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Introduction: Mohs surgery and reconstruction has enabled tissue-preserving resection of cutaneous malignancies. The goal of our case series evaluation is to present reconstructive techniques and functional outcomes in patients undergoing digit-sparing treatment for primary melanoma., Materials and Methods: A chart review was performed to identify consecutive patients undergoing Mohs surgery and reconstruction for melanoma of the digits. Quality of life (QOL) survey was performed to assess function after the procedure., Results: Thirty-two patients (13 hand, 19 foot, Age: 65.03 +/-17.78 years) who were undergoing Mohs surgery were identified. No recurrence was identified with an average follow-up of 16.1 months (1-95 months). The average defect size was 5.79 +/-4.54 cm 2 . Reconstruction was performed 0-4 days after resection. The most common techniques included full-thickness skin graft (FTSG) ( N = 7), collagen matrix + FTSG ( N = 4), and volar advancement flap ( N = 7). The reconstructive technique choice appears correlated with defect size ( p = 0.0125). Neuro-QOL upper extremity survey results showed a difference that approached statistical significance between patients who underwent digit-sparing treatment ( n = 7) versus direct to amputation controls ( n = 5) ( p = 0.072). No survey differences between digit-sparing treatment ( n = 10) and amputation ( n = 8) were identified in the lower extremity ( p = 0.61)., Conclusion: Our results show digit-sparing treatment can confirm clear surgical margins and a trend toward improvement in upper extremity function compared with immediate amputation., Competing Interests: None declared., (© 2024 Published by Elsevier B.V. on behalf of Society for Indian Hand Surgery and Micro Surgeons.)

