliable evidence demonstrates that routine supplementation with multi-, single or dual micronutrients above the recommended daily intake has clinical benefits (i.e. reduced death, increased cure rate at 6 and 12 months, improved nutritional status) in patients receiving antituberculosis treatment. In South Africa, most provinces implement a supplementation protocol based on nutritional assessment and classification of individuals rather than on disease diagnosis or treatment status.

Crystal form conversion of nevirapine solvates subjected to elevated temperature and humidity: a qualitative study.

Some known nevirapine solvates have been reported to undergo solvent exchange in aqueous media to form a stable hemihydrate. This study aimed to determine the effects of atmospheric moisture on said nevirapine solvates and to gain insight into which factors determine the end product of transformation. Solvates were prepared by solvent recrystallisation and stored, together with the anhydrous and hemihydrate forms, in a climate chamber at 40 °C and 75% RH for a period of 28 days. Samples were analyzed using DSC, TGA, FT-IR, PXRD and Karl Fischer titration. Some solvates were observed to undergo desolvation to the anhydrous form of nevirapine (Form I), whilst others converted to the hemihydrate. It was found that water miscibility of the guest solvent determined the stable form of nevirapine, anhydrous or hemihydrate, to which each solvate eventually transformed. Transformation to the hemihydrate only occurred if the guest solvent was sufficiently water soluble to allow water molecules to enter solvent channels and displace the original guest. Solvates with hydrophobic guests desolvated to the anhydrous form. We concluded that, in the absence of a guest, solvent channels are lost during transformation to the monoclinic crystal system and space group P21/c (Form I) so that water cannot enter after desolvation.

Hydroxychloroquine attenuates cigarette smoke induced autophagic signaling in the mouse ovary.

We previously demonstrated that Cigarette Smoke (CS) induces autophagy in the ovary. Therefore we aimed to determine if chloroquine (CQ) could inhibit CS-induced autophagy in the ovary. Eight week old mice were implanted with CQ pellets; 0, 25, and 50mg CQ/kg. Half of the animals in each group were exposed to room air and the other half were exposed to CS twice daily for 8 weeks. Ovaries were harvested for electron microscopy, gene and protein expression analysis. There was a significant increase in the production of autophagosomes in granulosa cells of mice exposed to CS (p=0.0297). However 25 and 50mg/kg CQ treatment significantly decreased the CS-induced autophagosomes (p=0.0505; p=0.0065) and attenuated the effects of CS on LC3B and BECN1 expression. In summary, this suggests that CQ attenuates CS-induced autophagy in the ovary and that ovarian protection from toxic insult is potentially feasible.

XoxF-type methanol dehydrogenase from the anaerobic methanotroph "Candidatus Methylomirabilis oxyfera".

"Candidatus Methylomirabilis oxyfera" is a newly discovered anaerobic methanotroph that, surprisingly, oxidizes methane through an aerobic methane oxidation pathway. The second step in this aerobic pathway is the oxidation of methanol. In Gramnegative bacteria, the reaction is catalyzed by pyrroloquinoline quinone (PQQ)-dependent methanol dehydrogenase (MDH). The genome of "Ca. Methylomirabilis oxyfera" putatively encodes three different MDHs that are localized in one large gene cluster: one so-called MxaFI-type MDH and two XoxF-type MDHs (XoxF1 and XoxF2). MxaFI MDHs represent the canonical enzymes, which are composed of two PQQ-containing large (α) subunits (MxaF) and two small (ß) subunits (MxaI). XoxF MDHs are novel, ecologically widespread, but poorly investigated types of MDHs that can be phylogenetically divided into at least five different clades. The XoxF MDHs described thus far are homodimeric proteins containing a large subunit only. Here, we purified a heterotetrameric MDH from "Ca. Methylomirabilis oxyfera" that consisted of two XoxF and two MxaI subunits. The enzyme was localized in the periplasm of "Ca. Methylomirabilis oxyfera" cells and catalyzed methanol oxidation with appreciable specific activity and affinity (Vmax of 10 micromole min(-1) mg(-1) protein, Km of 17 microM). PQQ was present as the prosthetic group,which has to be taken up from the environment since the known gene inventory required for the synthesis of this cofactor is lacking. The MDH from "Ca. Methylomirabilis oxyfera" is the first representative of type 1 XoxF proteins to be described.

Persistent self-consciousness about facial appearance, measured with the Derriford appearance scale 59, in patients after long-term biochemical remission of acromegaly.

