Plasma Levels of Biotin Metabolites Are Elevated in Hemodialysis Patients with Cramps.

Patients with renal failure undergoing hemodialysis (HD) are susceptible to muscle cramps during and after HD. Muscle cramps are defined as the sudden onset of a prolonged involuntary muscle contraction accompanied by severe pain. Through HD, water-soluble vitamins are drawn out with water. Since biotin, a water-soluble vitamin, plays an essential role as one of the coenzymes in producing energy, we have hypothesized that deficiency of biotin may be responsible for HD-associated cramps. We previously reported that biotin administration ameliorated the muscle cramps, despite the elevated plasma biotin levels before HD and biotin administration, as judged by an enzyme-linked immunosorbent assay (ELISA). However, the ELISA measures not only biotin but also total avidin-binding substances (TABS) including biotin metabolites. In the present study, we determined biotin in HD patients as well as healthy controls, using a newly developed method with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The plasma samples were collected from 28 HD patients (16 patients with cramps and 12 patients without cramps) before HD and biotin administration and from 11 controls. The results showed that the accumulation of biotin and TABS in plasma of HD patients compared to controls. Importantly, the levels of biotin metabolites, i.e. TABS subtracted by biotin, increased significantly in patients with cramps over those without cramps. Moreover, the levels of biotin metabolites were significantly higher in patients with a poor response to administered biotin, compared to those with a good response. We propose that accumulated biotin metabolites impair biotin's functions as a coenzyme.

Does a Reduction in Serum Sodium Concentration or Serum Potassium Concentration Increase the Prevalence of Exercise-Associated Muscle Cramps?

CLINICAL SCENARIO: Although exercise-associated muscle cramps (EAMC) are common in ultradistance runners and athletes in general, their etiology remains unclear. EAMC are painful, sudden, involuntary contractions of skeletal muscle occurring during or after exercise and are recognized by visible bulging or knotting of the whole, or part of, a muscle. Many clinicians believe EAMC occur after an imbalance in electrolyte concentrations, specifically serum sodium concentration ([Na+]s) and serum potassium concentration ([K+]s). Studies that have established a link between EAMC occurrence and serum electrolyte concentrations after an athletic event are unhelpful. Focused Clinical Question: Are [Na+]s and [K+]s different in athletes who experience EAMC than noncrampers?

Burnt sugarcane harvesting is associated with acute renal dysfunction.

Sugarcane harvesting has been associated with an epidemic of chronic kidney disease in Central America mainly affecting previously healthy young workers. Repeated episodes of acute kidney dysfunction are hypothesized to be one of the possible mechanisms for this phenomenon. Therefore, this exploratory study aimed to assess the acute effects of burnt sugarcane harvesting on renal function among 28 healthy non-African Brazilian workers. Urine and blood samples were collected at the beginning and at the end of the harvesting season and before and at the end of a harvesting workday. All individuals decreased their estimated glomerular filtration rate by ∼20% at the end of the daily shift, and 18.5% presented with serum creatinine increases consistent with acute kidney injury. Those changes were associated with increased serum creatine phosphokinase (a known marker for exertional rhabdomyolysis) and oxidative stress-associated malondialdehyde levels, increased peripheral blood white cell counts, decreased urinary and serum sodium, decreased calculated fractional sodium excretion, and increased urine density. Thus, burnt sugarcane harvesting caused acute renal dysfunction in previously healthy workers. This was associated with a combination of dehydration, systemic inflammation, oxidative stress, and rhabdomyolysis.

Effects of 100-km ultramarathon on acute kidney injury.