Cyanobacterial blooms present substantial challenges to managers and threaten ecological and public health. Although the majority of cyanobacterial bloom research and management focuses on factors that control bloom initiation, duration, toxicity, and geographical extent, relatively little research focuses on the role of loss processes in blooms and how these processes are regulated. Here, we define a loss process in terms of population dynamics as any process that removes cells from a population, thereby decelerating or reducing the development and extent of blooms. We review abiotic (e.g., hydraulic flushing and oxidative stress/UV light) and biotic factors (e.g., allelopathic compounds, infections, grazing, and resting cells/programmed cell death) known to govern bloom loss. We found that the dominant loss processes depend on several system specific factors including cyanobacterial genera-specific traits, in situ physicochemical conditions, and the microbial, phytoplankton, and consumer community composition. We also address loss processes in the context of bloom management and discuss perspectives and challenges in predicting how a changing climate may directly and indirectly affect loss processes on blooms. A deeper understanding of bloom loss processes and their underlying mechanisms may help to mitigate the negative consequences of cyanobacterial blooms and improve current management strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hypercalcaemia is a life-threatening electrolyte imbalance, which not only occurs in the context of an endocrinological disease but is also frequently associated with a tumour. Its severity is determined by the level of deviation from normal, acuity of occurrence, and severity of the symptoms. These are unspecific, can affect any organ system and ultimately result in a life-threatening hypercalcaemic crisis characterised by cardiac arrhythmia, metabolic acidosis, exsiccosis, fever, psychotic states and, ultimately, coma. Endocrinological disorders, drugs such as vitamin D3, vitamin A, checkpoint inhibitors, but also malignancies can be causative for the development of hypercalcaemia. Up to 30% of tumour patients are affected by hypercalcaemia. It is associated with a poor prognosis and a high tumour burden. Malignant hypercalcaemia is mainly caused by PTHrP (parathormone-related peptide), which is secreted by the tumour cells. In oncological patients, serum calcium (ionised calcium and non-ionised calcium) should be evaluated regularly. As the level of serum calcium depends on the albumin concentration, the latter should also be evaluated. Treatment consists of increasing the intravasal volume, increasing calcium excretion and inhibiting calcium reabsorption., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background & Aims: Objectives of this retrospective cohort study were to assess differences in patient survival between etiologies of cirrhosis while on the waitlist for liver transplantation (LT), and to identify cardiac risk factors that predict survival failure while on the waitlist for LT., Methods: This single-center retrospective cohort design included adult patients who were listed for LT at a tertiary academic hospital with a high-volume liver transplant center., Results: Of the 653 patients listed for LT during the study period, 507 (77.6%) survived to transplant and 146 (22.4%) died or clinically deteriorated prior to transplant. Cumulative incidence of death or clinical deterioration did not differ statistically between patient groups (log rank p = .11). In multivariate analysis, compared to patients with NAFLD, there were no significant differences between patients with alcoholic cirrhosis (HR .95, 95%, CI, .62-1.45), cryptogenic cirrhosis (HR 1.31, 95%, CI, .77-2.23), or hepatitis C cirrhosis (HR 1.12, 95%, CI, .66-1.90). However, higher MELD scores (HR = 1.52, 95% CI, 1.12-1.19), severe coronary artery disease (HR = 2.09 95% CI, 1.23-3.55), and tricuspid regurgitation (HR = 2.62, 95% CI, 1.31-5.26) were independently associated with increased risk for survival failure to LT., Conclusions: The presence of severe coronary artery disease and tricuspid regurgitation at the time of listing for transplant are associated with survival failure while on the LT waitlist across etiologies of liver disease. Diagnostic assessment of coronary and valvular disease should be considered in all patients undergoing evaluation for LT, such as cardiac catheterization and/or stress echocardiogram., (© 2023 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background: Evidence for modulating the sodium chloride (NaCl) intake of patients hospitalized with acute heart failure (AHF) is inconclusive. Salt restriction may not benefit; hypertonic saline may aid diuresis., Objective: To compare the safety and efficacy of oral NaCl during intravenous (IV) diuretic therapy in renal function and weight., Methods: Seventy hospitalized patients with AHF who were being treated with IV furosemide infusion consented to receive, randomly, 2 grams of oral NaCl or placebo 3 times a day in a double-blind manner during diuresis. Treatment efficacy (bivariate primary endpoints of change in serum creatinine levels and change in weight) was measured at 96 hours, and adverse safety events were tracked for 90 days., Results: Sixty-five patients (34 NaCl, 31 placebo) were included for analysis after 5 withdrew. A median of 13 grams of NaCl was given compared to placebo. At 96 hours, there was no significant difference between treatment groups with respect to the primary endpoint (P = 0.33); however, the trial was underpowered, and there was greater than expected standard deviation in weight change. The mean change in creatinine levels and weight was 0.15 ± 0.44 mg/dL and 4.6 ± 4.2 kg in the placebo group compared with 0.04 ± 0.40 mg/dL and 4.0 ± 4.3 kg in the NaCl group (P = 0.30 and 0.57, respectively). Across efficacy and safety endpoints, we observed no significant difference between the 2 groups other than changes in serum sodium levels (-2.6 ± 2.7 in the placebo group and -0.3 ± 3.3 mEq/L in the NaCl group; P < 0.001) and in serum blood urea nitrogen levels (11 ± 15 in the placebo group; 3.1 ± 13 mEq/L in the NaCl group; P = 0.025)., Conclusions: In this single-center study, liberal vs restrictive oral sodium chloride intake strategies did not impact the safety and efficacy of intravenous diuretic therapy in patients with AHF. (ClinicalTrials.gov registration NCT04334668.)., Competing Interests: Disclosures TM receives grant support from Ionis Therapeutics unrelated to this work, serves as an advisor to Recora Health and Cleveland Clinic American Well Joint Venture, and he or his institution has received fees as part of serving on advisory boards for AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk, and Vifor and is supported by a grant from the Belgian American Educational Foundation and the Frans Van de Werf Fund. JDE is a consultant for Abbott, Getinge and BioVentrix. WHWT is a consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, Boston Scientific, Kiniksa, WhiteSwell, and CardiaTec Biosciences and has received honoraria from Springer Nature and the American Board of Internal Medicine. All other authors have no relationships to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Nonalcoholic fatty liver disease (NAFLD) describes the hepatic manifestations of metabolic syndrome, which is estimated to affect 25% of adults, and currently represents the second most common indication for liver transplant in the United States. Studies have shown that patients with NAFLD are at an increased risk for heart failure, arrhythmia, and coronary artery disease (CAD), which may impact outcomes of liver transplantation. However, it remains unclear whether the presence of cardiac disease affects survival prior to liver transplant. If so, this would represent an important opportunity to optimize cardiac status and improve outcomes before liver transplant., Aim: To identify cardiac factors that impact survival to liver transplantation in patients with NAFLD and on the transplant waitlist., Methods: The aim of this study was to identify cardiac risk factors that limit survival to transplant in patients with NAFLD. We performed a retrospective analysis of patients with NAFLD listed for liver transplant at a tertiary academic medical center in the United States from January 2015 to January 2021, identified through United Network of Organ Sharing registry. Exclusion criteria included a concurrent etiology of liver disease and removal from the transplant list due to chemical dependency, lack of social support, improvement in liver disease, or being lost to follow-up. We manually reviewed patient charts including electrocardiogram, echocardiogram, and cardiac catheterization reports as well as physician notes to identify cardiac disease states ( i.e. , heart failure, arrhythmia, valvular disease and CAD) and other related diagnoses. We performed a survival analysis by Cox proportional hazards regression model to analyze the association between cardiac factors at the time listed for transplant and death or clinical deterioration prior to transplant., Results: Between January 2015 and January 2021, 265 patients with nonalcoholic fatty liver disease were listed for liver transplant at our institution. Our patient sample had a median age of 63 and an even distribution between sexes. The median Model for End-Stage Liver Disease (MELD) score was 17 and the median body mass index was 31.6. Of these 265 patients, 197 (74.3%) survived to transplant and 68 (25.7%) died or clinically deteriorated prior to transplant. The presence of mild or moderate CAD represented a hazard ratio of 2.013 (95%CI 1.078-3.759, P = 0.029) for death or clinical deterioration when compared to patients without CAD, after adjustment for age, sex, and MELD. MELD represented an adjusted hazard ratio of 1.188., Conclusion: Mild or moderate CAD represents a hazard for waitlist mortality prior to liver transplant in patients with NAFLD. Aggressive management of CAD may be needed to improve patient outcomes., Competing Interests: Conflict-of-interest statement: All authors have no conflicts of interest to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Tunnelled hemodialysis catheters are well accepted and widely used devices to provide vascular access for dialysis in patients when an arteriovenous shunt is not feasible or dysfunctional. In the literature complications after implantation are well documented but fatal or near-fatal events during implantation are seldom reported. In this article 3 such cases from a single tertiary center over a period of more than 10 years are presented and discussed. The (near) fatal complications occurred despite experienced surgeons and the use of ultrasound and fluoroscopy during implantation. Although the incidence is estimated to be much less than 1% at this centre, implantation of a tunnelled hemodialysis catheter is demanding, a thorough evaluation of vascular structures in advance is mandatory and experiencend professionals with high index of suspicion are essential. Performing the procedure with the patient under conscious sedation has benefits compared to general anesthesia. If the patient indicates atypical pain, the procedure should be stopped immediately and re-evaluated for any cause. If a perforation with relevant vascular damage is suspected, we recommend leaving the dilator/introducer/catheter in place to reduce major hemorrhage until the vascular or cardiothoracic surgeon can fix the problem., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The embryonic extracellular matrix (ECM) undergoes transition to mature ECM as development progresses, yet few mechanisms ensuring ECM proteostasis during this period are known. Fibrillin microfibrils are macromolecular ECM complexes serving structural and regulatory roles. In mice, Fbn1 and Fbn2, encoding the major microfibrillar components, are strongly expressed during embryogenesis, but fibrillin-1 is the major component observed in adult tissue microfibrils. Here, analysis of Adamts6 and Adamts10 mutant mouse embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics discovery of ADAMTS6-cleaved sites, identifies a proteostatic mechanism contributing to postnatal fibrillin-2 reduction and fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development defined by a drastic reduction of aggrecan and cartilage link protein, impaired BMP signaling in cartilage, and increased GDF5 sequestration in fibrillin-2-rich tissue. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of the defects in Adamts6 -/- embryos by genetic reduction of Fbn2 , but not Fbn1 ., Competing Interests: TM, DM, LW, SC, CG, EC, JM, DR, CL, CB, SA No competing interests declared, (© 2022, Mead et al.)

