Defining tetrahydrobiopterin responsiveness in phenylketonuria: Survey results from 38 countries.

BACKGROUND: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH4), although there is no consensus on the definition of BH4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH4 responsiveness being used around the world. METHODS: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other). RESULTS: We analysed 166 responses. Long-term BH4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently. CONCLUSION: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH4 treatment.

Prognostic relevance of pre- and postoperative plasma l-lactate measurements in calves with acute abdominal emergencies.

In both human and veterinary medicine, l-lactate is a well-established prognostic biomarker of disease severity and mortality and has also attracted increasing attention in bovine medicine due to the availability and validation of cheap and portable l-lactate analyzers. The aim of the present study was to evaluate the prognostic accuracy of plasma L-lactate measurements in calves with acute abdominal emergencies before and during the initial therapeutic period after surgical intervention. A prospective observational study was carried out involving 83 hospitalized calves up to an age of 7 mo, which required surgical intervention for reasons of an acute abdominal emergency such as gastrointestinal ileus or peritonitis. Plasma l-lactate (L-LAC) concentrations were determined immediately before initiation of surgery and 6, 12, 24, 48, and 72 h later. The outcome of calves was evaluated 3 mo after discharge by a phone call to the farmer, and a positive outcome was defined if the calf was still alive and the owner was satisfied with the animal's postsurgical progress. A total of 29% of calves were discharged from the hospital and the proportion of calves with a positive outcome after the 3-mo period was 24%. At all sampling times during the first 48 h after initiation of surgical intervention, calves with a negative outcome had significantly higher L-LAC than calves with a positive outcome. A binary logistic regression analysis indicated that the odds for a negative outcome during the 3-mo observation period increased by a factor of 1.23 [95% confidence interval (CI): 1.04-1.44] for every mmol/L increase of L-LAC before initiation of surgical intervention, but by a factor of 5.29 (95% CI: 1.69-16.6) and 5.92 (95% CI: 1.29-27.3) at 12 and 24 h, respectively. The largest area under the receiver operating characteristic curve for L-LAC was observed at 12 h (0.91; 95% CI: 0.83-0.99), and a cut-point of 2.75 mmol/L was identified that had a sensitivity and specificity for predicting a negative outcome of 68 and 100%, respectively. In conclusion, persistent hyper-l-lactatemia during the early postoperative period is a more reliable indicator for a negative outcome in calves with acute surgical abdominal emergencies than hyper-l-lactatemia before initiation of surgical intervention. Postoperative measurements of L-LAC are therefore a clinically useful tool to identify patients with an increased risk for a negative outcome at an early stage after surgical intervention was carried out.

Prognostic utility of pre- and postoperative plasma l-lactate measurements in hospitalized cows with acute abdominal emergencies.

The aim of the present analyses was to compare the prognostic value of pre- and postoperative l-lactate measurements in hospitalized cows requiring surgical intervention for an acute abdominal emergency, such as gastrointestinal ileus or peritonitis. For this purpose, we analyzed data from retro- and prospective case series, consisting of 754 and 98 cows, respectively. Plasma l-lactate concentrations (L-LAC) were determined upon admission to the hospital (both study populations), immediately before initiation of surgical intervention (prospective study population), and 6, 12, 24, 48, and 72 h later (prospective study population). The outcome of cows was evaluated until hospital discharge (both study populations) and 3 mo after discharge by a phone call to the farmer (prospective study population). A negative outcome was defined as death or euthanasia during hospitalization, or if discharged animals had an unsatisfied owner or were culled for medical reasons that were directly related to the initial abdominal emergency. For the retrospective study population, the overall survival rate until hospital discharge was 66%. Cows with a negative outcome (median: 6.81 mmol/L) had significantly higher L-LAC than cows with a positive outcome (3.66 mmol/L) of therapy. At the individual diagnosis level, L-LAC was associated with mortality in cows with a diagnosis of abomasal volvulus, local peritonitis, hemorrhagic bowel syndrome, and jejunal volvulus. Considering the whole study population, the area under the receiver operating characteristic curve was 0.66. For the prospective study population, the proportion of cows with a positive outcome was 65% until hospital discharge and 61% after the 3-mo observation period. At all sampling times, before and during the first 12 h after surgical intervention, cows with a negative outcome had significantly higher L-LAC than cows with a positive outcome. The largest area under the receiver operating characteristic curve for L-LAC was observed at 6 h (0.89). A cut-point of 1.77 mmol/L was identified, which had a sensitivity and specificity for predicting a negative outcome until hospital discharge of 88.9 and 73.4%, respectively. The present analyses confirmed previous findings in calves and show that persistent hyper-l-lactatemia during the early postoperative period is a more reliable indicator for a negative outcome than hyper-l-lactatemia before initiation of surgical intervention.

