Effects of spontaneous breathing during airway pressure release ventilation on renal perfusion and function in patients with acute lung injury

OBJECTIVE: Controlled mechanical ventilation can impair systemic and renal blood flow and function, which may be aggravated by respiratory acidosis. We hypothesized that partial ventilatory support using airway pressure release ventilation (APRV) with spontaneous breathing provides better cardiopulmonary and renal function than full ventilatory support using APRV without spontaneous breathing. DESIGN: Prospective randomized study. SETTING: Intensive care unit of a university hospital. PATIENTS: Twelve patients with acute lung injury (ALI). INTERVENTIONS: Airway pressure release ventilation with and without spontaneous breathing, maintaining either the same minute ventilation (V(E)) or the same airway pressure (Paw) limits. MEASUREMENTS: Systemic hemodynamics were estimated by double-indicator dilution, effective renal blood flow (ERBF) by para-aminohippurate, and glomerular filtration rate (GFR) by inulin clearance. RESULTS: Compared to APRV with spontaneous breathing, cardiac index (CI) was decreased when the upper Paw limit was increased to provide the same V(E) (4.26+/-1.21 l min(-1) m(-2)vs 3.72+/-0.99 l min(-1) m(-2); p<0.05) while CI was increased when Paw limits were held constant (4.91+/-1.41 l min(-1) m(-2); p<0.05). Effective renal blood flow and GFR were higher during APRV with spontaneous breathing (858+/-388 ml min(-1) m(-2) and 94+/-47 ml min(-1) m(-2)) than during APRV without spontaneous breathing and the same V(E) (714+/-236 ml min(-1) m(-2)and 82+/-35 ml min(-1) m(-2)) or the same Paw (675+/-287 ml min(-1) m(-2) and 80+/-41 ml min(-1) m(-2); p<0.05). Urine volume did not change. CONCLUSIONS: Spontaneous breathing during APRV was associated with better renal perfusion and function than APRV without spontaneous breathing applying either the same V(E) or the same Paw limits. Maintaining spontaneous breathing during ventilatory support may, therefore, be advantageous in preventing deterioration of renal function in patients with ALI.     

Human neural crest cells contribute to coat pigmentation in interspecies chimeras after in utero injection into mouse embryos