Vertebral compression fractures are very common, especially in the elderly. Benign osteoporotic and malignant vertebral compression fractures have extremely different management and prognostic implications. Although there is an overlap in appearances, characteristic imaging features can aid in the distinction between these 2 types of compression fractures. The aim of this review is to characterize the imaging features of benign and malignant vertebral compression fractures seen with CT, PET, SPECT, and MR imaging., (© 2018 by American Journal of Neuroradiology.)

As the field of vascularized composite allotransplantation continues to expand, new upper extremity transplant candidates are being considered. We recently evaluated a bilateral amputee who had a mid-forearm amputation and a contralateral metacarpal hand amputation. In the latter limb, a "partial" hand transplant that preserved the majority of the patient's existing hand, including a partially severed thumb with intact thenar muscle function, was proposed. The feasibility of this partial hand transplant was studied in fresh-frozen cadaver limbs. This report details the proposed approach, the cadaveric dissections, and the lessons learned from these dissections. Issues of osteosynthesis, microvascular planning, and intrinsic muscle recovery are discussed, all of which are critical considerations for partial hand transplant candidates. Ultimately, the partial hand approach was felt to be inferior to a more conventional distal forearm transplant in this particular candidate. Practical, functional, and ethical implications of such decision are presented., (Copyright © 2018 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Increasing Complexity in Performance Delivery - Management Approach for Tertiary Care Centers Abstract. General social trends such as individualization and female shift increase the complexity for management in both technical and system management in addition to the inherent development in the hospital industry such as subspecialization, ageing societies and multimorbidity. Reduction of complexity is therefore absolutely necessary in order to be able to manage in a patient-friendly way as a maximum care provider. Reducing complexity means resolving therapeutic conflicts. Essential tools for this are digitization, a comprehensive quality paradigm that includes patient experience, patient assessment of treatment outcomes, indication and service quality, and good management. The latter integrates the fragmentation of skills and knowledge of a subspecialized medicine through appropriate system design. This requires the appropriate functional strategies and a comprehensive process management competence that can transform the numerous interfaces into seams.

Challenging the innate immune machinery with the pro-inflammatory agent lipopolysaccharide (LPS) results in the development of a sickness syndrome characterized by numerous depressive-like behavioural and physiological manifestations, most of which overlap with the clinical symptoms of major depression. Although women are known to mount stronger pro-inflammatory responses during infections and being at higher risk to develop depressive disorders compared to men, the vast majority of experimental studies investigating the neurobiological effects of LPS administration have been conducted in males. Herein, we investigated the behavioural effects of LPS administration (0.83mg/kg) in male and female C57BL/6J mice subjected to tests screening for alterations in locomotor activity (open field test), anorexia (food consumption), anhedonia (sucrose preference test), behavioural despair (forced swim test) and grooming behaviour (splash-test). We further mapped the brain's serotonergic and dopaminergic activity in five limbic brain regions implicated in the pathophysiology of major depression (i.e., prefrontal cortex, hippocampus, striatum, amygdala, and hypothalamus) at two critical time-points post-LPS treatment; at 6h when depression of behavioural activity is maximal, and at 24h when depressive-like symptoms develop independently of obvious locomotor performance impairments associated with acute LPS administration. Our findings indicate that the two sexes present with differential behavioural sensitivity to this immune stressor, as impairment of grooming behaviour in the splash test was more persistent in female mice, and anorexia lasted longer in their male counterparts. Notably, LPS affects the brain's serotonergic neurochemistry in a sex-specific manner, as it induced sustained serotonergic hyperactivity in females at 24h post-LPS administration in all the brain regions examined. Moreover, the kinetics of dopaminergic activation appeared to be sex-differentiated upon LPS challenge. Given the higher prevalence of affective disorders in women, a focus of basic science on sex differences that underlie neuroinflammatory processes is imperative in order to elucidate the neuroimmunological substrate of major depression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

One of the most striking discoveries in the treatment of major depression was the finding that infusion of a single sub-anesthetic dose of ketamine induces rapid and sustained antidepressant effects in treatment-resistant depressed patients. However, ketamine's antidepressant-like actions are transient and can only be sustained by repeated drug treatment. Despite the fact that women experience major depression at roughly twice the rate of men, research regarding the neurobiological antidepressant-relevant effects of ketamine has focused almost exclusively on the male sex. Importantly, knowledge regarding the sex-differentiated effects, the frequency and the dose on which repeated ketamine administration stops being beneficial, is limited. In the current study, we investigated the behavioral, neurochemical and synaptic molecular effects of repeated ketamine treatment (10mg/kg; 21days) in male and female C57BL/6J mice. We report that ketamine induced beneficial antidepressant-like effects in male mice, but induced both anxiety-like (i.e., decreased time spent in the center of the open field arena) and depressive-like effects (i.e., enhanced immobility duration in the forced swim test; FST) in their female counterparts. Moreover, repeated ketamine treatment induced sustained sex-differentiated neurochemical and molecular effects, as it enhanced hippocampal synapsin protein levels and serotonin turnover in males, but attenuated glutamate and aspartate levels in female mice. Taken together, our findings indicate that repeated ketamine treatment induces opposite behavioral effects in male and female mice, and thus, present data have far-reaching implications for the sex-oriented use of ketamine in both experimental and clinical research settings., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Hypotension (HT) and/or hypocapnia (HC) are frequent complications occurring during pediatric anesthesia and may cause cerebral injury in the developing brain., Aim: The aim of this study is to investigate the effects of HT and/or HC on perfusion and metabolism in the developing brain., Methods: Twenty-eight piglets were randomly allocated to four groups: control (C), HT, HC, and hypotension and hyocapnia (HTC). Anesthesia was induced and maintained using sevoflurane. Fentanyl was added for instrumentation. Piglets were fully monitored and their lungs were artificially ventilated. Before treatment, conventional magnetic resonance imaging (MRI), dynamic susceptibility-contrast-enhanced T2*-weighted MRI (DSC-MRI), and single voxel proton MR spectroscopy ((1) H MRS) were performed. Hypotension (mean arterial blood pressure: 30 ± 3 mmHg) was induced by blood withdrawal and nitroprusside infusion, and hyperventilation was used to induce HC (PaCO2 : 2.7-3.3 kPa). (1) H MRS and DSC-MRI were repeated immediately once treatment goals were achieved and 120 min later. Radiologists were blinded to the groups. DSCI-MRI and (1) H MRS analyses were performed in the thalamus, occipital and parietal lobe, hippocampus, and watershed areas., Results: In comparison to C, mean time to peak (TTP) increased with HTC in all brain areas as assessed with DSC-MRI (n = 26). Using (1) H MRS, a significant decrease in N-acetyl aspartate, choline, and myoinositol, as well as an increase in glutamine-glutamate complex (Glx) were detected independent of group. Compared to C, changes were more pronounced for Glx (due to an increase in glutamate) and myoinositol with HTC, for N-acetyl aspartate with HT, and for Glx with HC. No lactate signal was present., Conclusions: The combination of HT and HC during sevoflurane anesthesia resulted in alteration of cerebral perfusion with signs of neuronal dysfunction and early neuronal ischemia. HT and HC alone also resulted in signs of metabolic disturbances despite the absence of detectable cerebral perfusion alterations., (© 2016 John Wiley & Sons Ltd.)

