Recurrent malignant ventricular arrhythmias and paresthesia-a mystery revealed as aconitine poisoning: a case report.

BACKGROUND: We report a case of a clinical challenge lasting for 12 months, with severe and unresolved clinical features involving several medical disciplines. CASE PRESENTATION: A 53-year-old Caucasian male, who had been previously healthy apart from a moderate renal impairment, was hospitalized 12 times during a 1-year period for a recurrent complex of neurological, cardiovascular, and gastrointestinal symptoms and signs, without any apparent etiology. On two occasions, he suffered a cardiac arrest and was successfully resuscitated. Following the first cardiac arrest, a cardiac defibrillator was inserted. During the 12th admission to our hospital, aconitine poisoning was suspected after a comprehensive multidisciplinary evaluation and confirmed by serum and urine analyses. Later, aconitine was also detected in a hair segment, indicating exposure within the symptomatic period. After the diagnosis was made, no further episodes occurred. His cardiac defibrillator was later removed, and he returned to work. A former diagnosis of epilepsy was also abandoned. Criminal intent was suspected, and his wife was sentenced to 11 years in prison for attempted murder. To make standardized assessments of the probability for aconitine poisoning as the cause of the eleven prior admissions, an "aconitine score" was established. The score is based on neurological, cardiovascular, gastrointestinal, and other clinical features reported in the literature. We also make a case for the use of hair analysis to confirm suspected poisoning cases evaluated after the resolution of clinical features. CONCLUSION: This report illustrates the medical challenge raised by cases of covert poisoning. In patients presenting with symptoms and signs from several organ systems without apparent cause, poisoning should always be suspected. To solve such cases, insight into the effects of specific toxic agents is needed. We present an "aconitine score" that may be useful in cases of suspected aconitine poisoning.

The effects of transitioning from immediate release to extended release cysteamine therapy in Norwegian patients with nephropathic cystinosis: a retrospective study.

BACKGROUND: Nephropathic cystinosis is a rare lysosomal storage disorder in which accumulation of cystine and formation of crystals particularly impair kidney function and gradually lead to multi-organ dysfunction. Lifelong therapy with the aminothiol cysteamine can delay the development of kidney failure and the need for transplant. The purpose of our long-term study was to explore the effects of transitioning from immediate release (IR) to extended release (ER) formulation in Norwegian patients in routine clinical care. METHODS: We retrospectively analysed data on efficacy and safety in 10 paediatric and adult patients. Data were obtained from up to 6 years before and 6 years after transitioning from IR- to ER-cysteamine. RESULTS: Mean white blood cell (WBC) cystine levels remained comparable between the different treatment periods (1.19 versus 1.38 nmol hemicystine/mg protein) although most patients under ER-cysteamine underwent dose reductions. For the non-transplanted patients, the mean estimated glomerular filtration rate (eGFR) change/year was more pronounced during ER-treatment (- 3.39 versus - 6.80 ml/min/1.73 m2/year) possibly influenced by individual events, such as tubulointerstitial nephritis and colitis. Growth measured by Z-height score tended to develop positively. Four of seven patients reported improvement of halitosis, one reported unchanged and two reported worsened symptoms. Most adverse drug reactions (ADRs) were of mild severity. One patient developed two serious ADRs and switched back to IR-formulation. CONCLUSIONS: The results from this long-term retrospective study indicate that switching from IR- to ER-cysteamine was feasible and well tolerated under routine clinical practice. ER-cysteamine allowed satisfactory disease control over the long period considered. A higher resolution version of the Graphical abstract is available as Supplementary information.

Pregnancy complications in women with systemic lupus erythematosus. / Svangerskapskomplikasjoner hos kvinner med systemisk lupus erythematosus.

Systemic lupus erythematosus is a rare inflammatory connective tissue disease that affects mainly women, often in their childbearing years. The disease entails an increased risk of fetal and maternal pregnancy complications. Inflammatory active disease and the occurrence of anticardiolipin antibodies are known risk factors. Planning before pregnancy and multidisciplinary structured follow-up reduce the risk of unwanted pregnancy outcomes. Only in exceptional cases should women with systemic lupus erythematosus be advised against pregnancy.

Major increase in creatine kinase after intensive exercise. / Kraftig stigning i kreatinkinase etter intensiv trening.

