Effects of a community-based healthy heart program on increasing healthy women's physical activity: a randomized controlled trial guided by Community-based Participatory Research (CBPR)

Background  

Cardiovascular disease remains the leading killer of women in most developed areas of the world. Rates of physical inactivity and poor nutrition, which are two of the most important modifiable risk factors for cardiovascular disease in women, are substantial. This study sought to examine the effectiveness of a community-based lifestyle-modification program on increasing women's physical activity in a randomized trial guided by community-based participatory research (CBPR) methods.     

An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line

Metastasis is the major cause of prostate cancer deaths and there is a need for clinically relevant in vivo models allowing elucidation of molecular and cellular mechanisms underlying metastatic behavior. Here we describe the development of a new in vivo model system for metastatic prostate cancer. Pieces of prostate cancer tissue from a patient were grafted in testosterone-supplemented male NOD-SCID mice at the subrenal capsule graft site permitting high tumor take rates. After five serial transplantations, the tumor tissues were grafted into mouse prostates. Resulting tumors and suspected metastatic lesions were subjected to histopathological and immunohistochemical analysis. Samples of metastatic tissue were regrafted in mouse anterior prostates and their growth and spread examined, leading to isolation from lymph nodes of a metastatic subline, PCa1-met. Orthotopic grafting of PCa1-met tissue in 47 hosts led in all cases to metastases to multiple organs (lymph nodes, lung, liver, kidney, spleen and, notably, bone). Histopathological analysis showed strong similarity between orthotopic grafts and their metastases. The latter were of human origin as indicated by immunostaining using antibodies against human mitochondria, androgen receptor, prostate-specific antigen and Ki-67. Spectral karyotyping showed few chromosomal alterations in the PCa1-met subline. This study indicates that transplantable subrenal capsule xenografts of human prostate cancer tissue in NOD-SCID mice can, as distinct from primary cancer tissue, be successfully grown in the orthotopic site. Orthotopic xenografts of the transplantable tumor lines and metastatic sublines can be used for studying various aspects of metastatic prostate cancer, including metastasis to bone.     

Complex mosaic structural variations in human fetal brains

Somatic mosaicism, manifesting as single nucleotide variants (SNVs), mobile element insertions, and structural changes in the DNA, is a common phenomenon in human brain cells, with potential functional consequences. Using a clonal approach, we previously detected 200–400 mosaic SNVs per cell in three human fetal brains (15–21 wk postconception). However, structural variation in the human fetal brain has not yet been investigated. Here, we discover and validate four mosaic structural variants (SVs) in the same brains and resolve their precise breakpoints. The SVs were of kilobase scale and complex, consisting of deletion(s) and rearranged genomic fragments, which sometimes originated from different chromosomes. Sequences at the breakpoints of these rearrangements had microhomologies, suggesting their origin from replication errors. One SV was found in two clones, and we timed its origin to ∼14 wk postconception. No large scale mosaic copy number variants (CNVs) were detectable in normal fetal human brains, suggesting that previously reported megabase-scale CNVs in neurons arise at later stages of development. By reanalysis of public single nuclei data from adult brain neurons, we detected an extrachromosomal circular DNA event. Our study reveals the existence of mosaic SVs in the developing human brain, likely arising from cell proliferation during mid-neurogenesis. Although relatively rare compared to SNVs and present in ∼10% of neurons, SVs in developing human brain affect a comparable number of bases in the genome (∼6200 vs. ∼4000 bp), implying that they may have similar functional consequences.

Somatic mosaicism, the presence of more than one genotype in the somatic cells of an individual, is a prominent phenomenon in the human central nervous system. Forms of mosaicism include aneuploidies and smaller copy number variants (CNVs), structural variants (SVs), mobile element insertions, indels, and single nucleotide variants (SNVs). The developing human brain exhibits high levels of aneuploidy compared to other tissues, generating genetic diversity in neurons (Pack et al. 2005; Yurov et al. 2007; Bushman and Chun 2013). Such aneuploidy was suggested to be a natural feature of neurons, rather than a distinctive feature of neurodegeneration. However, the frequency of aneuploidy in neurons has been debated, with a separate study suggesting that aneuploidies occur in only about 2.2% of mature adult neurons (Knouse et al. 2014). They hence infer that such aneuploidy could have adverse effects at the cellular and organismal levels. Additionally, analysis of single cells from normal and pathological human brains identified large, private, and likely clonal somatic CNVs in both normal and diseased brains (Gole et al. 2013; McConnell et al. 2013; Cai et al. 2014; Knouse et al. 2016; Chronister et al. 2019; Perez-Rodriguez et al. 2019), with 3%–25% of human cerebral cortical nuclei carrying megabase-scale CNVs (Chronister et al. 2019) and deletions being twice as common as duplications (McConnell et al. 2013). Given that CNVs often arise from nonhomologous recombination and replication errors, their likely time of origin is during brain development. However, when CNVs first arise in human brain development has not yet been investigated. The present work is the first to examine this question using clonal populations of neuronal progenitor cells (NPCs) obtained from fetal human brains.Detection of CNVs in single neurons is challenging, given the need to amplify DNA. Such amplification may introduce artifacts that could, in turn, be misinterpreted as CNVs. In order to address this technical limitation, Hazen et al. reprogrammed adult postmitotic neurons using somatic cell nuclear transfer (SCNT) of neuronal nuclei into enucleated oocytes (Hazen et al. 2016). These oocytes then made sufficient copies of the neuronal genome allowing for whole-genome sequencing (WGS), thus eliminating the need for amplification in vitro. Using this method, they identified a total of nine structural variants in six neurons from mice, three of which were complex rearrangements. However, it is not possible to extend such studies to humans, given the ethical issues involved, besides the technical challenges in obtaining and cloning adult neurons. To circumvent the need of single-cell DNA amplification or nuclear cloning, we examined clonal cell populations obtained from neural progenitor cells from the frontal region of the cerebral cortex (FR), parietal cortex (PA) and basal ganglia (BG) and describe here the discovery and analysis of mosaic SVs in these NPCs (Bae et al. 2018). These clones were sequenced at 30× coverage (much higher than most previous single-cell studies), allowing identification of SVs other than large deletions and duplications as well as precise breakpoint resolution.     

