Personalized medicine and chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: The current review summarizes ongoing developments in personalized medicine and precision medicine in chronic obstructive pulmonary disease (COPD). Our current approach is far away of personalized management algorithms as current recommendations for COPD are largely based on a reductionist disease description, operationally defined by results of spirometry. RECENT FINDINGS: Besides precision medicine developments, a personalized medicine approach in COPD is described based on a holistic approach of the patient and considering illness as the consequence of dynamic interactions within and between multiple interacting and self-adjusting systems. Pulmonary rehabilitation is described as a model of personalized medicine. Largely based on current understanding of inflammatory processes in COPD, targeted interventions in COPD are reviewed. Augmentation therapy for α-1-antitrypsine deficiency is described as model of precision medicine in COPD based in profound understanding of the related genetic endotype. SUMMARY: Future developments of precision medicine in COPD require identification of relevant endotypes combined with proper identification of phenotypes involved in the complex and heterogeneous manifestations of COPD.

Relationship between pulmonary rehabilitation and care dependency in COPD.

The aims of this study were to explore care dependency before and after pulmonary rehabilitation (PR) in patients with COPD (n=331) and to compare the response to PR between care dependent and independent patients. At baseline, 85 (25.7%) patients had a Care Dependency Scale (CDS) score ≤68 points and were considered as care dependent. CDS scores of these patients improved after PR (p<0.001). After PR, CDS score of 38 (44.7%) patients with a baseline CDS score ≤68 points increased to >68 points. Patients with a baseline CDS score ≤68 points or >68 points showed after PR a comparable improvement in COPD Assessment Test, Hospital Anxiety and Depression Scale and 6-min walk distance (all p<0.05). TRIAL REGISTRATION NUMBER: NTR3416 (The Netherlands).

Purification of DNA eluates from the ProbeTec GC Q(x) assay on BD Viper™ XTR allows for further analysis and confirmation of gonorrhea.

Low positive predictive values of Neisseria gonorrhoeae nucleic acid amplification tests in low-prevalence populations are a major challenge for accurate diagnostics. It is therefore necessary to verify all positive N. gonorrhoeae results with a different assay and target gene, preferably using the same sample. The BD ProbeTec™ Q(x) Collection Kit for Endocervical or Lesion Specimens, which is recommended for BD Viper™ XTR, is incompatible with other commercial platforms. Therefore, a confirmatory PCR has not been available for samples received on this transport medium. To be able to verify results from these samples with another assay, our objective was to establish a procedure for using the DNA eluates from BD Viper™ XTR for further analysis. DNA eluates from BD Viper™ XTR were collected and analyzed in two in-house confirmatory real-time PCRs targeting the porA pseudogene and the opa multicopy gene. BD Viper™ XTR DNA eluates were analyzed directly and also after purification with the nucleic acid extraction system NucliSENS® easyMag®. Purification of BD Viper™ XTR DNA eluates with the nucleic acid extraction system NucliSENS® easyMag® provided a sensitivity of the in-house PCR comparable to BD Viper™. With the inclusion of two target genes in the confirmatory PCR, specific and reliable verification of results were obtained. This study presents a simple, inexpensive procedure which allows for rapid verification of gonorrhea from samples received on the BD ProbeTec™ Q(x) Collection Kit for Endocervical or Lesion Specimens.

Process of pulmonary rehabilitation and program organization.

Pulmonary rehabilitation programs are highly directed to return patients suffering from chronic lung diseases to a state of self-help. These programs are largely organized as temporary interventions in a highly fragmented delivery care system for patients with chronic respiratory conditions. In an optimal health care organizational structure, pulmonary rehabilitation needs to be considered as an essential part of an individualized, integrated care process, organized from the vantage point of the patient and the patients'health continuum. Pulmonary rehabilitation programs need to become organized as patient-centered care, respectful of and responsive to individual patient preferences, needs and values. Partnering and communication skills are considered as drivers for successful rehabilitation. Assessment is considered as the cornerstone to evaluate the individual needs and problems in order to develop an individualized intervention. Pulmonary rehabilitation programs need to move away from a supply-driven functional organizational structure towards integrated structures, including the full range of medical expertise, technical skills and specialized facilities needed to compete on added value in the management of patients with chronic respiratory diseases.

Embedded multiple description coding of video.

