Similar Functional Changes Research Articles

Structural and functional plasticity specific to musical training with wind instruments.

Numerous neuroimaging studies have shown structural and functional changes resulting from musical training. Among these studies, changes in primary sensory areas are mostly related to motor functions. In this study, we looked for some similar functional and structural changes in other functional modalities, such as somatosensory function, by examining the effects of musical training with wind instruments. We found significant changes in two aspects of neuroplasticity, cortical thickness, and resting-state neuronal networks. A group of subjects with several years of continuous musical training and who are currently playing in university wind ensembles showed differences in cortical thickness in lip- and tongue-related brain areas vs. non-music playing subjects. Cortical thickness in lip-related brain areas was significantly thicker and that in tongue-related areas was significantly thinner in the music playing group compared with that in the non-music playing group. Association analysis of lip-related areas in the music playing group showed that the increase in cortical thickness was caused by musical training. In addition, seed-based correlation analysis showed differential activation in the precentral gyrus and supplementary motor areas (SMA) between the music and non-music playing groups. These results suggest that high-intensity training with specific musical instruments could induce structural changes in related anatomical areas and could also generate a new functional neuronal network in the brain.

Dynamic changes and functions of macrophages and M1/M2 subpopulations during ulcerative colitis-associated carcinogenesis in an AOM/DSS mouse model.

The high risk of developing colorectal carcinoma (CRC), from ulcerative colitis (UC), is well known. Macrophages are widely distributed immune cells that have an indispensable role in UC, as well as in CRC. However, little is currently known about the dynamic changes that occur in macrophage and M1/M2 macrophage subpopulations, during UC-associated carcinogenesis. The aim of the present study was to investigate the alteration of colorectal macrophages and M1/M2 macrophage subpopulations during UC-associated carcinogenesis. Both expression level alterations and functional changes were determined during UC-associated carcinogenesis in an azoxymethane/dextran sodium sulfate-induced chemically colitis-associated carcinoma mouse model of Crj:CD-1 (ICR) mice. Notable evidence from immunohistochemistry, flow cytometry, cytokine detection, and gene expression analyses demonstrated that M2 macrophages have a critical role in CRC initiation, promotion, and metastasis. M2 macrophages are associated with unbalanced pro-inflammatory and anti-inflammatory axes and aberrant enhancement of migration/invasion-associated factors. Functional changes, similar to M2 polarized macrophages, were shown to occur in the M1 macrophages, without phenotypical changes, during the development of carcinoma and metastasis. The results of the present study suggest that M2 macrophages have a pro-tumor role during UC-associated carcinogenesis. Furthermore, similar functional changes occurred in the M1 macrophages, without polarization alterations, during carcinogenesis and metastasis.

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases.

Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies.

Cognitive Effects of Cancer and Its Treatments at the Intersection of Aging: What Do We Know; What Do We Need to Know?

There is a fairly consistent, albeit non-universal body of research documenting cognitive declines after cancer and its treatments. While few of these studies have included subjects aged 65 years and older, it is logical to expect that older patients are at risk of cognitive decline.Here, we use breast cancer as an exemplar disease for inquiry into the intersection of aging and cognitive effects of cancer and its therapies. There are a striking number of common underlying potential biological risks and pathways for the development of cancer, cancer-related cognitive declines, and aging processes, including the development of a frail phenotype. Candidate shared pathways include changes in hormonal milieu, inflammation, oxidative stress, DNA damage and compromised DNA repair, genetic susceptibility, decreased brain blood flow or disruption of the blood-brain barrier, direct neurotoxicity, decreased telomere length, and cell senescence. There also are similar structure and functional changes seen in brain imaging studies of cancer patients and those seen with "normal" aging and Alzheimer's disease. Disentangling the role of these overlapping processes is difficult since they require aged animal models and large samples of older human subjects. From what we do know, frailty and its low cognitive reserve seem to be a clinically useful marker of risk for cognitive decline after cancer and its treatments. This and other results from this review suggest the value of geriatric assessments to identify older patients at the highest risk of cognitive decline. Further research is needed to understand the interactions between aging, genetic predisposition, lifestyle factors, and frailty phenotypes to best identify the subgroups of older patients at greatest risk for decline and to develop behavioral and pharmacological interventions targeting this group. We recommend that basic science and population trials be developed specifically for older hosts with intermediate endpoints of relevance to this group, including cognitive function and trajectories of frailty. Clinicians and their older patients can advance the field by active encouragement of and participation in research designed to improve the care and outcomes of the growing population of older cancer patients.