Evaluation of the analytical performance of a portable ion-selective electrode meter for measuring whole-blood, plasma, milk, abomasal-fluid, and urine sodium concentrations in cattle.

A portable ion-selective electrode (ISE) meter (LAQUAtwin B-722; Horiba Instruments Inc., Irvine, CA) is available for measuring the sodium ion concentration ([Na]) in biological fluids. The objective of this study was to characterize the analytical performance of the ISE meter in measuring [Na] in whole-blood, plasma, milk, abomasal fluid, and urine samples from cattle. Method comparison studies were performed using whole-blood and plasma samples from 106 sick calves and 11 sick cows admitted to a veterinary teaching hospital, 80 milk and 206 urine samples from 16 lactating Holstein-Friesian cows with experimentally induced free water, electrolyte, and acid-base imbalances, and 67 abomasal fluid samples from 7 healthy male Holstein-Friesian calves fed fresh milk with or without an oral electrolyte solution. Deming regression and Bland-Altman plots were used to determine the accuracy of the meter against reference methods. The meter used in direct mode on undiluted samples measured whole-blood [Na] 9.7 mmol/L (7.3%) lower than a direct ISE reference method and plasma [Na] 16.7 mmol/L (12.7%) lower than an indirect ISE reference method. The meter run in direct mode measured milk [Na] 3.1 mmol/L lower and abomasal fluid [Na] 9.0% lower than indirect ISE reference methods. The meter run in indirect mode on diluted samples accurately measured urine [Na] compared with an indirect ISE reference method. We conclude that, after adjustment for the bias determined from Bland-Altman plots, the LAQUAtwin ISE meter provides a clinically useful and low-cost cow-side instrument for measuring [Na] in whole blood, plasma, milk, and abomasal fluid.

Prognostic value of preoperative plasma l-lactate concentrations in calves with acute abdominal emergencies.

Acute abdominal emergencies in calves due to abomasal disorders, gastrointestinal ileus, or peritonitis are characterized by a rapid disease progression and usually require immediate surgical intervention. Those conditions are associated with a guarded prognosis, and the aim of the present study was to assess the prognostic relevance of preoperatively measured plasma l-lactate concentrations (l-LAC) in a large study population of calves with a broad spectrum of acute abdominal emergencies. For the purpose of this study, the medical records of 587 calves admitted to a veterinary teaching hospital over a 10-yr period were analyzed retrospectively. Plasma l-LAC was measured as part of a routinely performed biochemistry panel before initiation of surgical intervention. Hyper-l-lactatemia (plasma l-LAC >2.2 mmol/L) was evident in 75% of calves, and the overall survival rate until hospital discharge was 31%. Calves with a negative outcome were younger (median: 3.4 vs. 6 wk) and had higher plasma l-LAC (median: 4.96 vs. 3.09 mmol/L) than calves with a positive outcome. At the individual diagnosis level, l-LAC was associated with mortality in calves with a diagnosis of mesenteric torsion, right-sided dilated abomasum, small intestinal volvulus, or paralytic ileus, but not in calves suffering from peritonitis, malformations, abomasal volvulus, bloat, or small intestinal intussusceptions. Considering the whole study population, the area under the receiver operating characteristic (ROC) curve for plasma l-LAC was 0.66 [95% confidence interval (CI): 0.61-0.70]. A classification tree analysis indicated that l-LAC >8.84 mmol/L and age categories of <3 wk and <1 wk were independent predictors of mortality. The area under the ROC curve of this model was 0.75 (95% CI: 0.71-0.79) and the resulting sensitivity and specificity for the prediction of nonsurvival at the optimal probability cut-point of 0.62 were 67.7 and 76.6%, respectively. In conclusion, hyper-l-lactatemia is common in calves suffering from acute abdominal emergencies. Markedly increased plasma l-LAC is associated with an increased mortality risk, but it is not possible to reliably predict the outcome of affected calves based on a single, preoperative measurement. However, a clinically important finding of this study was that the ability to predict a negative outcome is improved when the age of the calf is considered in addition to plasma l-LAC.