OBJECTIVE: To evaluate the prevalence and characteristics of acute kidney injury (AKI) in 100-km ultramarathon runners. DESIGN: Prospective observational study. SETTING: The 2011 Soochow University ultramarathon, in which each athlete ran for 100 km. PARTICIPANTS: All Taiwanese entrants who participated in the 100-km race and lived in the northern part of Taiwan were invited to participate in the study. MAIN OUTCOME MEASURES: Acute kidney injury was defined using the Acute Kidney Injury Network criteria. Blood and urine samples were collected 1 week before, immediately after, and 1 day after the race. RESULTS: Immediately after the race, 85% (22) of the 26 subjects were diagnosed with AKI, 65% (16) with moderate dehydration, 23% (6) with muscle cramps, and 12% (3) with hematuria. Body weight was significantly decreased from prerace to all postrace measurements. Plasma levels of potassium ion, creatinine, renin, and aldosterone were significantly elevated immediately after the race and then significantly reduced 1 day after the race. Changes in plasma levels of sodium, creatine kinase, and creatine kinase-MB, as well as urine potassium and creatinine, were indicative of AKI. CONCLUSIONS: Transient AKI and muscle cramps are very common in 100-km ultramarathon runners. All transient ultra-runners who developed AKI in this study recovered their renal function 1 day later. CLINICAL RELEVANCE: Ultramarathon running is associated with a wide range of significant changes in hematological parameters, several of which can be associated with potentially serious renal and physiological abnormalities.

Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia.

Bosutinib, an orally active, Src/Abl tyrosine kinase inhibitor, has demonstrated clinical activity and acceptable tolerability in chronic phase chronic myeloid leukemia (CP CML). This updated analysis of the BELA trial assessed the safety profile and management of toxicities of bosutinib versus imatinib in adults with newly diagnosed (≤6 months) CP CML after >30 months from accrual completion. Among patients randomized to bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252), 248 and 251, respectively, received ≥1 dose of study treatment. Adverse events (AEs; any grade) with bosutinib versus imatinib were significantly more common for certain gastrointestinal events (diarrhea, 70% vs. 26%; P < 0.001; vomiting, 33% vs. 16%; P < 0.001), alanine aminotransferase (33% vs. 9%; P < 0.001) and aspartate aminotransferase (28% vs. 10%; P < 0.001) elevations, and pyrexia (19% vs. 12%; P = 0.046). AEs significantly less common with bosutinib included edema (periorbital, 2% vs. 14%; P < 0.001; peripheral, 5% vs. 12%; P = 0.006), musculoskeletal (myalgia, 5% vs. 12%; P = 0.010; muscle cramps, 5% vs. 22%; P < 0.001; bone pain, 4% vs. 11%; P = 0.003), increased creatine phosphokinase (8% vs. 20%; P < 0.001), neutropenia (13% vs. 30%; P < 0.001), and leukopenia (9% vs. 22%; P < 0.001). Between-group differences in the incidence of cardiac and vascular AEs were not significant. Diarrhea was typically transient, mostly Grade 1/2, occurring early during treatment, and was manageable with antidiarrheal medication. Despite higher rates of aminotransferase elevation with bosutinib, events were managed in most patients with dose modification and/or concomitant medication. Bosutinib had a manageable safety profile distinct from that of imatinib in patients with newly diagnosed CP CML.

Increased running speed and previous cramps rather than dehydration or serum sodium changes predict exercise-associated muscle cramping: a prospective cohort study in 210 Ironman triathletes.

BACKGROUND: Despite the high prevalence of exercise-associated muscle cramping (EAMC) in endurance athletes, the aetiology and risk factors for this condition are not fully understood. AIM: The aim of this prospective cohort study was to identify risk factors associated with EAMC in endurance triathletes. METHODS: 210 triathletes competing in an Ironman triathlon were recruited. Prior to the race, subjects completed a detailed validated questionnaire and blood samples were taken for serum electrolytes. Immediately before the race, pre-race body weight was obtained. Body weight and blood samples for serum electrolyte concentrations were obtained immediately after the race. Clinical data on EAMC experienced during or immediately after the race were also collected. RESULTS: 43 triathletes reported EAMC (cramping group) and were compared with the 166 who did not report EAMC (non-cramping group). There were no significant differences between groups in any pre-race-post-race serum electrolyte concentrations and body weight changes. The development of EAMC was associated with faster predicted race times and faster actual race times, despite similarly matched preparation and performance histories in subjects from both groups. A regression analysis identified faster overall race time (and cycling time) and a history of cramping (in the last 10 races) as the only two independent risk factors for EAMC. CONCLUSION: The results from this study add to the evidence that dehydration and altered serum electrolyte balance are not causes for EAMC. Rather, endurance runners competing at a fast pace, which suggests that they exercise at a high intensity, are at risk for EAMC.

