Ultrastructural Changes in Prostate Cells During Hormone-induced Canine Prostatic Hyperplasia

Benign prostatic hyperplasia is a prevalent disease that has received relatively little attention in spite of its morbidity and remarkable social impact. There are few animal models of prostatic hyperplasia. The dog is the only species, along with humans, in which prostatic hyperplasia develops spontaneously and almost universally with age. The aim of the present study has been to compare the ultrastructural findings in a model of experimentally induced canine prostatic hyperplasia with those of the spontaneously developed changes in untreated dogs. An experimental group of 5 male beagle dogs were castrated and treated with combined steroids (3 weekly doses for over 30 weeks). Prostate samples were surgically obtained every 42 days (experimental stages 0 through 6). The control group consisted of 3 noncastrated dogs that were treated with vehicle and in which samples were taken only at stages 0, 1, 4, and 6. Changes in the control groups were similar but of lower intensity compared to those of the experimental groups. In luminal cells, crowding with papillary projections, prominent, branching microvilli, and abundant, often compartmentalized granules were observed. The most striking change was the previously unreported finding of caveolae in basal cells. They were mostly located in the basal aspect of basal cells and were more prominent in the experimental group and in advanced stages of treatment. These ultrastructural findings have not been previously reported in canine or human prostatic hyperplasia and merit further research. The model of experimentally induced canine prostatic hyperplasia provides an adequate setting for the understanding of this disease.     

Notch3信号介导小胶质细胞活化在慢性前列腺炎疼痛中的作用

目的观察Notch3介导L5~S2脊段背角小胶质细胞活化在慢性前列腺炎疼痛中的作用。方法大鼠分为实验组(慢性前列腺炎组)和对照组,实验组通过完全弗氏佐剂(CFA)注射前列腺来制作大鼠慢性前列腺炎疼痛模型,对照组注射生理盐水,采用热辐射甩尾痛阈测定和前列腺组织病理学检查鉴定疼痛模型,分别在注射CFA后0、4、12、24 d,采用qRT-PCR检测L5~S2脊段后角小胶质细胞活化标志物IBA-1和受体Notch3 mRNA的表达,采用ELISA检测小胶质细胞炎症因子TNF-α和IL-1β的分泌,并在鞘内注射小胶质细胞和Notch3抑制剂后检测小胶质细胞TNF-α和IL-1β蛋白的表达。结果前列腺组织病理和热痛域实验证实慢性前列腺炎疼痛模型建立成功。实验组大鼠Notch3、IBA-1、TNF-α及IL-1β的表达在第4天开始增加,第12天达到最高水平,第24天开始下降,均显著高于对照组,差异有极显著性统计学意义(P<0.01)。抑制小胶质细胞和Notch3受体后,TNF-α和IL-1β的分泌明显减少(P<0.05)。结论慢性前列腺炎疼痛中Notch3介导L5~S2脊段中枢小胶质细胞活化,炎症因子分泌增加,与慢性前列腺炎呈现的持续顽固神经炎性疼痛有关。     

Cadaveric and radiologic study of the anatomical variations of the prostatic arteries: A review of the literature and a new classification proposal with application to prostatectomy

Development of prostatic arterial embolization (PAE) to treat benign prostatic hyperplasia (BPH) has raised interest in the variations of the prostatic arteries (PA). The aim of this study is to identify these vascular variations, to compare them with previous data, and to propose a simple classification. Ten adult male pelvis sides from embalmed cadavers were dissected, ages 69 to 92 years, and 10 PA were examined. In a retrospective analysis of 34 DSA pelvic angiographies on 28 patients aged 50 to 90 years, 48 PA were identified. A total of 58 PA were therefore analyzed. Six types are defined. Type I: PA originates from the anterior division (AD) of the internal iliac artery (IIA), 20.7%; Type II: PA emerges from the obturator artery (OA), 5.2%; type III: PA arises from the gluteal‐pudendal trunk (GPT), 27.5%; Type IV: PA originates from the internal pudendal artery (IPA), 29.3%; Type V: PA comes from the middle rectal artery (MRA), 15.5%. Other origins, not observed in our sample but described in the literature, were amalgamated under Type VI. The AD/GPT/IPA stem is the main source of the PA. Analysis of the definitions of IIA branches and the associated terminology is necessary for interpreting the results reported by several authors on different samples, but in general the results fit the meta‐analysis well. A new, simple, and complete classification for vascular variations of the PA is proposed. Clin. Anat. 30:71–80, 2017. © 2016 Wiley Periodicals, Inc.     

