Episodic replacement of clotting factor concentrates does not prevent bleeding or musculoskeletal damage - the MUSFIH study.

PATIENTS AND METHODS: A longitudinal study was carried out in 255 children from 10 centres in nine developing countries over 5 years to assess the musculoskeletal outcome of children on episodic factor replacement. Outcome was documented by assessment of the annual joint bleeding rate (AJBR), WFH clinical and Pettersson radiological joint scores as well as the FISH score for activities. Of the 203 patients for whom data was available at the end of 5 years, 164 who had received only episodic treatment are included in this report. RESULTS: The median age at the beginning of the study was 10 years (IQR 7-12). The median clotting factor concentrate (CFC) usage was 662 IU kg-1 year-1 (IQ range: 280-1437). The median AJBR was 10 (IQ range: 5-17). The median AJBR was higher in the older children with the median being 5 for the 5 year old child, while it was 9 for the 10 year old and 11 for children older than 15. Given the episodic nature of the replacement therapy, those with a higher AJBR used significantly greater annual CFC doses (P < 0.001); The median change in WFH clinical score and Pettersson radiological score over the 5 years was 0.4/year for each, while the FISH deteriorated at a rate of 0.2/year with poor correlation of these changes with CFC dose. WFH and FISH scores were significantly worse in those with an AJBR of >3 per year (P = 0.001). The change in the Pettersson score was significantly more in those with an AJBR of >5 per year (P = 0.020). Significant changes in FISH scores were only noted after 10 years of age. CONCLUSION: Episodic CFC replacement over a large range of doses does not alter the natural course of bleeding in haemophilia or the musculoskeletal deterioration and should not be recommended as a long term option for treatment. Prophylaxis is the only way to preserve musculoskeletal function in haemophilia.

QTL analysis in multiple sorghum populations facilitates the dissection of the genetic and physiological control of tillering.

KEY MESSAGE: A QTL model for the genetic control of tillering in sorghum is proposed, presenting new opportunities for sorghum breeders to select germplasm with tillering characteristics appropriate for their target environments. Tillering in sorghum can be associated with either the carbon supply-demand (S/D) balance of the plant or an intrinsic propensity to tiller (PTT). Knowledge of the genetic control of tillering could assist breeders in selecting germplasm with tillering characteristics appropriate for their target environments. The aims of this study were to identify QTL for tillering and component traits associated with the S/D balance or PTT, to develop a framework model for the genetic control of tillering in sorghum. Four mapping populations were grown in a number of experiments in south east Queensland, Australia. The QTL analysis suggested that the contribution of traits associated with either the S/D balance or PTT to the genotypic differences in tillering differed among populations. Thirty-four tillering QTL were identified across the populations, of which 15 were novel to this study. Additionally, half of the tillering QTL co-located with QTL for component traits. A comparison of tillering QTL and candidate gene locations identified numerous coincident QTL and gene locations across populations, including the identification of common non-synonymous SNPs in the parental genotypes of two mapping populations in a sorghum homologue of MAX1, a gene involved in the control of tiller bud outgrowth through the production of strigolactones. Combined with a framework for crop physiological processes that underpin genotypic differences in tillering, the co-location of QTL for tillering and component traits and candidate genes allowed the development of a framework QTL model for the genetic control of tillering in sorghum.

Prophylaxis is the new standard of care in patients with haemophilia.

Randomised controlled clinical trial evidence on prophylaxis as optimal care for patients with haemophilia was generated more than a decade ago. However, this knowledge has not translated into clinical practice in South Africa (SA) owing to many barriers to prophylaxis. These include the high treatment burden imposed by prophylaxis (frequent injections two to four times a week), the need for intravenous access to administer replacement clotting factor therapies, and the higher volume of clotting factor required compared with episodic treatment. The recently introduced non-factor therapies in haemophilia care have addressed many of these barriers. For example, emicizumab, which is currently the only globally approved non-factor therapy, can be administered subcutaneously less frequently (weekly, fortnightly or every 4 weeks) and has led to global adoption of prophylaxis as the standard of care in haemophilia by the bleeding disorders community. Haemophilia A is the most prevalent clotting factor deficiency in SA, with >2 000 people diagnosed to date. However, only a few of these patients are currently on prophylaxis. In this 'In Practice' article, we review the rationale for prophylaxis, outline its goals and benefits, and provide evidence-based guidance on which haemophilia patients should be prioritised for emicizumab prophylaxis. This consensus guidance facilitates the adoption of prophylaxis as a national policy and the new standard of care in haemophilia in SA.