Effectiveness of 4-Week Oral Taurine Treatment for Muscle Cramps in Patients with Liver Cirrhosis: A Single-Arm Pilot Study.

PURPOSE: Painful muscle cramps are a common complication in liver cirrhosis patients, and no effective treatment is available. This pilot study aimed to evaluate whether taurine supplementation improves muscle cramps in Korean cirrhotic patients. MATERIALS AND METHODS: Ten cirrhotic patients who experienced muscle cramps one or more times/week were enrolled in this prospective single-arm study and administered with an oral taurine solution (1 g/50 mL) thrice a day for 4 weeks. Taurine was discontinued for the subsequent 4 weeks. The frequency and intensity of muscle cramps were evaluated using a questionnaire at weeks 0, 2, 4, 6, and 8 after the start of treatment. RESULTS: At baseline, the median frequency of muscle cramps was six times/week, and all patients had severe pain. Muscle cramp scores (frequency×intensity) decreased in seven patients by weeks 4 and 8 after treatment initiation. Compared to baseline muscle cramp scores [median 21, interquartile range (IQR): 8-84], median muscle cramp scores were lower at week 4 (6.5, IQR: 3-12, p=0.126) and week 8 (5, IQR: 1.5-56, p=0.066). All five patients whose baseline plasma taurine levels were below the normal limit showed increased taurine levels at week 4; 60% of them experienced improvements in their muscle cramps. Of the five patients with normal or higher taurine levels, 80% experienced an improvement in symptoms at week 4. The safety and tolerability of the 4-week taurine therapy were excellent. CONCLUSION: Oral taurine therapy for 4 weeks improved muscle cramps safely in cirrhotic patients.

Effect of oral rehydration solution versus spring water intake during exercise in the heat on muscle cramp susceptibility of young men.

BACKGROUND: Muscle cramp is a painful, involuntary muscle contraction, and that occurs during or following exercise is referred to as exercise-associated muscle cramp (EAMC). The causes of EAMC are likely to be multifactorial, but dehydration and electrolytes deficits are considered to be factors. This study tested the hypothesis that post-exercise muscle cramp susceptibility would be increased with spring water ingestion, but reduced with oral rehydration solution (ORS) ingestion during exercise. METHODS: Ten men performed downhill running (DHR) in the heat (35-36 °C) for 40-60 min to reduce 1.5-2% of their body mass in two conditions (spring water vs ORS) in a cross-over design. The body mass was measured at 20 min and every 10 min thereafter during DHR, and 30 min post-DHR. The participants ingested either spring water or ORS for the body mass loss in each period. The two conditions were counter-balanced among the participants and separated by a week. Calf muscle cramp susceptibility was assessed by a threshold frequency (TF) of an electrical train stimulation to induce cramp before, immediately after, 30 and 65 min post-DHR. Blood samples were taken before, immediately after and 65 min after DHR to measure serum sodium, potassium, magnesium and chroride concentrations, hematocrit (Hct), hemoglobin (Hb), and serum osmolarity. Changes in these varaibles over time were compared between conditions by two-way repeated measures of analysis of variance. RESULTS: The average (±SD) baseline TF (25.6 ± 0.7 Hz) was the same between conditions. TF decreased 3.8 ± 2.7 to 4.5 ± 1.7 Hz from the baseline value immediately to 65 min post-DHR for the spring water condition, but increased 6.5 ± 4.9 to 13.6 ± 6.0 Hz in the same time period for the ORS condition (P < 0.05). Hct and Hb did not change significantly (P > 0.05) for both conditions, but osmolarity decreased (P < 0.05) only for the spring water condition. Serum sodium and chloride concentrations decreased (< 2%) at immediately post-DHR for the spring water condition only (P < 0.05). CONCLUSIONS: These results suggest that ORS intake during exercise decreased muscle cramp susceptibility. It was concluded that ingesting ORS appeared to be effective for preventing EAMC.

Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy.