Real-time delivery of video over best-effort error-prone packet networks requires scalable erasure-resilient compression systems in order to 1) meet the users' requirements in terms of quality, resolution, and frame-rate; 2) dynamically adapt the rate to the available channel capacity; and 3) provide robustness to data losses, as retransmission is often impractical. Furthermore, the employed erasure-resilience mechanisms should be scalable in order to adapt the degree of resiliency against transmission errors to the varying channel conditions. Driven by these constraints, we propose in this paper a novel design for scalable erasure-resilient video coding that couples the compression efficiency of the open-loop architecture with the robustness provided by multiple description coding. In our approach, scalability and packet-erasure resilience are jointly provided via embedded multiple description scalar quantization. Furthermore, a novel channel-aware rate-allocation technique is proposed that allows for shaping on-the-fly the output bit rate and the degree of resiliency without resorting to channel coding. As a result, robustness to data losses is traded for better visual quality when transmission occurs over reliable channels, while erasure resilience is introduced when noisy links are involved. Numerical results clearly demonstrate the advantages of the proposed approach over equivalent codec instantiations employing 1) no erasure-resilience mechanisms, 2) erasure-resilience with nonscalable redundancy, or 3) data-partitioning principles.

The synaptic vesicle priming protein Munc13-1 is absent from tonically active ribbon synapses of the rat retina.

Ribbon synapses, for example of the retina, are specialized synapses that differ from conventional, phasically active synapses in several aspects. Ribbon synapses can tonically and yet very rapidly release neurotransmitter via synaptic vesicle exocytosis. This requires an optimization of the synaptic machinery and is at least partly due to the presence of synaptic ribbons that bind large numbers of synaptic vesicles and which are believed to participate in priming synaptic vesicles for exocytosis. In this paper we analyzed whether ribbon synapses of the retina employ similar priming factors, i.e. Munc13-1, as do conventional, non-ribbon containing phasically active synapses. We found that though present in conventional synapses of the retina Munc13-1 was completely absent from ribbon-containing synapses of the retina, both in the outer as well as in the inner plexiform layer. This indicates that ribbon synapses of the retina employ other, possibly more potent priming factors than phasically active conventional synapses.

The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice.

Munc13 proteins form a family of three, primarily brain-specific phorbol ester receptors (Munc13-1/2/3) in mammals. Munc13-1 is a component of presynaptic active zones in which it acts as an essential synaptic vesicle priming protein. In contrast to Munc13-1, which is present in most neurons throughout the rat and mouse CNS, Munc13-3 is almost exclusively expressed in the cerebellum. Munc13-3 mRNA is present in granule and Purkinje cells but absent from glia cells. Munc13-3 protein is localized to the synaptic neuropil of the cerebellar molecular layer but is not found in Purkinje cell dendrites, suggesting that Munc13-3, like Munc13-1, is a presynaptic protein at parallel fiber-Purkinje cell synapses. To examine the role of Munc13-3 in cerebellar physiology, we generated Munc13-3-deficient mutant mice. Munc13-3 deletion mutants exhibit increased paired-pulse facilitation at parallel fiber-Purkinje cell synapses. In addition, mutant mice display normal spontaneous motor activity but have an impaired ability to learn complex motor tasks. Our data demonstrate that Munc13-3 regulates synaptic transmission at parallel fiber-Purkinje cell synapses. We propose that Munc13-3 acts at a similar step of the synaptic vesicle cycle as does Munc13-1, albeit with less efficiency. In view of the present data and the well established vesicle priming function of Munc13-1, it is likely that Munc13-3-loss leads to a reduction in release probability at parallel fiber-Purkinje cell synapses by interfering with vesicle priming. This, in turn, would lead to increases in paired-pulse facilitation and could contribute to the observed deficit in motor learning.

Disturbances in leptin metabolism are related to energy imbalance during acute exacerbations of chronic obstructive pulmonary disease.