The aim of this study was to test the effect of cardiac output (CO) and pulmonary artery hypertension (PHT) on volumetric capnography (VCap) derived-variables. Nine pigs were mechanically ventilated using fixed ventilatory settings. Two steps of PHT were induced by IV infusion of a thromboxane analogue: PHT25 [mean pulmonary arterial pressure (MPAP) of 25 mmHg] and PHT40 (MPAP of 40 mmHg). CO was increased by 50% from baseline (COup) with an infusion of dobutamine≥5 μg kg(-1) min(-1) and decreased by 40% from baseline (COdown) infusing sodium nitroglycerine≥30 μg kg(-1) min(-1) plus esmolol 500 μg kg(-1) min(-1). Another state of PHT and COdown was induced by severe hypoxemia (FiO2 0.07). Invasive hemodynamic data and VCap were recorded and compared before and after each step using a mixed random effects model. Compared to baseline, the normalized slope of phase III (SnIII) increased by 32% in PHT25 and by 22% in PHT40. SnIII decreased non-significantly by 4% with COdown. A combination of PHT and COdown associated with severe hypoxemia increased SnIII by 28% compared to baseline. The elimination of CO2 per breath decreased by 7% in PHT40 and by 12% in COdown but increased only slightly with COup. Dead space variables did not change significantly along the protocol. At constant ventilation and body metabolism, pulmonary artery hypertension and decreases in CO had the biggest effects on the SnIII of the volumetric capnogram and on the elimination of CO2.

Background: Early intravenous epinephrine administration may help to achieve return of spontaneous circulation in cardiac arrest (CA). However, venous access can be challenging in small children. This study investigates the effect of intravenous and intramuscular epinephrine in treatment of asphyxial CA., Methods: Twenty-eight, 2-5-weeks-old, anesthetized piglets were asphyxiated by ventilation withdrawal. CA was untreated for 8 min, followed by 2 min of basic life support. Following this, epinephrine iv (10 μg·kg(-1) , group IV), epinephrine im (100 μg·kg(-1) , group IM), or normal saline (group NS) were administered. Further doses of epinephrine were given in group IV every 4 min, in group IM after 10 min if required. After twenty-two minutes of CA, iv epinephrine was given to all animals still in CA. Outcome measures were survival and epinephrine plasma concentrations., Results: Ten animals regained spontaneous circulation after 2 min of basic life support. Therefore, no drug treatment was administered (drop out). Resuscitation was effective in 2 pigs of group IM (n = 6), in 6 of group NS (n = 8) and in all of group IV (n = 4). Nonsurvivors had higher epinephrine (P < 0.01) and norepinephrine (P < 0.01) plasma concentrations prior to start of resuscitation. Median increase in epinephrine plasma concentration from T0 to T5 was 138, 134, and 29 nm in group IV, IM, and NS, respectively., Conclusions: Intravenous and intramuscular administered epinephrine led to similar increase in plasma concentrations during resuscitation of asphyxial CA without hemodynamic or survival benefit. High endogenous epinephrine and norepinephrine plasma concentrations were negative predictors for survival., (© 2014 John Wiley & Sons Ltd.)

Background: Early epinephrine administration in cardiac arrest seems to be advantageous to achieve return of spontaneous circulation (ROSC). Because intravenous (i.v.) or intraosseous access is not always immediately available, this study compares efficacy of early intramuscular (i.m.) epinephrine administration with early and delayed i.v. epinephrine injection in an animal cardiac arrest model., Methods: Piglets anesthetized with sevoflurane were intoxicated by an i.v. ropivacaine infusion until circulatory arrest. After 1 min basic life support (chest compression and ventilation), epinephrine i.v. (10 μg·kg(-1), group IV) or epinephrine i.m. (100 μg·kg(-1), group IM) or normal saline (group NS) was applied. Further doses of epinephrine were given in group IV every 4 min and in group IM after 10 min if required. Twenty-one minutes after circulatory arrest, i.v. epinephrine - as necessary - was given to all animals. Thus, group NS represents late epinephrine administration. Outcomes were survival and time to ROSC., Results: Twenty-four pigs aged 19.5 (median, interquartile range 16-22) days, weighing 5.4 (5.0-5.7) kg were investigated. Total amount of ropivacaine administered was 8.9 (8.1-10.1) mg·kg(-1). Cardiac rhythm before starting CPR was pulseless electric activity and asystole in 15 and 9 pigs, respectively. Eight, seven, and four pigs survived in group IV, IM, and NS. Focusing on surviving animals, time to ROSC was 2, 4 and 19.5 min in group IV, IM, and NS., Conclusions: Early i.m. epinephrine provided similar survival compared with early i.v. epinephrine and was superior to delayed epinephrine administration in resuscitation of ropivacaine-induced cardiac arrest in piglets., (© 2013 John Wiley & Sons Ltd.)

