BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH

Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor beta (TGFbeta) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGFbeta-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGFbeta-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGFbeta-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH

PREVALENCE OF GASTROINTESTINAL PARASITES OF HORSES AND ASSOCIATED RISK FACTORS IN PLATEAU STATE, NIGERIA.

Horses are companion animals and highly resourceful in sports, national and traditional ceremonies, military and paramilitary involvements hence they play an important part in the economics of Nigeria. Gastrointestinal parasites are known to be deleterious to horses thus affecting the health, productivity and working capacity. In order to determine the prevalence of Gastrointestinal parasites and associated risk factors, fecal samples were collected from 107 horses comprising 58 females and 49 males from 3 local government areas including Jos North, Jos South and Riyom in Plateau State, samples were carefully examined using floatation and sedimentation techniques. The overall prevalence of gastrointestinal helminths was 46.7% out of which 11.2% were mixed infections. 7 different gastrointestinal parasites were observed in the animals studied: Ascaris equorum (12.1%), Eimeria spp (8.4%), Fasciola spp (3.7%), Gastrodiscus aegyptiacus (2.8%), Strongyloides spp (7.5%), Strongylus spp (11.2%) and Trichomena spp (14%). No significant differences (p>0.05) in the prevalence of gastrointestinal parasites were observed in relation to age, sex and breed but there was significant variation (p<0.05) in relation to location. The study reveals that gastrointestinal helminths are still a major constraint to the overall working and productivity of horses in the study areas hence the need for improved management practices

Spectrum of musculo-skeletal disorders in sickle cell disease in Lagos, Nigeria

<p>Abstract</p> <p>Background</p> <p>Sickle cell anemia (SCA) is a common genetic disease in Nigeria. Past studies from West Africa focused on isolated aspects of its medical and surgical presentations. To the best of our knowledge, the musculo-skeletal presentations amongst Nigerians with SCA have not been documented in a single all encompassing study. This work aims to prospectively document the musculo-skeletal disease burden among SCA patients.</p> <p>Methods</p> <p>In a prospective study of 318 consecutive patients with genotype-confirmed SCA at the Lagos University Teaching Hospital (LUTH), the musculo-skeletal pathologies, anatomic sites, grade of disease, age at presentation and management outcome were recorded over a one-year period. Data obtained were analyzed using Epi-Info software version 6.0. Data are presented as frequencies (%) and mean values (SD) as appropriate.</p> <p>Results</p> <p>The HbSS genotype occurred in 296 (93.0%), while 22 (7.0%) were HbSC. 100 (31.4%) patients with average presenting haemoglobin concentration of 8.2 g/100 ml in the study group, presented with 131 musculo-skeletal pathologies in 118 anatomic sites. Osteomyelitis 31 (31%) and septic arthritis 19 (19%) were most commonly observed in children less than 10 years. Skin ulcers and avascular necrosis (AVN) occurred predominantly in the older age groups, with frequencies of 13 (13.0%) and 26 (26.0%) respectively. 20 (71.5%) of diagnosed cases of AVN presented with radiological grade 4 disease. The lower limbs were involved in 84 (71.1%) of sites affected. Lesions involving the spine were rare 11 (0.9%). Multiple presentations occurred in 89 (28.0%) of patients; 62 (69.7%) of which were children below 10 years.</p> <p>Conclusions</p> <p>Musculo-skeletal complications are common features of sickle cell anaemia seen in 31.4%. Infectious aetiologies predominate with long bones and joints of lower limbs more commonly affected by osteomyelitis and septic arthritis. Healthcare providers managing SCA should be aware of the potential morbidity and mortality of these conditions to ensure early diagnosis and adequate management.</p

Inhibition of Overactive Transforming Growth Factor–β Signaling by Prostacyclin Analogs in Pulmonary Arterial Hypertension