BACKGROUND: Exercise-induced rhabdomyolysis is an increasingly frequent cause of hospitalisation and is much debated in the media. The real incidence of the condition is unknown. We wanted to investigate changes in creatine kinase (CK) levels in healthy students following intensive exercise and to look for a correlation between CK, pain and previous exercise history. METHOD AND MATERIAL: Twenty-four healthy students performed a single intensive workout and acted as their own controls with testing before and after the exercise session. RESULTS: All participants displayed an increase in CK levels after the workout, 58 % to above 5 000 IU/l. CK rose from a median of 104 IU/l (72-212) to a median of 6 071 IU/l (2 815-12 275) on day 4, p < 0.001. A negative Spearman's rank correlation was observed between the frequency of strength training prior to the experiment and the CK increase, rho = -0.477 (p = 0.021). INTERPRETATION: A major increase in CK levels is a normal phenomenon after intensive exercise, and the amount of the increase is related to previous exercise history. Further studies should evaluate whether patients with exercise-induced rhabdomyolysis should receive the same treatment as those with rhabdomyolysis caused by other mechanisms.

How can the examination failure rate be stabilised? / Hvordan kan strykprosenten ved eksamen stabiliseres?

BACKGROUND: The study programme in medicine at the Norwegian University of Science and Technology (NTNU) holds written examinations once annually. The limit to achieving a pass grade is at least 65 % correct answers. The failure rate varies from one year to the next. Our hypothesis was that the variations in the failure rate were caused by a varying degree of difficulty in the examination questions. We investigated whether relative standard-setting methods would reduce the variation in the failure rate without lowering the average limit for a pass grade. MATERIAL AND METHOD: Cohen's relative standard-setting methods correct for the degree of difficulty in the examination questions. They are easy to apply and provide an alternative to setting an absolute limit of 65 % for a pass grade. We used data from 34 examinations for medical studies at the Norwegian University of Science and Technology (NTNU) from the period 2010­2015 and compared the failure rates estimated using the existing assessment method with those produced by Cohen's methods. RESULTS: Using the existing 65 % limit for a pass grade, the failure rate varied from 0 % to 13.7 %, with a falling rate at later stages of the studies. With the exception of the examination held in the first year of study, the failure rate was lower and there was less variation in the failure rate with the original as well as the modified Cohen method when compared to the existing method. One of the Cohen methods resulted in a failure rate of 0 % to 10.4 % INTERPRETATION: In our data material, an absolute limit of 65 % for a pass grade can be defended because the failure rate was generally low. Cohen's methods could be an alternative in medical schools that have a high failure rate or where there are major variations in the failure rate from one year to the next in the same examination in the course of study.

Circulating immune mediators are closely linked in adult-onset type 1 diabetes as well as in non-diabetic subjects.

Relationships between circulating immune mediators (cytokines, chemokines and growth factors) and a beta cell destructive autoimmune process in adult-onset type 1 diabetes are poorly elucidated. We measured serum levels of immune mediators in type 1 diabetic patients in the context of ongoing deterioration of endogenous insulin secretion. Levels of 27 immune mediators were measured in 34 GADA (glutamic acid decarboxylase antibodies) positive type 1 diabetic patients, aged 27.4 ± 1.2 years at a mean of 7 weeks after diagnosis (designated 0 month) and 6 months later. Endogenous insulin secretion was assessed by C-peptide glucagon stimulation tests during 12 months. Additional data (for baseline analysis) was obtained in 9 GADA positive type 1 diabetic subjects and in 43 non-diabetic age- and sex-matched subjects. In general, the levels of immune mediators displayed large inter- but small intra-individual differences with only minor changes observed between measurements at 0 month and at 6 months. Levels of the majority of immune mediators were strongly and positively correlated to each other not only in the diabetic, but also in the non-diabetic subjects. Body weight (BMI) was positively associated with levels of IL-1 ra, IL-2, IL-4, IL-6, IL-17, Basic FGF, GCSF, IFN gamma and MIP-1 alpha. Adjustment for BMI removed most associations to C-peptide. When adjusted for BMI, levels at 0 month for Basic FGF and MIP-1 alpha were inversely associated with the percentage decline in stimulated C-peptide from 0 to 12 months (nominally p < 0.05). We conclude that associations between different immune mediators are strikingly but not exclusively tied in autoimmune diabetes. BMI is a major confounder in the analysis of associations to autoimmunity. Associations of beta cell decline to individual immune mediators need confirmation in further studies.