PD-1 Expression Defines Two Distinct T-Cell Subpopulations That Differentially Impact Patient Outcomes In Follicular Lymphoma

BackgroundThe role of intratumoral PD-1+ T cells and their contribution to patient outcome in follicular lymphoma (FL) has been controversial. While some studies have found that increased numbers of PD-1+ T cells correlate with an inferior prognosis or have no impact on patient outcomes, other studies observed that the numbers of intratumoral PD-1+ T cells are an indicator of a favorable outcome in FL. In previous work, we observed that PD-1 can be expressed by different subsets of intratumoral T cells in FL including T follicular helper (TFH) cells and exhausted T effector cells. However, the function, prevalence, distribution and clinical importance of the respective intratumoral PD-1+ T subsets in FL patients are largely unknown. GoalTo characterize PD-1+ T cell subsets and to determine the biological and clinical relevance of these T cell subsets in FL. ResultsIn an analysis of biopsy specimens from 33 previously untreated FL patients, we found that PD-1 is abundantly expressed on intratumoral T cells. A median of 54.9% (range: 17.2-92.6, n=33) of CD4+ or 45.8% (range: 12.8-81.7, n=33) of CD8+ T cells express PD-1 on the cell surface. We found by flow cytometry that PD-1 is expressed on intratumoral CD4+ T cells with bright or dim intensity that represents two different subpopulations in FL. By immunohistochemistry, we identified that CD4+PD-1bright T cells predominantly reside in the lymph node follicles while PD-1dim T cells are mainly located in an inter-follicular pattern. Intratumoral CD4+PD-1bright T cells have a TFH cell phenotype and express CXCR5, secret IL-21 and are BCL-6 positive with no TIM-3 expression. In contrast, CD4+PD-1dim T cells have an exhausted phenotype, express TIM-3 and do not express BCL-6 and CXCR5. Functionally, CD4+PD-1dim T cells displayed reduced proliferation, cytokine production and cell signal transduction. When the CD8+ T cells were analyzed, we found that intratumoral CD8+ T cells, primarily reside in the inter-follicular regions, express PD-1 with low intensity and exhibit similar phenotypic and functional changes to inter-follicular CD4+PD-1dim T cells. These cells express TIM-3 but lack CXCR5 and BCL-6. They also displayed reduced proliferation and cytokine production. Clinically, we observed that both the numbers of CD4+PD-1dim and CD8+PD-1dim exhausted T cells significantly correlate with a reduced progression-free survival in FL patients treated with single agent rituximab (p=0.007 and p=0.04 respectively; n=31). Although it did not reach statistical significance, CD4+PD-1bright TFH cells appeared to correlate with a favorable survival, suggesting that TFH and exhausted T cells differentially impact patient outcome in FL. ConclusionTaken together, these results indicated that PD-1 expression defines two subpopulations with distinct functions that differentially impact patient outcome in FL. This finding provides not only an explanation for the previously discrepant clinical observations, but is also important in the design of future anti-PD-1 antibody-based therapy in FL. Disclosures:No relevant conflicts of interest to declare.

Rhesus Macaque NK Cells Expanded Ex Vivo Undergo Similar Phenotypic and Functional Changes Observed With Expanded Human NK Cells Providing An Excellent Model To Optimize Adoptive NK Cell Transfer

