Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

Resting and Post Bronchial Challenge Testing Carbon Dioxide Partial Pressure in Individuals with and without Asthma

Objective: There is conflicting evidence about resting carbon dioxide levels in asthmatic individuals. We wanted to determine if transcutaneously measured carbon dioxide levels prior and during bronchial provocation testing differ according to asthma status reflecting dysfunctional breathing. Methods: We investigated active firefighters and policemen by means of a validated questionnaire on respiratory symptoms, spirometry, bronchial challenge testing with methacholine (MCT) and measurement of transcutaneous blood carbon dioxide partial pressure (PtcCO 2) at rest prior performing spirometry, one minute and five minutes after termination of MCT. A respiratory physician blinded to the PtcCO2 results assigned a diagnosis of asthma after reviewing the available study data and the files of the workers medical screening program. Results: The study sample consisted of 128 male and 10 female individuals. Fifteen individuals (11%) had physiciandiagnosed asthma. There was no clinically important difference in median PtcCO 2 at rest, one and five minutes after recovery from MCT in asthmatics compared to non-asthmatics (35.6 vs 35.7 mmHg, p = 0.466; 34.7 vs 33.4 mmHg, p = 0.245 and 37.4 vs 36.4 mmHg, p = 0.732). The median drop in PtcCO2 during MCT and the increase after MCT was lower in asthmatics compared to non-asthmatics (0.1 vs 3.2 mmHg, p = 0.014 and 1.9 vs 2.9 mmHg, p = 0.025). Conclusions: PtcCO2 levels at rest prior and during recovery after MCT do not differ in individuals with or without physicia

Multiple Geographic Origins of Commensalism and Complex Dispersal History of Black Rats

The Black Rat (Rattus rattus) spread out of Asia to become one of the world's worst agricultural and urban pests, and a reservoir or vector of numerous zoonotic diseases, including the devastating plague. Despite the global scale and inestimable cost of their impacts on both human livelihoods and natural ecosystems, little is known of the global genetic diversity of Black Rats, the timing and directions of their historical dispersals, and the risks associated with contemporary movements. We surveyed mitochondrial DNA of Black Rats collected across their global range as a first step towards obtaining an historical genetic perspective on this socioeconomically important group of rodents. We found a strong phylogeographic pattern with well-differentiated lineages of Black Rats native to South Asia, the Himalayan region, southern Indochina, and northern Indochina to East Asia, and a diversification that probably commenced in the early Middle Pleistocene. We also identified two other currently recognised species of Rattus as potential derivatives of a paraphyletic R. rattus. Three of the four phylogenetic lineage units within R. rattus show clear genetic signatures of major population expansion in prehistoric times, and the distribution of particular haplogroups mirrors archaeologically and historically documented patterns of human dispersal and trade. Commensalism clearly arose multiple times in R. rattus and in widely separated geographic regions, and this may account for apparent regionalism in their associated pathogens. Our findings represent an important step towards deeper understanding the complex and influential relationship that has developed between Black Rats and humans, and invite a thorough re-examination of host-pathogen associations among Black Rats

Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis

New hand bones of Hadropithecus stenognathus: implications for the paleobiology of the Archaeolemuridae

A partial, associated skeleton of Hadropithecus stenognathus (AHA-I) was discovered in 2003 at Andrahomana Cave in southeastern Madagascar. Among the postcranial elements found were the first hand bones (right scaphoid, right hamate, left first metacarpal, and right and left fifth metacarpals) attributed to this rare subfossil lemur. These hand bones were compared to those of extant strepsirrhines and catarrhines in order to infer the positional adaptations of Hadropithecus, and they were compared to those of Archaeolemur in order to assess variation in hand morphology among archaeolemurids. The scaphoid tubercle does not project palmarly as in suspensory and climbing taxa, and the hamate has no hook at all (just a small tubercle), which also points to a poorly developed carpal tunnel. There is a distinctive, radioulnarly directed “spiral” facet for articulation with the triquetrum that is most similar in orientation to that of more terrestrial primates (i.e., Lemur catta, Papio, and Gorilla). The first metacarpal is very reduced and represents only 48% of the length of metacarpal V, as in Archaeolemur, which suggests that pollical grasping of arboreal supports was not important. Compared to Archaeolemur, the shaft of metacarpal V is gracile, and the head has no dorsal ridge and lacks characteristics functionally associated with digitigrade, extended metacarpophalangeal joint postures. Proximally, the articular facet for the hamate is oriented more dorsally. Thus, the carpometacarpal joint V appears to have a distinctive hyperextended set, which has no analog among living or extinct primates. The carpals of Hadropithecus are diagnostic of a pronograde, arboreal and terrestrial (although not digitigrade) locomotor repertoire that typifies Lemur catta and some Old World monkeys. No clinging, suspensory, or climbing specializations that characterize indriids or lorises can be found in the hand of this subfossil lemur. The hand of Hadropithecus likely had similar ranges of movement at the radiocarpal and midcarpal joints as of those of pronograde primates, such as lemurids, for which the hand is held in a more extended, pronated, and neutral (i.e., showing less ulnar deviation) position during locomotion in comparison to that of vertical clingers or slow climbers. Although highly autapomorphic, the hand of Hadropithecus resembles that of its sister taxon, Archaeolemur, in having a very reduced pollex and an articular facet on the scaphoid for a sizeable prepollex. These unusual hand features reinforce the monophyly of the Archaeolemuridae