Background: The aim of the present study was to investigate the effect of the Lanz system on air sealing by self-inflation in high volume-low pressure (HVLP) tube cuffs., Methods: In vitro tracheal air sealing was studied in HVLP tracheal tube cuffs (internal diameter [ID] 8.0 mm) made from polyurethane ([PU] Seal Guard tracheal tube, Covidien, Athlone, Ireland) and from polyvinylchloride ([PVC] HiLo tracheal tube, Covidien) with and without Lanz pressure regulating valve. Tube cuffs were placed in a vertical 22 mm ID artificial trachea and inflated to 5, 10, 15, 20, 25, or 30 cm H2O cuff pressures. Pressure control ventilation with peak inspiratory pressures (PIPs) of 20 or 25 cm H2O was applied and air leakage was assessed spirometrically as the ratio of expiratory to inspiratory tidal volumes. Nonparametric Mann-Whitney test was applied to compare the air leakage with and without Lanz system for both cuff types at each cuff pressure and PIP (P < .05)., Results: The PVC tube cuffs with Lanz system resulted in significant air leakage at both 20 and 25 cm H2O PIP as compared to those without the Lanz system, especially at cuff pressures lower than the preset PIP (P < .05). Although PU tube cuffs with Lanz system showed reduced air sealing when compared with cuffs without Lanz, the difference was not statistically significant., Conclusion: Cuff pressure compensation with the Lanz system during cyclic respiratory pressure changes interferes with the self-sealing mechanism in HVLP tube cuffs at cuff pressures lower than PIP level. This results in larger air leak across tube cuffs particularly in tube cuffs made from PVC.

Background and Objectives: Impairment of blood coagulation is one of the main side effects of volume replacement, particularly if artificial colloids such as hydroxyethyl starch (HES) and gelatine preparations are used. This animal study aimed to evaluate the effect of a single fast intravenous crystalloid or colloid fluid bolus on blood coagulation as measured by rotation thromboelastometry (ROTEM)., Methods: Thirty-two anesthetized piglets were infused with a rapid 20 ml·kg(-1) fluid bolus of either normal saline (NS), 4% gelatine, 5% albumin or 6% HES 130/0.4 (n = 8 per group) over a period of 2 min. Hemostasis was assessed by ROTEM before and 1 min after fluid administration. Within-group differences were analyzed by Wilcoxon test, and additionally overall Kruskal-Wallis test followed by posthoc Mann-Whitney U-test were applied to detect differences between groups., Results: All fluids caused a significant weakening of clot strength within groups. HES and gelatine showed a significantly stronger impairment of clot growth and maximum clot firmness as compared with albumin and normal saline. Impairment of fibrin polymerization was more pronounced following HES as compared with all other fluids., Conclusion: After moderate but very fast volume loading, HES and gelatine impair blood coagulation to a larger extent as compared with albumin or normal saline, while no significant differences were observed between both artificial colloids., (© 2012 Blackwell Publishing Ltd.)

The activated clotting time (ACT) was invented as a whole blood test to detect coagulopathy, but nowadays is almost exclusively used to guide heparin anticoagulation. Although the ACT provides a fairly reliable and fast bedside test of the coagulation status, only a few studies have focused on its use to monitor pre- or intraoperative coagulation status as an early marker of impaired haemostasis or increased bleeding tendency. The aim of this study was to compare intraoperative i-STAT(®) ACT values with commonly used thresholds of standard coagulation tests for the diagnosis of coagulopathy during paediatric non-cardiac surgery. We performed a prospective, observational study in a University Children's hospital and included 50 paediatric patients who underwent major elective, non-cardiac, surgery. The i-STAT(®) kaolin ACT test was obtained intraoperatively and compared to the commonly used threshold of standard coagulation tests (PT/INR, aPTT, and plasma fibrinogen level). A total of 181 blood samples were taken from 50 pediatric patients. Moderate correlation was found between ACT and aPTT (r = 0.694; p < 0.001), and all other coagulation tests. The median ACT values remained within the normal range throughout the entire surgical phase, while standard coagulation tests were mostly abnormal during surgery. Intraoperative measurement of ACT did not provide comparable thresholds of normal haemostasis as compared to standard coagulation testing.

Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major cytogenetic subgroups. We identified 120 missense/nonsense mutations as well as 60 insertions/deletions affecting 73 different genes (∼ 3.6 tumor-specific aberrations/AML). While most of the newly identified alterations were nonrecurrent, we observed an enrichment of mutations affecting genes involved in epigenetic regulation including known candidates like TET2, TET1, DNMT3A, and DNMT1, as well as mutations in the histone methyltransferases NSD1, EZH2, and MLL3. Furthermore, we found mutations in the splicing factor SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21. These splicing-related mutations affected 10% of AML patients in a mutually exclusive manner. In conclusion, we could identify a large number of alterations in genes involved in aberrant splicing and epigenetic regulation in genomic regions commonly altered in AML, highlighting their important role in the molecular pathogenesis of AML.

Anesthesia care for infants and young children for proton beam radiotherapy demands great technical and vocational skills from the anesthesia team and also a high degree of competence in soft skills. The anesthesia team should be experienced and regularly trained in pediatric anesthesia, especially as the children are often in a reduced general condition. The infrastructure should be established according to the current standards in anesthesiology. Monitoring of vital data, thorax excursions and inadvertent movements of the remotely positioned and sedated patient need to be under constant technical and optical surveillance. Propofol is an ideal hypnotic for the sedation of children under spontaneous breathing for proton beam radiation therapy. It is well tolerated even when given on a daily basis over several weeks. A close cooperation between the pediatric oncologist, radiation oncologist and anesthetist is important in order to manage additional medical problems in an optimal way. The special needs of oncology patients must be taken into consideration when planning anesthesia care.

Caudal block is a safe procedure commonly used for pediatric perioperative analgesia. Complications are extremely rare but nevertheless local and systemic contraindications must be excluded. Optimal safety and quality result when strict attention is paid to technical details. A local anesthetic (LA) containing epinephrine allows early detection of inadvertent intravascular LA administration; therefore an epinephrine/LA mixture is recommended at least for the test dose. In terms of safety the choice of LA itself is probably of secondary importance. Clonidine as an adjuvant has an excellent risk/benefit profile with minimal side effects. Inadvertent systemic LA intoxication is a rare but potentially fatal complication of regional anesthesia and measures for prevention and early detection are essential. Should circulatory arrest occur, immediate resuscitation following standard guidelines is to be initiated including the use of epinephrine as the first line drug. Intravenous administration of lipid solutions may be beneficial as a secondary adjunct to stabilize hemodynamics but is not an alternative to epinephrine.

