A Longitudinal Analysis of Early Lesion Growth in Presymptomatic Patients with Cerebral Adrenoleukodystrophy.

BACKGROUND AND PURPOSE: Cerebral adrenoleukodystrophy is a devastating neurological disorder caused by mutations in the ABCD1 gene. Our aim was to model and compare the growth of early cerebral lesions from longitudinal MRIs obtained in presymptomatic patients with progressive and arrested cerebral adrenoleukodystrophy using quantitative MR imaging-based lesion volumetry. MATERIALS AND METHODS: We retrospectively quantified and modeled the longitudinal growth of early cerebral lesions from 174 MRIs obtained from 36 presymptomatic male patients with cerebral adrenoleukodystrophy. Lesions were manually segmented using subject-specific lesion-intensity thresholding. Volumes were calculated and plotted across time. Lesion velocity and acceleration were calculated between sequentially paired and triplet MRIs, respectively. Linear mixed-effects models were used to assess differences in growth parameters between progressive and arrested phenotypes. RESULTS: The median patient age was 7.4 years (range, 3.9-37.0 years). Early-stage cerebral disease progression was inversely correlated with age (ρ = -0.6631, P < .001), early lesions can grow while appearing radiographically stable, lesions undergo sustained acceleration in progressive cerebral adrenoleukodystrophy (ß = 0.10 mL/month2 [95% CI, 0.05-0.14 mL/month2], P < .001), and growth trajectories diverge between phenotypes in the presymptomatic time period. CONCLUSIONS: Measuring the volumetric changes in newly developing cerebral lesions across time can distinguish cerebral adrenoleukodystrophy phenotypes before symptom onset. When factored into the overall clinical presentation of a patient with a new brain lesion, quantitative MR imaging-based lesion volumetry may aid in the accurate prediction of patients eligible for therapy.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study.

INTRODUCTION: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. METHODS: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. RESULTS: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28-84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). CONCLUSION: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

Efficacy of single-dose 500 mg mebendazole in soil-transmitted helminth infections: a review.

Soil-transmitted helminthiasis (STH) is caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), and Ancylostoma duodenale and Necator americanus (hookworms). Mebendazole is one of the recommended preventive chemotherapy agents for STH. This review summarizes the efficacy data from 29 studies with single-dose 500 mg mebendazole in STH treatment and compares the results with those of a recently conducted phase 3 study of a 500 mg mebendazole chewable tablet against A. lumbricoides and T. trichiura infections. Studies that reported efficacy results against at least one STH infection were selected from the literature and efficacy data by each STH type were abstracted and pooled. Single-dose 500 mg mebendazole treatment resulted in a cure rate of 92.6% (range: 72.5-100%) for A. lumbricoides, 27.6% (range: 8.4-100%) for T. trichiura and 25.5% (range: 2.9-91.1%) for hookworms. Egg reduction rate for A. lumbricoides was 97.9% (range: 89.8-100%), for T. trichiura it was 72.9% (range: 31.6-93.0%) and for hookworms it was 72.0% (range: -6.5% (denoting an increase in egg count) to 98.3%). Similar results were observed in the studies that were placebo-controlled. In the phase 3 study, the cure rate and egg reduction rate reported was 83.7% and 97.9%, respectively, for A. lumbricoides and 33.9% and 59.7%, respectively, for T. trichiura. In conclusion, single-dose 500 mg mebendazole showed a high cure rate against A. lumbricoides and a substantial reduction in faecal egg count for all STH types. These results are consistent with the recently conducted phase 3 study of a new 500 mg chewable mebendazole tablet.

Systematic review of exercise training in colorectal cancer patients during treatment.

