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When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (Ctrough; Cmax) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose. Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal β-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration–time curve over 24 h to the MIC (AUC0–24/MIC) and Cmax/MIC. Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1 μg/mL (CV: 0.32) and 8.7 μg/mL (CV: 0.59), respectively; the mean calculated AUC0–24 was 742.7 μg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CLwp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average Cmax and AUC0–24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p

Busulfan (Bu) is an alkylating agent routinely used for conditioning regimens before allogeneic stem cell transplantation (allo-SCT). Bu shows wide pharmacokinetic (PK) variability among patients. Patients can have a higher systemic exposure (expressed as area under the curve [AUC]) with an increased risk of toxicity or a lower AUC with a higher probability of graft rejection and/or disease relapse. After i.v. administration, an optimal Bu therapeutic window (AUC target of 16,000 to 24,000 μM·minute) has been identified. The use of PK-guided Bu dosing leads to improved overall survival (OS) and progression-free survival (PFS) compared with fixed-dose administration in a variety of hematologic diseases. The aim of this study was to evaluate the outcomes and feasibility of a reduced-toxicity conditioning (RTC) regimen comprising thiotepa, Bu, and fludarabine (TBF) with therapeutic drug monitoring of Bu in patients with hematologic disorders. We report on 41 adult patients with myeloid or lymphoid malignancies who underwent an allo-SCT with a PK-guided Bu-based RTC regimen between January 2019 and October 2020. Patients received a total Bu dose to achieve a target AUC of 16,000 μM·minute in combination with Flu and thiotepa. The median time to absolute neutrophil count recovery and transfusion-independent platelet count recovery was 23 days (range, 15 to 42 days) and 29 days (range, 14 to 97 days), respectively. The cumulative incidence (CI) of nonrelapse mortality was 7% at 100 days and 13% at 1 year. Grade 3 liver toxicity was observed in 6 patients. One patient developed sinusoidal obstruction syndrome at day +27. Grade 3 mucositis occurred in 18 patients. Looking at grade ≥3 infections, the CI was 29% at 30 days, 34% at 60 days, 44% at 100 days, and 56% at 1 year. The 180-day CI of grade II-IV acute graft-versus-host disease (GVHD) was 15%, and the 1-year CI of overall chronic GVHD was 20%. With a median follow-up of alive patients of 14.4 months (range, 3.2 to 24 months), the CI of relapse at 1 year was 6%. The 1-year PFS was 81%, and 1-year OS was 84%. In conclusion, these data support the efficacy of PK-guided Bu dose in the context of a TBF conditioning regimen and the feasibility of therapeutic dosage monitoring of i.v. Bu for patients with hematologic diseases. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The aim of this report is to describe the experience in the management of busulphan-based conditioning regimen administered before hematopoietic stem cell transplantation (HSCT) in children. We report the values of the first dose AUC (area under the concentration-time curve, normal target between 3600 and 4800 ng·h/mL) in children treated with oral and intravenous busulphan, and we analyze the impact of some clinical variables in this cohort of patients. 82 children treated with busulphan before HSCT were eligible for the study: 57 received oral busulphan with a mean AUC of 3586 ng·h/mL, while 25 received intravenous busulphan with a mean AUC of 4158 ng·h/mL. Dose adjustment was based on first dose AUC. The dose was increased in 36 children (43.9%) and decreased in 26 patients (31.7%). Age at HSCT (P = 0.015), cumulative dose of busulphan as mg/m2 (P

Background: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention. Objective: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities. Methods: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status. Results: Wake after sleep onset (WASO) was higher (p

Retinol palmitate oral administration is convenient, but it is difficult to assess/monitor its nutritional status in preterm infants and literature is controversial about the administration route and the effectiveness of vitamin A supplementation. We primarily evaluated retinol plasma levels to assess the vitamin A nutritional status in preterm infants (

Busulfan (Bu) is an old drug, but is still well recommended as alkylating agent during the conditioning therapy, before hematopoietic stem cell transplantations (HSCT). Although its dose administrations are standardized and based on patients’ weight, the therapeutic drug monitoring (TDM) is required in order to maintain its exposure within a narrow therapeutic range and, if necessary, to adjust the dose.