Background:   Acquired deficiency of FXIII because of perioperative hemodilution has been described several times in adults; however, data in children are scarce. We performed a prospective observational trial to evaluate the intraoperative course of FXIII in children undergoing elective major surgery., Methods:   Blood samples were repeatedly taken from 46 children aged 0.3-16 years undergoing major surgery. Concentrations of FXIII and fibrinogen, thrombelastometry by ROTEM®, and cell count were assessed intraoperatively., Results:   A significant decrease in FXIII concentration (median 60%; IQR 49-69%) was already noted at beginning of surgical procedures, while most ROTEM® traces remain unchanged. FXIII levels further deteriorated intraoperatively to minimal levels of 33% (15-61%). Lowest intraoperative clot strength (ExTEM) was 44 mm (34-50 mm), and fibrinogen plasma levels decreased to minimal levels of 130 mg·dl(-1) (95-160 mg·dl(-1) ). In 43 of 46 children, transfusion therapy was necessary. Despite of transfusion of fresh frozen plasma (cumulative total dose 22 ml·kg(-1) [11-32 ml·kg(-1) ]) in 21 of 46 children, FXIII level remains low in all children till the end of surgery at levels of 39% (20-46%)., Conclusions:   Coagulation factor XIII decreased early during major surgery owing to hemodilution. Overall intraoperative FXIII levels remain low despite of transfusion of fresh frozen plasma., (© 2011 Blackwell Publishing Ltd.)

Perioperative dilutional coagulopathy is a major coagulation disorder during adult and pediatric surgery. Although the main underlying mechanisms are comparable, data of the development and management of dilutional coagulopathy in children are scarce. Observational data showed that intraoperative coagulation disorders mainly based on complex disturbances of clot firmness including acquired fibrinogen as well as factor XIII deficiencies, while clotting time and platelet counts remained fairly stable. A fast and reliable monitoring of the entire coagulation process (e.g. thrombelastometry) might be of extreme value for detection and guidance of effective coagulation management. Although the transfusion of fresh frozen plasma was recommended in several guidelines, the use of coagulation factors might offer an alternative and potentially superior approach in managing perioperative coagulation disorders. Further studies are urgently needed to determine the efficacy of modern coagulation management.

Objectives: Local anesthetic (LA) intoxication with cardiovascular arrest is a potential fatal complication of regional anesthesia. Lipid resuscitation has been recommended for the treatment of LA-induced cardiac arrest. Aim of the study was to compare four different rescue regimens using epinephrine and/or lipid emulsion and vasopressin to treat cardiac arrest caused by bupivacaine intoxication., Methods: Twenty-eight piglets were randomized into four groups (4 × 7), anesthetized with sevoflurane, intubated, and ventilated. Bupivacaine was infused with a syringe driver via central venous catheter at a rate of 1 mg·kg(-1)·min(-1) until circulatory arrest. Bupivacaine infusion and sevoflurane were then stopped, chest compression was started, and the pigs were ventilated with 100% oxygen. After 1 min, epinephrine 10 μg·kg(-1) (group 1), Intralipid(®) 20% 4 ml·kg(-1) (group 2), epinephrine 10 μg·kg(-1) + Intralipid(®) 4 ml·kg(-1) (group 3) or 2 IU vasopressin + Intralipid(®) 4 ml·kg(-1) (group 4) were administered. Secondary epinephrine doses were given after 5 min if required., Results: Survival was 71%, 29%, 86%, and 57% in groups 1, 2, 3, and 4. Return of spontaneous circulation was regained only by initial administration of epinephrine alone or in combination with Intralipid(®). Piglets receiving the combination therapy survived without further epinephrine support. In contrast, in groups 2 and 4, return of spontaneous circulation was only achieved after secondary epinephrine rescue., Conclusions: In cardiac arrest caused by bupivacaine intoxication, first-line rescue with epinephrine and epinephrine + Intralipid(®) was more effective with regard to survival than Intralipid(®) alone and vasopressin + Intralipid(®) in this pig model., (© 2011 Blackwell Publishing Ltd.)

Background: Management of difficult airways and difficult intubation differs in pediatric and in adult patients. In conscious children, fiberoptic intubation is not feasible because of limited compliance. The specially designed laryngeal mask for blind tracheal intubation, LMA Fastrach™, is available for adolescents and adults only. Therefore, fiberoptic-guided intubation through a supraglottic airway device (SAD) is a standard technique for the management of difficult intubation in children. While performing the procedure, stabile positioning of the endotracheal tube (ETT) and prevention of dislodgement are critical issues. The relationship between the length of the ETT and the SAD is highly important and was investigated in this in vitro study., Materials and Methods: In this study 6 different brands of SAD in the pediatric sizes 1-3 and 2 different ETT brands (cuffed, Microcuff(®), uncuffed, Sheridan PED-SOFT™) were investigated. Using pediatric growth tables, the recommended patient weight for each SAD size was correlated to patient age and then to appropriately sized cuffed and uncuffed ETTs. The ETT size was chosen according to the manufacturer's recommendations (cuffed ETT) and according to the literature (uncuffed ETT). The various SAD-ETT pairs were assessed with regard to differences in their length. After lubrication with silicone the ETT with a firmly attached 15 mm tube adapter was maximally inserted into the SAD and the ETT tip overlapping the SAD cuff was measured. Secondarily, an adapter for fiberoptic procedures was interposed and the measurements repeated., Results: For a defined patient uncuffed ETTs were usually selected with a larger internal diameter (ID) compared to cuffed ETTs. Therefore, the uncuffed ETT is the longer one and will overlap the SAD by a longer tip. Comparing the curved SAD brands AuraOnce™ and Aura-i™, the Aura-i™ devices generally showed shorter tubes resulting in a longer protruding ETT tip (median 1.5 cm, minimum-maximum 1.0-2.4 cm). The straight brands LMA classic™, AuraStraight™ and LMA Unique™ showed similarity in tube length. In comparison with i-gel(®), for the SAD sizes 1-2.5 the former provide a longer projecting ETT tip. Only i-gel(®) together with AuraStraight™ showed the longest overlapping ETT tip for SAD size 3. If a swivel adapter was used during the fiberoptic intubation procedure, the length of the ETT could be critically reduced in relation to the length of the SAD. Using a swivel adapter from VBM Medizintechnik, (Sulz a. N., Germany) a relative reduction in ETT length of 2.3 or 3.2 cm has to be taken into account., Conclusions: For fiberoptic-guided endotracheal intubation through an SAD, sufficient length of the ETT in relation to the SAD is mandatory. Differences in geometry between SAD and ETT brands have to be considered. The selection of a relatively small SAD in combination with an uncuffed ETT might be advantageous. Redesigned extra long ETTs would be desirable to decrease the risk for ETT dislocation and to increase the safety of the technique. Restrictive use of a swivel adapter during the procedure is important because of further and potentially critical decreases in ETT length. In addition, after successful intubation of the trachea, removal of the SAD via an airway exchange catheter and replacement of the cuffed ETT of choice in the correct position is recommended to secure the airway and provide unimpaired ventilation and oxygenation.