Colorectal cancer surgery results in considerable postoperative morbidity, mortality and reduced quality of life. As many patients will undergo additional (neo)adjuvant therapy, it is imperative that each individual optimize their physical function. To elucidate the potential of exercise in patient optimization, we investigated the evidence for an exercise program before and after surgical treatment in colorectal cancer patients. A systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions, the guidelines of the Physical Therapy Journal and the PRISMA guidelines. No literature pertaining to exercise training during preoperative neoadjuvant treatment was found. Seven studies, investigating the effects of regular exercise during adjuvant chemotherapy for patients with colorectal cancer or a mixed population, were identified. A small effect (effect size (ES) 0.4) of endurance/interval training and strength training (ES 0.4) was found in two studies conducted in patients with colorectal and gastrointestinal cancer. In five studies that included a mixed population of cancer patients, interval training resulted in a large improvement (ES 1.5; P≤.05). Endurance training alone was found to increase both lower extremity strength and endurance capacity. The effects of strength training in the lower extremity are moderate, whereas, in the upper extremity, the increase is small. There is limited evidence available on exercise training during treatment in colorectal cancer patients. One study concluded exercise therapy may be beneficial for colorectal cancer patients during adjuvant treatment. The possible advantages of training during neoadjuvant treatment may be explored by prehabilitation trials.

Contribution of cervical cytology in the diagnostic work-up of patients with endometrial cancer.

INTRODUCTION: Abnormal cervical cytology in patients with endometrial cancer (EC) has been associated with poor outcome. The aim of this study was to evaluate whether cervical cytology could contribute to an improved preoperative identification of high-grade EC (serous, clear cell, carcinosarcoma, high-grade endometrioid EC) in final histology. METHODS: A retrospective cohort study was performed in five hospitals in the Netherlands. A total of 554 patients with EC that underwent primary surgical treatment between 2002 and 2010 were included. Primary outcome was defined as the contribution of abnormal cervical cytology in the preoperative identification of high-grade EC. As secondary outcome, recurrence-free survival (RFS) and disease-specific survival were determined based on preoperative cervical cytology, and compared to the currently established risk factors: myometrial invasion, high-grade and lymph vascular space invasion. RESULTS: Abnormal cervical cytology was present in 45.1%. For patients with preoperative inconclusive and high-grade histology, the presence of abnormal cervical cytology contributed to an improved identification of high-grade EC in final histology (odds ratio [OR] 6.40 [95% confidence interval {CI}: 1.92-21.26]; OR 2.86 [95% CI: 1.14-7.14]), respectively. Patients with abnormal cervical cytology had a significant worse 5-year median RFS. Abnormal cervical cytology was independently related to RFS (hazard ratio 1.67 [95% CI: 1.04-2.68]) and disease-specific survival (hazard ratio 3.15 [95% CI: 1.74-5.71]). CONCLUSIONS: Abnormal cytology contributes to the preoperative identification of patients with high-grade EC, and is associated with compromised outcome. Future studies are warranted to determine whether cervical cytology could be incorporated into preoperative prediction models for lymph node metastasis.

Laparoscopic treated neuralgia after inguinal hernia repair: case report and literature review.

BACKGROUND: Neuralgia after inguinal hernia repair is a known but potential invalidating complication with a reported incidence of 10-12%. Diagnosis and treatment can be challenging. Based on a case report and literature review, disease aspects and treatment options including laparoscopic (triple) neurectomy are discussed. METHODS: A case of laparoscopic treated neuralgia after hernia inguinalis repair is reported. After an extensive MeSH-term based literature search, 26 articles were included for in-depth analysis and literature review. RESULTS: Pharmacotherapy encounters high numbers needed to treat and technical procedures often require re-intervention. Surgery should only be considered after one year of unsuccessful conventional treatment. Laparoscopic (triple) neurectomy is a minimal invasive procedure, providing optimal visualisation of the inguinal nerves. It is reported to be a safe and effective treatment option for refractory inguinal neuralgia. CONCLUSIONS: Chronic neuralgia can be a severe complication after inguinal hernia repair. When pharmacotherapy and technical interventions are not sufficient, a laparoscopic (triple) neurectomy can be a promising, safe and effective treatment option.

Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C.

BACKGROUND: Niemann-Pick type C (NP-C) is a rare autosomal recessive progressive neurodegenerative disorder caused by mutations in the NP-C 1 or 2 gene. Besides visceral symptoms, presentation in adolescent and adult onset variants is often with neurological symptoms. The most frequently reported presenting symptoms of NP-C in adulthood are psychiatric symptoms (38 %), cognitive decline (23 %) and ataxia (20 %). Myoclonus can be present, but its value in early diagnosis and the evolving clinical phenotype in NP-C is unclear. In this paper we present eight Dutch cases of NP-C of whom five with myoclonus. METHODS: Eight patients with genetically confirmed NP-C were recruited from two Dutch University Medical Centers. A structured interview and neuropsychological tests (for working and verbal memory, attention and emotion recognition) were performed. Movement disorders were assessed using a standardized video protocol. Quality of life was evaluated by questionnaires (Rand-36, SIP-68, HAQ). In four of the five patients with myoclonic jerks simultaneous EEG with EMG was performed. RESULTS: A movement disorder was the initial neurological symptom in six patients: three with myoclonus and three with ataxia. Two others presented with psychosis. Four experienced cognitive deficits early in the course of the disease. Patients showed cognitive deficits in all investigated domains. Five patients showed myoclonic jerks, including negative myoclonus. In all registered patients EEG-EMG coherence analysis and/or back-averaging proved a cortical origin of myoclonus. Patients with more severe movement disorders experienced significantly more physical disabilities. CONCLUSIONS: Presenting neurological symptoms of NP-C include movement disorders, psychosis and cognitive deficits. At current neurological examination movement disorders were seen in all patients. The incidence of myoclonus in our cohort was considerably higher (63 %) than in previous publications and it was the presenting symptom in 38 %. A cortical origin of myoclonus was demonstrated. Our data suggest that myoclonus may be overlooked in patients with NP-C. All patients scored significantly lower on physical domains of HRQoL. Symptomatic treatment of movement disorders may improve physical functioning and subsequently HRQoL.

[Metabolic diseases in psychiatry]. / Stofwisselingsziekten binnen de psychiatrie.

Metabolic diseases can be associated with psychiatric symptoms. We present two case histories that demonstrate the importance of correctly diagnosing a metabolic disease as being the cause of psychiatric symptoms. We also discuss which symptoms or signals may indicate a metabolic disease.

[Improving the speech with a prosthetic construction]. / Een prothetische constructie ter verbetering van de spraak.

A 12-year-old boy had problems with his speech due to a defect in the soft palate. This defect was caused by the surgical removal of a synovial sarcoma. Testing with a nasometer revealed hypernasality above normal values. Given the size and severity of the defect in the soft palate, the possibility of improving the speech with speech therapy was limited. At a centre for special dentistry an attempt was made with a prosthetic construction to improve the performance of the palate and, in that way, the speech. This construction consisted of a denture with an obturator attached to it. With it, an effective closure of the palate could be achieved. New measurements with acoustic nasometry showed scores within the normal values. The nasality in the speech largely disappeared. The obturator is an effective and relatively easy solution for palatal insufficiency resulting from surgical resection. Intrusive reconstructive surgery can be avoided in this way.

High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer.