Background: Wiskott-Aldrich syndrome (WAS) is a rare, X-linked, life-threatening primary immunodeficiency caused by mutations in the gene encoding the WAS protein (WASP). WASP-deficient immune cells have compromised immunological synapse formation, cell migration and cytotoxicity. Thus, WAS is characterized by development of recurrent or severe infections, eczema, and increased risk of autoimmunity and malignancies. In addition, WASP deficiency results in microthrombocytopenia, leading to severe bleeding episodes. When a suitable donor is available, WAS can be treated by hematopoietic stem cell transplant (HSCT), but HSCT can be impeded by complications such as graft versus host disease, rejection and autoimmunity. Importantly, HSCT may carry higher risks in older children (>2-5 yrs) [Shin et al, 2012; Moratto et al, 2011]. An alternative approach is gene therapy (GT). We previously reported interim results of a Phase I/II clinical trial (NCT01515462) in 8 subjects treated with OTL-103, a drug product composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a lentiviral vector (LV) encoding human WASP cDNA under the control of the endogenous promoter [Ferrua et al, 2019]. We now report updated results on the safety and efficacy of OTL-103 in 17 subjects treated at San Raffaele Hospital as part of the same clinical trial or expanded access programs (EAP) with up to 8 yrs follow up (FU). Methods: NCT01515462: As described in Ferrua et al, 8 male subjects (mean age at GT: 4.8 yrs, range 1.1-12.4) were treated with OTL-103. The source of autologous CD34+ HSPCs was bone marrow (BM; n=5), mobilized peripheral blood (mPB; n=2) or both (n=1). As part of a reduced-intensity conditioning regimen, rituximab was given 22 days prior and busulfan + fludarabine during the week before OTL-103 infusion. At time of reporting, all subjects had ≥3 yrs FU (range: 3-8 yrs). EAP: 9 male subjects (11.2 yrs, 1.4-35.1) received identical treatment to subjects in the clinical trial; autologous CD34+ HSPCs source was mPB in all subjects. At time of reporting, subjects had a median of 1.4 yrs FU (range: 0.1-3.0 yrs) with 6/9 having ≥1 yr FU. Results: At last FU for all subjects (median: 3.0 yrs, range 0.1-8.0), overall survival was 94% (16/17). One EAP subject died 4.5 mo post-GT, due to deterioration of an underlying neurodegenerative condition considered unrelated to OTL-103 by investigator. To date, there have been no reports of insertional oncogenesis or replication-competent LV. While most subjects experienced adverse events (AEs) due to the reduced-intensity conditioning regimen (mainly mild or moderate), there were no reports of AEs related to OTL-103. Efficacy endpoints analyses were performed on surviving patients with ≥1 yr FU. Evidence of engraftment of genetically corrected HSPCs and LV+ colonies in BM was observed within 3 mo and persisted up to 8 yrs - the longest published FU of LV vector durability to date (Figure). WASP expression was restored after GT, shown by increases in the fraction of WASP+ lymphocytes and platelets (PLT) within 3 mo and maintained thereafter (Table). After GT, PLT counts improved, leading to a reduction of frequency and severity of bleeding events. Independence from PLT transfusions and absence of severe bleeding events were observed in all subjects by 9 mo FU (Table). Immune function improved; all evaluable patients discontinued immunoglobulin supplementation after GT (median time to discontinuation: 0.9 years after GT, range: 0.2-5 years). Furthermore, reduction in severe infection rate was observed post-GT, suggestive of immune reconstitution (Table). The decrease in bleeding events and severe infection rates occurred despite the integration of subjects into normal daily activities. Eczema progressively resolved or was reduced compared to baseline. Conclusions: This combined analysis of 17 subjects treated in a clinical trial or EAP with up to 8 yrs FU demonstrates that GT continues to be an effective treatment for WAS. All surviving subjects achieved high levels of multilineage engraftment, sustained restoration of WASP expression in lymphocytes and PLTs, improved PLT counts, and fewer bleeding events. A significant reduction in severe infection rate suggests reconstitution of immune function. Importantly, clinical benefit was also attained in older subjects (>5 yrs), a group considered at higher risk when treated with allogeneic HSCT. Disclosures Jones: Orchard Therapeutics: Employment, Equity Ownership. Dott:Orchard Therapeutics: Employment, Equity Ownership. Naldini:Genenta Science: Consultancy, Equity Ownership; Magenta Therapeutics: Equity Ownership; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), a joint venture between Fondazione Telethon and Ospedale San Raffaele (OSR): Other: Wiskott-Aldrich Syndrome (WAS) gene therapy was licensed to GlaxoSmithKline (GSK) in 2014. It was then licensed to Orchard Therapeutics (OTL) in April 2018. OTL is the current sponsor of the clinical trial.. Aiuti:San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), a joint venture between Fondazione Telethon and Ospedale San Raffaele (OSR): Other: Wiskott-Aldrich Syndrome (WAS) gene therapy was licensed to GlaxoSmithKline (GSK) in 2014. It was than licensed to Orchard Therapeutics (OTL) in April 2018. OTL is the current sponsor of the clinical trial.; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), a joint venture between Fondazione Telethon and Ospedale San Raffaele (OSR): Other: Study PI.