Although pilot clinical trials have shown adoptive NK cell transfer can result in tumor regression in humans with cancer, additional insight from animal models are needed to optimize NK cell proliferation in vivo as well as to improve their homing and retention in the tumor microenvironment. Mice have provided fundamental insights into NK cell biology, although significant divergence from humans as a consequence of evolution limits their usefulness to optimize adoptive transfer of ex vivo expanded NK cells in humans. Rhesus macaques (RM) express orthologues to most human MHC class I and II genes, and unlike mice, express KIRs and CD56, making them phenotypically and functionally similar to human NK cells. Further, unlike murine NK cells, cultured macaque NK cells can be expanded ex vivo for prolonged periods of time augmenting their cytotoxicity. Although recent studies have provided detailed characterization of freshly isolated RM NK cells, little information exists on the phenotype and function of these cells following ex vivo expansion. We investigated the feasibility of expanding RM NK cells ex vivo using culture conditions similar to those used to expand clinical grade human NK cells and characterized the cytotoxic function of subsets of these cells based on CD16 and CD56 expression.NK cells were enriched from RM PBMCs by either bead immunodepletion of CD3+ cells or by flow sorting) CD3-/CD20-/CD14-/CD16+ single positive (CD16SP) or CD3-/CD20-/CD14-/CD16-/CD56+ single positive (CD56SP) or CD3-/CD20-/CD14-/CD16+/CD56+ double positive (CD16/56DP) NK cells. NK cells were expanded in vitro by co-culture with an irradiated human EBV lymphoblastoid cell line (EBV-LCL) in media containing 500IU/uL of human IL-2. In contrast to humans, where resting NK cells from the peripheral blood are mostly CD16/56DP with smaller SP populations, the majority of NK cells from RM peripheral blood were CD16SP (Figure). Despite this difference, RM NK cells appeared phenotypically similar to human NK cells following ex vivo expansion, and had similar expansion kinetics, typically yielding a 100-fold increase in cells that were 99% CD3- and mostly CD16/56DP or CD56SP with a minor fraction of CD16SP cells. Using NKG2A as a pan NK cell marker as well as expression levels of CD16 and CD56, we evaluated for changes in the cytotoxic function associated with ex vivo expansion in 5 distinct NK cell subsets; CDSP16bright, CD16SPdim, CD56SPbright, CD56SPdim, and CD16/56DP. After 7 days expansion, CD16SP populations contracted substantially in contrast to CD16/56DP and CD56SP populations which increased. After 14 days of expansion, the CD16SP population represented <5% of the expanded NK cells, while the CD16/56DP and the CD56SP populations represented approximately 60% and 40% of NK cells respectively, with distinctions between CD16 and CD56 bright and dim populations being lost (figure). To assess the cytotoxicity of specific subsets of expanded vs fresh NK cells, we evaluated CD107a expression at baseline and following co-culture with K562 cells (2hrs;1:1 ratio). Among fresh NK cells, the highest induction of CD107a was in the CD16SPdim subpopulation. In contrast, following ex vivo expansion, CD107a induction was highest in the dominant CD16/56DP population followed in decreasing order by the CDSP16bright and CD56SPbright populations. To confirm these data, we assessed target killing by expanded NK cells using a flow-based cytotoxicity assay measuring Annexin V and 7AAD expression on K562 cells following co-culture with one of 3 different flow-sorted NK populations; a) CD16SP or b) CD56SP or c) CD16/56DP NK cells. Similar to prior data, we found the dominant CD16/56DP populations to have the greatest cytotoxicity against K562 cells (25%) followed by the CD16SP (17%) and CD56SP (15%) populations. ConclusionThese data show RM NK cells can be expanded ex vivo using culture conditions similar to those used to expand clinical grade human NK cells. RM NK cells expanded using EBV-LCL feeder cells are phenotypically similar to expanded human NK cells and based on CD16 and CD56 expression, contain subpopulations that have varying degrees of cytotoxicity against K562 targets. The similarities between expanded RM and human NK cells establish this animal model as having excellent potential to optimize adoptive NK cell transfer in humans. We aim to establish this model and test expansions in vivo. Disclosures:No relevant conflicts of interest to declare.