High-Throughput Phenotyping of Dynamic Canopy Traits Associated with Stay-Green in Grain Sorghum.

Drought is a recurring phenomenon that puts crop yields at risk and threatens the livelihoods of many people around the globe. Stay-green is a drought adaption phenotype found in sorghum and other cereals. Plants expressing this phenotype show less drought-induced senescence and maintain functional green leaves for longer when water limitation occurs during grain fill, conferring benefits in both yield per se and harvestability. The physiological causes of the phenotype are postulated to be water saving through mechanisms such as reduced canopy size or access to extra water through mechanisms such as deeper roots. In sorghum breeding programs, stay-green has traditionally been assessed by comparing visual scores of leaf senescence either by identifying final leaf senescence or by estimating rate of leaf senescence. In this study, we compared measurements of canopy dynamics obtained from remote sensing on two sorghum breeding trials to stay-green values (breeding values) obtained from visual leaf senescence ratings in multienvironment breeding trials to determine which components of canopy development were most closely linked to the stay-green phenotype. Surprisingly, canopy size as estimated using preflowering canopy parameters was weakly correlated with stay-green values for leaf senescence while postflowering canopy parameters showed a much stronger association with leaf senescence. Our study suggests that factors other than canopy size have an important role in the expression of a stay-green phenotype in grain sorghum and further that the use of UAVs with multispectral sensors provides an excellent way of measuring canopy traits of hundreds of plots grown in large field trials.

Soluble, semivolatile phenol and nitrogen compounds in milk-processing wastewaters.

Potable water is an essential and major input in processing our food supplies, and the continued growth in food manufacturing is placing increased pressure on this limited resource. Recycling and reuse of factory wastewater can lessen potable water use but requires a detailed understanding of wastewater properties. This study uses solid-phase extraction techniques with gas chromatography-mass spectrometry analysis to investigate trace-level semivolatile organic species in various waste and reference waters associated with the Burra Foods milk-processing plant located in Southeastern Australia. Our focus was on contaminants containing phenolic and heterocyclic nitrogen functional groups, which, because of their toxicity and persistence, may limit options for water recycling and reuse. Effluent from the wastewater treatment plant of the factory showed both the highest soluble carbon burden (47 mg/kg) and concentrations of target compounds. The target species found in these effluents included methyl phenol (13 mg/kg), hydroxy indole (9.8 mg/kg), synthetic tolyltriazoles (5.1 mg/kg) and alkyl phenol ethoxylates (0.2 mg/kg). Given the environmental stability of the tolyltriazoles, they may act as chemical markers where these effluents are used for purposes such as irrigation. Milk evaporator condensate waters, in contrast to the effluent, contained very few target species, with only low levels of pyrrolidine and piperidine derivatives such as ethylglutarimide (450 mug/L) detected. Although there were fewer target microcontaminants overall in the potable and creek reference waters, these samples had characteristic profiles. The potable water analysis revealed hydroxy cineole (2.1 microg/L) and the creek analysis revealed dichlorohydroxyacetophenone (0.3 microg/L), which were not detected in other waters. The compounds found in the wastewaters are likely to have been derived from milk or synthetic chemicals used in factory operations. The presence of nitrogen compounds in all the different milk-processing waters suggest their likely source was milk, probably milk phosphoproteins subjected to thermal, chemical, or microbial degradation. Our benign results for the condensates suggest it may be possible to substitute condensate for potable water with minimal pretreatment, both within the plant and in other applications, such as irrigation of recreation turf.

Home therapy for inherited bleeding disorders in South Africa: Results of a modified Delphi consensus process.

BACKGROUND: Optimal care of patients with inherited bleeding disorders requires that bleeding episodes are treated early, or still better prevented, through extension of patient care beyond hospital-based treatment to home-based therapy. In South Africa (SA), adoption of home therapy is variable, in part owing to lack of consensus among healthcare providers on what constitutes home therapy, which patients should be candidates for it, how it should be monitored, and what the barriers to home therapy are. OBJECTIVES: To conduct a modified Delphi process in order to establish consensus on home therapy among haemophilia healthcare providers in SA. METHODS: Treaters experienced in haemophilia care were invited to participate in a consensus-seeking process conducted in three rounds. In round 1, provisional statements around home therapy were formulated as questions and collated in a structured list. In rounds 2 and 3, evolving versions of the questionnaire were administered to participants. Consensus was defined as ≥70% agreement among the participants. RESULTS: The panel composition included an equal number of physicians and non-physicians. The participation rate was 100% through all three consensus rounds. The group reached consensus for 92% of the statements. Consensus of 100% was reached on starting home therapy in paediatric patients, requiring all patients on home therapy to sign informed consent and indemnity, and providing round-the-clock support for patients on home therapy. CONCLUSIONS: The home therapy consensus statements in this report have the potential to translate to policy on home therapy and to guide the initiation, practice and evaluation of home therapy programmes in SA.