The aim of this study was to evaluate the influence of the method of delivery, the level of cord blood lidocaine, and the cortisol concentration on the cord blood natural killer (NK) activity in the full-term healthy newborn. We studied healthy newborns delivered by elective cesarean section without labor under general anesthesia (n = 24), delivered by cesarean section under epidural anesthesia (n = 21), and delivered vaginally with uncomplicated labor (n = 19). The NK cell activity was significantly lower in newborns delivered by cesarean section under epidural anesthesia than it was in the general anesthesia group, while it was similar to the levels found in vaginally delivered newborns. The cortisol concentration was highest in the vaginal delivery group (589.2 ± 200 mmol/l) and lowest in the general anesthesia group (199.2 ± 81.9 mmol/l). The mean serum lidocaine concentration was 414.1 ± 370 μg/l in the epidural anesthesia group and undetectable in the other groups. In conclusion, our data suggest that the cord blood NK activity was significantly influenced by the method of delivery. This effect could be related to anesthetics given to the mother for general or epidural anesthesia or to the endocrine-metabolic variations observed after different degrees of delivery-related stress. The NK cells being a first-line defense mechanism against viral infections, the results of this study suggest an association with the occurrence of early perinatal infections, especially in preterm infants.

OBJECTIVE: To evaluate the effect of passive smoking on thyroid function in infants. DESIGN AND METHODS: Cord serum tri-iodiothyronine (T3), free T3 (fT3), thyroxine (T4), free T4 (fT4), TSH, thyroxine binding globulin (TBG), thyroglobulin (TG) and cord plasma thiocyanate were measured at birth, and serum TG and thiocyanate after 1 year of life, in 18 infants born from parents who did not smoke (group A), in 18 infants with a father who smoked (group B) and in 18 infants with parents both being smokers (group C). RESULTS: No significant differences were observed in cord serum concentrations of T3, fT3, T4, fT4, TSH and TBG among the three groups. Median (range) TG concentrations (ng/ml) were 30.2 (5.0-102.0), 56.3 (20.5-208.0) and 76.0 (26.0-199.0) at birth (P=0.009 for groups A and B compared; P=0.0002 for groups A and C compared), and 14.9 (5.4-32.0), 19.5 (10.0-57.5) and 20.0 (14.0-40.7) at 1 year (P=0.017 for groups A and C compared), in the three groups respectively, and thiocyanate concentrations (mmol/l) were 3.3 (0.0-51.4), 12.9 (0.0-122.2) and 27.8 (3.3-184.5) at birth (P=0.015 for groups A and C compared), and 3.1 (0.0-32.7), 6.0 (0.0-47.3) and 20.3 (0.0-230.8) at 1 year (P=0.01 for groups A and C compared) in the three groups respectively. CONCLUSIONS: TG and thiocyanate concentrations at birth and at 1 year of age in infants of smoking parents are greater than in infants with non-smoking parents. These results indicate that the change in thyroid function as evaluated by serum TG concentrations observed at birth can persist at least for 1 year if the exposure to passive smoking from both parents is continued. Increased TG concentrations may be due to a direct effect of thiocyanate on the thyroid gland.

Anesthetic drugs can influence the immune system, particularly granulocyte function. The goal of the present study was to evaluate if lidocaine used for epidural anesthesia during cesarean section can influence neonatal neutrophil chemotaxis. We measured chemotaxis and plasma cord lidocaine and cortisol levels in (A) 15 infants born by cesarean section with epidural anesthesia, (B) 15 infants born by vaginal delivery, and (C) 20 infants born by cesarean section with general anesthesia. Chemotaxis levels were significantly lower in group A infants (35.5 ± 16.1 μm) compared to groups B (54.6 ± 10.5 μm) and C (71.4 ± 23 μm). The highest cortisol levels were observed in vaginally delivered infants. A significant inverse relationship was observed between chemotaxis and lidocaine levels (r = −0.6, P = 0.016) in infants born by cesarean section after epidural anesthesia, while no significant correlation was observed between chemotaxis and cortisol level. In conclusion, lidocaine, transferred through the placenta to the fetus during epidural anesthesia, may have an inhibitory effect on chemotaxis.