Expression of the c-Kit receptor in germ cells of the seminiferous epithelium in rats with hormonal imbalance

The aim of the study was to investigate the effects of pharmacologically induced hormonal imbalance in adult male rats treated with letrozole and rats exposed to soya isoflavones on the testicular morphology and c-Kit receptor (c-Kit-R) expression in germ cells. The study was conducted during all developmental periods: prenatal period, lactation, youth, and sexual maturity. Morphological and morphometrical analyses were performed on testicular section, and c-Kit-R was identified using immunohistochemistry. In addition, concentration of circulating steroids was measured in mature rats exposed to soya isoflavones. A significant reduction in testosterone level in rats exposed to soya isoflavones, and the sloughing of the premature germ cells into the lumen of the seminiferous tubules in the testes of both groups of rats were observed. Immunohistochemistry showed a decrease in c-Kit-R expression in germ cells of both experimental groups. Morphometric analysis indicated a decreased thickness of the layers occupied by c-Kit-R-positive spermatogonia, and a decreased diameter of the seminiferous tubules in the testes of both experimental groups of animals. In conclusion, the pharmacologically induced reduction of the estradiol level in adult rats and the diminished level of testosterone in rats exposed to soya isoflavones during the prenatal period, lactation and up to maturity caused similar morphological and functional changes associated with the decreased c-Kit-R expression in germ cells in the seminiferous epithelium. These findings demonstrate the importance of the estrogen/androgen balance for normal testicular morphology and spermatogenesis.

Evaluation of Correlation between Aortic Elastic Parameters and Atrial Electromechanical Abnormalities in Hypertensive Patients

Arterial hypertension leads to instability and heterogeneity in atrial conduction by these hemodynamic and morphological changes in heart and aorta. These changes can be evaluated by transthoracic echocardiography. The aim of this study was to evaluate the correlation of aortic elastic parameters and atrial electromechanical delay (AEMD) parameters in patients with hypertension. Eighty-one hypertensive patients and 55 control subjects were included in the study. All subjects underwent transthoracic echocardiography for detecting aortic elastic parameters and AEMD parameters. There was no difference between HT and control groups regarding age and gender. Aortic strain (8.1±4.3% vs. 10.3±5.1%, P=0.008) and aortic distensibility (0.35±0.18cm(2) /dyn vs. 0.45±0.23cm(2) /dyn, P=0.003) were decreased in hypertensive patients than in controls. Intra-left AEMD (25.5±7.3 vs. 21.8±9.2 P<0.009) was significantly higher in hypertensive patients compared to control subjects. No statistically significant difference was found in intra-right AEMD and inter-AEMD between the groups. There was a positive significant moderate correlation between aortic strain and intra-left AEMD (r=0.501, P<0.001). This study demonstrated that intra-left AEMD was increased in hypertensive patients and aortic elastic parameters was correlated with intra-left AEMD. These findings may be related to similar structural and functional changes in heart and aorta in hypertension.

Dynamic changes of peritoneal macrophages and subpopulations during ulcerative colitis to metastasis of colorectal carcinoma in a mouse model

Patients with ulcerative colitis have increased risk of colorectal carcinoma, but little is known about how peritoneal macrophages are involved in ulcerative colitis-associated carcinogenesis. We investigated the alteration of peritoneal macrophages and M1/M2 subpopulations during ulcerative colitis-associated carcinogenesis. Expression and functional changes in peritoneal macrophages and M1/M2 subpopulations were investigated by histopathology, flow cytometry, immunofluorescence, cytokines expression by ELISA and QRT-PCR in an azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced chemical colitis-associated carcinoma mouse model using male Crj:CD-1 (ICR) mice. Striking evidence observed in histopathology, flow cytometry, cytokine detection, and gene expression analysis all revealed that inflammation-associated cytokines (IL-1β, IL-10, IL-12, IL-6, TNF-α) and migration/invasion-associated factors (G-CSF, GM-CSF, CXCR4, VEGF, TGF-β, ICAM-1) induced by peritoneal M2 macrophages increased significantly during the progression from inflammatory hyperplasia to carcinoma and metastasis. Similar functional changes occurred during peritoneal metastasis in M1 macrophages without changed polarization. These results suggested that peritoneal M2 macrophages played a critical role in ulcerative colitis-associated carcinogenesis, including unbalanced pro-inflammatory and anti-inflammatory axis and enhanced expression of migration/invasion-associated factors. Furthermore, functional changes of M1 macrophages occurred without changed polarization during carcinogenesis and metastasis.