Effects of profound acidemia on the dynamic glucose and insulin response and plasma potassium and phosphorus concentrations during an intravenous glucose tolerance test in neonatal calves.

Acidemia and electrolyte imbalances such as hyperkalemia are common in neonatal calves with diarrhea. Acidemia negatively affects the cellular response to insulin and may therefore result in deranged glucose, potassium, and phosphorus homeostasis. The primary aim of this study was to compare indices that characterize the dynamic glucose and insulin response between acidemic and nonacidemic neonatal diarrheic calves and a healthy control group during an intravenous glucose tolerance test (IVGTT) that consisted of i.v. administration of 0.3 g of glucose per kg of body weight. Secondary aims were to characterize the associated changes in plasma potassium and phosphorus concentrations. The effect of correction of profound acidemia with a sodium bicarbonate containing infusion on these parameters was also assessed. Thirty calves (age ≤21 d) were purposively assigned to one of the following groups: 10 calves with diarrhea and profound acidemia (venous blood pH <7.20) where an IVGTT was performed before and after treatment with sodium bicarbonate, 10 calves with diarrhea and minimal acid-base disturbance (venous blood pH >7.35), and 10 healthy control calves. Profoundly acidemic diarrheic calves (jugular venous blood pH 6.99 ± 0.10) had a similar initial increase in plasma insulin concentration to that in healthy control calves or nonacidemic calves with diarrhea. However, insulin concentrations remained relatively stable in acidemic calves between 15 and 60 min after the start of the IVGTT, whereas a marked decrease in plasma insulin concentrations occurred in all other groups during the same period of time. We conclude that acidemia does not alter cell glucose availability or the dynamic response of glucose, phosphorus, and potassium to insulin; however, acidemia markedly prolongs plasma insulin concentrations following an IVGTT through an unidentified mechanism. Results of this study emphasize the importance of correcting acidemia and metabolic acidosis in neonatal calves with diarrhea.

The challenges of managing coexistent disorders with phenylketonuria: 30 cases.

INTRODUCTION: The few published case reports of co-existent disease with phenylketonuria (PKU) are mainly genetic and familial conditions from consanguineous marriages. The clinical and demographic features of 30 subjects with PKU and co-existent conditions were described in this multi-centre, retrospective cohort study. METHODS: Diagnostic age of PKU and co-existent condition, treatment regimen, and impact of co-existent condition on blood phenylalanine (Phe) control and PKU management were reported. RESULTS: 30 patients (11 males and 19 females), with PKU and a co-existent condition, current median age of 14 years (range 0.4 to 40 years) from 13 treatment centres from Europe and Turkey were described. There were 21 co-existent conditions with PKU; 9 were autoimmune; 6 gastrointestinal, 3 chromosomal abnormalities, and 3 inherited conditions. There were only 5 cases of parental consanguinity. Some patients required conflicting diet therapy (n=5), nutritional support (n=7) and 5 children had feeding problems. There was delayed diagnosis of co-existent conditions (n=3); delayed treatment of PKU (n=1) and amenorrhea associated with Grave's disease that masked a PKU pregnancy for 12 weeks. Co-existent conditions adversely affected blood Phe control in 47% (n=14) of patients. Some co-existent conditions increased the complexity of disease management and increased management burden for patients and caregivers. CONCLUSIONS: Occurrence of co-existent disease is not uncommon in patients with PKU and so investigation for co-existent disorders when the clinical history is not completely consistent with PKU is essential. Integrating care of a second condition with PKU management is challenging.

Hyperkalemia in neonatal diarrheic calves depends on the degree of dehydration and the cause of the metabolic acidosis but does not require the presence of acidemia.