Clinical assessment and management of sleep disturbances in patients with mild cognitive impairment and dementia has important clinical and social implications. Poor sleep results in an increased risk of morbidities and mortality in demented patients and is a source of stress for caregivers. Sleep disturbances show high prevalence in mild cognitive impairment and dementia patients and they are often associated one to another in the same patient. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of individuals with cognitive decline. The Sleep Study Group of the Italian Dementia Research Association (SINDem) reviewed evidence from original research articles, meta-analyses and systematic reviews published up to December 2013. The evidence was classified in quality levels (I, II, III) and strength of recommendations (A, B, C, D, E). Where there was a lack of evidence, but clear consensus, good practice points were provided. These recommendations may not be appropriate for all circumstances and should therefore be adopted only after a patient's individual characteristics have been carefully evaluated.

Background and Objective: Melatonin, a pineal gland hormone secreted at night, is involved in the sleep-wake cycle and has been extensively used in the treatment of primary sleeping disorders. Up to 90% of blood melatonin is cleared by the liver in a single passage, thus its half-life is very short (30-60 minutes). To avoid the first pass effect responsible for up to 90% loss of the melatonin oral dosage and to ensure rapid onset of activity, a new food grade liquid emulsion has been formulated in a spray form, which assures an additional increase of the contact surface and the possibility of efficient mucosal absorption. The purpose of the present study was to investigate the bioavailability profile of this new food grade liquid emulsion compared with a standard melatonin formulation in commercially available oral tablets. Methods: In a single-dose, open-label, crossover study, eight subjects were randomly assigned to receive 5 mg of oral spray or oral melatonin (tablet). After a washout of one week, plasma was collected at six hours post dosing and assayed by a validated liquid chromatography tandem mass spectrometry method to determine the main pharmacokinetic parameters. Results and Discussion: The student t Test for paired data highlighted a significant difference between Cmax values (p=0.021) and the AUC (p=0.045). The absorption rate (Tmax) of the two melatonin formulations did not show statistically significant differences (Friedman test). The amount of melatonin reaching the systemic circulation after oral spray administration was significantly higher than after oral tablet administration.

beta-thalassemia is a major health problem worldwide, and stem cell transplantation (SCT) is the only curative option. Oral Busulfan (Bu) based conditioning is widely used in this setting. Due to the variability of Bu systemic exposure, intravenous (i.v.) Bu has been proposed as a standard of care, with no need for drug monitoring and dose adjustment. Patients with beta-thalassemia from countries with limited resources might be at higher risk of erratic Bu metabolism because of liver dysfunction, severe iron overload, and specific ethnic/genetic features. We studied Bu pharmacokinetics in 53 children with advanced beta-thalassemia from Middle Eastern countries who underwent a total of 57 matched related donor SCTs. Forty-two percent of the children required dose adjustment because they did not achieve the therapeutic window after the first dose. With a Bu dose-adjustment policy, regimen-related toxicity was limited. At a median follow-up of 564 days, the probabilities of 2-year survival, current thalassemia-free survival, rejection, and treatment-related mortality were 96%, 88%, 21%, and 4%, respectively. Conditioning with i.v. Bu and dose adjustment is feasible and well tolerated, although recurrence of thalassemia remains an unsolved problem in children with advanced disease. beta-thalassemia is a major health problem worldwide, and stem cell transplantation (SCT) is the only curative option. Oral Busulfan (Bu) based conditioning is widely used in this setting. Due to the variability of Bu systemic exposure, intravenous (i.v.) Bu has been proposed as a standard of care, with no need for drug monitoring and dose adjustment. Patients with beta-thalassemia from countries with limited resources might be at higher risk of erratic Bu metabolism because of liver dysfunction, severe iron overload, and specific ethnic/genetic features. We studied Bu pharmacokinetics in 53 children with advanced beta-thalassemia from Middle Eastern countries who underwent a total of 57 matched related donor SCTs. Forty-two percent of the children required dose adjustment because they did not achieve the therapeutic window after the first dose. With a Bu dose-adjustment policy, regimen-related toxicity was limited. At a median follow-up of 564 days, the probabilities of 2-year survival, current thalassemia-free survival, rejection, and treatment-related mortality were 96%, 88%, 21%, and 4%, respectively. Conditioning with i.v. Bu and dose adjustment is feasible and well tolerated, although recurrence of thalassemia remains an unsolved problem in children with advanced disease. Abstract beta-thalassemia is a major health problem worldwide, and stem cell transplantation (SCT) is the only curative option. Oral Busulfan (Bu) based conditioning is widely used in this setting. Due to the variability of Bu systemic exposure, intravenous (i.v.) Bu has been proposed as a standard of care, with no need for drug monitoring and dose adjustment. Patients with beta-thalassemia from countries with limited resources might be at higher risk of erratic Bu metabolism because of liver dysfunction, severe iron overload, and specific ethnic/genetic features. We studied Bu pharmacokinetics in 53 children with advanced beta-thalassemia from Middle Eastern countries who underwent a total of 57 matched related donor SCTs. Forty-two percent of the children required dose adjustment because they did not achieve the therapeutic window after the first dose. With a Bu dose-adjustment policy, regimen-related toxicity was limited. At a median follow-up of 564 days, the probabilities of 2-year survival, current thalassemia-free survival, rejection, and treatment-related mortality were 96%, 88%, 21%, and 4%, respectively. Conditioning with i.v. Bu and dose adjustment is feasible and well tolerated, although recurrence of thalassemia remains an unsolved problem in children with advanced disease.

