Randomised trial of intravenous thiamine and/or magnesium sulphate administration on erythrocyte transketolase activity, lactate concentrations and alcohol withdrawal scores.

Alcohol withdrawal syndrome (AWS) occurs in 2% of patients admitted to U.K. hospitals. Routine treatment includes thiamine and benzodiazepines. Laboratory studies indicate that thiamine requires magnesium for optimal activity, however this has not translated into clinical practice. Patients experiencing AWS were randomized to three groups: (group 1) thiamine, (group 2) thiamine plus MgSO4 or (group 3) MgSO4. Pre- and 2-h post-treatment blood samples were taken. AWS severity was recorded using the Glasgow Modified Alcohol Withdrawal Score (GMAWS). The primary outcome measure was 15% change in erythrocyte transketolase activity (ETKA) in group 3. Secondary outcome measures were change in plasma lactate concentrations and time to GMAWS = 0. 127 patients were recruited, 115 patients were included in the intention-to-treat analysis. Pre-treatment, the majority of patients had normal or high erythrocyte thiamine diphosphate (TDP) concentrations (≥ 275-675/> 675 ng/gHb respectively) (99%), low serum magnesium concentrations (< 0.75 mmol/L) (59%), and high plasma lactate concentrations (> 2 mmol/L) (67%). Basal ETKA did not change significantly in groups 1, 2 or 3. Magnesium deficient patients (< 0.75 mmol/L) demonstrated less correlation between pre-treatment basal ETKA and TDP concentrations than normomagnesemic patients (R2 = 0.053 and R2 = 0.236). Median plasma lactate concentrations normalized (≤ 2.0 mmol/L) across all three groups (p < 0.001 for all groups), but not among magnesium deficient patients in group 1 (n = 22). The median time to achieve GMAWS = 0 for groups 1, 2 and 3 was 10, 5.5 and 6 h respectively (p < 0.001). No significant difference was found between groups for the primary endpoint of change in ETKA. Co-administration of thiamine and magnesium resulted in more consistent normalization of plasma lactate concentrations and reduced duration to achieve initial resolution of AWS symptoms.ClinicalTrials.gov: NCT03466528.

Development of age-dependent micronutrient centile charts and their utility in children with chronic gastrointestinal conditions at risk of deficiencies: A proof-of-concept study.

BACKGROUND & AIMS: Interpretation of blood micronutrient levels requires age-appropriate reference intervals. This study developed age-dependent micronutrient centiles for healthy children (HC) and explored their utility in sick children. METHODS: 244 blood samples were collected from normal HC who underwent tests for acute illness. Age-dependent, centile charts were fitted for zinc, copper, magnesium and selenium in plasma and erythrocytes (RBC), and for vitamins B1, B2 and B6 in RBC. For 34 children with Crohn's disease (CrD) and 55 with coeliac disease (CoeD), Z-scores for the levels of these micronutrients were computed, using the new charts. Associations were explored between plasma and RBC micronutrient Z-scores, and in CrD with CRP and serum albumin. RESULTS: In HC, plasma zinc and selenium increased and plasma copper, magnesium and RBC vitamins B1, B2 and B6 decreased with age. In HC and in CrD, plasma and RBC Z-scores for copper, selenium and magnesium (all p < 0.001) were positively correlated, but not for zinc. In CrD, albumin was related with plasma zinc (rho = 0.62; p < 0.001) and selenium Z-scores (rho = 0.65; p < 0.001) and plasma copper Z-score with CRP (rho = 0.45; p = 0.02). A higher proportion of CrD children had low levels for B2 (21% vs 0%; p = 0.01) and B6 (18% vs 0%; p = 0.02) using the new centile charts than the local laboratory references. CONCLUSION: Age-dependent micronutrient centile charts enable tracking of micronutrient status, Z-score calculation and may prevent misdiagnosis and inappropriate treatment of deficiencies. In systemic inflammatory conditions, RBC measurements of certain micronutrients may be more reliable to use than measurements in plasma.

Uretero-duodenal fistula: Risk factors and management.

In this case report we explore the clinical journey of a 66-year-old female patient that developed a uretero-duodenal fistula. This urological complication is extremely rare and to our knowledge, this is only the third female described in the literature with this finding. We discuss the risk factors associated with uretero-duodenal fistula and its management in the acute setting.

Mechanisms of obesity in children and adults with phenylketonuria on contemporary treatment.