Atropine maintenance dosage in patients with severe organophosphate pesticide poisoning.

Although the importance of atropine in therapy of organophosphate (OP) poisoning is generally recognized, its dosing is a matter of debate. A retrospective analysis of atropine dosing was undertaken in 34 patients who had been enrolled in a clinical study assessing obidoxime effectiveness in OP-poisoning. All patients were severely intoxicated (suicidal attempts) and required artificial ventilation. Atropine was administered routinely by intensive care physicians for life-threatening muscarinic symptoms, with the recommendation to favor low dosage. The pharmacological active enantiomere S-hyoscyamine was determined by a radioreceptor assay. When RBC-AChE activity ranged between 10% and 30%, S-hyoscyamine plasma concentrations of approx. 5 nmol L⁻¹ were sufficient. This concentration could be maintained with about 0.005 mg h⁻¹ kg⁻¹ atropine. Only when RBC-AChE was completely inhibited, therapy of cholinergic crisis required atropine doses up to 0.06 mg h⁻¹ kg⁻¹. Elimination half-life of S-hyoscyamine was 1.5 h, showing occasionally a second slow elimination phase with t(½)=12 h. Malignant arrhythmias were observed in some 10% of our cases, which occurred late and often in the absence of relevant glandular cholinergic signs, when the S-hyoscyamine concentration was below 2.5 nmol L⁻¹. Arrhythmias mostly resolved on reinstitution of atropine.

Six months of diazoxide treatment at bedtime in newly diagnosed subjects with type 1 diabetes does not influence parameters of {beta}-cell function and autoimmunity but improves glycemic control.

OBJECTIVE Continuous beta-cell rest with diazoxide preserves residual endogenous insulin production in type 1 diabetes. However, side effects have hampered therapeutic usefulness. In a double-blind study, we tested whether lower, intermittent dosing of diazoxide had beneficial effects on insulin production, metabolic control, and autoimmunity markers in the absence of side effects. RESEARCH DESIGN AND METHODS Forty-one newly diagnosed type 1 diabetic patients were randomized to 6 months of treatment with placebo or 100 mg diazoxide at bedtime. A1C, C-peptide (fasting and glucagon stimulated), and FoxP3(+) regulatory T-cells (Tregs) were measured. Patients were followed for 6 months after intervention. RESULTS Of six dropouts, three were due to perceived side effects; one subject in the diazoxide group experienced rash, another dizziness, and one in the placebo group sleep disturbance. Adverse effects in others were absent. Diazoxide treatment reduced A1C from 8.6% at baseline to 6.0% at 6 months and 6.5% at 12 months. Corresponding A1C value in the placebo arm were 8.3, 7.3, and 7.5% (P < 0.05 for stronger reduction in the diazoxide group). Fasting and stimulated C-peptide decreased during 12 months similarly in both arms (mean -0.30 and -0.18 nmol/l in the diazoxide arm and -0.08 and -0.09 nmol/l in the placebo arm). The proportion of Tregs was similar in both arms and remained stable during intervention but was significantly lower compared with nondiabetic subjects. CONCLUSIONS Six months of low-dose diazoxide was without side effects and did not measurably affect insulin production but was associated with improved metabolic control.

Heterogeneity of patients with latent autoimmune diabetes in adults: linkage to autoimmunity is apparent only in those with perceived need for insulin treatment: results from the Nord-Trøndelag Health (HUNT) study.

