Assessing Global Kidney Nutrition Care.

BACKGROUND AND OBJECTIVES: Nutrition intervention is an essential component of kidney disease management. This study aimed to understand current global availability and capacity of kidney nutrition care services, interdisciplinary communication, and availability of oral nutrition supplements. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The International Society of Renal Nutrition and Metabolism (ISRNM), working in partnership with the International Society of Nephrology (ISN) Global Kidney Health Atlas Committee, developed this Global Kidney Nutrition Care Atlas. An electronic survey was administered among key kidney care stakeholders through 182 ISN-affiliated countries between July and September 2018. RESULTS: Overall, 160 of 182 countries (88%) responded, of which 155 countries (97%) answered the survey items related to kidney nutrition care. Only 48% of the 155 countries have dietitians/renal dietitians to provide this specialized service. Dietary counseling, provided by a person trained in nutrition, was generally not available in 65% of low-/lower middle-income countries and "never" available in 23% of low-income countries. Forty-one percent of the countries did not provide formal assessment of nutrition status for kidney nutrition care. The availability of oral nutrition supplements varied globally and, mostly, were not freely available in low-/lower middle-income countries for both inpatient and outpatient settings. Dietitians and nephrologists only communicated "sometimes" on kidney nutrition care in ≥60% of countries globally. CONCLUSIONS: This survey reveals significant gaps in global kidney nutrition care service capacity, availability, cost coverage, and deficiencies in interdisciplinary communication on kidney nutrition care delivery, especially in lower-income countries.

Predicting the safety of medicines in pregnancy: A workshop report.

The framework for developmental toxicity testing has remained largely unchanged for over 50 years and although it remains invaluable in assessing potential risks in pregnancy, knowledge gaps exist, and some outcomes do not necessarily correlate with clinical experience. Advances in omics, in silico approaches and alternative assays are providing opportunities to enhance our understanding of embryo-fetal development and the prediction of potential risks associated with the use of medicines in pregnancy. A workshop organised by the Medicines and Healthcare products Regulatory Agency (MHRA), "Predicting the Safety of Medicines in Pregnancy - a New Era?", was attended by delegates representing regulatory authorities, academia, industry, patients, funding bodies and software developers to consider how to improve the quality of and access to nonclinical developmental toxicity data and how to use this data to better predict the safety of medicines in human pregnancy. The workshop delegates concluded that based on comparative data to date alternative methodologies are currently no more predictive than conventional methods and not qualified for use in regulatory submissions. To advance the development and qualification of alternative methodologies, there is a requirement for better coordinated multidisciplinary cross-sector interactions coupled with data sharing. Furthermore, a better understanding of human developmental biology and the incorporation of this knowledge into the development of alternative methodologies is essential to enhance the prediction of adverse outcomes for human development. The output of the workshop was a series of recommendations aimed at supporting multidisciplinary efforts to develop and validate these alternative methodologies.

Exosome-Mediated miR-29 Transfer Reduces Muscle Atrophy and Kidney Fibrosis in Mice.

Our previous study showed that miR-29 attenuates muscle wasting in chronic kidney disease. Other studies found that miR-29 has anti-fibrosis activity. We hypothesized that intramuscular injection of exosome-encapsulated miR-29 would counteract unilateral ureteral obstruction (UUO)-induced muscle wasting and renal fibrosis. We used an engineered exosome vector, which contains an exosomal membrane protein gene Lamp2b that was fused with the targeting peptide RVG (rabies viral glycoprotein peptide). RVG directs exosomes to organs that express the acetylcholine receptor, such as kidney. The intervention of Exo/miR29 increased muscle cross-sectional area and decreased UUO-induced upregulation of TRIM63/MuRF1 and FBXO32/atrogin-1. Interestingly, renal fibrosis was partially depressed in the UUO mice with intramuscular injection of Exo/miR29. This was confirmed by decreased TGF-ß, alpha-smooth muscle actin, fibronectin, and collagen 1A1 in the kidney of UUO mice. When we used fluorescently labeled Exo/miR29 to trace the Exo/miR route in vivo and found that fluorescence was visible in un-injected muscle and in kidneys. We found that miR-29 directly inhibits YY1 and TGF-ß3, which provided a possible mechanism for inhibition of muscle atrophy and renal fibrosis by Exo/miR29. We conclude that Exo/miR29 ameliorates skeletal muscle atrophy and attenuates kidney fibrosis by downregulating YY1 and TGF-ß pathway proteins.