BACKGROUND & AIMS: Obesity prevalence in people with phenylketonuria (PKU) is comparable to that of the general population but the underlying aetiology remains unknown. To assess body composition, dietary intake, moderate physical activity duration (MPAD) and energy expenditure (MPAEE), resting metabolic rate (RMR), diet-induced thermogenesis (DIT), fasting and postprandial fat (FOx) and carbohydrate oxidation (CHOOx), in PKU people and healthy Controls. METHODS: Participants were PKU people (n = 16) and healthy controls (n = 15). Body composition was measured with stable isotopes using deuterium as tracer, dietary intake from 4-day food diaries, MPAD and MPAEE from 7-day activity counts measured by triaxial accelerometers, calibrated against individual rates of oxygen consumption and carbon dioxide production, RMR, DIT, FOx and CHOOx by indirect calorimetry. RESULTS: Body composition, DIT, FOx, CHOOx and RMR did not differ between the PKU and the Control groups. MPAD (PKU, 73 ± 26 min/week; Control, 152 ± 43 min/week) and MPAEE (PKU, 404 ± 127 kcal/week; Control, 741 ± 153 kcal/week) were lower (P < 0.05) in the PKU than the Control group. Raised phenylalanine levels were inversely related with MPAD and MPAEE. Energy intake and energy provided by protein did not differ between the groups, while energy proportion obtained from carbohydrate was higher (PKU, 60 ± 2%; Control, 51 ± 2%; P < 0.05) and from fat lower (PKU, 24 ± 2%; Control, 35 ± 3%; P < 0.05) in the PKU than in the Control group. CONCLUSION: People with PKU spent less time and expend less energy in moderate physical activity and have a higher intake of energy from CHO which may be involved in the underlying mechanisms of obesity in PKU.

A prospective evaluation of thiamine and magnesium status in relation to clinicopathological characteristics and 1-year mortality in patients with alcohol withdrawal syndrome.

BACKGROUND: Alcohol withdrawal syndrome (AWS) is routinely treated with B-vitamins. However, the relationship between thiamine status and outcome is rarely examined. The aim of the present study was to examine the relationship between thiamine and magnesium status in patients with AWS. METHODS: Patients (n = 127) presenting to the Emergency Department with AWS were recruited to a prospective observational study. Blood samples were drawn to measure whole blood thiamine diphosphate (TDP) and serum magnesium concentrations. Routine biochemistry and haematology assays were also conducted. The Glasgow Modified Alcohol Withdrawal Score (GMAWS) measured severity of AWS. Seizure history and current medications were also recorded. RESULTS: The majority of patients (99%) had whole blood TDP concentration within/above the reference interval (275-675 ng/gHb) and had been prescribed thiamine (70%). In contrast, the majority of patients (60%) had low serum magnesium concentrations (< 0.75 mmol/L) and had not been prescribed magnesium (93%). The majority of patients (66%) had plasma lactate concentrations above 2.0 mmol/L. At 1 year, 13 patients with AWS had died giving a mortality rate of 11%. Male gender (p < 0.05), BMI < 20 kg/m2 (p < 0.01), GMAWS max ≥ 4 (p < 0.05), elevated plasma lactate (p < 0.01), low albumin (p < 0.05) and elevated serum CRP (p < 0.05) were associated with greater 1-year mortality. Also, low serum magnesium at time of recruitment to study and low serum magnesium at next admission were associated with higher 1-year mortality rates, (84% and 100% respectively; both p < 0.05). CONCLUSION: The prevalence of low circulating thiamine concentrations were rare and it was regularly prescribed in patients with AWS. In contrast, low serum magnesium concentrations were common and not prescribed. Low serum magnesium was associated more severe AWS and increased 1-year mortality.

Quantification of urinary sodium concentrations in term infants.

