Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment,stratification and management

Background and hypothesis

Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.

Objective and method

To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.

Results

(1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

Conclusions

The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.

     

Systems Medicine: from molecular features and models to the clinic in COPD

Background and hypothesis

Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice.

Objective and method

Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework.

Results

In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice.

Conclusions

The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.

     

Intramuscular innervations of lower leg skeletal muscles: applications in their clinical use in functional muscular transfer

Purpose

This study aims to investigate nerve distribution patterns of human lower leg skeletal muscles using a modified Sihler’s staining method.

Methods

Sixteen lower leg from eight fresh adult cadavers were used in this study and all the skeletal muscles were dissected. The muscle specimens were classified according to Lim’s classification. The specimens were then stained by further modified Sihler’s staining technique. Data were analyzed according to research results.

Results

After the staining, we found four patterns of nerve distribution in human lower leg muscles: (1) Type 1: single nerve pattern in which the nerve branches into two either running parallel to each other or radiating in a spray pattern (such as the extensor digitorum longus, extensor hallucis longus, fibularis brevis and flexor hallucis longus). (2) Type 2: double nerve pattern, one being proximal and the other being distal (such as the extensor digitorum longus, flexor digitorum longus, flexor hallucis longus). (3) Type 3: multiple branch pattern (such as the tibialis anterior, fibularis longus, gastrocnemius, soleus, tibialis anterior and popliteus).

Conclusion

Our modified Sihler’s staining method is useful for research of large muscles and intramuscular nerves in human. These findings might provide guidance for clinicians for muscle reconstruction surgery.

     

Topographical relationships of intramuscular nerves and vessels of the motor endplates in the thigh and gluteal regions of human fetuses: an immunohistochemical study

Purpose

The aim of this study was to describe topography of vessels and nerves in striated muscles to understand individual muscle function.

Materials and methods

Immunohistochemistry for nerve and artery was used to examine the thigh and gluteal muscles of six human midterm fetuses.

Results

The supplying nerves often accompanied arteries along epimysium bundling muscle fibers as well as in the covering fascia surrounding the entire muscle mass. However, courses of nerve twigs were usually independent of those of vessels in muscle bundles. Notably, irrespective of whether or not the vascular bundle accompanied the nerves at the muscle surface or hilus, most of the motor endplate bands did not accompany the vessels.

Conclusion

Since the motor endplates were low vascularised, a chemical induction of vessels for nerve terminal development (or the reversed induction) seemed unlikely in striated muscles. In contrast to proprioceptive neuromuscular facilitation, manual stimulation of the endplate bands may stimulate muscle activity without sympathetic reflexes through vessel-accompanying nerves.

     

Ethical Assessment of Human Embryonic Stem Cell Research According to Turkish Muslim Scholars: First Critical Analysis and Some Reflections

Background

Turkey, with a Muslim population of officially over 99 %, is one of the few secular states in the Muslim world. Although state institutions are not based on Islamic juridical and ethical norms, the latter play a significant role in defining people’s attitudes towards controversial issues in the modern world, especially when backed by opinions of Muslim scholars living in Turkey. Accordingly, opinions of Muslim scholars undoubtedly have an important effect on bioethical decisions made by institutions and individuals.

Objective(s)

To explore the ethical positions of Muslim scholars living in Turkey and their arguments used in the ethical assessment of embryonic stem cell research; to discuss the biological-moral tensions arising in medical research on human embryos.

Design

Qualitative study.

Setting

Muslim scholars located in different parts of Turkey.

Methods

Qualitative method, involving the collection of opinions of various scholars, by means of 15 individual semi-structured interviews, evaluated using thematic qualitative analysis.

Results

Positions regarding embryonic stem cell research differ among Muslim scholars in Turkey. On the other hand, even where positions are similar, they are often supported by different arguments.

Conclusion

Despite the heterogeneity of the arguments presented, the dominant position considers embryonic stem cell research as morally acceptable.

     

Ultra-high b-value diffusion-weighted imaging features of the prostatic leiomyoma-case report

Background

Leiomyoma of the prostate is a rare benign tumor arising from smooth muscle fibers. Most cases are incidental findings observed during pathological examinations after resection of the prostate. To the best of our knowledge, only few studies have reported the conventional magnetic resonance imaging (MRI) findings of such tumors; however, no reports have described the ultra-high b-value diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) findings of prostatic leiomyomas.