Thrombocytopenia with or without microangiopathy following quinine is often referred to as quinine "hypersensitivity." When schistocytes are present it is frequently termed "quinine-associated TTP/HUS." A severe deficiency of the vWF-cleaving protease, ADAMTS13, is associated with idiopathic TTP. A previous study of patients with "quinine-associated TTP/HUS" found that ADAMTS13 activities were not abnormal in 12/12 patients. A retrospective review of TTP patients with quinine-associated thrombotic microangiopathy (TMA) for whom ADAMTS13 was measured before plasma exchange was performed. Six patients were identified. All were females (age range: 43 to 73, mean = 61.7 years) and had taken quinine for leg cramps. Four of the six experienced renal failure requiring dialysis. Five of the patients had D-Dimers levels measured, all were elevated. In four patients the levels were > or = 18 times the upper limit of normal. ADAMTS13 was normal in four patients and mildly decreased in two patients. We conclude that while thrombocytopenia and schistocytosis can be seen in quinine-associated TTP/HUS, the pathophysiology seems to be distinct from that seen in most cases of idiopathic TTP (i.e., severely decreased ADAMTS13 with an inhibitor). We recommend that a TMA in association with quinine be consistently referred to as quinine-associated thrombotic microangiopathy (quinine-TMA) to better distinguish this entity from idiopathic TTP. The use of plasma exchange in quinine-TMA is called into question.

Correlation of symptoms to serum vitamin D levels?

BACKGROUND AND OBJECTIVE: Recent studies have shown that vitamin D plays an important role in many disease processes. However, data is lacking which correlates the common symptoms attributed with vitamin D levels. This study was undertaken to find the correlation of symptoms and Vitamin D levels among ethnic Saudi Arabian population. METHODS: A structured questionnaire was made and translated in the Arabic language, which included, age, weight and height, ethnicity and marital status. Patients who were visiting orthopaedic clinics for the first time were included after a detailed history, which ruled out any associated metabolic conditions. Patient's biometric data and the answering of the questionnaire were conducted by one of the senior members of the research group. The symptoms which were included in the questionnaire were fatigue, muscle cramps, joint and back pain, blood sugar levels, recurrent infections, hair loss, mood swings, weight gain, irritable bowel, fractures and history of malignancy. All the scores were graded between 1 and 9 (mildest 1 and severe 9) and only for fracture and malignancy it was yes/no answer. A score of ≤4 was accepted as no impact of the vitamin D levels on symptoms and answer of ≥5 was accepted as impact on the symptoms. Residents whose mother tongue was Arabic conducted all interviews. Blood was collected for 25 OHD levels, calcium and parathyroid hormone levels. Deficiency of vitamin D was defined as ≤20 ng/ml, insufficiency 21-29 ng/ml and normal level ≥30 ng/ml. The data was entered in the data base and analyzed using SPSS Inc Version 20. RESULTS: Two hundred one patients completed the questionnaire but for final analysis the data of 187 was available for analysis as in 14 patients some of the data was missing. All were females and the average age was 55.9 ± 12.4 years, weight 78.9 ± 14.2 kg and height was 1.56 ± 7.01 m. The mean calcium level was 9.12 ± 0.33 mg/dl and, parathyroid hormone was 8.1 ± 6.06 pc/ml. The average 25 hydroxy vitamin D3 (25OHD) level was 21.8 ± 10.22 ng/ml. Forty-four (23.5%) of women had a normal vitamin D level, 51 (27.27%) had insufficiency and 92 (49.19%) had deficiency. Patients who complained of muscle cramps had 25OHD level of 18.86 ± 8.73 compared to patients who had no complains of cramps, 23.45 ± 9.2 ng/ml (p < 0.001) and symptom severity score (SSC) p value of p < 0.000. The results were similar for fatigue, Back pain, hair loss, mood swings and weight gain of P < 0.04, p < 0.07, p < 0.05, <0.03 and p < 0.09 for vitamin D levels and p < 0.001 for SSS. Forty-eight (25.6%) had a previous fracture in their history. CONCLUSIONS: This study shows that many symptoms, which have been attributed to low vitamin D levels, are not true. Muscle Cramps, fatigue, mood swings, hair loss, back pain and weight gains appears to be more common in patients with low 25OHD levels.

Treatment of Myasthenia Gravis With High-Dose Cholinesterase Inhibitors and Calcineurin Inhibitors Caused Spontaneous Muscle Cramps in Patients.