Hyperkalemia is a clinically important electrolyte imbalance in neonatal diarrheic calves that has previously been associated with skeletal muscle weakness and life-threatening cardiac arrhythmias. The aim of the present retrospective analysis was to identify risk factors for hyperkalemia in a convenience sample of 832 calves (≤ 21 d of age) with a clinical diagnosis of diarrhea admitted to a veterinary teaching hospital. Plasma potassium concentrations were most closely associated with parameters of dehydration and renal function such as serum creatinine [Spearman correlation (rs) = 0.61], urea (rs = 0.51), and inorganic phosphorus concentrations (rs = 0.64). Plasma potassium concentrations were weakly associated with venous blood pH (rs = -0.21). Although venous blood pH was not predictive in a multivariate linear regression analysis, the odds of having hyperkalemia (>5.8 mmol/L) in acidemic calves was found to be 8.6 times as high as in nonacidemic calves [95% confidence interval (CI): 4.8-15.4]. However, the presence of hyperkalemia depended on the nature of an existing acidosis, and the odds for the presence of hyperkalemia in acidemic calves with hyper-D-lactatemia (>3.96 mmol/L) were only 0.15 times as high as in acidemic calves with normal D-lactate concentrations (95% CI, 0.11-0.22). Acidemia in hyperkalemic diarrheic calves was associated with hyponatremia and increased concentrations of inorganic phosphorus, L-lactate, and unidentified strong anions that presumably included uremic anions such as sulfate. We conclude that hyper-D-lactatemia in neonatal diarrheic calves is not usually associated with elevated plasma potassium concentrations. Application of the simplified strong ion acid-base model indicated that dehydration is an important contributor to the pathogenesis of hyperkalemia and acidemia in neonatal calves with diarrhea.

Adult phenylketonuria outcome and management.

The problem to evaluate treatment outcome in adult PKU (phenylketonuric) patients lies in the heterogeneity of the adult PKU population. This heterogeneity is not only based on the different treatment history of every individual patient but also on the different severity of the underlying defect of the enzyme phenylalanine hydroxylase. Recent, partly double blind studies in adult PKU patients further support recommendation for lifelong treatment. However, it has become evident that dietary treatment is suboptimal and continuation to adulthood often not accepted. Late detected PKU patients (up to 4-6 years of age) benefit from strict dietary treatment and are able to catch up in intellectual performance. Untreated, severely retarded patients with behavioral changes may benefit from introduction of dietary treatment. However, individual decision is necessary and based on the personal situation of the patient. In early and well treated patients a number of studies have demonstrated that cognitive and neurosychologic tests are different from controls. In addition there is evidence that patients with higher blood phenylalanine (phe) levels demonstrate more often psychiatric symptoms like depression and anxiety. Medical problems are more often observed: there are certain risks as impaired growth, decreased bone mineral density and nutrional deficits probably caused by dietary treatment with an artificial protein substitute and/or missing compliance with an unpleasant diet. The long term risk of a strict dietary treatment must be balanced with the risk of higher blood phe (mean blood phenylalanine >600-900 µmol/L) on cognitive and neuropsychological functions and psychiatric symptoms. Further studies should consider the role of blood phe exposure for brain development in childhood and for brain function in all ages. Besides mean blood phe, fluctuation of blood phe over time is important. Fluctuation of blood phe is decreased by sapropterin treatment in responsive patients which would on the long term may have positive effects on cognitive outcome. Further studies also should include adult PKU patients.

Additive prognostic value of preoperative plasma glucose concentrations in calves undergoing abdominal surgery.