Case presentation

We report MR imaging characteristics and surgical pathologic findings of a case of prostatic leiomyoma treated by robot-assisted transperitoneal laparoscopic approach. Typical MR features showed a homogeneous lesion with slightly hypointense signal compared to the skeletal muscle on T2-weighted images, and isointense signal relative to the muscle on T1-weighted images with fat suppression, which collectively demonstrate apparent homogeneous enhancement with a non-enhanced envelope. A slightly hyperintense signal compared to the skeletal muscle was observed on ultra-high b-value DWI, and higher ADC values were observed as compared to the prostate cancer.

Conclusions

Prostatic leiomyoma is a benign tumor. This case indicates that MRI features of prostatic leiomyoma are helpful for the differential diagnosis of prostate cancer.

     

Cognitive and Perceptual Factors,Not Disease Severity,Are Linked with Anxiety in COPD: Results from a Cross-Sectional Study

Purpose

Guided by the Transactional Model of Stress and Coping, the purpose of this cross-sectional study was to examine clinical factors—demographics, chronic obstructive pulmonary disease (COPD) severity, cognitive/perceptual variables (appraisal and coping)—and their relationship to clinically elevated symptoms of anxiety in a sample of veterans with COPD.

Method

Participants included a sample of veterans with COPD, with or without comorbid congestive heart failure, and clinically significant symptoms of anxiety (n = 172, mean age = 65.3, SD = 8.1), who previously presented to an outpatient VA setting. Participants completed questionnaires examining COPD severity (respiratory impairment and dyspnea- and fatigue-related quality of life); perceptions of a stressor (COPD illness intrusiveness); perceptions of control (locus of health control, mastery over COPD, self-efficacy); coping strategies (adaptive and maladaptive); and anxiety and depressive symptoms.

Results

Multivariable linear regressions revealed that anxiety was positively associated with more maladaptive coping and locus of control (attributed to other people), above and beyond disease severity, demographics, and depressive symptoms.

Conclusion

These findings suggest that cognitive and perceptual factors are concurrent with anxiety; however, longitudinal investigations are needed to fully understand this relationship. Future research should also focus on identifying optimal assessment and treatment procedures when evaluating and treating patients with COPD and symptoms of anxiety.

Trial Registration

NCT01149772

     

Is the content of guidelines/pathways a barrier for the integration of palliative Care in Chronic Heart Failure (CHF) and chronic pulmonary obstructive disease (COPD)? A comparison with the case of cancer in Europe

Background

There is a notable inequity in access to palliative care (PC) services between cancer and Chronic Heart Failure (CHF)/Chronic Obstructive Pulmonary Disease (COPD) patients which also translates into discrepancies in the level of integration of PC. By cross-examining the levels of PC integration in published guidelines/pathways for CHF/COPD and cancer in Europe, this study examines whether these discrepancies may be attributed to the content of the guidelines.

Design

A quantitative evaluation was made between integrated PC in published guidelines for cancer and CHF/COPD in Europe. The content of integrated PC in guidelines/pathways was measured using an 11 point integrated PC criteria tool (IPC criteria). A statistical analysis was carried out to detect similarities and differences in the level of integrated PC between the two groups.

Results

The levels of integration between CHF/COPD and cancer guidelines/pathways have been shown to be statistically similar. Moreover, the quality of evidence utilized and the date of development of the guidelines/pathways appear not to impact upon the PC integration in the guidelines.

Conclusion

In Europe, the empirically observed imbalance in integration of PC for patients with cancer and CHF/COPD may only partially be attributed to the content of the guidelines/pathways that are utilized for the PC implementation. Given the similarities detected between cancer and CHF/COPD, other barriers appear to play a more prominent role.

     

Trapezius muscle activity increases during near work activity regardless of accommodation/vergence demand level

Aim

To investigate if trapezius muscle activity increases over time during visually demanding near work.