Previously we reported an impaired energy balance in patients with chronic obstructive pulmonary disease (COPD) during an acute disease exacerbation, but limited data are available on the underlying mechanisms. Experimental and clinical research supports the hypothesis of involvement of the hormone leptin in body weight and energy balance homeostasis. The aim of this study was to investigate the course of the energy balance in relation to leptin and the soluble tumor necrosis factor (TNF) receptors (sTNF-R) 55 and 75, plasma glucose, and serum insulin in patients with severe COPD during the first 7 d of hospitalization for an acute exacerbation (n = 17, 11 men, age mean [SD] 66 [10] yr, FEV(1) 36 [12] %pred). For reference values of the laboratory parameters, blood was collected from 23 (16 men) healthy, elderly subjects. On admission, the dietary intake/resting energy expenditure (REE) ratio was severely depressed (1.28 [0.57]), but gradually restored until Day 7 (1.65 [0. 45], p = 0.005 versus Day 1). Glucose and insulin concentrations were elevated on admission, but on Day 7 only plasma glucose was decreased. The sTNF-Rs were not different from healthy subjects and did not change. Plasma leptin, adjusted for fat mass expressed as percentage of body weight (%FM), was elevated on Day 1 compared with healthy subjects (1.82 [3.85] versus 0.32 [0.72] ng%/ml, p = 0.008), but decreased significantly until Day 7 (1.46 [3.77] ng%/ml, p = 0. 015 versus Day 1). On Day 7, sTNF-R55 was, independently of %FM, correlated with the natural logarithm (LN) of leptin (r = 0.65, p = 0.041) and with plasma glucose (r = 0.81, p = 0.015). In addition, the dietary intake/REE ratio was not only inversely related with LN leptin (-0.74, p = 0.037), but also with sTNF-R55 (r = -0.93, p = 0. 001) on day seven. In conclusion, temporary disturbances in the energy balance were seen during an acute exacerbation of COPD, related to increased leptin concentrations as well as to the systemic inflammatory response. Evidence was found that the elevated leptin concentrations were in turn under control of the systemic inflammatory response, and, presumably, the high-dose systemic glucocorticosteroid treatment.

Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles.

Neurotransmitter release at synapses between nerve cells is mediated by calcium-triggered exocytotic fusion of synaptic vesicles. Before fusion, vesicles dock at the presynaptic release site where they mature to a fusion-competent state. Here we identify Munc13-1, a brain-specific presynaptic phorbol ester receptor, as an essential protein for synaptic vesicle maturation. We show that glutamatergic hippocampal neurons from mice lacking Munc13-1 form ultrastructurally normal synapses whose synaptic-vesicle cycle is arrested at the maturation step. Transmitter release from mutant synapses cannot be triggered by action potentials, calcium-ionophores or hypertonic sucrose solution. In contrast, release evoked by alpha-latrotoxin is indistinguishable from wild-type controls, indicating that the toxin can bypass Munc13-1-mediated vesicle maturation. A small subpopulation of synapses of any given glutamatergic neuron as well as all synapses of GABA (gamma-aminobutyric acid)-containing neurons are unaffected by Munc13-1 loss, demonstrating the existence of multiple and transmitter-specific synaptic vesicle maturation processes in synapses.

Differential expression of two novel Munc13 proteins in rat brain.

Munc13-1, a mammalian homologue of Caenorhabditis elegans unc-13p, is a presynaptic phorbol ester receptor that enhances neurotransmitter release. In the present study we analysed the regional, cellular and subcellular expression patterns in rat of two novel Munc13 proteins, Munc13-2 and Munc13-3. We demonstrate by hybridization in situ that Munc13-1 mRNA is expressed throughout the brain, whereas Munc13-2 mRNA is preferentially present in rostral brain regions, and Munc13-3 mRNA in caudal areas. In an analysis of subcellular brain fractions with isoform-specific antibodies, we show that the novel Munc13 proteins are enriched in synapses. Immunocytochemical examination of rat cerebellar sections indicates that Munc13-3, like Munc13-1, is concentrated in presynaptic terminals. Our results characterize Munc13 proteins as a family of neuron-specific, synaptic molecules that bind to syntaxin, an essential mediator of neurotransmitter release. Munc13-2 and Munc13-3 are expressed in a complementary fashion and might act in concert with Munc13-1 to modulate neurotransmitter release.

Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release.

Munc13-1, a mammalian homolog of C. elegans unc-13p, is thought to be involved in the regulation of synaptic transmission. We now demonstrate that Munc13-1 is a presynaptic high-affinity phorbol ester and diacylglycerol receptor with ligand affinities similar to those of protein kinase C. Munc13-1 associates with the plasma membrane in response to phorbol ester binding and acts as a phorbol ester-dependent enhancer of transmitter release when overexpressed presynaptically in the Xenopus neuromuscular junction. These observations establish Munc13-1 as a novel presynaptic target of the diacylglycerol second messenger pathway that acts in parallel with protein kinase C to regulate neurotransmitter secretion.