OBJECTIVE: Subjects with the diagnosis of latent autoimmune diabetes in adults (LADA) are more prone to need insulin treatment than those with type 2 diabetes. However, not all patients with LADA develop the need for insulin treatment, indicating the heterogeneity of LADA. We investigated this heterogeneity by comparing phenotypes of LADA with and without perceived need for insulin treatment (data obtained at times when diagnosis of LADA was not investigated) and also compared LADA and type 2 diabetes phenotypes. RESEARCH DESIGN AND METHODS: We used data from the all population-based Nord-Trøndelag Health study (n = 64,931), performed in 1995-1997. Data were assembled for individuals with LADA (n = 106) and type 2 diabetes (n = 943). RESULTS: In the comparison of individuals with LADA both with and without the need for insulin, insulin-treated subjects had higher titers of GAD antibodies (P < 0.001) and lower fasting C-peptide levels (P < 0.001). GAD antibodies and C-peptide correlated negatively (r = -0.40; P = 0.009). In the comparison of individuals with LADA and type 2 diabetes, all without the need for insulin, markers of metabolic syndrome were equally prevalent and pronounced. Age, C-peptide, and glucose levels were also similar. In the comparison of insulin-treated individuals with LADA and type 2 diabetes, more patients with LADA received insulin (40 vs. 22%, P < 0.001) and C-peptide levels were lower (P < 0.001). Patients with LADA were leaner but were still overweight (mean BMI 28.7 vs. 30.9 kg/m2 in type 2 diabetes, P < 0.001). In the comparison of type 2 diabetic patients with and without insulin, insulin-treated subjects were more obese and had higher A1C and lower C-peptide levels (P < 0.001). CONCLUSIONS: Our conclusions are that 1) the need for insulin treatment in LADA is linked to the degree of autoimmunity and beta-cell failure, 2) subjects with LADA and type 2 diabetes without the need for insulin treatment are phenotypically similar, and 3) insulin treatment in type 2 diabetic patients is associated with both insulin resistance and beta-cell insufficiency.

Reactions of isodimethoate with human red cell acetylcholinesterase.

Isodimethoate is a thermal decomposition product that is present in usual pesticide formulations of dimethoate. Owing to its PO structure the compound is a direct anticholinesterase agent whose properties, to the best of our knowledge, are presented here for the first time. Isodimethoate shows an inhibition rate constant towards human red blood cell acetylcholinesterase (AChE) of 2.3x10(3) M(-1) min(-1) (pH 7.4, 37 degrees C), indicating a somewhat higher potency than found with omethoate, the CYP450-mediated active metabolite of pure dimethoate. Isodimethoate-inhibited AChE shows fast spontaneous reactivation and aging kinetics (half-life 2.3 and 25 min, respectively). The inhibited, non-aged enzyme is readily reactivated by obidoxime (k(r)=9 min(-1); K(D)=0.1 mM) but hardly by pralidoxime at therapeutic concentrations. Interestingly, isodimethoate hydrolyzes readily in buffered solutions at pH 7.4 and 37 degrees C with liberation of methylmercaptan (half-life 16 min). Liberation of N-(methyl)mercaptoacetamide, the expected leaving group, was not observed. These properties make isodimethoate a hit-and-run agent that renders part of AChE non-reactivatable within a short period of time. The clinical consequences of exposure to or intentional ingestion of isodimethoate-containing dimethoate formulations are a partly untractable AChE shortly after incorporation. In fact, aging of AChE in dimethoate-poisoned patients on admission was much more advanced than expected from the reaction with omethoate. Manufacturers, researching scientists and clinical toxicologists should be aware of this problem.

Changes in water transport across the peritoneum during treatment with continuous ambulatory peritoneal dialysis in selected patients with and without peritonitis.