OBJECTIVES: The objective of this study was to investigate the influence of treatment with cholinesterase inhibitors (ChEIs) and calcineurin inhibitors (CNIs) on the occurrence of cramps in myasthenia gravis (MG) patients. METHODS: The frequency and duration of cramp and serum electrolytes were evaluated in 81 patients with MG. The patients were classified using Myasthenia Gravis Foundation of America postintervention status scores based on the treatment and the responsiveness to the treatment. Quantitative MG score, MG activities of daily living score, MG composite score, or MG quality of life 15 score was used to assess the health-related quality of life (QOL). RESULTS: Muscle cramps developed in 44 (54.3%) of 81 MG patients. The scores of MG activities of daily living, MG composite, or MG-QOL 15-item questionnaire in patients with cramp were significantly higher than those in patients without cramps (P = 0.002, P = 0.01, or P = 0.0022, respectively). The serum magnesium concentrations were lower in patients treated with CNI (n = 16) than in those not treated with CNI (n = 65) (P = 0.002). The probability of cramps was significantly higher in patients treated with ChEIs (≥180 mg/d) in addition to CNI than in patients who were treated with a low dose of ChEIs (≤60 mg/d) without concomitant CNI treatment (P = 0.017). CONCLUSIONS: Our data suggested that treatment with a high dose of ChEI and CNI accelerated the probability of cramps and reduced the QOL in MG patients.

Serum electrolytes in Ironman triathletes with exercise-associated muscle cramping.

PURPOSE: To compare serum electrolyte concentrations of cramping and control Ironman triathletes. METHODS: Triathletes suffering from acute exercise-associated muscle cramping (EAMC) after the 2000 South African Ironman Triathlon formed the cramping group (CR, N = 11). Non-cramping triathletes matched for race finishing time and body mass formed the control group (CON, N = 9). All subjects were weighed at race start and immediately post-race. Blood samples were drawn from both groups during recovery for the analysis of serum magnesium, glucose, sodium, potassium and chloride concentrations. Hemoglobin concentration and hematocrit were also measured. Surface electromyography (EMG) (mV) was recorded from a non-cramping control muscle (triceps) and the most severely cramping lower limb muscle of the CR group. EMG was recorded at the beginning of every minute for a 10-min period during recovery. RESULTS: There were no significant differences between the groups for body mass or percent body mass loss during the race. Post-race sodium concentration was significantly lower (P = 0.01) in the CR group than the CON group (140 +/- 2 vs 143 +/- 3 mmol.L) but was within the normal clinical range of post-race serum sodium concentrations. There were no significant differences between the two groups for post-race serum electrolytes, glucose, hemoglobin concentrations or hematocrit. Surface EMG (mV) was significantly higher (P < 0.05) in the cramping muscles than the control muscle of the CR group at 0, 3, 4, and 5 min of the 10-min recording period. CONCLUSION: Acute EAMC in ironman triathletes is not associated with a greater percent body mass loss or clinically significant differences in serum electrolyte concentrations. The increased EMG activity of cramping muscles may reflect increased neuromuscular activity.

Relationship of creatine kinase to body composition, disease state, and longevity in ALS.

Our objective was to explore if creatine kinase (CK) levels correlate with survival in amyotrophic lateral sclerosis (ALS), and whether a correlation is independent of other well-studied predictors such as location of onset, gender, age, fat free mass, spasticity, cramps, and fasciculations. We analyzed data from 80 ALS patients from a 48-week non-interventional longitudinal multicenter nutrition study with long term follow-up. The overall mean CK was 214 ± 191.8 U/l (range 22-1992 U/l). Forty-five percent of patients had at least one high CK value (> 200 U/l), and about half maintained a high CK value, but there was no trend over the study period. Male gender and extremity onset were significantly associated with high CK. In univariate analysis, age, bioelectric impedance spectroscopy (BIS) fat free mass, spasticity, and fasciculations were not associated with CK level. There was an association between CK and muscle cramps (p < 0.001). In survival analysis, low CK (≤ 200 U/l) was associated with a longer overall survival (p = 0.02), when adjusting for location of onset, age, race, gender, BIS fat free mass, and study site. In conclusion, CK may be a useful marker for ALS survival, which has implications for clinical care and the design of future clinical trials.