BACKGROUND: Conventional nutritional supplements are not or only partly successful in inducing protein accretion in advanced cancer, suggesting an attenuated anabolic response. To prevent muscle wasting and its deleterious consequences, generating an anabolic response is crucial. Dietary essential amino acids (EAA) have anabolic properties in other wasting diseases; however, data in advanced cancer are lacking. PATIENTS AND METHODS: In 13 patients with advanced nonsmall-cell lung cancer (NSCLC) (stage III and IV) and 11 healthy age-matched subjects, we measured protein synthesis and breakdown of the whole body, and net protein anabolism (difference between protein synthesis and breakdown) after intake of 14 g of free EAA with high leucine levels (EAA/leucine) versus a balanced amino acid mixture containing both EAA and non-EAA as present in whey protein, according to a randomized, double-blind, crossover design. RESULTS: Protein synthesis and net protein anabolism were higher after intake of the EAA/leucine than the balanced amino acid mixture (P < 0.001), independent of presence of cancer. A highly significant linear relationship between net protein anabolism and the amount of EAA available in the systemic circulation (R(2): 0.85, P < 0.001) was found in both groups. The presence of muscle or recent weight loss, systemic inflammatory response, or length of survival did not influence this relationship. High leucine levels in the EAA/leucine mixture was of no anabolic benefit. CONCLUSIONS: There is no anabolic resistance or attenuated anabolic potential to intake of 14 g of EAA/leucine or balanced amino acid mixture in advanced (mainly stage III) NSCLC. The high anabolic potential of dietary EAA in cancer patients is independent of their nutritional status, systemic inflammatory response or disease trajectory, suggesting a key role of EAA in new nutritional approaches to prevent muscle loss, thereby improving outcome of patients with advanced cancer. CLINICALTRAILSGOV: NCT01172314.

[Lack of retention of the upper denture: is placement of 2 palatal implants the solution?]. / Retentieproblemen van de bovenprothese: is het plaatsen van 2 palatinale implantaten de oplossing?

A 72-year-old man, edentulous in the maxilla for 20 years, presented himself at his dentist in 2006 with complaints concerning retention of his upper denture. The placement of implants was only possible if bone augmentation was undertaken; this was definitively rejected by the man. As an alternative, Muchor anchors were placed, but these did not provide an adequate solution to the retention problem. In the end, 2 palatal implants were placed, with magnetic anchoring. One year later, the man was very satisfied with this solution.

Effect of sugars in solutions on subjective appetite and short-term food intake in 9- to 14-year-old normal weight boys.

BACKGROUND AND OBJECTIVE: The role of sugars in solutions on subjective appetite and food intake (FI) has received little investigation in children. Therefore, we examined the effect of isocaloric solutions (200 kcal/250 ml) of sugars including sucrose, high-fructose corn syrup-55 (HFCS) or glucose, compared with a non-caloric sucralose control, on subjective appetite and FI in 9- to 14-year-old normal weight (NW) boys. PARTICIPANTS AND METHODS: NW boys (n=15) received each of the test solutions, in random order, 60 min before an ad libitum pizza meal. Subjective appetite was measured at baseline (0 min), and 15, 30, 45 and 60 min. RESULTS: Only glucose (P=0.003), but neither sucrose nor HFCS, reduced FI compared with the sucralose control. This led to a higher cumulative energy intake, compared with sucralose, after sucrose (P=0.009) and HFCS (P=0.01), but not after glucose. In all treatment sessions, subjective average appetite increased from baseline to 60 min, but change from baseline average appetite was the highest after sucrose (P<0.005). Furthermore, sucrose (r=-0.59, P=0.02) and HFCS (r=-0.56, P=0.03), but not glucose, were inversely associated with test meal FI when the treatment dose (200 kcal) was expressed on a body weight (kg) basis. CONCLUSIONS: Change from baseline subjective average appetite was the highest after sucrose, but only the glucose solution suppressed FI at the test meal 60 min later in NW boys.

Increased whole body hydroxyproline production as assessed by a new stable isotope technique is associated with hip and spine bone mineral loss in cystic fibrosis.