This study aimed to assess intrarater and interrater variability of coagulation point-of-care testing (POCT) using ROTEM delta operated by trained staff. Arterial blood samples were taken from 43 anesthetized piglets aged up to 6 weeks and weighing 4-6 kg. The following clotting measurements were recorded: clotting time, clot formation time (CFT), maximum clot firmness (MCF) and alpha angle using ROTEM delta assays ExTEM, InTEM, FibTEM and ApTEM. Intrarater variability was assessed when a single operator performed the same assay simultaneously in all four channels of the ROTEM device. Interrater variability was assessed by two different operators simultaneously performing the same assay. Variance components of the data were analyzed using linear mixed modeling. Three hundred and forty-three tests from 86 samples were loaded and analyzed. The intraclass correlation coefficient (ICC) was more than 0.7 for clotting measurements except for CFT and alpha in InTEM. For intrarater and interrater assessment, different relative variability for the ROTEM measurements were found with consistently higher variability for clotting time and CFT and lower variability of MCF and alpha angle. Interrater variability was not statistically significant as supported using Akaike's information criterion. Piglet coagulation testing using ROTEM delta showed a high ICC. Variability was significantly lower in MCF and angle alpha compared with clotting time and CFT. No further variability was added by a second user. Based on these data, ROTEM delta appears to be suitable as POCT.

Objectives: Local anesthetic (LA) intoxication with severe hemodynamic compromise is a potential catastrophic event. Lipid resuscitation has been recommended for the treatment of LA-induced cardiac arrest. However, there are no data about effectiveness of Intralipid for the treatment of severe cardiovascular compromise prior to cardiac arrest. Aim of this study was to compare effectiveness of epinephrine and Intralipid for the treatment of severe hemodynamic compromise owing to bupivacaine intoxication., Methods:   Piglets were anesthetized with sevoflurane, intubated, and ventilated. Bupivacaine was infused with a syringe driver via a central venous catheter at a rate of 1 mg·kg(-1) ·min(-1) until invasively measured mean arterial pressure (MAP) dropped to 50% of the initial value. Bupivacaine infusion was then stopped, and epinephrine 3 μg·kg(-1) (group 1), Intralipid(®) 20% 2 ml·kg(-1) (group 2), or Intralipid 20% 4 ml·kg(-1) (group 3) was immediately administered. Survival, hemodynamic course, and ET(CO2) were recorded., Results:   Twenty-one piglets (3 × 7), with median age of 26 days (19-43) and weighing 4.9 kg (4.3-5.8), were investigated. All animals in group 1 (100%) but only four of seven (57%) piglets in group 2 and group 3, respectively, survived. Normalization of hemodynamic parameters (HR, MAP) and ET(CO2) was fastest in group 1 with all piglets achieving HR and MAP values at or above baseline within 1 min., Conclusion:   For the treatment of severe hemodynamic compromise owing to bupivacaine intoxication in piglets, first-line rescue with epinephrine was more effective than Intralipid with regard to survival as well as normalization of hemodynamic parameters and ET(CO2) ., (© 2011 Blackwell Publishing Ltd.)

Purpose: Systemic local anesthetic (LA) toxicity resulting from inadvertent intravascular injection of LA is a rare but potentially fatal event. Early recognition of intravascular injection and approaches to improve therapeutic safety are required. This study investigated the influence of intravascular injection dose rate of bupivacaine on bupivacaine plasma levels and timing of LA-induced cardiovascular compromise., Methods: Forty-five piglets, anesthetized with sevoflurane, were randomized into three groups. Bupivacaine was intravenously infused at a rate of 1, 4, or 16 mg/kg/min (groups A, B, and C, respectively) until mean arterial pressure (MAP) dropped to 50% of initial value. Thereafter, bupivacaine infusion was stopped and spontaneous hemodynamic course was observed. Time to MAP 50%, amount of bupivacaine infused, bupivacaine plasma level at infusion stop, spontaneous survivors, or time from bupivacaine stop to circulatory arrest were recorded., Results: Median time to MAP 50% was 297, 119, and 65 s, respectively, in groups A, B, and C (P < 0.001). Median corresponding total amounts of bupivacaine infused were 5.0, 7.8, and 17.0 mg/kg (P < 0.01), and median bupivacaine plasma levels were 53.8, 180.0, and 439.8 μmol/l (P < 0.001). Five of 15 piglets in group A recovered spontaneously; in groups B and C, all animals died within 120 and 21 s, respectively., Conclusion: Higher dose rates of bupivacaine showed much higher plasma bupivacaine levels related to absolute infused dose at MAP 50% and were associated with an increased mortality. Slow administration of LA is recommended to allow timely detection and stopping of inadvertent intravascular administration.

We report an unusual case of acquired dermal melanocytosis occurring in a 57-year-old African-American woman. Macular pigmentation over the patient's cheeks, back, and sclerae developed over the course of 18 months without identifiable antecedent. The patient was taking only hormone replacement therapy and was generally healthy. Histologic examination of the skin revealed dendritic melanocytes and melanophages in the mid- to upper dermis. We briefly review the literature surrounding acquired dermal melanocytosis and continue discussion regarding its pathogenesis.

A 42-year-old white woman presented with clinical and histologic manifestations of both calcinosis cutis and pseudoxanthoma elasticum: discrete milia-like calcifications at the anterior aspect of the neck, a funduscopic examination with classic eye findings, peripheral vascular disease, and a mottled appearance of the skin at the axillae, groin, and lateral aspects of the neck. A younger sibling had similar skin lesions and deteriorating visual acuity. The patient was normocalcemic and normophosphatemic. This case may represent the coincidental occurrence of two rare entities in the same person or may be suggestive of a pattern of dystrophic calcification associated with pseudoxanthoma elasticum.