BACKGROUND: Infants with gastrointestinal conditions and poor weight gain are administered sodium supplementation based on urinary sodium concentrations. However, the reference range of urinary electrolytes is unknown. The aim of this study was to ascertain the normal values of urinary electrolytes in healthy, term infants. Secondary aims were to establish the relationship between urinary electrolytes with weight velocity and feeding practices. METHODS: Healthy, term (≥37 weeks' gestation) infants were recruited. Parental questionnaires were completed before discharge and at six weeks. Electrolytes were quantified from a urine sample at six weeks. t-Tests and Mann-Whitney U tests were conducted for parametric and non-parametric electrolytes, respectively. RESULTS: A total of 200 infants were recruited before discharge. Twenty-nine follow-up questionnaires and urine samples were returned (nine female; mean gestational age 39 + 6 weeks [SD 9.9 days]; mean birthweight 3350 g [SD 483 g]; 17 breastfed, nine formula and three mixed; mean change in Z score for weight -0.914 [SD 0.814]). Majority (25/29) of infants had urinary sodium <20 mmo/L. Change in Z score for weight was similar between infants with sodium <20 mmol/L and >20 mmol/L ( P = 0.78). All exclusively breastfed infants had sodium <20 mmol/L, however, not statistically dissimilar to formula-fed infants ( P = 0.27). CONCLUSION: Most term infants in this study had urinary sodium values <20 mmol/L with no identified relationship to weight velocity. Lower concentrations of sodium could be not quantified reliably because of the limitations of the analytical method that were used. More evidence is required to identify candidates for sodium supplementation.

Use of Cortisol and Adrenal Weight at Pediatric Postmortem.

We studied the relationship between adrenal weight and postmortem cortisol level in cases of infant death, and examined use of these measurements in adrenal insufficiency. We analyzed procurator-fiscal postmortem reports in the West of Scotland over a three year period. Combined adrenal weight was expressed as percentage of total body weight (%TBW). Of 106 cases, median (5th, 95th) %TBW was 0.056 (0.025, 0.23) and median plasma cortisol was 8.4 ug/dl (1.0, 47.1). There was no correlation between %TBW and plasma cortisol (r = 0.09, p = 0.4). The lowest and highest plasma cortisol quartile had medians of 1.9 ug/dl (1.0, 3.4) and 34.3 ug/dl (17.3, 71.5), respectively. Infection was present in 6 cases (23.1%) in the lowest quartile and in 16 cases (61.5%) in the highest quartile (p = 0.01). Our results highlight the difficulty in interpretation of cortisol at postmortem and suggest that adrenal weight measurement alone may be insufficient for diagnosis of adrenal insufficiency.

Vitamin K antagonists predispose to calciphylaxis in patients with end-stage renal disease.

BACKGROUND/AIMS: Calciphylaxis is associated with a poor prognosis in dialysis patients, and its pathogenesis remains incompletely understood. Although the use of vitamin K antagonists (VKA) has been implicated, previous reports are conflicting. We aimed to determine if vitamin K antagonists conferred an increased risk of calciphylaxis in patients on dialysis. METHODS: We performed a single-centre, retrospective cohort study of 2,234 patients receiving dialysis, and compared the characteristics of those with and without calciphylaxis. RESULTS: We identified 5 cases of calciphylaxis (all female) between January 2009 and December 2013. Overall, 142 patients (6.4%) were treated with VKA during the study period. Calciphylaxis was more common in the VKA group (4 of 142 patients, OR = 61, 95% CI 6.7-546, p = 0.0001). VKA was withdrawn in all cases and treatment instituted with sodium thiosulphate, cinacalcet and supportive measures. All patients recovered, although there was one sudden cerebrovascular death during follow-up. CONCLUSION: Treatment with VKA predisposes to the development of calciphylaxis.

An electronic surveillance system for monitoring the hospital presentation of nutritional vitamin D deficiency in children in Scotland.

BACKGROUND: Routine surveillance would be valuable for vitamin D deficiency as symptomatic vitamin D deficiency may be common in Scotland. AIM: To assess the effectiveness of an electronic surveillance system to determine the current incidence of hospital-based presentation of childhood vitamin D deficiency in Scotland. METHODS: Active surveillance was performed for 2 years as part of an electronic web-based surveillance programme by the Scottish Paediatric Surveillance Unit. Notifications were followed by completion of a questionnaire. To further examine the validity of the system, cases with severe vitamin D deficiency in Glasgow and Edinburgh were identified from the regional laboratory and their clinical details were checked against those identified through the surveillance system. RESULTS: Between September 2009 and August 2011, 109 cases of vitamin D deficiency were notified. The majority of cases (n=82) were reported in Glasgow with an annual incidence of 41 cases per year. Fourteen cases were reported in Edinburgh during the first year of the study and two cases during the second year. At the time of clinical diagnosis, the median age of the children was 2 years (range 3 months-16 years). Cross-validation of data showed that among symptomatic cases that had a measured serum vitamin D of <14 nmol/L, 89% of eligible cases had been reported in Glasgow and 33% of cases had been reported in Edinburgh. CONCLUSION: The incidence of vitamin D deficiency remains high in Scotland. An electronic surveillance system can provide data for studying the epidemiology of vitamin D deficiency but may underestimate the number of positive cases.