Vascular Function During Prolonged Progression and Regression of Atherosclerosis in Mice

Endothelial dysfunction is associated with atherosclerosis in mice, but it is difficult to reduce cholesterol levels enough to study regression of atherosclerosis in genetically modified mice. The goal of this study was to examine vascular structure and function before and after reducing elevated plasma lipid levels with a genetic switch in Reversa mice, and identify novel mechanisms contributing to structural and functional improvements in the vasculature after reduction of blood lipids. After 6 months of hypercholesterolemia, endothelial function (maximum relaxation to acetylcholine) in aorta was impaired and responses to nitric oxide were unaffected. Further impairment in endothelial function was observed after 12 months of hypercholesterolemia and was associated with reductions in sensitivity to nitric oxide. Expression of dihydrofolate reductase was reduced at 6 and 12 months, and addition of the tetrahydrobiopterin precursor sepiapterin significantly improved endothelial function. Reducing cholesterol levels at 6 months normalized dihydrofolate reductase expression and prevented further impairment in endothelial function. Similar functional changes were observed after 12 months of hypercholesterolemia followed by 2 months of lipid lowering. Our data suggest that endothelial dysfunction after prolonged hypercholesterolemia is the result of both impairment of sensitivity to nitric oxide and reduced nitric oxide synthase cofactor bioavailability. Both of these changes can be prevented by normalizing blood lipids during moderately severe or advanced atherosclerosis.

The phenotype and functional alterations of macrophages in mice with hyperglycemia for long term

Abnormal immunity and its related complications are the major causes of mortality and morbidity in diabetes patients. Macrophages, as one of the important innate cells, play pivotal roles in controlling immune homeostasis, immunity, and tolerance. The effects of hyperglycemia on the function of macrophages in hosts remain to be determined. Here we used mice with streptozotocin (STZ)-induced diabetes for long term to study the changes of macrophages. We found that F4/80(+) peritoneal exudate macrophages (PEMs) from mice with diabetes for 4 months displayed significantly reduced CD86 and CD54 expression and tumor necrosis factor (TNF)-α and IL-6 production but enhanced nitric oxide (NO) secretion compared with control mice when treated with interferon (IFN)-γ and lipopolysaccharide (LPS), while the activity of arginase in PEMs from diabetic mice was significantly higher than control mice when stimulating with IL-4. These dysfunctions of macrophages could be efficiently reversed by insulin treatment. Importantly, in vitro bone marrow-derived macrophages showed similar functional changes, indicating the epigenetic alteration of macrophage precursors in these mice. In an in vitro culture system, high glucose and insulin significantly altered TNF-α, IL-6, and NO production and arginase activity of macrophages, which was reversed by the treatment with AKT and ERK inhibitors. Therefore, hyperglycemia and insulin deficiency can modify macrophage function through AKT-mTOR and ERK pathways and through epigenetic effects on macrophage precursors. To further identify different components of diabetes on the dysfunction of macrophages is important for efficient prevention of diabetic complications.

P2-09-15: Functional Measurements of Tumor Response during Neoadjuvant Chemotherapy Infusion and Early during Treatment Using Diffuse Optical Spectroscopic Imaging.