Surgical abdominal emergencies in calves are associated with a guarded prognosis, especially if neonates are affected. Because hypoglycemia has been associated with sepsis and endotoxemia, this study aimed to assess the prognostic relevance of preoperative plasma glucose concentrations (GLUC) in calves requiring surgery for an acute abdominal disorder. For this purpose, data from retrospective and prospective case series were analyzed, consisting of 586 and 83 hospitalized calves, respectively. The outcomes of calves were evaluated until hospital discharge (both study populations) and for 3 mo following discharge by a phone call to the farmer (prospective study population). For the retrospective study population, the overall survival rate was 31.2%. Calves with a negative outcome (NO) had significantly lower median GLUC (4.3 mmol/L) than calves with a positive outcome (PO; 5.0 mmol/L). The survival rates of calves with GLUC <2.4 mmol/L and 2.4 to 3.1 mmol/L were 3.6 and 8.3%, respectively. The inclusion of GLUC improved a previous prognostic model based on plasma l-lactate concentration and age. The resulting analyses indicated that NO was associated with low age (<7 d), hyper-l-lactatemia (>8.84 mmol/L), and GLUC <4.4 mmol/L (age 7-20 d) and <3.3 mmol/L (age ≥21 d), respectively. The area under the receiver operating characteristic curve of this model was 0.79 (95% confidence interval: 0.76-0.83) and the resulting sensitivity and specificity for NO at the optimal probability cut-point of 0.69 were 66.7 and 85.8%, respectively. For the prospective study population, the established model had sensitivity and specificity for predicting NO after 3 mo (proportion 24%) of 61.9 and 85%, respectively. In both study populations, hypoglycemia was significantly associated with intraoperative evidence of a septic process within the abdominal cavity. The present analyses show that hypoglycemia was highly indicative of a poor prognosis and serious intraoperative findings such as peritonitis. Determination of GLUC should therefore be part of the diagnostic work-up in calves suffering from an acute abdominal emergency.

Patient's thoughts and expectations about centres of expertise for PKU.

BACKGROUND: In the Netherlands (NL) the government assigned 2 hospitals as centres of expertise (CE) for Phenylketonuria (PKU), while in the United Kingdom (UK) and Germany no centres are assigned specifically as PKU CE's. METHODS: To identify expectations of patients/caregivers with PKU of CEs, a web-based survey was distributed through the national Phenylketonuria societies of Germany, NL and UK. RESULTS: In total, 105 responded (43 patients, 56 parents, 4 grandparents, 2 other) of whom 59 were from NL, 33 from UK and 13 from Germany. All participants (n = 105) agreed that patients and/or practitioners would benefit from CEs. The frequency patients would want to visit a CE, when not treated in a CE (n = 83) varied: every hospital visit (24%, n = 20), annual or bi-annual (45%, n = 37), at defined patient ages (6%, n = 5), one visit only (22%, n = 18), or never (4%, n = 3). Distance was reported as a major barrier (42%, n = 35). 78% (n = 65) expected CE physicians and dieticians to have a higher level of knowledge than in non-CE centres. For participants already treated in a CE (n = 68), 66% requested a more extensive annual or bi-annual review. In general, psychology review and neuropsychologist assessment were identified as necessary by approximately half of the 105 participants. In addition, 66% (n = 68) expected a strong collaboration with patient associations. CONCLUSION: In this small study, most participants expected that assigning CEs will change the structure of and delivery of Phenylketonuria care.

PKU dietary handbook to accompany PKU guidelines.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. MAIN BODY: In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment. CONCLUSION: This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

Correction to: PKU dietary handbook to accompany PKU guidelines.

An amendment to this paper has been published and can be accessed via the original article.

Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria.

BACKGROUND: The value of genotyping to identify tetrahydrobiopterin-responsive (BH(4)-responsive) patients with phenylalanine hydroxylase (PAH) deficiency is a matter of debate. METHODS: We reviewed 250 cases of patients with PAH deficiency, using published data from 198 cases and unpublished data from 52 cases of patients attending our own clinic. Patients underwent analyses for BH(4) load and genetic mutations. Partial and full BH(4) responses were defined as a 10-29% decrease and a >or=30% decrease from baseline in blood phenylalanine levels, respectively. BH(4)-responsive alleles were identified from BH(4)-responsive patients as either homozygous for a specific allele or compound heterozygous for that allele with a null mutation. RESULTS: Most inconsistencies between observed genotype and BH(4) response were associated with mutations in the regulatory domain of PAH (p.R68S, p.I65T, p.L48S and p.F39C), where 20/62 alleles (32.2%) were non-responsive. In the catalytic domain (mutations p.Y414C, p.R261Q, p.E390G, p.A300S, p.R241C, p.A403V and p.V388M), only 8/125 alleles (6.4%) were non-responsive. Seven patients had a genotype with two BH(4)-responsive alleles resulting in no response or only a partial response to BH(4). Ten patients had identical genotypes but inconsistent responses in BH(4) load. CONCLUSIONS: These results show that BH(4) non-responsiveness is associated with genotype. However, patients with mutations in the regulatory domain show inconsistent results. In patients with two responsive alleles, non-responsiveness may be related to negative inter-allelic complementation. In patients with the same genotype and inconsistent results for BH(4) load, external factors such as intestinal absorption of BH(4), catabolic conditions or other genetic factors may be responsible. Further in vitro studies are necessary to clarify the genotype-phenotype correlation in patients with BH(4)-responsive PKU.