Alcoholic ketoacidosis.

Alcoholic ketoacidosis (AKA) is a common reason for investigation and admission of alcohol dependent patients in UK emergency departments. Although well described in international emergency medicine literature, UK emergency physicians rarely make the diagnosis of AKA. There is increasing evidence that rather than being benign and self limiting, AKA may be a significant cause of mortality in patients with alcohol dependence. This literature review discusses the history, characterisation, pathophysiology, diagnosis, and management of AKA.

Direct in situ observation of ZnO nucleation and growth via transmission X-ray microscopy.

The nucleation and growth of a nanostructure controls its size and morphology, and ultimately its functional properties. Hence it is crucial to investigate growth mechanisms under relevant growth conditions at the nanometer length scale. Here we image the nucleation and growth of electrodeposited ZnO nanostructures in situ, using a transmission X-ray microscope and specially designed electrochemical cell. We show that this imaging technique leads to new insights into the nucleation and growth mechanisms in electrodeposited ZnO including direct, in situ observations of instantaneous versus delayed nucleation.

Phospholipase A2 enhances [3H]AMPA binding to a putative homomeric GluR-B receptor in the rat spinal cord.

[3H]AMPA and [3H]kainate binding to rat spinal cord was localised most densely in the substantia gelatinosa of the dorsal horn. Phospholipase A2 elicited a dose-dependent increase in specific [3H]AMPA binding but not in [3H]kainate binding. The enhancement of [3H]AMPA binding was blocked by bromophenacyl bromide and at 0 degree C and was not mimicked by arachidonic acid. Since GluR-B is the only AMPA receptor subunit detectable in the rat spinal cord, and recombinant homomeric GluR-B assemblies do not bind [3H]kainate, these results suggest phospholipase A2 may modulate [3H]AMPA binding to putative homomeric GluR-B receptors.

Influence of etofibrate on low density lipoprotein metabolism.

This study examined the effect of single dose etofibrate (1.0 g/day) on plasma lipids and lipoproteins in a group of eleven hypercholesterolemic individuals. The drug lowered plasma triglyceride and cholesterol by 32% and 14%, respectively (P less than 0.005). The cholesterol reduction came from a decrement in both VLDL and LDL. The cholesterol content of HDL did not change although its mass as determined by analytical ultracentrifugation rose by 29%. LDL metabolism was followed before and during drug therapy. Treatment increased catabolism of this lipoprotein by 14%, without affecting synthesis. The increased clearance resulted from activation (64%) of the LDL receptor pathway. There was a reciprocal decrease in the amount of lipoprotein channelled into the receptor-independent route.

ACP Best Practice No 166: CSF spectrophotometry in the diagnosis of subarachnoid haemorrhage.

After subarachnoid haemorrhage (SAH), cerebral angiography is usually performed to establish a site of bleeding, which may then be treated surgically to prevent a potentially catastrophic re-bleed. The investigation of choice in the diagnosis of SAH is computerised tomography (CT). However, because CT can miss some patients with SAH, cerebrospinal fluid (CSF) spectrophotometry should be performed in those patients with negative or equivocal CT scans or those who have presented several days after the suspected bleed. Spectrophotometry should aim to detect the presence of both oxyhaemoglobin and bilirubin because either one or both of these pigments may contribute to xanthochromia following SAH. CSF supernatant is scanned using a double beam spectrophotometer at wavelengths between 350 nm and 650 nm. Oxyhaemoglobin alone produces an absorption peak at 413-415 nm, bilirubin alone produces a broad peak at 450-460 nm, and bilirubin together with oxyhaemoglobin produce a shoulder at 450-460 nm on the downslope of the oxyhaemoglobin peak. To minimise the frequency of false positive and false negative results, a protocol has been developed, which is described.

Increased interleukin 6 concentrations in the absence and presence of HIV-1 infection in haemophilia.