Introduction: High dose BUS is an important component of pre-transplant conditioning regimen in children with advanced hematological malignancies or solid tumor undergoing allogeneic or autologous stem cell transplantation. Variable intra and inter systemic drug exposure as measured by area under curve (AUC), can occurs following oral administration and may be influenced by age, body weight, absorption variability and, particularly in infants, by difficulties to assumption. Aims: to compare the PK, the toxicity and the compliance of iv versus oral BUS administration in children undergoing pre-transplant conditioning regimen. Patients and methods: 12 patients (pts), median age 37 (7–177) mos, body weight 6–69 kg, affected by AML (3), ALL (4), NB (3), Thalassemia (2), undergoing to autoSCT (4) or alloSCT (8), received as preparative regimen oral BUS at the dose of 1 mg/kg every 6 hours for a total of 16 doses (6 pts, GR1), or 2 hours i.v. infusion of BUS at the dose of 0.8 mg/kg every 6 hours for a total of 16 doses (6 pts, GR2). Four out of 6 GR1 pts (7–30 mos) had a nasogastric radiolus to allow BUS assumption. PK studies were performed after the first dose of BUS on blood samples collected at 0, 1, 2, 4, 6 hours after first administration in GR1 and at 0, 2, 3, 4, 6 hours from the beginning of the first infusion in GR2. BUS plasma level was determined by high-performance liquid chromatography as described by Henner et al. Results: GR were comparable as for age (p= 0.07) and body weight (p= 0.14). Comparison of PK median values (+SD) in GR1 versus GR2 didn’t highlighted statistically significant differences as for AUC (p= 0.20) and for T1/2 (p= 0.11). Peak concentration was higher in GR2 (p= 0.058). Bioavailability was 0.61. Variation factor (VF%) were constantly low in GR2. No pt showed acute or late treatment-related extra-medullary toxicity and all pts developed a rapid and sustained hematopoietic recovery. Conclusions: systemic exposure to 0.8 mg/kg iv BUS versus 1 mg/kg oral BUS is overlapping. Low VF% highlight a smaller interpatient variability in exposure compared to oral BUS. Moreover allows to avoid assumption difficulties in younger pts.

Background: The aim of this study was to verify if variations of thyroid hormones related to circumstances of delivery and mode of maternal anaesthesia can contribute to neonatal neutrophil respiratory burst and natural killer cell activity. Methods: We evaluated 10 infants born by vaginal delivery (group A), 10 infants born by caesarean section after epidural anaesthesia with lidocaine (group B) and 10 infants born by caesarean section after general anaesthesia with sevoflurane (group C). Results: A significant reduction of neutrophil respiratory burst test was found in groups A and C compared with group B. Natural killer cell (NK) activity with an effector : target ratio of 30 : 1 (NK30) and 10 : 1 (NK10) was significantly higher in group A compared with the B and C groups. In addition, thyroid stimulating hormone (TSH) concentration was significantly reduced in group A compared with the B and C groups. A significant negative correlation was found between TSH and NK30 or NK10. Conclusions: Our results suggest that the mode of delivery and anaesthesia can significantly modify the endocrine-immune system in the newborn. Caesarean section delivery with regional anaesthesia seems to produce fewer modifications of neonatal immune function compared with general anaesthesia.