Antacids in the treatment of duodenal ulcer

Fifty patients with endoscopically proven pyloric-prepyloric ulcers (PU/PPU) and 50 with duodenal ulcers (DU) completed a six-week double-blind clinical trial initially comprising 124 patients. The antacid-treated patients received 10 ml of an antacid suspension seven times a day (buffering 367.5 mmol acid). Healing rate after three weeks of treatment was 74% in the antacid and 42% in the placebo group (p less than 0.01). After six weeks the corresponding figures were 96 and 68% (p less than 0.001). Regarding the PU/PPU and DU subgroups we found significant differences compared to placebo in the PU/PPU group only. Antacids caused a significantly faster and more perceptible pain relief than placebo. We found no significant correlation between ulcer healing and smoking habits. Regression analyses showed that, besides antacids, ulcer size and peak acid output influenced the healing rate significantly.     

Intrathoracic gastric fistula after bariatric surgery: a systematic review and pooled analysis

Even in the hands of highly experienced bariatric surgeons, perioperative complications are inevitable. Of these, leaks and fistulas are amongst the scariest complications. Intrathoracic gastric fistulas (ITGF) can be associated with serious morbidity, mostly when cases are misdiagnosed or detected with delay. This is a systematic review of the literature to investigate the clinical and surgical outcomes of morbidly obese adult patients with a confirmed diagnosis of ITGF following bariatric surgery. A pooled analysis of 25 articles, encompassing 76 patients with post-bariatric ITGF, showed that the clinical outcome depends on the initial presentation, timing of the diagnosis in relation to symptom onset, and prompt and effective treatment. Any septic or unstable patient must undergo urgent surgical intervention, while stable patients might tolerate a step-up approach and watchful waiting for nonsurgical treatment. Among those who undergo surgery, treatment failure and the mortality rate are substantially high. Contingent upon a prompt management strategy, patients with postbariatric ITGF can generally have a favorable outcome in the long term.     

Natural Convection Heat Transfer in a Porous Cavity with Sinusoidal Temperature Distribution Using Cu/Water Nanofluid: Double MRT Lattice Boltzmann Method

In this study, natural convection flow in a porous cavity with sinusoidal temperature distribution has been analyzed by a new double multi relaxation time (MRT) Lattice Boltzmann method (LBM). We consider a copper/water nanofluid filling a porous cavity. For simulating the temperature and flow fields, D2Q5 and D2Q9 lattices are utilized respectively, and the effects of different Darcy numbers (Da) (0.001-0.1) and various Rayleigh numbers (Ra) ($10^3$-$10^5$) for porosity ($ε$) between 0.4 and 0.9 have been considered. Phase deviation ($θ$) changed from 0 to $π$ and the volume fraction of nanoparticles (Ø) varied from 0 to 6%. The present results show a good agreement with the previous works, thus confirming the reliability the new numerical method proposed in this paper. It is indicated that the heat transfer rate increases at increasing Darcy number, porosity, Rayleigh number, the volume fraction of nanoparticles and phase deviation. However, the most sensitive parameter is the Rayleigh number. The maximum Nusselt deviation is 10%, 32% and 33% for Ra=$10^3$, $10^4$ and $10^5$, respectively, with $ε = 0.4$ to $ε = 0.9$. It can be concluded that the effect of Darcy number on the heat transfer rate increases at increasing Rayleigh number, yielding a maximum enhancement of the average Nusselt number around 12% and 61% for Ra=$10^3$ and Ra=$10^5$, respectively.     

Nicotine-induced hypothermia through an indirect dopaminergic mechanism

The effect of nicotine on core body temperature was studied in mice. Intraperitoneal (i.p.) injection of nicotine (0.5, 1 and 2 mg/kg) induced a dose-dependent hypothermia. The response was inhibited by reserpine (5 mg/kg), the centrally active nicotinic receptor antagonist mecamylamine (0.1-1 mg/kg) and the D-2 dopamine receptor antagonist sulpiride (25-100 mg/kg). The β-adrenoceptor antagonist propranolol (5 and 10 mg/kg) and the serotonergic blocker methysergide (5 and 10 mg/kg) did not inhibit but increased the nicotine response. The α-adrenoceptor antagonist phenoxybenzamine, the antimuscarinic agent atropine, the D-1 dopamine receptor antagonist SCH 23390, the peripheral dopamine antagonist domperidone and the peripheral nicotinic antagonist hexamethonium did not alter the nicotine-induced hypothermia. It is concluded that nicotine may cause a fall in core body temperature through a central dopaminergic mechanism.