The neural crest (NC) represents multipotent cells that arise at the interphase between ectoderm and prospective epidermis of the neurulating embryo. The NC has major clinical relevance because it is involved in both inherited and acquired developmental abnormalities. The aim of this study was to establish an experimental platform that would allow for the integration of human NC cells (hNCCs) into the gastrulating mouse embryo. NCCs were derived from pluripotent mouse, rat, and human cells and microinjected into embryonic-day-8.5 embryos. To facilitate integration of the NCCs, we used recipient embryos that carried a c-Kit mutation (W^sh/W^sh), which leads to a loss of melanoblasts and thus eliminates competition from the endogenous host cells. The donor NCCs migrated along the dorsolateral migration routes in the recipient embryos. Postnatal mice derived from injected embryos displayed pigmented hair, demonstrating differentiation of the NCCs into functional melanocytes. Although the contribution of human cells to pigmentation in the host was lower than that of mouse or rat donor cells, our results indicate that hNCCs, injected in utero, can integrate into the embryo and form mature functional cells in the animal. This mouse–human chimeric platform allows for a new approach to study NC development and diseases.Genetically engineered mice have been highly informative in studying the developmental origin of many inherited diseases (1–3). However, mouse models often fail to reproduce the pathophysiology of human disorders due to interspecies divergence, such as metabolic differences between mouse and human (4), or differences in genetic background (5). To overcome some of the limitations of transgenic mouse models, transplantation of disease-relevant human cells into mice has been informative and is frequently used in cancer research. However, this approach is primarily restricted to the study of end-stage-disease cell types and provides only limited insight into tumor initiation and early progression of the disease under in vivo conditions, with the exception of the hematopoietic lineages, where human hematopoietic stem cells were found to successfully engraft into immune-deficient mice and provided a powerful approach for studying blood diseases (6).Somatic cell reprogramming provides patient-specific induced pluripotent stem cells (iPSCs) that carry all genetic alterations contributing to the disease pathophysiology and thus allows for generating the disease-relevant cell types in culture (7). However, many complex diseases involve progressive cellular or genetic alterations that occur before the manifestation of a clinical phenotype. Therefore, it is not clear whether a disease-relevant phenotype can be observed in short-term cultures of cells derived from patients with long-latency diseases, such as Parkinson''s or Alzheimer’s disease or cancers like melanoma. A major challenge is establishing model systems that, using human embryonic stem cells (hESCs) or hiPSCs, will allow for the investigation of human disease under appropriate in vivo conditions.Transplantation of hiPSCs or hiPSC-derived cells into mouse embryos would present an attractive solution to many of the aforementioned limitations. The main advantage of such an approach is that the transplanted cells would integrate into the embryo and participate in normal embryonic development, and consequently could be studied over the lifetime of the mouse. Currently, it is controversial whether the injection of hESCs/hiPSCs into preimplantation mouse blastocysts can generate even low-grade chimeric embryos (8–11). As an alternative approach, we explored whether multipotent somatic cells would be able to functionally integrate into postgastrulation mouse embryos and allow for the generation of mouse–human chimeras. We investigated the potential of human neural crest cells (hNCCs), derived from hESCs/hiPSCs, to integrate into the mouse embryo and contribute to the NC-associated melanocyte lineage. The NC, a multipotent cell population, arises at the boundary between the neuroepithelium and the prospective epidermis of the developing embryo. Trunk NCCs migrate over long distances, with the lateral migrating NCCs generating all of the melanocytic cells of the animal’s skin (12).NCC migration, development, and differentiation into various tissues have been studied in vivo by generating quail–chick NC chimeras. In this model, donor quail tissues were grafted into similar regions of developing chicken embryos (13). The experimental approach of our present study was based on the generation of mouse–mouse NC chimeras that had been created by injection of primary mouse NCCs into the amniotic cavity of embryonic-day (E) 8.5 embryos (14, 15). The donor mouse NCCs (mNCCs), having been placed outside of the embryo, enter into the neural tube, presumably through the still-open neural pores, and transverse the epidermis. The donor mNCCs used in this previous study were collected from pigmented C57BL/6 mice, whereas the host embryos were derived from BALB/c albino mice. Thus, contribution of the donor mNCCs to the host embryo could be determined by the presence of pigmentation in the coats of the injected mice. The injected primary mNCCs contributed to coat color formation in the head and hind limb regions only, but not in the midtrunk area, likely reflecting the entry point of the cells through the neural pores with the anterior–posterior movement of the cells being hindered by endogenous melanoblasts (15). Indeed, when embryos carrying the white-spotted c-Kit mutation (W^sh/W^sh), which lack melanoblasts, were used as a host, extensive coat color contribution revealing anterior–posterior cell migration was observed, presumably because the donor NCCs could spread into the empty niches (14).Here, we differentiated mouse, rat, and human ESCs or iPSCs into NCCs that were injected in utero into E8.5 albino wild-type and c-Kit–mutant W^sh/W^sh embryos. Both the mouse and human NCCs migrated laterally under the epidermis and ventrally into deeper regions of the embryo. Importantly, analysis of postnatal animals derived from mouse, rat, or human NCC-injected embryos displayed coat color pigmentation from the donor cells. Our results demonstrate that NCCs from different species can integrate into the developing mouse embryo, migrate through the dermis, and differentiate into functional pigment cells in postnatal mice. The generation of postnatal mouse–human chimeras carrying differentiated and functional human cells allows for a novel experimental system in which to study human diseases in an in vivo, developmentally relevant environment.     