Abstract Background: Non-invasive markers of neoadjuvant chemotherapy response early during treatment would provide physicians a valuable tool to make evidence-based changes to treatment strategies. In a retrospective study of 23 patients presented at SABCS 2011 we demonstrated that Diffuse Optical Spectroscopic Imaging (DOSI) can discriminate non-responding from responding subjects on the first day after the start therapy based on the presence or absence of an oxyhemoglobin flare. Here we present results of an ongoing prospective study designed to confirm the predictive nature and biological origins of oxyhemoglobin flare and to determine if similar functional changes occur at even earlier timepoints such as during infusion. Methods: DOSI was used to measure hemodynamic and metabolic information from tumors and surrounding normal tissue in patients prior to neoadjuvant chemotherapy, during chemotherapy infusion, and daily for the first week of treatment. DOSI uses temporally modulated near-infrared light to determine absolute tissue concentrations of oxyhemoglobin, deoxyhemoglobin, water and lipid content and requires no exogenous contrast agent. Measurements are made using a simple handheld probe placed on the skin. Blood samples were also collected at baseline and daily for seven days after the first infusion and tested for a panel inflammatory cytokines. Patients received paclitaxel + carboplatin + bevacizumab. Overall response to therapy was determined by the decrease in anatomic tumor size. Results: To date three subjects have been measured, two of which have completed neoadjuvant chemotherapy and undergone surgery. One subject was a pathologic complete responder (pCR) and the other a non-responder (NR). In both the pCR subject and the subject still undergoing therapy there were significant functional changes measured in the tumor during infusion. A decrease in oxyhemoglobin and oxygen saturation occurred after paclitaxel infusion (saturation changes: −4.8% and −9.7% for each subject respectively), followed by an increase in these quantities after carboplatin infusion (saturation: 3.8% and 5.9% respectively). In the NR subject both oxyhemoglobin and oxygen saturation had only small fluctuations during infusion (saturation: 1.1%). Oxyhemoglobin flare was also observed 24 hours after infusion for each of the patients. Plasma levels of several inflammatory cytokines including G-CSF, MIP-1α, and C-reactive protein increased 24 hours after infusion for the first two subjects and subsequently decreased at 48 hours. Discussion: We have confirmed the presence of oxyhemoglobin flare on day one after infusion in this small prospective patient cohort. Increased plasma levels of inflammatory cytokines were correlated in time with the presence of oxyhemoglobin flare suggesting a possible link between optical measurements and inflammatory processes induced by chemotherapy. Additionally, we report for the first time significant changes in tumoral oxyhemoglobin and oxygen saturation during chemotherapy infusion. These changes may be of prognostic significance. DOSI allows functional measurements of tumor response at timepoints unachievable with current functional medical imaging modalities. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-15.

Dacarbazine Promotes Stromal Remodeling and Lymphocyte Infiltration in Cutaneous Melanoma Lesions

Dacarbazine (DTIC) is the standard first-line drug for advanced stage melanoma, but it induces objective clinical responses in only 15% of patients. This study was designed to identify molecular changes specifically induced by treatment in chemo-sensitive lesions. Using global transcriptome analysis and immunohistochemistry, we analyzed cutaneous metastases resected from patients with melanoma before and after DTIC treatment. The treatment induced similar functional changes in different lesions from the same patient. Stromal and immune response-related genes were the most frequently upregulated, particularly in lesions that responded to treatment by stabilizing or regressing. T-cell infiltration and enhanced major histocompatibility complex class II expression were observed in a subset of patients. Stable, chemo-sensitive lesions exhibited activation of genetic programs related to extracellular matrix remodeling, including increased expression of secreted protein acidic and rich in cysteine (SPARC) by tumor cells. These events were associated with local response to treatment and with superior survival in our group of patients. In contrast, SPARC expression was downregulated in lesions resistant to DTIC. Thus, chemotherapy drugs originally selected for their direct cytotoxicity to tumor cells may also influence disease progression by inducing changes in the tumor microenvironment.

Disruption of the sEH Gene Does Not Prevent Hypoxia‐Induced Right Ventricular Hypertrophy in Mice

It is reported that disruption of the sEH gene in mice decreases blood pressure and protects against ischemia/reperfusion injury in the brain and heart. Others found that sEH disruption reduced survival due to cardiac arrest in mice. We tested the hypothesis that disruption of sEH in mice protects against the development of hypoxia‐induced right ventricular hypertrophy (RVH). Cardiac magnetic resonance (CMR) imaging was conducted on wild‐type (WT) and sEH knockout (KO) mice housed under the hypoxia (10% O2) condition for 5 weeks. Serial short‐axis MR images of heart from apex to base covering both right (RV) and left ventricles (LV) were captured in real time. From these images, RV and LV end diastole volumes, ejection fraction and wall thickness were determined. Following 5 wks of hypoxia, WT mice developed hypoxia‐induced RVH characterized by enlarged RV volume, increased wall thickness and reduced ejection fraction. The KO mice also developed RVH under the same conditions, similar cardiac structural and functional changes as that of WT mice. Exposure to hypoxia for 5 wks had no impact on LV structure and function in WT mice. However, 7 out of 9 KO mice survived hypoxia while all WT mice survived. Among the 7, 2 KO mice showed enlarged LV end‐diastole volume accompanied by reduced ejection fraction. In summary, our data revealed that sEH deficiency is not cardio‐protective when mice are challenged with hypoxia.