Methods

The vision task consisted of sustained focusing on a contrast-varying black and white Gabor grating. Sixty-six participants with a median age of 38 (range 19–47) fixated the grating from a distance of 65 cm (1.5 D) during four counterbalanced 7-min periods: binocularly through ?3.5 D lenses, and monocularly through ?3.5 D, 0 D and +3.5 D. Accommodation, heart rate variability and trapezius muscle activity were recorded in parallel.

Results

General estimating equation analyses showed that trapezius muscle activity increased significantly over time in all four lens conditions. A concurrent effect of accommodation response on trapezius muscle activity was observed with the minus lenses irrespective of whether incongruence between accommodation and convergence was present or not.

Conclusions

Trapezius muscle activity increased significantly over time during the near work task. The increase in muscle activity over time may be caused by an increased need of mental effort and visual attention to maintain performance during the visual tasks to counteract mental fatigue.

     

REM sleep behavior disorder (RBD)

Background

REM sleep behavior disorder (RBD) is parasomnia characterized by dream enactment and enabled by disruption of physiological muscle atonia during REM sleep. Over the past few years, diagnostic criteria and the methods used to confirm diagnosis have been updated.

Objective

In this review article, the current knowledge regarding RBD diagnosis and treatment is presented.

Methods

A selective literature search was carried out.

Results and discussion

Although several RBD screening questionnaires have been developed, diagnosis can only be definitely confirmed on the basis of polysomnography. New methods for scoring electromyography (EMG) activity during REM sleep have been proposed during recent years and cutoff values have been established. The latest cutoff values for scoring EMG activity during REM sleep are included in the International Classification of Sleep Disorders (ICSD). The cutoff of 27?% muscle activity during REM sleep suggested by the Sleep Innsbruck Barcelona (SINBAR) group was also included in the third edition of the ICSD. The best-researched treatments for RBD are clonazepam and melatonin.

     

Clinical Decision Support Systems (CDSS) for preventive management of COPD patients

Background

The use of information and communication technologies to manage chronic diseases allows the application of integrated care pathways, and the optimization and standardization of care processes. Decision support tools can assist in the adherence to best-practice medicine in critical decision points during the execution of a care pathway.

Objectives

The objectives are to design, develop, and assess a clinical decision support system (CDSS) offering a suite of services for the early detection and assessment of chronic obstructive pulmonary disease (COPD), which can be easily integrated into a healthcare providers' work-flow.

Methods

The software architecture model for the CDSS, interoperable clinical-knowledge representation, and inference engine were designed and implemented to form a base CDSS framework. The CDSS functionalities were iteratively developed through requirement-adjustment/development/validation cycles using enterprise-grade software-engineering methodologies and technologies. Within each cycle, clinical-knowledge acquisition was performed by a health-informatics engineer and a clinical-expert team.

Results

A suite of decision-support web services for (i) COPD early detection and diagnosis, (ii) spirometry quality-control support, (iii) patient stratification, was deployed in a secured environment on-line. The CDSS diagnostic performance was assessed using a validation set of 323 cases with 90% specificity, and 96% sensitivity. Web services were integrated in existing health information system platforms.

Conclusions

Specialized decision support can be offered as a complementary service to existing policies of integrated care for chronic-disease management. The CDSS was able to issue recommendations that have a high degree of accuracy to support COPD case-finding. Integration into healthcare providers' work-flow can be achieved seamlessly through the use of a modular design and service-oriented architecture that connect to existing health information systems.

     

Continued Interest and Controversy: Vitamin D in HIV

Purpose of Review

Vitamin D (VitD) deficiency is highly prevalent among HIV-infected individuals. Given the overlapping risk for several chronic disease and immunomodulatory outcomes from both long-standing HIV and VitD deficiency, there is great interest in clarifying the clinical role of VitD for this population.

Recent Findings

Recent studies have expanded our knowledge regarding the epidemiology and mechanisms of VitD deficiency-associated outcomes in the setting of HIV. Clinical trials focusing on VitD supplementation have demonstrated a positive impact on bone mineral density in subgroups of HIV-infected individuals initiating ART or on suppressive ART regimens; however, significant heterogeneity exists between studies and data are less consistent with other clinical outcomes.