Until now few patients with renal failure on hemodialysis have undergone haematopoietic stem-cell transplantation (HSCT), and none with thalassaemia. Case report. Patient of 45 years, UPN 168, with β Thalassaemia major, genetic compound β0 39 C-->T/β0 6-A, non transfusible due to red blood cell immunization (positive DAT, Hb 5–7 g/dl), under hemodialytic treatment for three years for bilateral focal nephrosclerosis. He suffered from cardiopathy (atrial thrombosis, pulmonary hypertension, atrial and ventricular dilatation), hypothyroidism, hepatopathy (HCV positive with grade II haemosiderosis). Quality of life was much harmed by the severe chronic anaemia and nephropathy. In December 2007 we performed HSCT from his HLA identical brother. Conditioning regimen included: Busulfan (Bu) IV (Busilvex Pierre Fabre Médicament) in single daily dose (3.5 mg/kg/day) for 4 days, Cyclophosphamide 40 mg/kg/day for 3 days. GvHD prophylaxis consisted of Cyclosporin 3 mg/kg/day IV (days -2 to +1), 2 mg/kg/day IV (days +2 to +42), changed to oral administration of 4 mg/kg/day from day +43. Hemodialysis was performed every other day in sterile room. Nucleated marrow cells infused: 4.4 × 108/kg. A mixed chimerism (VNTR more than 90% donor) was documented at day +19. ANC >0.5 × 109/L at day +21. PLT >20 × 109/L at day +15. Eight months after transplantation, patient is in good general condition, with stable mixed chimerism (more than 95% donor), haemoglobin above 11 g/dl, leucocytes and platelets in normal range. Substantial improvement of chronic anaemia ameliorated patient’s quality of life and now patient can be considered a kidney transplant candidate. This single case report does not allow definitive conclusions to be drawn regarding HSCT suitability of patients with chronic renal failure on hemodialysis. We can observe that once-daily intravenous busulfan administration (after the hemodialysis session) has made it possible to keep therapeutic range, as has been ascertained by pharmacokinetic study of busulfan.

Objectives: The purpose of this study was to test the hypothesis that differences in autonomic responses might modify clinical severity in long QT syndrome type 1 (LQT1) patients, those with KCNQ1 mutations and reduced IKs, in whom the main arrhythmia trigger is sympathetic activation. Background: Some long QT syndrome (LQTS) patients experience life-threatening cardiac arrhythmias, whereas others remain asymptomatic throughout life. This clinical heterogeneity is currently unexplained. Methods: In a South African LQT1 founder population segregating KCNQ1-A341V, we correlated major cardiac events to resting heart rate (HR) and to baroreflex sensitivity (BRS) on and off beta-adrenergic blockers (BB). Results: In 56 mutation carriers (MCs), mean HR was lower among asymptomatic patients (p < 0.05). Among MCs with a QT interval corrected for heart rate ≤500 ms, those in the lower HR tertile were less likely to have suffered prior cardiac events (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.04 to 0.79, p < 0.02). The BRS was lower among asymptomatic than symptomatic MCs (11.8 ± 3.5 ms/mm Hg vs. 20.1 ± 10.9 ms/mm Hg, p < 0.05). A BRS in the lower tertile was associated with a lower probability of being symptomatic (OR 0.13, 95% CI 0.02 to 0.96, p < 0.05). A similar trend was observed during BB. The MCs in the lower tertile for both HR and BRS were less frequently symptomatic than MCs with different patterns (20% vs. 76%, p < 0.05). Subjects with either ADRA2C-Del322-325 or homozygous for ADRB1-R389, 2 polymorphisms predicting enhanced adrenergic response, were more likely to have BRS values above the upper tertile (45% vs. 8%, p < 0.05). Conclusions: Lower resting HR and "relatively low" BRS are protective factors in KCNQ1-A341V carriers. A plausible underlying mechanism is that blunted autonomic responses prevent rapid HR changes, arrhythmogenic when IKs is reduced. These findings help understanding phenotypic heterogeneity in LQTS and identify a physiological risk modifier, which is probably genetically determined