AIMS: To measure IL-6 concentrations in asymptomatic HIV-1 antibody positive and negative haemophilic patients and to correlate these with IgG concentrations and CD4 positive cell numbers. METHODS: IL-6 concentrations were measured by bioassay in stored serum from a prospective cohort of haemophilic patients in whom immunoglobulins and T cell subsets had been determined. Values of IL-6 and immunoglobulins were also correlated with severity of liver disease. RESULTS: IL-6 concentrations were raised in haemophilic patients independent of HIV-1 antibody status. In HIV-1 antibody positive patients there was no correlation between IL-6 concentrations and CD4 positive cell numbers, but there was a correlation with IgG (r = 0.4; p = 0.05). In HIV-1 antibody negative patients there were no significant correlations. CONCLUSIONS: Haemophilic patients have increased IL-6 concentrations; in HIV-1 positive patients this is independent of the decline in CD4 cell count. The raised concentrations do not correlate with the clinical severity of liver disease.

Thiamine deficiency in the critically ill.

There have been recent reports of hospitalised patients developing clinical thiamine deficiency, combined with much debate on the optimal supplementation of thiamine for the parenterally fed patient, particularly in the intensive therapy environment. We performed a retrospective study on 158 patients admitted to the Intensive Care Unit who required nutritional support. Patients who survived had significantly higher body thiamine status than those who died (p less than 0.01). There was no difference between serum albumin concentrations of the two groups. Twenty percent of the patients had biochemical evidence of thiamine deficiency and the mortality rate in these patients was 72% as compared with 50% mortality overall. Follow-up results suggest that current levels of thiamine supplementation are insufficient for critically ill intravenously fed patients. We suggest that patients be given a loading dose of 50-250 mg thiamine on admission to the Intensive Care Unit.

Effect of combined therapy with bezafibrate and cholestyramine on low-density lipoprotein metabolism in type IIa hypercholesterolemia.

This study was designed to examine the influence of combined therapy with bezafibrate and cholestyramine on plasma lipids and on the metabolism of low-density lipoprotein (LDL). Twenty-one type II hyperlipidemic subjects were treated with bezafibrate alone or in combination with cholestyramine. A 17% fall in plasma cholesterol was seen with bezafibrate, and addition of cholestyramine produced an additional 9% reduction in this lipid. The effectiveness of the combination therapy was mediated through a 47% decrement in very-low-density lipoprotein (VLDL) cholesterol, a 37% reduction in LDL cholesterol, and a 15% increase in the level of that lipid in high-density lipoprotein (HDL). Plasma triglyceride fell 43% when bezafibrate was given alone, and did not change further when cholestyramine was added. The metabolism of LDL was examined in nine individuals to determine the mechanism underlying these changes. No significant modification in LDL synthetic rate was incurred with either drug regimen, whereas the fractional catabolic rate of LDL via the receptor pathway rose by 66% with bezafibrate alone and by 79% (compared to baseline) following the addition of cholestyramine. Plasma HDL rose during bezafibrate therapy due to an increase in the HDL3 subfraction. Compositional analysis of LDL showed a reduction in cholesterol ester and an increase in triglyceride and phospholipid during combined drug therapy. These results demonstrate that combined therapy with bezafibrate and cholestyramine markedly improves the lipoprotein profile in type II hyperlipidemia. The drugs appear to be complementary in their actions upon the LDL receptor pathway.

Effect of combined prednisolone, epidural analgesia, and indomethacin on the systemic response after colonic surgery.

Twenty patients undergoing colonic resection were randomized to either conventional postoperative pain treatment with morphine chloride and acetaminophen (group 1, n = 9) or methylprednisolone sodium succinate 90 minutes before surgery plus intraoperative neural blockade, with a postoperative analgesic regimen with combined bupivacaine hydrochloride-morphine and indomethacin sodium for systemic effect (group 2, n = 11). Assessments of pain, pulmonary function, convalescence, and various injury factors were done several times until 8 days after surgery. Postoperative pain and hyperthermic response were eliminated in group 2. Conventional reduction in pulmonary function measures was improved in group 2, and fatigue and mobility were less pronounced. Prostaglandin E2, interleukin 6, and C-reactive protein levels increased in both groups, but significantly less in group 2. These results suggest that a combined neural and humoral blockade may more effectively inhibit the global stress response to elective surgery than previously observed with neural blockade with or without indomethacin.