Autoimmunity in chronic obstructive pulmonary disease: clinical and experimental evidence

Over the past few decades, neutrophils and macrophages had co-occupied center stage as the critical innate immune cells underlying the pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease and lung parenchymal destruction (i.e., emphysema). While chronic exposure to smoke facilitates the recruitment of innate immune cells into the lung, a clear role for adaptive immunity in emphysema has emerged. Evidence from human studies specifically point to a role for recruitment and activation of pathogenic lymphocytes and lung antigen-presenting cells in emphysema; similarly, animal models have confirmed a significant role for autoimumnity in progressive smoke-induced emphysema. Increased numbers of activated antigen-presenting cells, Th1 and Th17 cells, have been associated with smoke-induced lung inflammation and production of the canonical cytokines of these cells, IFN-γ and IL-17, correlates with disease severity. These exciting new breakthroughs could open new avenues for developing effective new therapies for smoke-induced emphysema.     

前列腺增生及前列腺癌患者f-PSA/T-PSA的变化

目的:探讨诊断灰区内血清游离态前列腺特异性抗原与总前列腺特异性抗原的比值,在前列腺增生与前列腺癌的鉴别诊断中的应用价值.方法:选择血清总前列腺特异性抗原(4.0～10.0)μg/L的39例前列腺癌患者和36例前列腺增生患者,检测血清中总前列腺特异性抗原(T-PSA)和游离态前列腺特异性抗原(f-PSA),计算f/T比值.结果:T-PSA在(4.0～10.0)μg/L,组间T-PSA浓度无显著性差异(P＞0.05),而(f/T)PSA比值有显著性差异(P＜0.05),前列腺癌患者f/T比值明显低于前列腺增生患者(P＜0.01).结论:应用f/T比值＜0.16为鉴别点,提高了对前列腺癌诊断灵敏性和特异性,尤其T-PSA在(4.0～10.0)μg/L更有意义.     

Frequency of IL-10+CD19+ B cells in patients with prostate cancer compared to patients with benign prostatic hyperplasia

BackgroundThe function of the immune system in prostate cancer (PC) might promote carcinogenesis. PC is a common cancer in men. Regulatory B cells (Bregs) are a new subtype of B cells that have suppressive roles in the immune system. Interleukin-10 (IL-10) is a dominant mediator of immune suppression released by Bregs.ObjectiveThe purpose of this research was to examine the frequency of CD19+IL10+ B cells and IL-10 mRNA expression in patients with PC compared to patients with benign prostatic hyperplasia (BPH).MethodsForty paraffin tissue samples from patients with PC and 32 paraffin tissue samples from patients with BPH were entered in this study. The immunohistochemistry staining was used to evaluate the pattern expression of CD19 and IL-10 markers. IL-10 mRNA expression in fresh tissue was determined by real time-polymerase chain reaction (RT-PCR).ResultsThe frequency of CD19+IL-10+ B cells and IL-10 mRNA expression in PC patients were significantly higher than patients with BPH. Also, there was no meaningful relationship between the frequency of IL-10+CD19+ B cells and gleason scores in patients with PC.ConclusionsOur findings suggested that frequency of IL-10+CD19+ B cells correlates with progressive stage of PC.     

Defective functional response to membrane stimuli in lymphocytes from patients with benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a local disturbance in the prostate that may involve an inflammatory infiltrate predominantly composed of activated lymphocytes and macrophages. The activation and proliferative response of T lymphocytes to different mitogenic signals has been analysed in peripheral blood mononuclear cells (PBMC) from 45 patients with BPH and 55 healthy controls. The PBMC obtained from the patients showed a significant specific impairment in proliferation, CD25 expression and IL-2 production in response to stimulation with lectins (phytohaemagglutinin (PHA), concanavalin A (Con A)), that was not corrected by the addition of IL-2 or of phorbol esters (phorbol myristate acetate (PMA)). Also, the CD28 response was defective in patient PBMC. Activation with anti-CD3 or anti-CD2 MoAbs was normal, but the addition of PMA to these stimuli provoked a significant defective response. Only the use of transmembrane stimuli (PMA and ionomycin) elicited responses similar to those found in the control group. The results indicate that peripheral T lymphocytes from BPH patients show a functional impairment that is mainly explained by an alteration of membrane signals (PHA, CD28) and is distal to protein kinase C (PKC) activation.     