Airway responsiveness to methacholine and deep inhalations in subjects with rhinitis without asthma

Airway hyperresponsiveness in asthma is believed to be caused in part by the inability of deep inspirations to modulate airway narrowing. We investigated whether deep inspirations taken before or after methacholine inhalation attenuate bronchoconstriction in subjects with rhinitis. The results were compared with a group of healthy subjects. Ten subjects with rhinitis without asthma and 10 healthy subjects were studied on 3 different occasions at random. Bronchial challenges were performed with a single dose of methacholine known to decrease the FEV(1) by 17% to 40%. Challenges were performed with avoidance of deep inspirations, or with 5 deep inspirations preceding or following the inhalation of methacholine. Lung function measurements were specific airway conductance, forced expiratory flow at 30% to 40% of vital capacity on a maneuver started from end-tidal inspiration (partial flow), and residual volume (partial residual volume). In healthy subjects, deep inspirations taken after methacholine caused less changes in specific airway conductance, partial flow, and partial residual volume (P < .005 for all) than deep inspirations taken before methacholine or avoidance. In subjects with rhinitis, methacholine produced similar functional changes independently of the presence or absence of any deep inspirations. Compared with normal subjects, the attenuating effects of deep inspirations after methacholine on partial flow and partial residual volume were blunted in the subjects with rhinitis (P = .02 and P = .05, respectively). The ability to dilate methacholine-constricted airways by deep inspirations is impaired in subjects with rhinitis, possibly because of an abnormal behavior of airway smooth muscle.

Pulmonary and extrapulmonary acute lung injury: inflammatory and ultrastructural analyses

To test whether pulmonary and extrapulmonary acute lung injury (ALI) of identical mechanical compromise would express diverse morphological patterns and immunological pathways. For this purpose, a model of pulmonary (p) and extrapulmonary (exp) ALI with similar functional changes was developed and pulmonary morphology (light and electron microscopy), cytokines levels, and neutrophilic infiltration in the bronchoalveolar lavage fluid (BALF), elastic and collagen fiber content in the alveolar septa, and neutrophil apoptosis in the lung parenchyma were analyzed. BALB/c mice were divided into four groups. In control groups, saline was intratracheally (it, 0.05 ml) instilled and intraperitoneally (ip, 0.5 ml) injected, respectively. In the ALIp and ALIexp groups, mice received E. coli lipopolysaccharide (10 microg it and 125 microg ip, respectively). The changes in lung resistive and viscoelastic pressures and in static elastance, alveolar collapse, and cell content in lung tissue were similar in the ALIp and ALIexp groups. The ALIp group presented a threefold increase in KC (murine function homolog to IL-8) and IL-10 levels in the BALF in relation to ALIexp, whereas IL-6 level showed a twofold increase in ALIp. Neutrophils in the BALF were more frequent in ALIp than in ALIexp. ALIp showed more extensive injury of alveolar epithelium, intact capillary endothelium, and apoptotic neutrophils, whereas the ALIexp group presented interstitial edema and intact type I and II cells and endothelial layer. In conclusion, given the same pulmonary mechanical dysfunction independently of the etiology of ALI, insult in pulmonary epithelium yielded more pronounced inflammatory responses, which induce ultrastructural morphological changes.

Is major depression a neurologic disorder with psychiatric symptoms?

In the last decade, multiple investigator groups have identified structural changes of various neuroanatomic structures in patients with idiopathic major depression and bipolar disorders. Using high-resolution MRI of the brain and functional neuroimaging studies (i.e., PET, SPECT), researchers have described decreases in the volume of hippocampal formation, amygdala, entorhinal cortex, various frontal lobe structures, and basal ganglia, in addition to abnormal cerebral blood flow and metabolic activity in these structures as well as in thalamic nuclei. Similar structural and functional changes have been identified in patients with depression associated with a variety of neurologic disorders (i.e., stroke, Parkinson’s disease, epilepsy, Alzheimer’s dementia). In addition, recent data have shown that depression is a risk factor for the development of several neurologic disorders, including epilepsy, stroke, and Parkinson’s disease and bears a negative impact on the course and outcome of most neurologic disorders. This article reviews these data and provides evidence that major depressive and bipolar disorders may in fact be neurologic disorders with psychiatric symptoms.