BACKGROUND & AIMS: Bone mineral loss, reduced lung function and impaired nutritional status are frequently present in children with Cystic Fibrosis (CF). Blood concentrations and urinary excretion of hydroxyproline (OH-PRO) have been used as markers of bone mineral status and lung function in CF. OBJECTIVE: To examine whether whole body hydroxyproline production, as assessed by a new stable isotope methodology, is increased in pediatric patients with CF and associated with bone mineral loss, lung function decline and impaired nutritional status. DESIGN: In a cross-sectional study in 15 pediatric patients with CF and 17 healthy young control subjects, whole body hydroxyproline production (Wb OH-PRO) was assessed in the postabsorptive state by primed-constant and continuous infusion of the stable isotope 2-D-OH-PRO for 3 h. Bone mineral density (BMD) of whole body, hip and spin, and body composition (fat mass and fat-free mass) were determined by dual-energy X-ray Absorptiometry (DXA). Plasma isotopic enrichments and OH-PRO concentrations were measured by LC/MS/MS. RESULTS: Higher values for WbOH-PRO production and plasma OH-PRO concentrations were found in pediatric CF patients than in the healthy young subjects (p < 0.001). WbOH-PRO production was significantly correlated with plasma OH-PRO concentrations in the CF (r: 0.70, p = 0.007) but not in the healthy group. WbOH-PRO production in CF was associated with low BMD values in hip (r = -0.61, p = 0.02) and spine (r = -0.59, p = 0.02) but not with whole body BMD, lung function or body composition. CONCLUSION: A new stable isotope approach revealed enhanced levels of whole body hydroxyproline production rate in pediatric patients with CF, indicative of enhanced whole body collagen breakdown. Increased levels for whole body hydroxyproline production in CF were associated with severe bone mineral loss in hip and spine but not with lung function decline or impaired nutritional status. Registration ClinicalTrials.gov = NCT01172301.

New stable isotope method to measure protein digestibility and response to pancreatic enzyme intake in cystic fibrosis.

BACKGROUND & AIMS: Adequate protein intake and digestion are necessary to prevent muscle wasting in cystic fibrosis (CF). Accurate and easy-to-use methodology to quantify protein maldigestion is lacking in CF. OBJECTIVE: To measure protein digestibility and the response to pancreatic enzyme intake in CF by using a new stable isotope methodology. DESIGN: In 19 CF and 8 healthy subjects, protein digestibility was quantified during continuous (sip) feeding for 6 h by adding (15)N-labeled spirulina protein and L-[ring-(2)H5]phenylalanine (PHE) to the nutrition and measuring plasma ratio [(15)N]PHE to [(2)H5]PHE. Pancreatic enzymes were ingested after 2 h in CF and the response in protein digestibility was assessed. To exclude difference in mucosal function, postabsorptive whole-body citrulline (CIT) production rate was measured by L-[5-(13)C-5,5-(2)H2]-CIT pulse and blood samples were taken to analyze tracer-tracee ratios. RESULTS: Protein digestibility was severely reduced in the CF group (47% of healthy subjects; P < 0.001). Intake of pancreatic enzymes induced a slow increase in protein digestibility in CF until 90% of values obtained by healthy subjects. Maximal digestibility was reached at 100 min and maintained for 80 min. Stratification into CF children (n = 10) and adults showed comparable values for protein digestibility and similar kinetic responses to pancreatic enzyme intake. Whole-body citrulline production was elevated in CF indicating preserved mucosal function. CONCLUSION: Protein digestibility is severely compromised in patients with CF as measured by this novel and easy-to-use stable isotope approach. Pancreatic enzymes are able to normalize protein digestibility in CF, albeit with a severe delay. Registration ClinicalTrials.gov = NCT01494909.

The value of imaging of the lungs in the diagnostic workup of patients with endometrial cancer.