[Findings of digital intensive or bed lung radiographs at the monitor vs. hard copy: a clinical ROC study]. / Befundung von digitalen Intensiv- bzw. Bettlungenaufnahmen am Monitor vs. Hardcopy: eine klinische ROC-Studie.

45 bedside chest examinations acquired with storage phosphorus radiography, were displayed on a viewing box as single-format hard copies and at a high-performance digital reporting console. 6 observers performed an ROC study. For the pathologies under question, significantly better results were shown in monitor reporting due to pneumonic infiltration whereas no significant differences were found for pulmonary or mediastinal masses, or for pneumothoraces.

[The radiologic clinical picture of primary bone lymphoma]. / Radiologisches Erscheinungsbild des primären Knochenlymphoms.

Primary lymphoma of bone is a rare form of non-Hodgkin lymphoma which involves a single bone and has a relatively good prognosis following radiation therapy. We observed 17 histologically verified cases and found 97 cases in the literature. This rare tumour may occur at any time in adults and usually affects the metaphyses of long bones. It produces osteolytic changes and usually only mild periosteal reactions. Radiologically as well as histologically, differentiation from other highly malignant bone tumours is extremely difficult and sometimes impossible. A correct diagnosis can only be made from an accurate knowledge of the radiological appearances, localisation of the tumour and age of the patient.

Forced oscillation technique and spirometry in cold air provocation tests.

BACKGROUND: Impedance measurements by the forced pseudo random noise oscillation technique can be used to study the mechanical characteristics of the respiratory system. The objective of this study was to analyse the changes in impedance to a cold air provocation test in patients with asthma, and to correlate these changes with those in the forced expiratory volume in one second (FEV1). METHODS: The response to isocapnic hyperventilation with cold air was assessed by respiratory impedance measurements and spirometry in 60 patients with bronchial asthma in whom the provocative dose of histamine resulting in a 20% fall in FEV1 (PD20) was < or = 8 mumol. RESULTS: Cold air provocation resulted in a mean(SD) fall in FEV1 from 3.75(0.85) litres to 3.10(0.90) litres. The mean(SD) decrease in FEV1 as a percentage of predicted was 15.4(3.8)%. The oscillatory resistance at 8 Hz increased from a mean(SD) of 0.367(0.108) kPa/l/s to 0.613(0.213) kPa/l/s and at 28 Hz the resistance increased from 0.348(0.089) to 0.403(0.099) kPa/l/s. Frequency dependence of resistance became significantly more negative. The reactance at 8 Hz decreased from a mean(SD) of -0.035 (0.041) kPa/l/s to -0.234(0.199) kPa/l/s, and the resonant frequency increased from 12.5(4.9) Hz to 25.7(9.1) Hz. Significant correlations were calculated between the decrease in FEV1 and changes in the various impedance parameters, especially between the decrease in FEV1 and the increase in resistance at 8 Hz (r = -0.66), and the decrease in FEV1 and the increase in the resonant frequency (r = -0.63). CONCLUSION: Cold air provocation in asthmatic subjects results in changes in the impedance of the respiratory system that correlate well with the changes in FEV1. These changes in impedance reflect ventilatory inhomogeneities in the peripheral compartment of the bronchial tree. These observations show the value of this technique in the evaluation of induced bronchoconstriction, as both a quantitative and a qualitative analysis of the response is possible.

MRI in the diagnosis of primary lymphoma of bone: correlation with histopathology.

Seven patients with primary non-Hodgkin lymphoma of the skeleton were examined with MRI. The results were compared to "small cell" primary malignant bone tumors. The latter showed marked hyperintensity on SE T2-weighted images; in contrast, the lymphomas appeared as inhomogeneous lesions of low signal intensity on T2-weighted images. Histologic examination with silver stains of specimens of these lesions revealed a high content of fibrous tissue, which could explain the signal behavior on MR. All seven lymphomas were located in the epiphysis or metaphysis of the appendicular skeleton; intraarticular tumor growth was demonstrated in five cases.

Nucleolar organizer regions in soft tissue sarcomas.