Regulation of mitochondrial proliferation in the heart: power-plant failure contributes to cardiac failure in hypertrophy

During hypertrophy, proliferation of mitochondria does not keep pace with the increasing energy demand of the heart. This probably contributes importantly to cardiac failure, together with other phenotypic changes occurring during the growth process. The problem may be even aggravated if defects of mitochondrial function itself and not external factors cause the hypertrophic process. Here we review the basic mechanisms controlling mitochondrial biogenesis, especially the pathways coordinating expression of nuclear encoded mitochondrial genes and the small mitochondrial genome, and how these mechanisms may be connected to the cardiomyocyte differentiation program during development as well as under physiological and pathological circumstances.     

The prevalence of symptoms of sensorimotor and autonomic neuropathy in Type 1 and Type 2 diabetic subjects

The aim of this study was to analyze the prevalence and severity of sensorimotor and autonomic neuropathic symptoms within an outpatients diabetic population. A total of 350 consecutive Type 1 (26.9%) and Type 2 diabetic subjects were investigated using the Michigan Neuropathy Screening Instrument (MNSI). The original questionnaire was extended with questions on autonomic neuropathy and to include a six-point scale to rate the severity of symptoms, which were recorded accurately in order to avoid overrating. More than one half of Type 2 and nearly a third of Type 1 diabetic subjects suffer from at least one neuropathic symptom; the former suffered significantly more often from paresthesia (P<.05) and burning pain (P=.05). Less than 10% of the study population had autonomic symptoms. The prevalence of symptomatic polyneuropathy (PNP), diagnosed by an abnormal MNSI together with the presence of any symptom, was 16.0% in Type 1 and 37.5% (P<.001) in Type 2 diabetic subjects. Subjects with an abnormal ankle reflex (54.6%) had in 48.2% any sensorimotor, in 35.1% any autonomic, and in 25.7% any sensorimotor plus autonomic symptoms. The corresponding percentages for subjects with an abnormal vibration perception threshold (VPT; 28.9%) were 59.4%, 46.5%, and 34.7%, respectively. An abnormal ankle reflex was significantly correlated to numbness, and to the the sum of sensorimotor and autonomic symptoms. An abnormal vibration perception was significantly correlated to numbness, to paresthesia pain, and to the sum of sensorimotor and autonomic symptoms. A higher percentage of Type 2 diabetic subjects had symptoms of neuropathy and the most frequent symptoms were numbness, muscle cramps and postural hypotension.     

Reduced longevity in untreated patients with isolated growth hormone deficiency

Increased longevity of hypopituitary dwarf mice and GH- resistant knockout mice appears to be in contrast with observations made in clinical practice. In humans, on one hand hypopituitarism and GH deficiency (GHD) are believed to constitute risk factors for cardiovascular disease and, therefore, early death. But on the other hand, patients with a PROP-1 gene mutation, presenting with a combined pituitary-derived hormonal deficiency, can survive to a very advanced age, apparently longer than normal individuals in the same population. The aim of this study was to analyze the impact of untreated GHD on life span. Hereditary dwarfism was recognized in 11 subjects. Genetic analysis revealed an underlying 6.7-kb spanning deletion of genomic DNA encompassing the GH-1 gene causing isolated GHD. These patients (five males and six females) were never treated for their hormonal deficiency and thus provide a unique opportunity to compare their life span and cause of death directly with their unaffected brothers and sisters (11 males and 14 females) as well as with the normal population (100 males and females). Although the cause of death did not vary between the two groups, median life span in the GH-deficient group was significantly shorter than that of unaffected brothers and sisters [males, 56 vs. 75 yr (P < 0.0001); females, 46 vs. 80 yr (P < 0.0001)]. Therefore, with the wealth of information regarding the beneficial effects of GH replacement and the dramatic findings of this study, GH treatment in adult patients suffering from either childhood- or adult-onset GHD is crucially important.     