YesHeterozygous loss of function mutations in the type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-β) receptor family, underlie the majority of familial cases of pulmonary arterial hypertension (PAH). The TGF-β1 pathway is activated in PAH and inhibitors of TGF-β1 signaling prevent the development and progression of PAH in experimental models. However, the effect of currently utilized therapies on the TGF-β pathway is not known. Prostacyclin analogues remain the first line of treatment for clinical PAH. We hypothesized that these agents effectively decrease the activity of the TGF-β1 pathway. Beraprost sodium (BPS), a prostacyclin analogue selectively inhibits proliferation in a dose-dependent manner in mouse primary pulmonary arterial smooth muscle cells (PASMCs) harbouring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-β1 stimulation. This study demonstrates that this agent inhibits TGF-β1–induced SMAD-dependent and -independent signaling via a PKA dependent pathway by reducing the phosphorylation of SMADs 2 and 3 and p38MAPK proteins. Finally, in a monocrotaline (MCT)-induced rat model of PAH, which is associated with increased TGF-β signaling, this study confirms that treprostinil (TPS), a stable prostacyclin analogue, inhibits the TGF-β pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogues inhibit dysregulated TGF-β signaling in vitro and in vivo and reduce BMPR-II-mediated proliferation defects in mutant mice PASMCs.The authors acknowledge financial support from the British Heart Foundation, United Kingdom (Programme Grant 1-2004-357 to R.C.T. and N.W.M.), a Heptagon Life Science Proof of Concept Fund (grants KCL24 and KCL25 to M.T.N. and R.C.T., respectively), and the Great Britain Sasakawa Foundation (grant B70 to M.T.N.

Characterization of barley (Hordeum vulgare L.) NAC transcription factors suggests conserved functions compared to both monocots and dicots

<p>Abstract</p> <p>Background</p> <p>The NAC transcription factor family is involved in the regulation of traits in both monocots and dicots of high agronomic importance. Understanding the precise functions of the NAC genes can be of utmost importance for the improvement of cereal crop plants through plant breeding. For the cereal crop plant barley (<it>Hordeum vulgare </it>L.) only a few <it>NAC </it>genes have so far been investigated.</p> <p>Results</p> <p>Through searches in publicly available barley sequence databases we have obtained a list of 48 barley <it>NAC </it>genes (<it>HvNACs</it>) with 43 of them representing full-length coding sequences. Phylogenetic comparisons to Brachypodium, rice, and Arabidopsis NAC proteins indicate that the barley NAC family includes members from all of the eight NAC subfamilies, although by comparison to these species a number of <it>HvNACs </it>still remains to be identified. Using qRT-PCR we investigated the expression profiles of 46 <it>HvNACs </it>across eight barley tissues (young flag leaf, senescing flag leaf, young ear, old ear, milk grain, late dough grain, roots, and developing stem) and two hormone treatments (abscisic acid and methyl jasmonate).</p> <p>Conclusions</p> <p>Comparisons of expression profiles of selected barley <it>NAC </it>genes with the published functions of closely related <it>NAC </it>genes from other plant species, including both monocots and dicots, suggest conserved functions in the areas of secondary cell wall biosynthesis, leaf senescence, root development, seed development, and hormone regulated stress responses.</p

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd

A high fat diet during adolescence in male rats negatively programs reproductive and metabolic function which is partially ameliorated by exercise

An interaction between obesity, impaired glucose metabolism and sperm function in adults has been observed but it is not known whether exposure to a diet high in fat during the peri-pubertal period can have longstanding programmed effects on reproductive function and gonadal structure. This study examined metabolic and reproductive function in obese rats programmed by exposure to a high fat (HF) diet during adolescence. The effect of physical training (Ex) in ameliorating this phenotype was also assessed. Thirty-day-old male Wistar rats were fed a HF diet (35% lard w/w) for 30 days then subsequently fed a normal fat diet (NF) for a 40-day recovery period. Control animals were fed a NF diet throughout life. At 70 days of life, animals started a low frequency moderate exercise training that lasted 30 days. Control animals remained sedentary (Se). At 100 days of life, biometric, metabolic and reproductive parameters were evaluated. Animals exposed to HF diet showed greater body weight, glucose intolerance, increased fat tissue deposition, reduced VO 2max and reduced energy expenditure. Consumption of the HF diet led to an increase in the number of abnormal seminiferous tubule and a reduction in seminiferous epithelium height and seminiferous tubular diameter, which was reversed by moderate exercise. Compared with the NF-Se group, a high fat diet decreased the number of seminiferous tubules in stages VII-VIII and the NF-Ex group showed an increase in stages XI-XIII. HF-Se and NF-Ex animals showed a decreased number of spermatozoa in the cauda epididymis compared with animals from the NF-Se group. Animals exposed to both treatments (HF and Ex) were similar to all the other groups, thus these alterations induced by HF or Ex alone were partially prevented. Physical training reduced fat pad deposition and restored altered reproductive parameters. HF diet consumption during the peri-pubertal period induces long-term changes on metabolism and the reproductive system, but moderate and low frequency physical training is able to recover adipose tissue deposition and reproductive system alterations induced by high fat diet. This study highlights the importance of a balanced diet and continued physical activity during adolescence, with regard to metabolic and reproductive health