[Propionic acidemia and sensorineural hearing loss: is there a connection at the molecular genetics level?]. / Propionazidämie und Schallempfindungsschwerhörigkeit: Gibt es eine molekulargenetische Basis?

CURRENT KNOWLEDGE: Propionic acidemia is caused by a gene defect leading to malfunction of the enzyme propionyl-CoA carboxylase (PCC) and in turn to a pathologic accumulation of propionic acid. Many mutations have been found at the molecular genetic level over the past 20 years, and their implications for the limitation of enzyme activity of PCC in propionic acidemia are discussed. SCIENTIFIC QUESTION AND AIMS OF THE STUDY: As an elevated incidence of deafness has been observed in patients with propionic acidemia, the question arises of whether mutations primarily responsible for this disease could also be the underlying cause for a genetic form of deafness. METHODS AND RESULTS: As well as a standard pure tone audiogram, a pedigree was elaborated and DNA isolated for each family concerned. In one family several subjects displayed mutations of both the PCCA and the PCCB -subunits; these included only one girl whose phenotype was affected, however. CONCLUSIONS: Mutation of the PCCB subunit p.R113X has not previously been mentioned in the literature. According to our present knowledge no connection can be assumed between either of the two mutations and the severe sensorineural hearing loss.

Evaluation of a portable ion-selective electrode meter for measuring potassium concentrations in whole blood and plasma of calves.

An ion-selective electrode (ISE) handheld meter (LAQUAtwin B-731; Horiba) has recently become available for the measurement of potassium concentrations [K+] in biological fluids. The ISE meter has the potential to facilitate the diagnosis and treatment of potassium balance disorders of critically ill cattle. The objective of this study was to characterise the analytical performance of the ISE meter in a study sample of hospitalised calves with a broad range of plasma [K+]. For the purpose of the study, whole blood and plasma samples from 125 calves (age≤3months) were used for analysis. The accuracy of the meter against the reference method (indirect ISE, Cobas c 311, Roche) was assessed using Passing-Bablok regression and Bland-Altman plots. The [K+] in whole blood as measured by the ISE meter in direct mode ranged from 2.4 to 9.9mmol/L. The meter measured whole blood [K+] as 3.8% higher than plasma [K+]. Passing-Bablok regression for whole blood [K+] measured by the meter against plasma [K+] determined by indirect potentiometry revealed a linear relationship that was almost identical to the line of identity. However, the Bland-Altman plot indicated that the meter measured plasma [K+] 5.1% lower than the reference method. This result was consistent with analytical differences of direct and indirect ISE methods in respect to variation in the plasma protein concentration. In conclusion, the LAQUAtwin B-731 meter provides an accurate, rapid and low-cost tool for the diagnosis of potassium derangements in critically ill calves, particularly when whole blood samples are analysed.

Zinc Deficiency-Like Syndrome in Fleckvieh Calves: Clinical and Pathological Findings and Differentiation from Bovine Hereditary Zinc Deficiency.

BACKGROUND: Zinc deficiency-like (ZDL) syndrome is an inherited defect of Fleckvieh calves, with striking similarity to bovine hereditary zinc deficiency (BHZD). However, the causative mutation in a phospholipase D4 encoding gene (PLD4) shows no connection to zinc metabolism. OBJECTIVES: To describe clinical signs, laboratory variables, and pathological findings of ZDL syndrome and their utility to differentiate ZDL from BHZD and infectious diseases with similar phenotype. ANIMALS: Nine hospitalized calves with crusting dermatitis and confirmed mutation in PLD4 and medical records from 25 calves with crusting dermatitis or suspected zinc deficiency. METHODS: Prospective and retrospective case series. RESULTS: The 9 calves (age: 5-53 weeks) displayed a moderate to severe crusting dermatitis mainly on the head, ventrum, and joints. Respiratory and digestive tract inflammations were frequently observed. Zinc supplementation did not lead to remission of clinical signs in 4 calves. Laboratory variables revealed slight anemia in 8 calves, hypoalbuminemia in 6 calves, but reduced serum zinc concentrations in only 3 calves. Mucosal erosions/ulcerations were present in 7 calves and thymus atrophy or reduced thymic weights in 8 calves. Histologically, skin lesions were indistinguishable from BHZD. Retrospective analysis of medical records revealed the presence of this phenotype since 1988 and pedigree analysis revealed a common ancestor of several affected calves. CONCLUSIONS AND CLINICAL IMPORTANCE: ZDL syndrome should be suspected in Fleckvieh calves with crusting dermatitis together with diarrhea or respiratory tract inflammations without response to oral zinc supplementation. Definite diagnosis requires molecular genetic confirmation of the PLD4 mutation.