Argyrophilic proteins of nucleolar organizer regions (AgNORs) were studied in a series of 65 sarcomas of the soft tissues and 2 cases of fibrohistiocytic tumors of intermediate malignancy. The numbers of AgNORs per nucleus and the size of AgNORs were determined and compared with pathomorphologic parameters such as grading of malignancy, cellularity and tumor diameter. The main finding of this study was that AgNOR counts showed significant differences between low-grade malignant (G 1) and high-grade malignant (G 3) tumors predominantly based on a correlation with the frequency of mitosis. All the other criteria of tumor grading (nuclear pleomorphism, differentiation, amount of necrosis), tumor diameter and cellularity showed no differences with regard to AgNOR counts. Though it was observed that tumor giant cells possessed predominantly coarse granular AgNORs, no correlation was found between AgNOR size and any of the parameters investigated. In spite of a clear statistically significant result gained by an evaluation of all cases, a heterogeneity of AgNORs in relation to mitotic activity within a few histological tumor types could be observed, making it difficult to suggest the determination of AgNORs as a parameter with general validity for all soft tissue sarcomas.

Peripheral T-cell lymphomas: a clinicopathologic study of 75 cases.

Seventy-five peripheral T-cell lymphomas (PTLs) were classified according to the recently proposed "Updated Kiel Classification of Non-Hodgkin's Lymphomas" (mycosis fungoides and Sezary's syndrome excluded). Thirty-seven PTLs belonged to the low-grade category (T-cell chronic lymphocytic leukemia [T-CLL], 3; lymphoepithelioid, 4; angioimmunoblastic, 22; T-zone, 6; pleomorphic small cell, 2) and 38 belonged to the high-grade category (pleomorphic medium and large cell, 24; immunoblastic, 1; large-cell anaplastic Ki-1-positive, 13). Loss of pan-T antigens occurred exclusively in high-grade PTLs; on paraffin sections UCHL 1 was slightly more sensitive than MT 1. Sixty patients presented with lymphadenopathy and 15 patients (20%) presented with extranodal disease most frequently affecting the skin and upper aerodigestive tract. B-cell lymphoma symptoms were found in 43 cases (57%) and bone marrow involvement (T-CLL excluded) was found in 12 cases (17%). Staging (T-CLL excluded) revealed stage I in 13%, stage II in 15%, and stages III and IV in 72% of the cases. Among the intensively treated patients, 37% achieved complete remission and 15 are still in complete remission after 4 to 79 months (median: 24 months). The overall median survival (MS) rate was 23 months. Peripheral T-cell lymphoma of pleomorphic medium and large-cell type was the most aggressive lymphoma (MS: 8 months). B-cell lymphoma symptoms, bone marrow involvement, and Ki-67 positivity 60% or greater significantly shortened survival times, whereas age (under 60 versus over 60 years), stage (I and II versus III and IV), and grade had no significant influence. Ki-67 reactivity was found to be a prognostic factor which allows prediction of probable poor outcome, especially in cases with limited stage of disease.

Ki-1-positive large cell lymphoma. A clinicopathologic study of 41 cases.

We report the clinicopathologic findings of 41 patients with Ki-1 (CD30)-positive large cell lymphoma. The median age was 50 years; 13 patients were under 40 years of age. Ten patients presented with extranodal disease. Fifty-five percent of the patients presented with stage I or II disease, and bone marrow involvement was histologically documented in 30% and occurred exclusively in patients over 40 years of age. Two cytomorphologically distinct groups of Ki-1--positive large cell lymphomas could be separated. Group A lymphomas consisted of pleomorphic large cells, sometimes with wreathlike and embryo-like nuclei, whereas group B lymphomas displayed a rather monomorphic appearance. Clinically the two groups of lymphomas differed with respect to stage of disease, frequency of bone marrow involvement, and median survival. On paraffin sections, the Ki-1--related antibody Ber-H2 provided excellent staining results in all cases. Immunologic phenotyping disclosed a T cell type in the majority of cases, revealed marked loss of differentiation antigens, and frequent expression of HLA-DR and IL-2 receptor. The overall median survival was 13 months. Age below 40 years, limited stage of disease (I and II), and, although not statistically significant, lymphoma morphology were associated with longer survival. We conclude, that Ki-1--positive large cell lymphomas represent a morphologically and immunologically heterogeneous category of hematolymphoid neoplasms derived from dedifferentiated and activated lymphoid cells with marked age-dependent prognosis.