Parallel functional changes in the digestive RNases of ruminants and colobines by divergent amino acid substitutions.

A morphological or physiological trait may appear multiple times in evolution. At the molecular level, similar protein functions may emerge independently in different lineages. Whether these parallel functional changes are due to parallel amino acid substitutions has been a subject of debate. Here, I address this question using digestive ribonucleases (RNases) of two groups of foregut-fermenting mammals: ruminant artiodactyls and colobine monkeys. The RNase1 gene was duplicated twice in ancestral ruminants at least 40 MYA, and it was also duplicated in the douc langur, an Asian colobine, approximately 4 MYA. After duplication, similar functional changes occurred in the ruminant and monkey enzymes. Interestingly, five amino acid substitutions in ruminant RNases that are known to affect its catalytic activity against double-stranded (ds) RNA did not occur in the monkey enzyme. Rather, a similar functional change in the monkey was caused by a different set of nine substitutions. Site-directed mutagenesis was used to make three of the five ruminant-specific substitutions in the monkey enzyme. Functional assays of these mutants showed that one of the three substitutions has a similar effect in monkeys, the second has a stronger effect, and the third has an opposite effect. These results suggest that (1) an evolutionary problem can have multiple solutions, (2) the same amino acid substitution may have opposite functional effects in homologous proteins, (3) the stochastic processes of mutation and drift play an important role even at functionally important sites, and (4) protein sequences may diverge even when their functions converge.

I. Age-related changes in the enteric nervous system

As we enter the 21st century, the segment of the population that is the most rapidly expanding is that comprised of individuals 85 yr of age and older. Dysfunctions of the gastrointestinal (GI) system, including dysphagia, constipation, diarrhea, and irritable bowel syndrome are more common complaints of the elderly, yet our knowledge of the aging GI tract is incomplete. Compared with the rapid advances in the neurobiology of aging in the central nervous system, the understanding of age-related changes in the enteric nervous system (ENS) is poor. In this brief review, I recap experiments that reveal neurodegenerative changes and their functional correlates in the ENS of mice, rats, and guinea pigs. Clinical literature seems indicative of similar structural and functional age-related changes in the human ENS. Current studies that address the mechanisms underlying age-related changes in the ENS are introduced. The future directions for this field include physiological and pharmacological studies, especially at cellular and molecular levels. Research in the aging ENS is poised to make major advances, and this new knowledge will be useful for clinicians seeking to better understand and treat GI dysfunction in the elderly.

The preliminary characterization of a vasoactive circulating factor(s) in preeclampsia

Objective: The endothelium-dependent behavior of myometrial resistance vessels from women with preeclampsia differs dramatically from that of healthy pregnant women. Similar functional changes may be induced in vessels from healthy pregnant women by incubation with plasma from women with preeclampsia. Study Design: Myometrial arterioles, obtained from healthy pregnant women at elective cesarean section, were incubated with plasma from women with preeclampsia or plasma from healthy pregnant women. Myographic techniques were used to study the endothelium-dependent relaxation to bradykinin. The effects of subjecting plasma from women with preeclampsia to heat treatment, charcoal stripping, protein extraction and digestion, and column fractionation on the inducible changes in endothelial function were likewise investigated. Results: Incubation with plasma from women with preeclampsia resulted in a significant reduction in the vessel’s endothelium-dependent relaxation, a change that was reversible. This effect was reduced by heat treating and charcoal stripping, maintained within a plasma protein concentrate, and completely removed by protease digestion. The vasoactive component(s) of the plasma had a molecular weight greater than 100 kd. Conclusions: Plasma of women with preeclampsia alters the endothelium-dependent relaxation of myometrial vessels. Our findings suggest that such alterations are induced by a high-molecular-weight protein/glycoprotein, with possible contributions from a hydrophobic, lipophilic factor. (Am J Obstet Gynecol 2001;184:1196-203.)