Urinary gonadotrophins: a useful non-invasive marker of activation of the hypothalamic pituitary-gonadal axis.

BACKGROUND: Non-invasive screening investigations are rarely used for assessing the activation and progression of the hypothalamic-pituitary gonadal axis through puberty. This study aimed to establish a normal range for urinary gonadotrophins in children progressing through puberty. METHODS: Urine samples were collected from 161 healthy school children (76 boys, 85 girls) aged 4-19 yrs. Height and weight were converted to standard deviation score. Pubertal status, classified by Tanner staging, was determined by self-assessment. Urinary gonadotrophins were measured by chemiluminescent microparticle immunoassay. Results were grouped according to pubertal status (pre-pubertal or pubertal). RESULTS: Of the 161 children, 50 were pre-pubertal (28 boys; 22 girls) and 111 were pubertal (48 boys; 63 girls). Overall, urinary gonadotrophins concentrations increased with pubertal maturation. All pre-pubertal children had a low urinary LH:Creatinine ratio. LH:Creatinine ratios were significantly higher in pubertal compared to pre-pubertal boys (p<0.001). In girls, FSH:Creatinine ratios were significantly higher in the pubertal group (p = 0.006). However, LH:FSH ratios were a more consistent discriminant between pre-pubertal and pubertal states in both sexes (Boys 0.45 pubertal vs 0.1 pre-pubertal; girls 0.23 pubertal vs 0.06 pre-pubertal). CONCLUSION: Urinary gonadotrophins analyses could be used as non-invasive integrated measurement of pubertal status which reflects clinical/physical status.

A new method for the measurement of lysosomal acid lipase in dried blood spots using the inhibitor Lalistat 2.

BACKGROUND: Cholesterol ester storage disease (CESD) and Wolman Disease (WD) are due to deficiency of lysosomal acid lipase (LAL). A new method is described for the measurement of LAL in dried blood spots (DBS) using Lalistat 2 an inhibitor of LAL. METHODS: LAL activity in DBS extracts was measured using the substrate 4-methylumbelliferyl palmitate. LAL activity was determined by measuring total lipase activity and lipase activity in the presence of Lalistat 2. The specificity of Lalistat 2 was investigated using human recombinant LAL (hrLAL) and human pancreatic lipase (hPL). RESULTS: Lalistat 2 inhibited hrLAL with 1% residual activity at 1 µM inhibitor but had no effect on hPL up to 10 µM. LAL activity in DBS samples obtained from normal controls (n=140) was 0.50-2.30 nmol/punch/h and in patients with CESD was <0.03 nmol/punch/h (n=11). Activity in carriers showed intermediate activity: 0.15-0.40 nmol/punch/h (n=15). CONCLUSIONS: Measurement of LAL using DBS is made difficult by the presence of other lipases in whole blood. Lalistat 2 is a specific inhibitor of LAL which allows the determination of LAL in DBS. Results show the method differentiates clearly between normal controls, carriers and affected cases.

Long-term risk of intraocular pressure elevation and glaucoma escalation after deep anterior lamellar keratoplasty.

BACKGROUND: To determine the prevalence and severity of intraocular pressure changes after deep anterior lamellar keratoplasty and its effect on visual function. DESIGN: Retrospective cohort study. PARTICIPANTS: All patients undergoing deep anterior lamellar keratoplasty procedures at a tertiary referral centre (Leeds University Hospitals, UK) using a manual dissection technique. METHODS: Case note review of all cases between the 1st of January 2000 and the 31st of December 2005. MAIN OUTCOME MEASURES: Raised intraocular pressure, glaucoma incidence or escalation. RESULTS: Data were collected for 69 of eyes of 58 patients. The mean period of follow-up was 54.9 months (median 60, range 6-95 months). The initial diagnosis was keratoconus in 56 cases (81%), corneal scarring in four cases (5.8%), herpes simplex keratitis in four cases (5.8%), lattice dystrophy in four cases (5.8%) and one case of corneal dermoid. Temporarily intraocular pressure was thought to be related to topical steroid use occurred in 12 (17%) cases. Ocular hypertension requiring treatment occurred in three eyes. None of these eyes had progressive disc changes or visual field defects suggestive of glaucoma, and all had well-controlled intraocular pressure on topical, single-drug therapy. Overall, there was a small insignificant rise in intraocular pressure after deep anterior lamellar keratoplasty (P = 0.11). CONCLUSIONS: The long-term risk of glaucoma following deep anterior lamellar keratoplasty using the manual dissection technique appears to be low. Ocular hypertension after deep anterior lamellar keratoplasty is infrequent and can be controlled on topical medication alone.