Summary

Further research is needed to clarify uncertainly in several domains, including identifying patients at greatest risk for poor outcomes from VitD deficiency, standardizing definitions and measurement techniques, and better quantifying the benefits and risks of VitD supplementation across different demographic strata for skeletal and extra-skeletal outcomes.

     

<Emphasis Type="Italic">Helicobacter bilis</Emphasis>-Associated Suppurative Cholangitis in a Patient with X-Linked Agammaglobulinemia

?

Helicobacter bilis is a commensal bacterium causing chronic hepatitis and colitis in mice. In humans, enterohepatic Helicobacter spp. are associated with chronic hepatobiliary diseases.

Purpose

We aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis.

Methods

16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis.

Results

Clinical outcome resulted in the normalization of clinical and biological parameters under antibiotic treatment by a combination of ceftriaxone, metronidazole, and doxycyclin followed by a 2-week treatment with moxifloxacin and a 2-month treatment with azithromycin.

Conclusion

In conclusion, these data suggest a specific clinical and microbiological approach in patients with humoral deficiency in order to detect H. bilis hepatobiliary diseases.

     

An anatomic study of the attachments on the condylar process of the mandible: muscle bundles from the temporalis

Purpose

The aim of this study was to evaluate anatomically the relationship between bone and muscles by detailed observation of the bone shape and the structure of muscles to facilitate an understanding of the function of the muscles involved in jaw movement.

Methods

36 specimens of 24 Japanese cadavers were examined. The insertion areas were marked using a radiopaque marker and examined by micro-computed tomography. For morphological observation, we used 101 condylar processes. In addition, we made histological sections in some specimens to observe the detailed attachments of the muscle.

Results

Based on the micro-CT images and dissection findings, the lateral pterygoid muscle was found to be most frequently inserted into the anterior impression and attached to the medial impression of the process. According to the histological observations, the lateral pterygoid muscle mainly inserted to the condylar process. The micro-CT images indicated that the obvious bony ridge was lateral to the pterygoid fovea on the condylar process in all specimens. The midmedial muscle bundle of the temporalis was attached to the ridge. Based on the morphological observations, the ridge was situated on the lateral area of the condylar process.

Conclusions

Since dysfunction of the temporomandibular joint is likely closely related to both the lateral pterygoid muscle and also the temporalis, further studies are necessary to evaluate the function of these muscles and consider jaw movement.

     

Glücklich als Paar – glücklicher Schlaf?

Background

Millions of people share a bed with their partner. Sleep und relationship could possibly influence each other.

Objectives

To identify and discuss connections between relationship and sleep quality.

Methods

Review of the literature in electronic databases.

Results

Conflict and violence in relationships lead to decreases in both partners’ sleep quality. Constructive approaches to resolving conflicts is necessary for good sleep, and vice versa. Women prefer partners with sleep-wake rhythms matching their own and report higher relationship satisfactions when the couple’s chronotypes are compatible.

Conclusions

Sleep and circadian rhythms play important roles in relationships. When treating insomnia, the relationship and the partner’s sleep should be taken into account.

     

Micronized palmitoylethanolamide reduces joint pain and glial cell activation

Objective and design

Temporomandibular disorder (TMD) is a common painful condition in the temporomandibular joint (TMJ). Joint inflammation is believed to be a chief cause of pain in patients with TMD, through the release of pro-inflammatory cytokines that induce peripheral sensitization of nerve terminals followed by microglial stimulation.

Materials and subject

TMJ was induced in rats with the injection of complete Freund’s adjuvant (CFA) emulsion into the left TMJ capsule.

Treatment

The present study would assess the effects of micronized palmitoylethanolamide (m-PEA) on glial activation and trigeminal hypersensitivity.

Methods

Ten mg/kg m-PEA or corresponding vehicle was administered 1 h after CFA and mechanical allodynia and edema were evaluated at 24 and 72 h after CFA injection.

Results

CFA-injected animals showed TMJ edema and ipsilateral mechanical allodynia accompanied by a robust growth in GFAP protein-positive satellite glial cells and activation of resident macrophages in the TG. Moreover, m-PEA administration significantly reduced the degree of TMJ damage and pain, macrophage activation in TG and up-regulation of Iba1.

Conclusions

The results confirm that m-PEA could represent a novel approach for monitoring pain during trigeminal nerve sensitization.