CONTEXT: Acromegaly is associated with impaired quality of life (QoL) and causes anatomical disproportions, which may contribute to the decreased QoL after successful treatment. The Derriford appearance scale 59 (DAS59) is a questionnaire measuring psychological distress and disruptions to everyday life associated with self-consciousness of appearance. OBJECTIVE: Investigate the psychological distress and dysfunction related to self-consciousness about appearance and its effect on QoL in patients in long-term remission of acromegaly. PATIENTS, DESIGN AND METHODS: Patients (>18 years old) treated for acromegaly at the Department of Endocrinology of the Radboud University Medical Center Nijmegen were invited to participate. A gender-, age- and body mass index matched control group was provided by the patients themselves. Participants were asked to complete the modified DAS59-, research and development 36- (RAND-36), acromegaly quality of life questionnaire (AcroQoL) and a sociodemographic questionnaire. Differences between patient- and control groups and correlations between questionnaire scores and clinical characteristics collected from medical records were analyzed. MAIN OUTCOME MEASURES: Questionnaire scores. RESULTS: Of the 120 respondents, 73 agreed to participate [all cured or under biochemical control, median remission time 10.5 years (range 2.3-43.6 years)]. Of these, 34 (46.6%) reported self-consciousness about their appearance. Twenty-nine of these patients (85.3%) pointed out their face to be a prominent source of self-consciousness. Fifty-seven matched control subjects were included as well. Significant correlations were found between the scores of the DAS59 and the AcroQoL, RAND-36 and VAS in patients. CONCLUSIONS: Even after long-term remission of acromegaly, a large number of patients are self-conscious about their appearance, leading to psychological distress and disruptions to everyday life and decreased QoL. Facial features were the most important source of self-consciousness. This stresses the importance of addressing self-consciousness of appearance and the need for additional support in this regard during follow-up in these patients.

Are pharmacological interventions between conception and birth effective in improving reproductive outcomes in North American swine?

The objective of this review is to evaluate the effectiveness of using pharmacological compounds on reproductive outcomes, particularly litter size, in North American swine. While the opportunity to improve reproduction in North American pigs exists, numerous hurdles need to be overcome in order to achieve measureable results. In the swine industry, the majority of piglet losses are incurred during pregnancy and around farrowing. Over the last 20 years, a reduction in losses has been achieved through genetic selection and nutritional management; however, these topics are the focus of other reviews. This review will evaluate attempts to improve litter size by reducing losses at various stages of the reproductive process, from the time of conception to the time of farrowing, using pharmacological compounds. Generally, these compounds are used to either alter physiological processes related to fertilization, embryonic attachment or uterine capacity, etc., or to facilitate management aspects of the breeding females such as inducing parturition. Although some of the pharmacological agents reviewed here show some positive effects on improving reproductive parameters, the inconsistent results and associated risks usually outweigh the benefits gained. Thus, at the present time, the use of pharmacological agents to enhance reproduction in North American swine may only be recommended for herds with low fertility and presents an avenue of research that could be further explored.

Clinical markers of endometriosis: have we been too quick to judge?

Numerous biochemical differences have been documented in women with endometriosis compared to controls; however, identification of a clinically useful marker of endometriosis remains elusive. We postulate that the diversity of clinical presentations, patient objectives, and complexity of the pathophysiology of endometriosis mandates rigorous attention to study design and standardization of procedures and questionnaires that has heretofore been overlooked in the pursuit of clinical markers of this enigmatic disease. We further propose that it is premature to conclude that clinical markers of endometriosis brought forward in the literature lack clinical value in the diagnosis of endometriosis. To address this hypothesis we reviewed the literature and assessed papers according to a modified version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria from which 55 high quality papers were reviewed. While pelvic inflammation and pain is a known significant component of endometriosis, control group definitions were widely divergent and included healthy women through to women with other inflammatory conditions. Although pain is a common presenting complaint in women with endometriosis, it was assessed in only 4 of 55 studies (7.3%) whereas infertility was documented in 34/55 studies (61.8%). Disease severity was assessed in 44 of 55 studies (80%) whilst the association between active vs. inactive disease was attempted in only 2 of the studies reviewed (3.6%). We conclude that experimental design criteria are inconsistently applied making comparisons across studies difficult. Thus, the clinical utility of previously described diagnostic markers of endometriosis remains uncertain.

CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.

The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication.

Polymorphisms in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) predict sunitinib-induced hypertension.

Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.