A randomized, double-blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: short- and long-term efficacy and safety results

OBJECTIVE: In an international, multicenter, double-blind, randomized clinical trial we evaluated the short-term (3 months) and long-term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular-course (oligo-course) or polyarticular-course (poly-course) juvenile idiopathic arthritis (JIA). METHODS: Children ages 2-16 years who had active oligo-course or poly-course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double-blind, double-dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups. RESULTS: Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty-two patients (81%) completed the 12-month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups. CONCLUSION: The short- and long-term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo-course and poly-course JIA. The once-daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.     

Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations

Natriuretic peptide [NP; B‐type NP (BNP), N‐terminal proBNP (NT‐proBNP), and midregional proANP (MR‐proANP)] concentrations are quantitative plasma biomarkers for the presence and severity of haemodynamic cardiac stress and heart failure (HF). End‐diastolic wall stress, intracardiac filling pressures, and intracardiac volumes seem to be the dominant triggers. This paper details the most important indications for NPs and highlights 11 key principles underlying their clinical use shown below.

1. NPs should always be used in conjunction with all other clinical information.
2. NPs are reasonable surrogates for intracardiac volumes and filling pressures.
3. NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use facilitates the early diagnosis and risk stratification of HF.
4. NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the likelihood that dyspnoea is caused by HF.
5. Optimal NP cut‐off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting to the emergency department with acute dyspnoea are higher compared with those used in the diagnosis of chronic HF in patients with dyspnoea on exertion (mild increase in filling pressures at rest).
6. Obese patients have lower NP concentrations, mandating the use of lower cut‐off concentrations (about 50% lower).
7. In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial fibrillation or pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization.
8. Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with cardiovascular risk factors may help to identify patients at increased risk, therefore allowing targeted preventive measures to prevent HF.
9. BNP, NT‐proBNP and MR‐proANP have comparable diagnostic and prognostic accuracy.
10. In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic.
11. NPs cannot identify the underlying cause of HF and, therefore, if elevated, must always be used in conjunction with cardiac imaging.

     

MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes

MRP14 (S100A9) is the major calcium-binding protein of neutrophils and monocytes. Targeted gene disruption reveals an essential role of this S100 protein for transendothelial migration of phagocytes. The underlying molecular mechanism comprises major alterations of cytoskeletal metabolism. MRP14, in complex with its binding partner MRP8 (S100A8), promotes polymerization of microtubules. MRP14 is specifically phosphorylated by p38 mitogen-activated protein kinase (MAPK). This phosphorylation inhibits MRP8/MRP14-induced tubulin polymerization. Phosphorylation of MRP14 is antagonistically regulated by binding of MRP8 and calcium. The biologic relevance of these findings is confirmed by the fact that MAPK p38 fails to stimulate migration of MRP14(-/-) granulocytes in vitro and MRP14(-/-) mice show a diminished recruitment of granulocytes into the granulation tissue during wound healing in vivo. MRP14(-/-) granulocytes contain significantly less polymerized tubulin, which subsequently results in minor activation of Rac1 and Cdc42 after stimulation of p38 MAPK. Thus, the complex of MRP8/MRP14 is the first characterized molecular target integrating MAPK- and calcium-dependent signals during migration of phagocytes.     

Oligoclonal bands predict multiple sclerosis in children with optic neuritis

We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow‐up of 4.0 years. Multiple Cox proportional‐hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.39–10.39, p < 0.001), presence of cerebrospinal fluid immunoglobulin G oligoclonal bands (OCB; HR = 3.69, 95% CI = 2.32–5.86, p < 0.001), and age (HR = 1.08 per year of age, 95% CI = 1.02–1.13, p = 0.003) as independent predictors of conversion, whereas sex and laterality (unilateral vs bilateral) had no influence. Combined cMRI and OCB positivity indicated a 26.84‐fold higher HR for developing MS compared to double negativity (95% CI = 12.26−58.74, p < 0.001). Accordingly, cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON. Ann Neurol 2015;77:1076–1082