BACKGROUND: The natural course of longitudinal changes in peritoneal permeability and membrane area has been studied mostly by performing single-dwell studies in selected patients during treatment with peritoneal dialysis. PURPOSE: To evaluate the permeability characteristics of the peritoneal membrane by measuring drained ultrafiltration volume relative to initial glucose concentration in dialysis fluid from the start to the end of continuous ambulatory peritoneal dialysis (CAPD) treatment in a selected cohort of patients with and without peritonitis. DESIGN: A retrospective analysis of a group of patients whose peritoneal function was prospectively followed by recording drained ultrafiltration volume and glucose concentration in dialysis fluid for each dwell time, every day, during the time in CAPD treatment. Mean values from a 1-month period starting after the first 3 weeks of CAPD treatment were compared with the mean values from the last month of treatment. Approximately 11 500 exchanges were analyzed. Evaluations were done separately for short (day) and long (night) dwell times. PATIENTS AND STATISTICS: Of 132 patients commencing CAPD treatment in the time period selected for inclusion, 51 had enough data to be included in this study. Of these, 29 patients experienced one or more episodes of successfully treated peritonitis. The selection of patients was not based upon patient characteristics, but upon criteria to satisfy predefined demands, such as number of measurements in each period, time since an episode of peritonitis, and time on CAPD treatment. Data were analyzed in three different groups: patients with episodes of peritonitis, patients without peritonitis, and both groups together. To assess changes between monthly mean at the start and at the end of CAPD, paired t-test was performed. Patients were also stratified into two groups according to low and high glucose in dialysis fluid at the start of CAPD (cutoff = 2 g/dL). Additionally, we used linear regression analyses to predict the level of drained ultrafiltration volume for a given level and change in glucose concentration. Mean treatment time for the entire group was 20 months (median 14.3 months), ranging from 6 to 69 months. RESULTS: No statistical differences in glucose concentrations were found between the periods compared. In the entire group there was an increase in ultrafiltration volume from the start to the end of CAPD treatment, for both day (p = 0.009) and night (p = 0.013) exchanges. Also, for patients without peritonitis, an increase appeared for day (p = 0.046) and night exchanges (p = 0.053). However, for the cohort with peritonitis, only an insignificant increase was indicated. Patient characteristics, diabetic patients, the need for glucose in dialysis fluid when commencing CAPD treatment, the number of episodes of peritonitis, and time on CAPD did not influence the change in ultrafiltration. Regression analyses showed higher ultrafiltration response to a given level and change in glucose concentration at the end of CAPD treatment compared to the start values, also for the cohort with peritonitis. The regression coefficient between these variables was also significantly changed for both day (p < 0.0001) and night (p = 0.027) exchanges. CONCLUSION: A significant change in the regression coefficient between glucose in dialysis fluid and ultrafiltration volume reflects an increase in ultrafiltration response to a given level and change in glucose concentration during time on CAPD treatment. A parallel change after 5- and 9-hour dwells can be explained by a decrease in peritoneal surface area combined with a lesser decrease in peritoneal conductivity. However, changes in Starling forces across the peritoneal membrane are possible even in the absence of changes in peritoneal membrane characteristics.

Transperitoneal water transport before, during, and after episodes with infectious peritonitis in patients treated with CAPD.

BACKGROUND: Peritonitis is considered to change peritoneal permeability and influences the long-term change in permeability during peritoneal dialysis. The objective of this study is to evaluate water transport across the peritoneum, expressed as drained ultrafiltration volume, before, during, and after episodes of peritonitis. METHODS: A retrospective analysis of data from a group of patients was performed in which drained ultrafiltration volume and glucose concentration in dialysis fluid were recorded for each dwell time every day during time on continuous ambulatory peritoneal dialysis treatment as a part of the clinical routine performed. Days with peritonitis and average of daily measurements 1 month before and after each peritonitis episode were evaluated separately for day and night exchanges. In all, 64 episodes of peritonitis in 30 patients were included in this study. Approximately 15,000 exchanges were recorded. Paired t-test and repeated-measures analysis of variance were performed. RESULTS: Compared with the average for the previous month, there was a significant decrease in ultrafiltration volume for day exchanges occurring 2 days before the appearance of other clinical symptoms of peritonitis (P = 0.029). For night exchanges, the decrease in ultrafiltration volume occurred 24 hours before diagnosis (P < 0.001). Ultrafiltration volume was at its minimum the day of diagnosis for both the day (P < 0.001) and night (P < 0.001) exchanges compared with average volume for the previous month. Ultrafiltration volumes remained low for 2 days after diagnosis during both the day (P = 0.009) and night (P = 0.017) exchanges. Relative to the previous month, glucose concentration on the day of clinical diagnosis of peritonitis did not differ significantly (P = 0.328 and P = 0.963 for day and night shifts, respectively). Overall, no significant changes in ultrafiltration volumes or glucose concentrations from the month before to the month after the peritonitis episode were found (P = 0.99 and P = 0.27 for measurements during the day, respectively). CONCLUSION: Osmotic forced ultrafiltration decreased during infectious peritonitis, most significantly for a long dwell time, consistent with an increase in both functional peritoneal surface area and hydraulic conductivity. This finding appeared 2 days before other clinical symptoms and remained significantly low 2 days after diagnosis.