Serum electrolyte concentrations and hydration status are not associated with exercise associated muscle cramping (EAMC) in distance runners.

OBJECTIVES: To determine whether acute exercise associated muscle cramping (EAMC) in distance runners is related to changes in serum electrolyte concentrations and hydration status. METHODS: A cohort of 72 runners participating in an ultra-distance road race was followed up for the development of EAMC. All subjects were weighed before and immediately after the race. Blood samples were taken before the race, immediately after the race, and 60 minutes after the race. Blood samples were analysed for glucose, protein, sodium, potassium, calcium, and magnesium concentrations, as well as serum osmolality, haemoglobin, and packed cell volume. Runners who suffered from acute EAMC during the race formed the cramp group (cramp, n = 21), while runners with no history of EAMC during the race formed the control group (control, n = 22). RESULTS: There were no significant differences between the two groups for pre-race or post-race body weight, per cent change in body weight, blood volume, plasma volume, or red cell volume. The immediate post-race serum sodium concentration was significantly lower (p = 0.004) in the cramp group (mean (SD), 139.8 (3.1) mmol/l) than in the control group (142.3 (2.1) mmol/l). The immediate post-race serum magnesium concentration was significantly higher (p = 0.03) in the cramp group (0.73 (0.06) mmol/l) than in the control group (0.67 (0.08) mmol/l). CONCLUSIONS: There are no clinically significant alterations in serum electrolyte concentrations and there is no alteration in hydration status in runners with EAMC participating in an ultra-distance race.

Muscle cramps and neuropathies in patients with allogeneic hematopoietic stem cell transplantation and graft-versus-host disease.

OBJECTIVE: Graft-versus-host disease (GVHD) is an immune-mediated multisystemic disorder and the leading cause of morbidity after allogeneic hematopoietic stem cell transplantation. Peripheral nervous system manifestations of GVHD are rare but often disabling. Whereas immune-mediated neuropathies are an established feature of GVHD, muscle cramps are not well characterized. METHODS: In a single-centre retrospective cohort we studied 27 patients (age 23 to 69 years) with GVHD (acute n = 6, chronic n = 21) who complained of symptoms suggestive of peripheral nervous system complications. Clinical, laboratory and neurophysiological findings were evaluated by descriptive statistics and regression analysis to detect factors associated with muscle cramps. Patient's sera were examined for anti-neuronal antibodies. RESULTS: Nine patients had polyneuropathy, 4 had muscle cramps, and 14 had both. Median onset of polyneuropathy and muscle cramps was 6 and 9 months after allogeneic hematopoietic stem cell transplantation, respectively. Neurophysiology revealed a predominantly axonal polyneuropathy in 20 of 26 patients. In 4 of 19 patients electromyography showed signs of myopathy or myositis. Muscle cramps were more frequent during chronic than acute GVHD and affected muscles other than calves in 15 of 18 patients. They typically occurred daily, lasted 1 to 10 minutes with medium to severe pain intensity, compromised daily activity or sleep in 12, and were refractory to therapy in 4 patients. Muscle cramps were less likely with tacrolimus treatment and signs of severe polyneuropathy, but more likely with myopathic changes in electromyography and with incipient demyelinating polyneuropathy, shown by increased high frequency attenuation of the tibial nerve. Serological studies revealed antinuclear or antimitochondrial antibodies in a subset of patients. Two of 16 patients had a serum reactivity against peripheral nervous tissue. CONCLUSION: Muscle cramps are associated with chronic GVHD, often compromise daily activity, and correlate negatively with axonal polyneuropathy and positively with myopathy and incipient demyelination.

Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia.

The authors analyzed muscle biopsy specimens of 104 patients with creatine kinase activity greater than 500 UI/L (normal 10 to 170 UI/L) without signs of muscle weakness. They achieved a definite or probable diagnosis in 55% of cases. The most frequently identified diseases were glycogen storage diseases, muscular dystrophies, and inflammatory myopathies. The probability of making a diagnosis was higher in children and when creatine kinase level was greater than 2,000 UI/L.