Interlocking intramedullary nailing has become the preferred method of internal fixation for diaphyseal fractures of the lower extremity. In shaft fractures of the humerus however open reduction and internal fixation with plates and screws is still considered the gold standard for operative treatment. The unreamed humerus nail (UHN) is a new implant for interlocking intramedullary nailing, which allows for stable fixation of humerus shaft fractures and immediate functional after treatment. The UHN could thus become an equal alternative to plate osteosynthesis. From this point of view we analyzed retrospectively 19 shaft fractures of the humerus, which have been treated at our institution with an UHN. Infections and iatrogenic nerve lesions did not occur. One patient with a rotational malalignment of 45 degrees underwent a secondary procedure. In two out of ten fresh fractures the bone healing failed and resulted in a non-union. In all cases of pathological fractures a good palliation could be achieved. With exception of two patients the range of motion of the shoulder and elbow was symmetric. We conclude that the UHN is a real alternative to plate osteosynthesis. Compared with most series of plate osteosynthesis published in the literature the risk for iatrogenic lesions of the radial nerve appears to be lower. Even in this small series we found however a rather high rate of non-unions.

Acute symptomatic groin hernias with potential or definite ischemia represent a special group of all the groin hernias. The method of choice to treat these hernias has to fulfill the following criteria: 1. Easy reduction of the hernia sac and its contents without causing damage. 2. Good exposure and easy access for possible resection. 3. Safe hernia repair through the same access. According to our experience with 44 incarcerated and strangulated groin hernias operated between 1993 and 1997 and after a literature review, we took the following procedure as our routine: Posterior approach and mesh repair. We do not use a meshgraft only in the presence of colonic necrosis or peritonitis.

The goal of this research was to delineate the post-transcriptional mechanisms responsible for the increased elastin synthesis characteristic of sundamaged skin. In this study, a unique molecular variant of the tropoelastin mRNA transcript was identified in human sundamaged skin that was derived from the usage of an alternate polyadenylation site. Nonsolar exposed human skin expressed one tropoelastin mRNA species whereas sundamaged human skin expressed the primary tropoelastin mRNA and a larger, alternate tropoelastin mRNA formed from the utilization of a second polyadenylation site. Cultured human skin fibroblasts expressed both tropoelastin transcripts and in vitro UV treatment increased the amount of the unique tropoelastin mRNA. Hairless mouse skin (normal and UV treated) expressed the primary tropoelastin transcript although UV irradiation increased the length of its poly (A) tail two-fold. Therefore, UV radiation may stimulate elastin production by affecting polyadenylation site selection and the poly (A) tail length of tropoelastin mRNA.

This study investigated the relationship between senior nursing faculty mentoring activities and support for faculty mentoring provided by nursing program administrators. Eighty nurse administrators and 389 senior nursing faculty from NLN-accredited MSN programs completed questionnaires. Twenty-five percent of the faculty sample reported that they did not mentor junior faculty in their present work setting, while 75% reported being engaged in mentoring activities which focused on career and personal development. Mentoring activities reported by senior nursing faculty were not significantly related to the three levels of administrative support: (1) formal support, (2) conceptual support, and (3) no support. The majority of institutions expressed support for the concept of mentoring and nurse administrators used informal mechanisms to support faculty mentoring. Significant differences were found between the three different levels of support and two supportive activities used by nurse administrators to facilitate mentoring relationships: (1) to arrange gatherings, and (2) to provide funding for joint projects.

Several overlapping cDNA clones were isolated from a lambda gt10 cDNA library constructed using poly A+ RNA from neonatal sheep lung. DNA sequence analysis of these cDNA recombinants revealed the complete derived amino acid sequence of sheep tropoelastin. A comparison of DNA sequences from individual sheep tropoelastin cDNA also confirmed the presence of several tropoelastin mRNA isoforms in neonatal lung tissue. Coding domains corresponding to exons 13, 14 and 33 were present in several of the sheep tropoelastin cDNA fragments but absent in others. The relative amount of alternate usage of these exons was quantitated by polymerase chain amplification. In confirmation of previous studies in other mammalian species, extensive alternate usage of exon 33 was observed in total RNA isolated from aorta, nuchal ligament and pulmonary artery from neonatal sheep. In striking contrast to all previous studies, however, exons 13 and 14 were shown to be subject to almost the same level of alternate usage as exon 33 in all three neonatal sheep tissues examined.

The incidence of retroperitoneal soft tissue sarcomas is with 0.1 to 0.2 percent very low. The tumors most often present as asymptomatic masses until the lesions are quite large, compared with the anatomic part, resulting in compression of nerves, vessels, bowel etc. The recommended management is the aggressive radical tumor excision including the pseudocapsule followed by a consequent clinical, ultrasonography and CT-scan follow-up. Tumor recurrences should be attempted in the same manner as primary tumors.

Neonatal rat pups were treated either with ciclosporin at 10 mg/kg/day dissolved in olive oil (experimental) or with pure olive oil (control). Lung protein biosynthesis was evaluated in a protocol which involved the measurement of total accumulated protein, collagen and elastin. Four time points were studied in the first 21 days of life, 12 animals contributing to each point (6 control and 6 ciclosporin). Ciclosporin levels in the treated group ranged widely (2,000-4,000 ng/ml). There were significant differences in total body weight and lung weight in treated vs. controls during and after the first week. DNA contents per unit wet weight varied significantly during the second week of life, indicating increased cellularity of the ciclosporin-treated animals. Associated with this was an increase in the lung protein/DNA ratio as well as the elastin/DNA ratio in the control animals, but not in the treated ones. The lung collagen/DNA ratio was not as dramatically affected by the ciclosporin treatment. However, the collagen content per unit wet weight of lung tissue was increased in the ciclosporin-treated animals at 15 days of life. We conclude that ciclosporin has a marked effect on lung connective tissue metabolism in early life, the long-term effects of which are unappreciated and undocumented but may well be of vital importance in the lungs of long-surviving organ transplant patients.