Precision Medicine for Nutritional Management in End-Stage Kidney Disease and Transition to Dialysis.

Chronic kidney disease (CKD) is a global public health burden. Dialysis is not only costly but may not be readily available in developing countries. Even in highly developed nations, many patients may prefer to defer or avoid dialysis. Thus, alternative options to dialysis therapy or to complement dialysis are needed urgently and are important objectives in CKD management that could have huge clinical and economic implications globally. The role of nutritional therapy as a strategy to slow CKD progression and uremia was discussed as early as the late 19th and early 20th century, but was only seriously explored in the 1970s. There is a revival of interest recently owing to encouraging data as well as the increase of precision medicine with an emphasis on a personalized approach to CKD management. Although part of the explanation for the inconclusive data may relate to variations in study design and dietary prescription, diversity in genetic make-up, variations in the non-nutritional management of CKD, intra-individual variations in responses to dietary and nondietary treatment, psychosocial factors, and dietary compliance issues, these all may contribute to the heterogeneous data and responses. This brings in the evolving concept of precision medicine, in which disease management should be tailored and individualized according not only to clinical manifestations but also to the genetic make-up and biologic responses to therapy, which may vary depending on genetic composition. Precision nutrition management also should take into account patient demographics, social, psychological, education, and compliance factors, which all may influence the therapeutic needs and responses to the nutritional therapy prescribed. In this review, we provide a novel concept of precision medicine in nutritional management in end-stage kidney disease with a transition to dialysis and propose how this may be the way forward for nutritional therapy in the CKD population.

The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure.

The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Cre-positive (SM22α)CaSR(Δflox/Δflox) [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca(2+)) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-l-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca(2+) concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.

Exploring the Needs and Concerns of Women with Early Breast Cancer during Chemotherapy: Valued Outcomes during a Course of Traditional Acupuncture.

Women diagnosed with breast cancer experience symptom clusters in addition to existential issues from a life-threatening diagnosis during chemotherapy. A complementary therapy, such as traditional acupuncture (TA) with its whole-person orientation, may help to modify these effects, alongside inducing other patient benefits. Exploring the needs and concerns of women and perceived benefits of TA would add to knowledge about its integrative treatment potential. Methods. A longitudinal qualitative study recruited fourteen women to receive up to ten sessions of TA during chemotherapy. They were interviewed before, during, and after chemotherapy. Two practitioners of TA delivered treatment and were interviewed before and after the study, and kept treatment logs and diaries. Interviews were recorded and transcribed, and the data were analysed using grounded theory. Findings. Both broad and specific benefits were reported by the women; a highly valued outcome was enabling coping through the alleviation of symptoms and increased well-being. Practitioners dealt with the presented symptom clusters facilitating outcome patterns, including and beyond individual symptom changes. Further research on TA as a flexible intervention able to respond to the changing needs and concerns of woman during chemotherapy along with the measure of such outcome patterns is warranted.

Factors influencing antibiotic prescribing habits and use of sensitivity testing amongst veterinarians in Europe.

The Heads of Medicines Agencies and the Federation of Veterinarians of Europe undertook a survey to gain a better insight into the decision-making process of veterinarians in Europe when deciding which antibiotics to prescribe. The survey was completed by 3004 practitioners from 25 European countries. Analysis was to the level of different types of practitioner (food producing (FP) animals, companion animals, equines) and country for Belgium, Czech Republic, France, Germany, Spain, Sweden and the UK. Responses indicate no single information source is universally considered critical, though training, published literature and experience were the most important. Factors recorded which most strongly influenced prescribing behaviour were sensitivity tests, own experience, the risk for antibiotic resistance developing and ease of administration. Most practitioners usually take into account responsible use warnings. Antibiotic sensitivity testing is usually performed where a treatment failure has occurred. Significant differences were observed in the frequency of sensitivity testing at the level of types of practitioners and country. The responses indicate a need to improve sensitivity tests and services, with the availability of rapid and cheaper testing being key factors.

In vivo alteration of Strata valve setting by vagus nerve stimulator-activating magnet.

We report the unexpected adjustment of a Strata shunt valve by a vagus nerve stimulator-activating magnet, resulting in symptomatic under-drainage of CSF. Implantable devices using magnets for calibration and activation are becoming more prevalent within neurosurgery and the present case highlights the potential for adverse interactions.

Effect of bicarbonate on muscle protein in patients receiving hemodialysis.

BACKGROUND: Metabolic acidosis stimulates whole-body net protein breakdown in healthy adults and patients with kidney failure, but few studies investigated how acidosis affects protein metabolism in individual tissues, such as skeletal muscle. METHODS: We evaluated the effect of metabolic acidosis on protein turnover in skeletal muscle, assessed by means of phenylalanine kinetics and free amino acid concentrations in plasma and muscle. Long-term hemodialysis patients (n = 16) were divided into 2 groups in an open crossover study design. In group A, we administered bicarbonate supplements and increased blood standard bicarbonate levels from 17.8 +/- 0.03 to 27.1 +/- 1.2 mEq/L (17.8 +/- 0.03 to 27.1 +/- 1.2 mmol/L). In group B, we decreased bicarbonate supplements, which caused a decrease in standard bicarbonate levels from 26.6 +/- 0.7 to 18.6 +/- 0.3 mEq/L (26.6 +/- 0.7 to 18.6 +/- 0.3 mmol/L). RESULTS: Net phenylalanine efflux from leg tissues (muscle) was significantly less when acid-base balance was corrected compared with acidosis (10.8 +/- 1.5 versus 18.6 +/- 3.8 nmol/min/100 g tissue; P = 0.014), as was the rate of phenylalanine appearance (28.3 +/- 3.0 versus 38.4 +/- 5.9 nmol/min/100 g tissue; P = 0.016); the rate of phenylalanine disposal was unchanged. Cortisol and C-reactive protein levels in blood were unchanged after correction of acidosis, as were levels of messenger RNAs encoding components of the ubiquitin-proteasome pathway in muscle biopsy specimens. CONCLUSION: Our findings indicate that acidosis increases protein breakdown in skeletal muscle, but additional studies are needed to identify the pathways stimulated to degrade muscle protein in response to acidosis.

Hypocalcaemia and parathyroid hormone assay following total thyroidectomy: predicting the future.

BACKGROUND: Ambulatory surgery (23:59-hour hospital stay) is gaining popularity in endocrine surgery. Hypocalcaemia is common following total thyroidectomy. Identifying patients with low risk of hypocalcaemia may facilitate early discharge (24-hour stay). METHODS: We conducted a prospective study including all patients undergoing total thyroidectomy. Blood samples were taken immediately following skin closure and the following morning for parathyroid hormone (PTH) and calcium measurement. Calcium supplements were routinely given when serum calcium was below 2.0 mmol/l. RESULTS: Thirty patients (27 females, 3 males) underwent total thyroidectomy (including 4 nodal dissection) for multinodular goitre (14), Graves' disease (11), papillary (4) and follicular (1) thyroid carcinoma. Twelve patients developed symptomatic transient hypocalcaemia. Based on morning calcium of < 2.0 mmol/l as trigger for calcium supplementation, 8 patients received calcium supplement with 4 false negatives, resulting in a specificity of 94.4%, sensitivity of 66.7%, positive predictive value (PPV) of 88.9% and negative predictive value (NPV) of 81%. Based on PTH levels (< 1.5 pmol/l) immediately following skin closure, 11 patients would receive calcium supplement, with 1 false negative resulting in a specificity of 83.3%, sensitivity of 91.7%, PPV of 78.6% and NPV of 93.8%. If supplementation is based on PTH levels (< 1.5 pmol/l) immediately following skin closure and morning calcium level (< 2.0 mmol/l), all 12 symptomatic patients will be correctly treated, with 4 false positives resulting in a combined specificity of 77.8%, sensitivity of 100%, PPV of 75% and NPV of 100%. CONCLUSIONS: Combining the immediate postoperation PTH levels (< 1.5 pmol/l) and morning serum calcium (< 2.0 mmol/l) can accurately identify patients at risk of hypocalcaemia following total thyroidectomy, allowing safe, early discharge.

Antibody responses of hens fed vitamin E and passively acquired antibodies of their chicks.

Antibody responses of hens and their progeny were studied in commercial broiler nuclear lines. Starting at 168 days of age, individually housed pullets from lines A and B were fed a 16% crude protein and 2752 kcal metabolizable energy/kg mash diet supplemented with either 10 or 300 IU/kg of vitamin E fed as dl-alpha-tocopherol acetate. Fifty-eight days later (226 days of age), 12 hens per line-vitamin E subclass were inoculated i.v. with 0.1 ml of a 2.5% suspension of sheep red blood cells (SRBC). Plasma antibody titers were measured 6, 20, 40, 54, 70, and 88 days after inoculation. Hens from both lines were artificially mated to males from line C, and progeny from eggs collected 9-15, 25-30, and 65-70 days after inoculation were tested for antibodies to SRBC. Hens were reinoculated i.v. with 0.1 ml of 0.25% SRBC 88 days after the first inoculation, and their antibody levels were measured 3, 6, and 20 days later. Eggs laid 10-13 days after reinoculation were incubated, and antibody titers of chicks were measured at hatch. Antibody response of hens to an initial inoculation of SRBC was line-diet-time after inoculation specific. In line A, titers were greater for hens fed the lower than the higher vitamin E diet, whereas diet had no effect on the antibody levels in line B. Line effects (A > B) were observed on days 6 and 20 after inoculation but not thereafter. After the second inoculation, dietary vitamin E level had no effect on antibody levels of hens within lines, whereas a between-line difference (A > B) was observed for the lower but not the higher level of dietary vitamin E. Although there was no difference between diets for antibody transferred to progeny by line B, there was a difference (lower > higher) for line A. After reinoculation of their dams, antibody titers of chicks from line A, but not line B, reached levels similar to those after the first inoculation. Antibody levels were higher for chicks at hatch than in 16-day embryos or 10 days posthatch. The results of this research suggest genetic variation in response to immune stimulation by dietary vitamin E.

Vitamin E and immune responses of broiler pureline chickens.

Immunological responses of cockerels fed diets containing either 10 or 300 mg/kg of vitamin E were measured in three commercial broiler nuclear lines designated as A, B, and C. All cockerels were fed the 10 mg/kg diet to 91 d of age, at which time half were continued on that diet and the other half were fed a diet supplemented to contain 300 mg/kg of vitamin E. Sixteen days after feeding the diets, cutaneous basophil hypersensitivity (CBH), which is an in vivo, cell-mediated immune response, was determined as the increase in toe-web skin thickness 24 h after an injection with phytohemagglutinin-P (PHA-P). Twenty-two days after feeding the diets, heterophils and lymphocytes were enumerated. At this time cockerels were also inoculated intravenously with 0.1 mL of 0.25% SRBC. The injection with SRBC was repeated 27 d later. Six and 20 d after each injection, antibody titers were determined. Mercaptoethanol-resistant (IgG) and mercaptoethanol-sensitive (IgM) antibodies were also measured in the secondary titers. The ratio of heterophils to lymphocytes increased, and CBH response was depressed by feeding the higher vitamin E diet. For cockerels of Lines A and B, the higher level of vitamin E maintained primary and secondary SRBC antibody levels, whereas for Line C, levels were depressed. The effect of the higher vitamin E diet on IgG and IgM was also stock-dependent. The enhanced heterophil:lymphocyte ratio from feeding vitamin E suggests an improved phagocytic ability of the immune system. Relative asymmetries for toe-web skin thickness and shank length were similar for the three lines.

Slowing of cisplatin aquation in the presence of DNA but not in the presence of phosphate: improved understanding of sequence selectivity and the roles of monoaquated and diaquated species in the binding of cisplatin to DNA.

1H-15N HSQC NMR spectroscopy is used to study the aquation reactions of cisplatin in 9 mM NaClO4 and 9 mM phosphate (pH 6) solutions at 298 K. For the first time in a single reaction and, therefore, under a single set of reaction conditions, the amounts of all species formed are followed and the rates of aquation, diaquation, and related anation processes are determined in both media. Binding of phosphate to aquated Pt species is observed, but the initial rate of aquation is not affected by the presence of 9 mM phosphate. The reaction between cisplatin and the 14-base-pair self-complementary oligonucleotide 5'-d(AATTGGTACCAATT)-3', having a GpG intrastrand binding site, is investigated. Various kinetic models for this reaction are evaluated and the most appropriate found to be that with a reversible aquation step and a single binding site for the self-complementary duplex. The rate constant for aquation is (1.62 +/- 0.02) x 10(-5) s-1, with the anation rate constant fixed at 4.6 x 10(-3) M-1 s-1, the value obtained from the aquation studies. The rate constants for monofunctional binding of cis-[PtCl(15NH3)2-(OH2)]+ to the sequence were 0.48 +/- 0.19 and 0.16 +/- 0.06 M-1 s-1 for the 3'- and 5'-guanine bases, respectively. Closure rate constants for the monofunctional adducts are (2.55 +/- 0.07) x 10(-5) and (0.171 +/- 0.011) x 10(-5) s-1, for the 3'- and 5'-guanines, respectively. The presence of DNA slows the aquation of cisplatin by 30-40% compared to that observed in 9 mM NaClO4 or 9 mM phosphate, and there is some evidence that the degree of slowing is sequence dependent. The possibility that cis-[Pt(OH)(NH3)2(OH2)]+ contributes to the binding of cisplatin to DNA is investigated, and it is found that about 1% followed this route, the majority of the binding occurring via the monoaquated species cis-[PtCl(NH3)2(OH2)]+. Comparison of the rates of disappearance of cisplatin in reactions at single defined GpG, ApG, GpA, GpTpG and 1,2-interstrand GG binding sites shows that the adduct profile is determined at the level of monofunctional adduct formation.

Microstimulation of movements from cerebellar-receiving, but not pallidal-receiving areas of the macaque thalamus under ketamine anaesthesia.

The motor thalamic areas receiving input from the globus pallidus (VA) and the cerebellar nuclei (VL) appear to have different roles in the generation and guidance of movements. In order to further test these differences, we used electrical stimulation to map the ventro-anterior and ventro-lateral nuclei of the thalamus in three ketamine anaesthetised monkeys. Movements were readily evoked from VL at currents of down to 10 microA. The movements were typically multijoint, and stimulation could evoke arm and trunk or arm and facial movement at the same current threshold. Evoked arm movements often involved multiple joints, with or without finger movements. Facial movements included the lips, tongue, jaw, eyebrows and, occasionally, the eyes. The thalamic map was topographic, but complex with at least two separate regions related to arm movement. Very few sites within the VA could stimulate movement, even at high currents. We therefore suggest that the cerebellar projections to motor regions of the cortex, which pass through the VL thalamic nuclei, have a different relationship and are closer to movement execution than the projections from basal ganglia via the ventro-anterior nucleus.

Using essential oils in professional practice.

As the use of aromatherapy within a health care setting has grown so rapidly in recent years, and will continue to do so, the need for suitable training has become apparent. No health service can afford the risk of having staff who are inadequately trained in the practice of aromatherapy using essential oils incorrectly on those in a state of ill-health, especially if the essential oils used are not to a standard suitable for therapeutic use. Training to an acceptable level in aromatic therapy is essential for safety and effectiveness. Knowledge of the nature and make-up of essential oils, their effect on the body and the emotions, and how, when, and where to apply them is imperative in order for them to be beneficial to a patient's health. Contraindications to certain oils, patients, or treatment have also to be thoroughly understood, and the dosage employed is related to some extent to the standard of training undertaken.

Platination of a GG site on single-stranded and double-stranded forms of a 14-base oligonucleotide with diaqua cisplatin followed by NMR and HPLC -- influence of the platinum ligands and base sequence on 5'-G versus 3'-G platination selectivity.

Detailed studies of the kinetics of platination of the single-stranded 14-base DNA oligonucleotide d(ATACATGGTACATA) and the corresponding duplex by cis-[Pt(NH3)2(H2O)2]2+ show that HPLC and NMR are complementary methods which provide similar results. The 5'-G and 3'-G monofunctional intermediates were trapped, separated and characterized by NMR (via 15NH3 labeling) and enzymatic digestion followed by mass spectrometry. The kinetic data are compared with those for the corresponding reactions of cis-[PtCl2(NH3)2] (cisplatin) and its monohydrolysed analogue. For both single and double strands of the oligonucleotide, the aqua complex shows little selectivity for the 5'-G or the 3'-G in the initial platination step, whereas the chloro-complex preferentially platinates the 3'-G. The base on the 3' side of the GG sequence appears to play an important role in controlling this selectivity; replacement of T by C increases the selectivity of duplex platination by the diaqua complex by a factor of about 6, and the selectivity of chelation of the 3'-G monofunctional adduct by a factor of about 3. In general the reactivity of the 5'-G in a GG sequence appears to be enhanced in a duplex compared with a single-strand. For both the aqua-monoadduct and chloro-monoadduct, cis-[Pt(NH3)2(N7G)(H2O or Cl)], the 5'-G monoadduct is much longer lived (t1/2 approximately 4 h at 288 K for aqua, 80 h at 298 K for chloro) than the 3'-G monoadduct (t1/2 < or = 45 min at 288 K for aqua, 6 h at 298 K for chloro). Inspection of molecular mechanics models of the end states of various monofunctional adducts provided insight into H-bonding and destacking interactions in these adducts and the sequence selectivity observed in their formation. Such adducts may play an important role in the mechanism of action of platinum anticancer drugs.

Antimicrobial activity of hop extracts against Listeria monocytogenes in media and in food.

Growth of Listeria monocytogenes was inhibited in culture media and in certain foods by four hop extracts (I-IV) containing varying concentrations of alpha-and beta-acids. Extracts (II and III) containing the highest concentrations of beta-acids were inhibitory at 0.01 mg/l in trypticase soy broth. In food, these hop extracts showed varying magnitudes of inhibition. In coleslaw, hop extract III at 1 mg/g enhanced the rate of inactivation of L. monocytogenes Scott A. Hop extract II was inhibitory at 0.1 and 1 mg/ml in skim and 2% milk, and was inhibitory at 1 mg/ml in whole milk. Hop extract II was listericidal in cottage cheese at 0.1 to 3 g/kg. No inhibition of L. monocytogenes by hop extract III was observed in Camembert cheese. Overall, the antimicrobial activity of hop extracts in food appeared to increase with acidity and lower fat content. Our results indicate that hop extracts could be used to control L. monocytogenes in minimally processed food with low fat content.