     

The styloauricular muscle: clinical relevance and literature review of this rare muscle

Purpose

In humans, the styloauricularis is a rare muscle extending from the tragal cartilage of the auricle to the styloid process. When it contracts, by bearing on the styloid process, it increases the cephalo-auricular angle. It can be a landmark for the facial nerve. We report a case with bilateral presence of the styloauricularis.

Methods

Bilateral presence of the styloauricularis was discovered during routine dissection of the head and neck.

Results

In the presented case, styloauricularis muscles arose from the cartilage of the external acoustic meatus on both sides of the head, crossing halfway along the facial nerve trunk and inserting the styloid process. Both muscles were vascularized by a branch of the posterior auricular artery, and innervated by the facial nerve.

Conclusions

The ventral auricular muscle, formed by the auricular parotid and the styloauricular muscles, is a muscle that lowers and abducts the auricle in animals. There is generally considered to be no equivalent for these muscles in humans, however, this bilateral case reveals evidence to the contrary. There is a dearth of scientific literature about the styloauricularis. The study of this muscle demonstrated the usefulness of comparative anatomy in understanding its action in increasing the cephalo-auricular angle.

     

Picture perfect—how seeking perfection influences sleep and romantic relationships

Background

Studies have shown that sleep quality is negatively affected by perfectionism. Moreover, partner- or relationship-oriented perfectionism negatively influences relationship quality.

Objective

This paper aims to investigate the association of general perfectionism with sleep quality and relationship quality.

Materials and methods

A study assessing perfectionism, sleep quality, and relationship quality was performed via analyzing online questionnaires completed by 489 German adults from the general population.

Results

Participants with impaired sleep showed a higher level of maladaptive perfectionism (concern over mistakes and doubts, parental expectations, and criticism) than participants with good sleep, whereby the severity of sleep problems was not determining. Relationship quality is affected by perfectionism. However, this association is mediated by sleep quality.

Conclusion

Perfectionism is associated with worse sleep quality but not with worse relationship quality when sleep quality is integrated into the model as a mediator.

     

New anatomo-radiological findings of the lateral pterygoid muscle

Purpose

The discrepancies in the literature regarding the anatomy of the temporomandibular joint (TMJ), particularly at the level of the lateral pterygoid muscle, led us to compare plastinated section techniques and magnetic resonance imaging (MRI) to enable the better interpretation of both, and to describe the features of the lateral pterygoid muscle and the exact location of its insertions.

Methods

A total of 24 blocks of human TMJ were used. Seven were studied by MRI, obtaining images of the oblique-sagittal, oblique-coronal, and axial planes. Four of these blocks were then cut and processed by means of the E12 plastination technique. The remaining blocks were dissected. Finally, we performed a comparative morphological analysis of the different techniques used.

Results

New aspects about the morphology and the insertions of the lateral pterygoid muscle are described. The muscle is inserted into the disc, capsule, condyle, and the pterygoid fovea, through muscle and tendon fibres that alternate, giving it the characteristic of a multipennate muscle. This insertion caudally exceeded the pterygoid fovea and descends to near the lingula of mandible. A profuse pterygoid venous plexus surrounds the whole joint complex, and also the insertion zone of the lateral pterygoid muscle.

Conclusions

We consider that the use of transparent-plastinated anatomical sections and its good correlation with MRI images (in axial and oblique-sagittal planes) led to an accurate identification of TMJ structures, especially in relation to the lateral pterygoid muscle, that is now described as a multipennate muscle.

     

Deficiencies in elements involved in TLR4-receptor signalling in RBL-2H3 cells

Objective

RBL-2H3 cells express Toll-like receptors, including TLR4. This study aims to assess various aspects of the TLR4 pathway.

Methods

RBL-2H3 cells were indirectly stained for cell surface TLR4, 25 CD14 and intracellular MyD88 proteins and analysed through flow cytometry for single-colour staining.

Results

While TLR4-receptors are expressed in RBL-2H3 cells, associated elements involved in the signaling pathway, CD14 and MyD88, are not.

Conclusion

Care should be taken if RBL-2H3 cells are used to study aspects of the innate immune system in mast cells.