Effects of cholesterol and simvastatin treatment in patients with Smith-Lemli-Opitz syndrome (SLOS).

Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome caused by deficiency of 7-dehydrocholesterol reductase catalysing the last step of cholesterol biosynthesis. This results in an accumulation of 7- and 8-dehydrocholesterol (7 + 8-DHC) and, in most patients, a deficiency of cholesterol. Current therapy consists of dietary cholesterol supplementation, which raises plasma cholesterol levels, but clinical effects have been reported in only a few patients. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors were shown to reduce 7 + 8-DHC levels and increase cholesterol concentrations in two small trials with divergent clinical outcome. This retrolective study evaluates the effects of cholesterol only and of cholesterol plus the HMG-CoA reductase inhibitor simvastatin on plasma sterols in 39 SLOS patients and on anthropometric measures in 20 SLOS patients. Cholesterol as well as additional simvastatin decreased the plasma (7 + 8-DHC)/cholesterol ratio. However, the mechanism leading to the decreasing ratio was different. Whereas it was due to an increasing cholesterol concentration in the cholesterol-only cohort, a decreasing 7 + 8-DHC concentration was demonstrated in the cohort receiving additional simvastatin. We could not confirm a positive effect of simvastatin treatment on anthropometric measures or behaviour, as previously reported.

Effect of Intravenous Small-Volume Hypertonic Sodium Bicarbonate, Sodium Chloride, and Glucose Solutions in Decreasing Plasma Potassium Concentration in Hyperkalemic Neonatal Calves with Diarrhea.

BACKGROUND: Hyperkalemia is a frequently observed electrolyte imbalance in dehydrated neonatal diarrheic calves that can result in skeletal muscle weakness and life-threatening cardiac conduction abnormalities and arrhythmias. HYPOTHESIS: Intravenous administration of a small-volume hypertonic NaHCO3 solution is clinically more effective in decreasing the plasma potassium concentration (cK) in hyperkalemic diarrheic calves than hypertonic NaCl or glucose solutions. ANIMALS: Twenty-two neonatal diarrheic calves with cK >5.8 mmol/L. METHODS: Prospective randomized clinical trial. Calves randomly received either 8.4% NaHCO3 (6.4 mL/kg BW; n = 7), 7.5% NaCl (5 mL/kg BW; n = 8), or 46.2% glucose (5 mL/kg BW; n = 7) IV over 5 minutes and were subsequently allowed to suckle 2 L of an electrolyte solution. Infusions with NaHCO3 and NaCl provided an identical sodium load of 6.4 mmol/kg BW. RESULTS: Hypertonic NaHCO3 infusions produced an immediate and sustained decrease in plasma cK. Hypertonic glucose infusions resulted in marked hyperglycemia and hyperinsulinemia, but cK remained unchanged for 20 minutes. Between 30 and 120 minutes after initiation of treatment, the most marked decrements in cK from baseline occurred in group NaHCO3 , which were significantly (P < .05) larger during this period of time than in calves in group NaCl, but not group glucose. After 120 minutes, the mean decrease in cK from baseline was -26 ± 10%, -9 ± 8%, and -22 ± 6% in groups NaHCO3 , NaCl, and glucose, respectively. CONCLUSIONS/CLINICAL IMPORTANCE: Small-volume hypertonic NaHCO3 infusions appear to have clinical advantages for the rapid resuscitation of hyperkalemic diarrheic calves, compared to hypertonic NaCl or glucose solutions.

The complete European guidelines on phenylketonuria: diagnosis and treatment.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.