Vitamin A supplementation improves retinal function in infants at risk of retinopathy of prematurity.

OBJECTIVE: Preterm infants show reduced retinal sensitivity at term corrected age compared with newborn term infants. We tested the hypothesis that retinal sensitivity in preterm infants is improved by early, high-dose vitamin A. STUDY DESIGN: We report a double-blind, randomized controlled trial of infants <32 weeks' gestation and/or <1501 g birth weight. Supplemented infants received additional intramuscular vitamin A 10 000 IU 3 times weekly from day 2 for a minimum of 2 weeks or until establishment of oral feeding. Hepatic stores were assessed by relative dose response (RDR). The primary outcome measure was cone-corrected dark-adapted retinal rod sensitivity measured by electroretinogram at 36 weeks' postmenstrual age (PMA). RESULTS: Eighty-nine infants (42 supplemented and 47 controls) were recruited. Plasma retinol was higher in supplemented infants at 7 and 28 days (median, 1.0 vs 0.5 µmol/L and 0.7 vs 0.6 µmol/L; P < .001 and .03, respectively). Neither plasma retinol nor RDR differed between groups at 36 weeks' PMA. Retinal sensitivity was greater in supplemented infants (-0.81 vs -0.61 log cd • s • m(-2); P < .03) and was not related to RDR. CONCLUSIONS: Early high-dose intramuscular vitamin A supplementation for infants at risk of retinopathy of prematurity improves retinal function at 36 weeks' PMA.

Novel mutations in GALNT3 causing hyperphosphatemic familial tumoral calcinosis.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is known to be caused by mutations in at least three genes: FGF23, GALNT3 and KL. Two families with two affected members suffering from HFTC were scrutinized for mutations in these candidate genes. We identified in both families homozygous missense mutations affecting highly conserved amino acids in GALNT3. One of the mutations is a novel mutation, whereas the second mutation was reported before in a compound heterozygous state. Our data expand the spectrum of known mutations in GALNT3 and contribute to a better understanding of the phenotypic manifestations of mutations in this gene.

A web-based information system for management and analysis of patient data after refractive eye surgery.

The aim was to develop a software tool for refractive surgeons using a standard user-friendly web-based interface, providing the user with a secure environment to protect large volumes of patient data. The software application was named "Internet-based refractive analysis" (IBRA), and was programmed with the computer languages PHP, HTML and JavaScript, attached to the opensource MySQL database. IBRA facilitated internationally accepted presentation methods including the stability chart, the predictability chart and the safety chart; it was able to perform vector analysis for the course of a single patient or for group data. With the integrated nomogram calculation, treatment could be customised to reduce the postoperative refractive error. Multicenter functions permitted quality-control comparisons between different surgeons and laser units.

Helicobacter pylori infection and the risk for open-angle glaucoma.

PURPOSE: To determine the frequency of exposure to Helicobacter pylori infection in glaucoma patients. DESIGN: Prospective case-control study. PARTICIPANTS: Ninety-seven consecutive patients attending a glaucoma clinic. These included 38 patients with primary open-angle glaucoma (POAG), 19 with normal pressure glaucoma (NPG), 16 with pseudoexfoliation glaucoma (PXE), and 24 with ocular hypertension (OHT). Ninety-four age-matched participants without glaucoma served as a control population. METHODS: Serum was analyzed for the presence of H. pylori-specific immunoglobulin G antibodies by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Serologic analysis for H. pylori. RESULTS: Seropositivity for H. pylori was higher in patients with glaucoma (26.0%) than in controls (20.2%), but this did not achieve statistical significance (P = 0.46). A total of 26.3% of POAG patients, 26.3% of NPG patients, 25.0% of PXE patients, and 25.0% of OHT patients were seropositive. CONCLUSIONS: This study suggests that exposure to H. pylori infection is not associated with open-angle glaucoma.