OBJECTIVE: Imaging of the lungs is part of the routine diagnostic workup of patients with endometrial cancer. The present study aimed to determine the incidence of lung metastases in patients with endometrial cancer and to evaluate the clinical relevance of preoperative chest imaging in this population. METHODS: A retrospective cross-sectional study was performed in four regional and one university hospital in the southeastern part of the Netherlands. A total of 784 patients with epithelial endometrial cancer diagnosed between 2002 and 2010 in five hospitals were included. Patients were followed up for at least 1 year. RESULTS: Of 784 patients, 541 (69.0%) underwent thoracic imaging and 11 showed findings suspicious for metastases perioperatively or during the 1-year follow-up period. In eight patients, the thoracic metastases were related to their endometrial cancer, resulting in an overall incidence of 1.0% (8/784, 95% CI=0.3-1.7%). These eight patients had high-risk subtypes of endometrial cancer (serous, clear cell or poorly differentiated endometrioid), and the incidence was 4.1% (8/193, 95% CI=1.9-8.3%) for these subtypes. Lung metastases were not detected in any of the patients with low-risk subtypes of endometrial cancer (n=566) at the time of diagnosis (95% CI=0-0.8%). CONCLUSIONS: The probability of detecting thoracic metastases during the diagnostic workup of patients with endometrial cancer is low. The present data suggest that thoracic imaging could be omitted from the diagnostic workup of patients with low-risk endometrial cancer.

Enhanced anabolic response to milk protein sip feeding in elderly subjects with COPD is associated with a reduced splanchnic extraction of multiple amino acids.

BACKGROUND & AIMS: We previously observed in elderly subjects with Chronic Obstructive Pulmonary Disease (COPD) an enhanced anabolic response to milk protein sip feeding, associated with reduced splanchnic extraction (SPE) of phenylalanine. Milk proteins are known for their high Branched-chain Amino Acids (BCAA) content, but no information is present about splanchnic extraction and metabolism of the individual BCAA in COPD. OBJECTIVE: To investigate whether BCAA metabolism and SPE of the individual BCAA are altered in COPD during milk protein sip feeding. DESIGN: In elderly subjects with COPD and in healthy age-matched elderly SPE, endogenous rate of appearance (Raendo) of the leucine (LEU), isoleucine (ILE) and valine (VAL) were measured before and during sip feeding of a Whey protein meal. To study the effect of aging, the healthy elderly were compared to a group of healthy young subjects. Stable isotopes of l-[(2)H(3)]-LEU, l-[1-(13)C]-ILE and l-[1-(13)C]-VAL were given on two separate test days orally or intravenously. Simultaneously, l-[ring-(2)H(5)]-phenylalanine (PHE) and l-[ring-(2)H(2)]-tyrosine (TYR) were given to determine the whole body protein breakdown (WbPB), synthesis (WbPS) and NetPS. RESULTS: SPE of all BCAA, TYR, and PHE (p < 0.01) were lower in the COPD group, and the increase in netPS during feeding was higher in the COPD group (P < 0.01) due to higher values for PS (P < 0.001). Raendo of all BCAA, PHE and TYR were higher in the COPD than the healthy elderly group (P < 0.05) before and during feeding (P < 0.001). Sip feeding resulted in a reduction of Raendo of PHE, ILE and VAL (P < 0.05). Postabsorptive Raendo was not different for any of the measured amino acids between the healthy elderly and young group, while sip feeding resulted in a reduction of Raendo of PHE. Only SPE of TYR was higher in the elderly (P < 0.05) and the increase in netPS during sip feeding was independent of aging. CONCLUSION: The enhanced anabolic response to milk protein sip feeding in normal-weight COPD patients is associated with a reduced splanchnic extraction of multiple amino acids including all branched-chain amino acids. Registration ClinicalTrials.gov = NCT01418469.

Calcineurin inhibitor-free immunosuppression using everolimus (Certican) after heart transplantation: 2 years' follow-up from the University Hospital Münster.

BACKGROUND: Everolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)-free immunosuppression using everolimus. METHODS: After heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed. RESULTS: After switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 ± 0.6 vs 1.8 ± 1 mg/dL; P < .001; creatinine clearance, 41.8 ± 22 vs 48.6 ± 21.8 mL/min; P < .001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 (P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n = 2), skin disorders (n = 2); reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)]. CONCLUSION: CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients.