Isolated Pyridoxine Deficiency Presenting as Muscle Spasms in a Patient With Type 2 Diabetes: A Case Report and Literature Review.

Pyridoxine is an important co-factor for many biochemical reactions in cellular metabolism related to the synthesis and catabolism of amino acids, fatty acids, neurotransmitters. Deficiency of pyridoxine results in impaired transcellular signaling between neurons and presents with muscular convulsions, hyperirritability, and peripheral neuropathy. Deficiency of pyridoxine is usually found in association with other vitamin B deficiencies such as folate (vitamin B9) and cobalamin (vitamin B12). Isolated pyridoxine deficiency is extremely rare. We present the case of a 59-year old female with type 2 diabetes who complained of painful muscle spasms. Her muscle spasms involved in both feet, which have spread proximally to her legs. She also experienced intermittent muscle spasms in her left arm, which is not alleviated by baclofen, cyclobenzaprine. Her plasma pyridoxal 5-phosphate confirmed pyridoxine deficiency. Vitamins B1, B3, B12, and folate were within normal limits. The patient received standard-dose intramuscular pyridoxine injections for three weeks followed by oral supplements for 3 months and her symptoms resolved. This case illustrates the rare instance of isolated pyridoxine deficiency in type 2 diabetes patient manifesting as myoclonic muscle spasms involving the legs and arms in the absence of objective polyneuropathy. Pyridoxine level should, therefore, be assessed in patients with type 2 diabetes, including newly diagnosed patients.

Combined zinc and vitamin B6 deficiency in a patient with diffuse red rash and angular cheilitis 6 years after Roux-en-Y gastric bypass.

A 39-year-old woman with a history of Roux-en-Y gastric bypass (RYGB) surgery and alcohol use presented with a confluent erythematous rash involving the perineum spreading outward to the abdomen, thighs and lower back. She had angular cheilitis and glossitis. The rash was painful and blistering in scattered areas. She was hypotensive and appeared to be in septic or hypovolemic shock at presentation. Serum levels of zinc and vitamin B6 were critically low and biopsy of her rash returned suggestive of a nutritional deficiency as its source. The rash slowly improved over the following 2 weeks with oral zinc and vitamin B6 replacement. The body rash resembled that of infants born with inherited defects in zinc transporters, referred to as acrodermatitis enteropathica (AE). This case may represent an acquired case of AE in the setting of prior RYGB.

[A microcytic sideroblastic anemia successfully treated with B6 vitamin]. / Une anémie microcytaire sidéroblastique carentielle traitée efficacement par de la vitamine B6.

INTRODUCTION: Sideroblastic anemia is a rare cause of microcytic anemia, which is characterized by ring sideroblasts on bone marrow aspirate. This anemia can be congenital or acquired. CASE REPORT: We report the case of an alcoholic 49-year-old man who presented with a severe microcytic sideroblastic anemia related to pyridoxine (B6 vitamin) deficiency. Acid folic deficiency was associated. The blood count normalized within one month after vitamin supplementation. CONCLUSION: Pyridoxine deficiency must be sought in sideroblastic anemia in patients at risk.

Homocysteine, Pyridoxine, Folate and Vitamin B12 Levels in Children with Attention Deficit Hyperactivity Disorder.

BACKGROUND: In our study, we aimed to evaluate the serum homocysteine levels, pyridoxine, folate and vitamin B12 levels in children with attention deficit hyperactivity disorders (ADHD). SUBJECTS AND METHODS: This study included 30 newly diagnosed drug-naive children with ADHD (23 males and 7 female, mean age 9.3±1.8 years) and 30 sex-and age matched healthy controls. The diagnosis of ADHD was made according to DSM-V criteria. Children and adolescents were administered the Schedule for Affective Disorders and Schizophrenia for School Aged Children, Present and Lifetime Version, the Conners' Parent Rating Scale-Revised, Long Form, the Conners' Teacher Rating Scale and the Wechsler Intelligence Scale for Children Revised (WISC-R) for all participants. Homocysteine, pyridoxine, folate and vitamin B12 levels were measured with enzyme-linked immunosorbent assay. RESULTS: Homocysteine, pyridoxine, folate and vitamin B12 levels were significantly lower in children with ADHD compared with their controls (p<0.05). A positive significant correlation was observed between the all WISC-R scores and vitamin B12 level in patients (r=0.408, p=0.025). CONCLUSIONS: The results obtained in this study showed that reduced homocysteine, pyridoxine, folate and vitamin B12 levels could be a risk factor in the etiology of ADHD.

Vitamin B6 blood concentrations in paediatric dialysis patients.

OBJECTIVES: We investigated vitamin B6 blood concentrations in children on long-term dialysis at our centre. METHODS: Retrospective cross-sectional review of vitamin B6 blood concentrations in children on maintenance dialysis [peritoneal dialysis (PD), intermittent haemodialysis (IHD)]. RESULTS: We reviewed 28 children (16 boys), 15 IHD and 13 PD with median (interquartile range, IQR) age of 9.4 (2.4, 14.3) years. The median (IQR) vitamin B6 concentration was 223.4 (74.2, 392.8) nmol/L measured a median (IQR) of 9 (4, 16.5) months following commencement of dialysis. None of the children had vitamin B6 deficiency. Vitamin B6 concentrations were raised in 17 (61%), eight of these received a supplement. Nineteen (68%) received vitamin B6 and/or a supplement containing vitamin B6 whilst 11 (39%) received an enteral feed and a supplement. In those with normal vitamin B6 concentrations who were not receiving an enteral feed or an oral nutritional supplement (n = 6), all achieved normal concentrations without need for vitamin B6 supplementation. There were no differences between those on PD versus IHD (269.2 nmol/L vs. 130 nmol/L, P = 0.65). CONCLUSIONS: We report no children with vitamin B6 deficiency although > 50% had elevated vitamin B6 concentrations. We suggest if dietary assessment of vitamin B6 intake indicates insufficient intake, measurement of blood concentrations will help confirm if supplementation is required. Routine vitamin B6 supplementation and monitoring is currently not indicated in children on chronic dialysis.

Prevalence and Predictors of Low Vitamin B6 Status in Healthy Young Adult Women in Metro Vancouver.

Low periconceptional vitamin B6 (B6) status has been associated with an increased risk of preterm birth and early pregnancy loss. Given many pregnancies are unplanned; it is important for women to maintain an adequate B6 status throughout reproductive years. There is limited data on B6 status in Canadian women. This study aimed to assess the prevalence of B6 deficiency and predictors of B6 status in young adult women in Metro Vancouver. We included a convenience sample of young adult non-pregnant women (19-35 years; n = 202). Vitamin B6 status was determined using fasting plasma concentrations of pyridoxal 5'-phosphate (PLP). Mean (95% confidence interval) plasma PLP concentration was 61.0 (55.2, 67.3) nmol/L. The prevalence of B6 deficiency (plasma PLP < 20 nmol/L) was 1.5% and that of suboptimal B6 status (plasma PLP = 20-30 nmol/L) was 10.9%. Body mass index, South Asian ethnicity, relative dietary B6 intake, and the use of supplemental B6 were significant predictors of plasma PLP. The combined 12.4% prevalence of B6 deficiency and suboptimal status was lower than data reported in US populations and might be due to the high socioeconomic status of our sample. More research is warranted to determine B6 status in the general Canadian population.

4-Pyridoxic Acid in the Spent Dialysate: Contribution to Fluorescence and Optical Monitoring.

AIM: In this work we estimated the contribution of the fluorescence of 4-pyridoxic acid (4-PA) to the total fluorescence of spent dialysate with the aim of evaluating the on-line monitoring of removal of this vitamin B-6 metabolite from the blood of patients with end-stage renal disease (ESRD). METHODS: Spectrofluorometric analysis of spent dialysate, collected from hemodialysis and hemodiafiltration sessions of 10 patients receiving regularly pyridoxine injections after dialysis treatment, was performed in the range of Ex/Em 220-500 nm. 4-PA in dialysate samples was identified and quantified using HPLC with fluorescent and MS/MS detection. RESULTS: Averaged HPLC chromatogram of spent dialysate had many peaks in the wavelength region of Ex320/Em430 nm where 4-PA was the highest peak with contribution of 42.2±17.0% at the beginning and 47.7±18.0% in the end of the dialysis. High correlation (R = 0.88-0.95) between 4-PA concentration and fluorescence intensity of spent dialysate was found in the region of Ex310-330/Em415-500 nm, respectively. CONCLUSION: 4-PA elimination from the blood of ESRD patients can be potentially followed using monitoring of the fluorescence of the spent dialysate during dialysis treatments.

Investigation of vitamin B6 inadequacy, induced by exposure to the anti-B6 factor 1-amino D-proline, on plasma lipophilic metabolites of rats: a metabolomics approach.

PURPOSE: Vitamin B6 status in the body is affected by several factors including dietary supply of the antivitamin B6 factor, 1-amino D-proline (1ADP), which is present in flaxseed. Owing to the prevalence of moderate B6 deficiency in the general population, a co-occurrence of 1ADP may lead to a further deterioration of B6 status. To this end, we applied a nontargeted metabolomics approach to identify potential plasma lipophilic biomarkers of deleterious effect of 1ADP on moderately vitamin B6-deficient rats using a high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. METHODS: Twenty-four rats were fed with a semi-purified diet containing pyridoxine·HCl (PN·HCl) either 7 mg/kg diet (optimal B6) or 0.7 mg/kg diet (moderate B6). The rats were divided into four treatments (n = 6), and one treatment in each B6 diet group was also fed ad libitum with 10 mg/kg diet of synthetic 1ADP. After 5 weeks of study, plasma was collected from the rats and lipophilic metabolites were extracted using acetonitrile as a solvent for analysis. RESULTS: Ten potential plasma lipophilic biomarkers were identified out of >2500 detected entities, which showed significant differences between the treatments. Plasma glycocholic acid, glycoursodeoxycholic acid, murocholic acid, N-docosahexaenoyl GABA, N-arachidonoyl GABA, lumula, nandrolone and orthothymotinic acid concentrations were significantly elevated, while plasma cystamine and 3-methyleneoxindole concentrations were significantly reduced as a result of either low B6 status or 1ADP or their interaction. CONCLUSION: Changes in these metabolites revealed a potential defect in pathways linked with the biosynthesis and metabolism of bile acid components, N-acyl amino acids, analgesic androgens, anti-inflammatory and neuroprotective molecules. We also noted that the changes in these biomarkers can be alleviated by the application of adequate vitamin B6.

Isoniazid exposure and pyridoxine levels in human immunodeficiency virus associated distal sensory neuropathy.

SETTING: Distal sensory polyneuropathy (DSP) may manifest in human immunodeficiency virus (HIV) infected individuals before or after antiretroviral therapy (ART). DSP can also occur in response to isoniazid (INH); this can be prevented by pyridoxine supplementation. N-acetyltransferase 2 (NAT2) polymorphisms influence drug acetylation and possibly the risk for INH-associated DSP. OBJECTIVE: To investigate the relationship between previous/current TB, pyridoxine deficiency and DSP in HIV-infected individuals enrolled in a government-sponsored HIV programme. DESIGN: Neuropathy assessments were performed among 159 adults pre-ART and 12 and 24 weeks thereafter. DSP was defined as ⩾1 neuropathic symptom and sign. NAT2 genotypes predicted acetylation phenotype. Serum pyridoxine levels (PLP) were quantified at baseline and week 12. RESULTS: DSP was present in 16% of individuals pre-ART and was associated with previous/current TB (P = 0.020). Over 50% were pyridoxine deficient (PLP < 25 nmol/l), despite supplementation with vitamin B complex supplements (2-4 mg/day pyridoxine). Those with a history of TB and pre-ART DSP were more likely to be pyridoxine deficient (P = 0.029), and slow/intermediate NAT2 phenotypes impacted on their PLP levels. Incident/worsening DSP after ART developed in 21% of the participants. PLP levels remained low after ART, particularly among those with prior TB, but without an association between DSP or NAT2 phenotypes. CONCLUSION: Adequate pyridoxine supplementation before ART initiation should be prioritised, particularly in those with a history of TB or current TB.

Characterization of modified proteins in plasma from a subtype of schizophrenia based on carbonyl stress: Protein carbonyl is a possible biomarker of psychiatric disorders.

Although it's well known that protein carbonyl (PCO) and advanced glycation end-products (AGEs) levels are elevated in plasma from patients with renal dysfunction, we recently identified patients who had no renal dysfunction but possessed high levels of plasma pentosidine (PEN), which is an AGEs, and low vitamin B6 levels in serum. In this study, we investigated the status of carbonyl stress to characterize the subtype of schizophrenia. When plasma samples were subjected to Western blot analysis for various AGEs, clear differences were only observed with the anti-PEN antibody in the plasma from schizophrenic patients. Moreover, we determined the formation of protein carbonyl (PCO), a typical indicator of carbonyl stress, occurred prior to the accumulation of PEN in the plasma of schizophrenic patients. PCO levels in the plasma from schizophrenic patients were significantly higher than that from healthy subjects. Western blots analysis clearly showed that albumin and IgG were markedly carbonylated in the plasma of some patients. Thus, PCOs may be a novel marker of carbonyl stress-type schizophrenia in addition to albumin containing PEN structure.

Anemia attributed to vitamin B6 deficiency in post-pancreaticoduodenectomy patients.

Micronutrient deficiencies such as vitamin A, iron, zinc, and selenium have been known to occur as a consequence of pancreaticoduodenectomy (PD), but vitamin B6 deficiency has not been previously reported. We report two post-PD patients who developed anemias attributed to vitamin B6 deficiency. Oral supplementations of vitamin B6 significantly improved anemias in both cases. Micronutrients including vitamin B6 should be monitored in post-PD patients, and supplementations should be carried out when necessary.

Sensory polyneuropathy in human immunodeficiency virus-infected patients receiving tuberculosis treatment.

SETTING: Human immunodeficiency virus (HIV) infection and treatments for HIV infection and tuberculosis (TB) are associated with the risk of developing sensory polyneuropathy (SPN). Vitamin B6 and genetically determined slow isoniazid (INH) acetylation are believed to play key roles in the development of SPN in a TB treatment setting. OBJECTIVE: To investigate slow acetylation and risk factors for SPN in HIV-infected patients receiving TB treatment, and establish vitamin B6 status and its association with SPN. METHODS: HIV-infected in-patients were prospectively assessed after initiating TB treatment and vitamin B6 supplementation, and monthly during hospitalisation. SPN was defined as ≥1 symptom plus ≥1 sign. NAT2 genotyping predicted acetylation status, and plasma high performance liquid chromatography estimated vitamin B6 status. A survival analysis estimated hazard ratios (HRs) for SPN during TB treatment. RESULTS: Of 116 participants, 56% had SPN at study entry. Participants developed SPN at a rate of 26/100 person-months (95%CI 18-35) during TB treatment, which was independently associated with slow acetylation (HR 2.5; 95%CI 1.1-5.9), as well as black race, previous TB and extra-pulmonary/disseminated TB. Vitamin B6 status was normal, irrespective of SPN. CONCLUSIONS: Risk factors for SPN suggest a multi-factorial pathogenesis related to INH and other potential nervous system insults. SPN developed despite normal vitamin B6 status, suggesting other mechanisms of injury.

Novel spectrophotometric method for the quantitation of urinary xanthurenic acid and its application in identifying individuals with hyperhomocysteinemia associated with Vitamin B6 deficiency.

A novel spectrophotometric method for the quantification of urinary xanthurenic acid (XA) is described. The direct acid ferric reduction (DAFR) procedure was used to quantify XA after it was purified by a solid-phase extraction column. The linearity of proposed method extends from 2.5 to 100.0 mg/L. The method is precise, yielding day-to-day CVs for two pooled controls of 3.5% and 4.6%, respectively. Correlation studies with an established HPLC method and a fluorometric procedure showed correlation coefficients of 0.98 and 0.98, respectively. Interference from various urinary metabolites was insignificant. In a small-scale screening of elderly conducted at Penghu county in Taiwan (n = 80), we were able to identify a group of twenty individuals having hyperhomocysteinemia (>15 µ mole/L). Three of them were found to be positive for XA as analyzed by the proposed method, which correlated excellently with the results of the activation coefficient method for RBC's AST/B6 functional test. These data confirm the usefulness of the proposed method for identifying urinary XA as an indicator of vitamin B6 deficiency-associated hyperhomocysteinemic condition.

Vitamin B6: deficiency diseases and methods of analysis.

Vitamin B6 (pyridoxine) is closely associated with the functions of the nervous, immune and endocrine systems. It also participates in the metabolic processes of proteins, lipids and carbohydrates. Pyridoxine deficiency may result in neurological disorders including convulsions and epileptic encephalopathy and may lead to infant abnormalities. The Intravenous administration of pyridoxine to patients results in a dramatic cessation of seizures. A number of analytical methods were developed for the determination of pyridoxine in different dosage forms, food materials and biological fluids. These include UV spectrometric, spectrofluorimetric, mass spectrometric, thin-layer and high-performance liquid chromatographic, electrophoretic, electrochemical and enzymatic methods. Most of these methods are capable of determining pyridoxine in the presence of other vitamins and complex systems in µg quantities. The development and applications of these methods in pharmaceutical and clinical analysis mostly during the last decade have been reviewed.

Pyridoxine and pyridoxalphosphate-dependent epilepsies.

To date we know of four inborn errors of autosomal recessive inheritance that lead to vitamin B6-dependent seizures. Among these, pyridoxine-dependent seizures due to antiquitin deficiency is by far the most common, although exact incidence data are lacking. In PNPO deficiency, samples have to be collected prior to treatment, while PDE, hyperprolinemia type II and congenital HPP can be diagnosed while on vitamin B6 supplementation. A vitamin B6 withdrawal for diagnostic purposes is nowadays only indicated in patients with a clear vitamin B6 response but normal biochemical work-up. In the presence of therapy-resistant neonatal seizures, early consideration of a vitamin B6 trial over 3 consecutive days is crucial in order to prevent irreversible brain damage. While PLP would be effective in all four disorders, pyridoxine fails to treat seizures in PNPO deficiency. As PLP is unlicensed within Europe and North America, pyridoxine is widely used as the first line drug, but if it is ineffective it should be followed by a trial with PLP, especially in neonates. As severe apnea has been described in responders, resuscitation equipment should be at hand during a first pyridoxine/PLP administration. Patients and parents have to be informed about the lifelong dependency and recurrence risks in forthcoming pregnancies.

Vitamin B6 deficiency and diseases in elderly people--a study in nursing homes.

BACKGROUND: Vitamin deficiency is a cause of health related problems in elderly people. The aims were to study associations between vitamin B6 (B6) and diseases (primarily functional gastrointestinal disorders) in elderly people in nursing homes, the prevalence of B6 deficiency and factors associated with B6 deficiency. METHODS: This cross-sectional study included residents in nursing homes. Demographics, nutritional status (Mini Nutritional Assessment, MNA®), physical activity, activity of daily living (Katz Index), dietary habits, use of drugs, and psychiatric and somatic diseases were recorded. A blood sample was collected for haematological and biochemical screening, including B6 (p-PLP); p-PLP values < 20 nmol/l indicates B6 deficiency. The results are given as mean (SD). RESULTS: Sixty-one residents (men/women: 22/39) with an age of 85.3 (6.8) years and BMI 25.7 (4.5) kg/m2 were included. Malnutrition and risk of malnutrition were present in 11.5% and 61% respectively. Dietary intake of B6 (mg/day) in men and women were 1.60 (0.30) and 1.18 (0.31) (recommended 1.6 and 1.2 respectively), and 14 (23%) used B6 supplements. Median p-PLP was 20.7 (range <4.0-175.8), 30 subjects (49%) had B6 deficiency. B6 deficiency was associated with old age, low s-alanine aminotransferase and s-albumin, elevated s-homocysteine and inactivity (p-values 0.01-0.03). There were no clinically significant associations between B6 deficiency and somatic or psychiatric disorders, and B6 deficiency was not observed in subjects given B6 supplements. CONCLUSIONS: Half of the residents had vitamin B6 deficiency. Vitamin supplement was effective prophylaxis for deficiency and should be recommended to all elderly people in nursing homes.

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration.

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration. Am J Physiol Endocrinol Metab 301: E000-E000, 2011. First published September 20, 2011; 10.1152/ajpendo.00345.2011.-We carried out a (1)H-NMR metabolomic analysis of sera from vitamin B(12)-deficient rats. In addition to the expected increases in methylmalonate and homocysteine (Hcy), we observed an approximately sevenfold increase in formate levels, from 64 µM in control rats to 402 µM in vitamin B(12)-deficient rats. Urinary formate was also elevated. This elevation of formate could be attributed to impaired one-carbon metabolism since formate is assimilated into the one-carbon pool by incorporation into 10-formyl-THF via the enzyme 10-formyl-THF synthase. Both plasma and urinary formate were also increased in folate-deficient rats. Hcy was elevated in both the vitamin B(12)- and folate-deficient rats. Although plasma Hcy was also elevated, plasma formate was unaffected in vitamin B(6)-deficient rats (impaired transsulfuration pathway). These results were in accord with a mathematical model of folate metabolism, which predicted that reduction in methionine synthase activity would cause increased formate levels, whereas reduced cystathionine ß-synthase activity would not. Our data indicate that formate provides a novel window into cellular folate metabolism, that elevated formate can be a useful indicator of deranged one-carbon metabolism and can be used to discriminate between the hyperhomocysteinemia caused by defects in the remethylation and transsulfuration pathways.

Nutritional intake and prevalence of nutritional deficiencies prior to surgery in a Spanish morbidly obese population.

BACKGROUND: The prevalence of obesity in Spain is on the rise with the consequent increase in bariatric surgery. Studies in non-Mediterranean populations have shown that micronutrient deficits are present before surgery. However, there is no data on this topic in a Spanish population. METHODS: We evaluated food intake and the prevalence of nutritional deficiencies in 231 obese patient (72.3% women, 45.6 ± 9.9 years, BMI 48.2 ± 7.8 kg/m(2)) candidates for bariatric surgery. Forty-six normal weight individuals with similar demographic variables except BMI were included for comparison of deficiencies. RESULTS: In obese subjects, the mean estimated energy intake was 2,584 ± 987 kcal/day in males and 2,094 ± 669 kcal/day in females (p < 0.05). After adjusting for kilocalorie intake, carbohydrate intake was of 38.7% [CI 36.2 to 41.1] and 39.9% [CI 37.8 to 40.8] (n.s.), lipid intake was 41.9% [CI 39.6 to 44.2] and 43.0% [CI 41.7 to 44.8] (n.s.) and protein intake was 19.1% [CI 17.7 to 20.5] and 17.3% [CI 16.4 to 18.1] (n.s.) for men and women, respectively. The most prevalent deficiency was vitamin D25(OH): obese 94%, control 24%; (p < 0.0001). Above normal PTH levels were observed in 41.0% and 20.0% of obese and normal weight subjects, respectively (p < 0.0497). Increased prevalence of deficiencies in obese patients included magnesium, vitamin B6 and anaemia (p < 0.05). Other vitamin deficiencies were observed although did not reach statistical significance. CONCLUSIONS: Nutritional deficiencies are commonly found in the Spanish obese population undergoing bariatric surgery and are significantly more prevalent than in normal weight individuals.

Kidney damage in acute intermittent porphyria.

BACKGROUND: Acute intermittent and variegate porphyria are an autosomal dominant hereditary diseases caused by the deficient activity of porphobilinogen deaminase in the haem biosynthesis. Acute intermittent porphyria (AIP) in 11 patients (8 women and 3 men) and variegate porphyria (VP) in one patient were diagnosed and long-term treated during 15-22 years. Eleven patients had in acute attack abdominal pain, they were agitated and restless and suffered from insomnia. Besides they had various neurological signs. Examination of kidney function during remission showed hypertension and tubulointerstitial impairment of the kidneys in 10 patients (hyposthenuria and impairment of tubular excretory phase in isotopic renography). Deficiency of serum erythropoietin in 4 patients, significant deficiency of plasma and erythrocyte vitamin B6, significant hyperoxalaemia and hyperoxaluria in all patients were found. Direct relationship between plasma oxalic acid and effect of pyridoxal-5-phosphate (PLP), (effect of PLP was in indirect relationship with the concentration of erythrocyte vitamin B6), in AIP patients was found. Deficiency of vitamin B6 was probably a cause of hyperoxalaemia and hyperoxaluria in those patients. The effective therapy was repeated i.v. administration of haem-arginate during acute attacks (4-5 days). Besides during remission the patients were treated by pyridoxine (40-60 mg/day), by glucose, sodium chloride and phenothiazines. All patients showed significant improvement and had regular ambulatory check-up every three months. Currently, they are in clinical and laboratory remission.