Antibodies to Sperm in Benign and Malignant Diseases of the Prostate in Man: Incidence,Disease-Associated Specificity,and Implications

ABSTRACT: Initial investigation demonstrated antibodies to sperm (ASA) in patients with benign prostatic hypertrophy (BPH) and prostate cancer (PCa). The occurrence of ASA under a variety of normal and pathological circumstances indicated the need for confirmation and extension, including delineation of their possible disease-associated specificity and implications. As countercurrent Immunoelectrophoresis (CIEP) employing sonicated allogeneic sperm (Sp) extracts appeared most efficient from initial studies of ASA, CIEP was employed for the present further study of 200 serum specimens from patients with and without prostatic disease. While ubiquitous, the continuing presence of ASA in BPH and PCa, with a combined incidence in this study of 57(52%) of 109 vs. 9 (10%) of 91 in the absence of prostatic disease remains provocative in view of the hypothesized role of Sp in the development of BPH and PCa. The presence, however, of ASA in patients with genitourinary neoplasms other, than prostate, raises doubt as to their disease specificity. Implications of ASA, other than in their more commonly related role in infertility, including their cross-reactivity with foetal antigens and lymphocytes and higher incidence in association with tumours and the presence of tumour-associated immunity are considered. However, pending further investigation, the present data may most appropriately be viewed as being reflective of a host response (marker?) to aberrant genitourinary cellular alterations.     

Chronic,Intractable, Benign Pain: A Syndrome and its Treatment with Intensive Short-term Group Psychotherapy

Abstract

There is sufficient reason to classify some ongoing pain problems as syndromes. Patients who suffer with chronic, intractable, benign pain syndromes (CIBPS) have truly functional biopsychosocial disorders. There is no longer any current pathophysiology operative, and the pain syndrome persists with its psychosocially perpetuating and disrupting features. An intense group psychotherapy approach in the therapeutic milieu of a medical-surgical setting fosters and evokes affect expression and understanding. This encourages the formation of cognitive patterns that are therapeutically useful in that they extend coping abilities and, hence, diminish the pain and suffering experience and life problems attendant to it.     

Reduction of blood nitric oxide levels is associated with clinical improvement of the chronic pelvic pain related to endometriosis

The objective of this prospective study was to determine the plasma levels of nitric oxide (NO) in women with chronic pelvic pain secondary to endometriosis (n=24) and abdominal myofascial pain syndrome (n=16). NO levels were measured in plasma collected before and 1 month after treatment. Pretreatment NO levels (μM) were lower in healthy volunteers (47.0±12.7) than in women with myofascial pain (64.2±5.0, P=0.01) or endometriosis (99.5±12.9, P<0.0001). After treatment, plasma NO levels were reduced only in the endometriosis group (99.5±12.9 vs 61.6±5.9, P=0.002). A correlation between reduction of pain intensity and reduction of NO level was observed in the endometriosis group [correlation = 0.67 (95%CI = 0.35 to 0.85), P<0.0001]. Reduction of NO levels was associated with an increase of pain threshold in this group [correlation = -0.53 (-0.78 to -0.14), P<0.0001]. NO levels appeared elevated in women with chronic pelvic pain diagnosed as secondary to endometriosis, and were directly associated with reduction in pain intensity and increase in pain threshold after treatment. Further studies are needed to investigate the role of NO in the pathophysiology of pain in women with endometriosis and its eventual association with central sensitization.     

Neutrophil migration: moving from zebrafish models to human autoimmunity

There has been a resurgence of interest in the neutrophil's role in autoimmune disease. Classically considered an early responder that dies at the site of inflammation, new findings using live imaging of embryonic zebrafish and other modalities suggest that neutrophils can reverse migrate away from sites of inflammation. These ‘inflammation-sensitized’ neutrophils, as well as the neutrophil extracellular traps and other products made by neutrophils in general, may have many implications for autoimmunity. Here, we review what is known about the role of neutrophils in three different autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus, and small vessel vasculitis. We then highlight recent findings related to several cytoskeletal regulators that guide neutrophil recruitment including Lyn, Rac2, and SHIP. Finally, we discuss how our improved understanding of the molecules that control neutrophil chemotaxis may impact our knowledge of autoimmunity.     

B cells in cardiac transplants: from clinical questions to experimental models

After many years of debate, there is now general agreement that B cells can participate in the immune response to cardiac transplants. Acute antibody-mediated rejection (AMR) is the best defined manifestation of B cell responses, but diagnostic and mechanistic questions still surround AMR. Many complement dependent mechanisms of antibody-mediated injury have been elucidated. C5 has become a therapeutic target that may not just truncate complement activation, but also may tip the balance away from inflammation by altering macrophage function. Additional complement independent effects have been identified. These may escape diagnosis and progress to chronic graft injury. The function of B cell infiltrates in cardiac transplants is even more enigmatic. Nodular endocardial infiltrates that contain B cells and plasma cells have been described in protocol biopsies of cardiac transplants for decades, but an understanding of their significance is still evolving based on more critical morphological and molecular evaluation of these infiltrates. A range of infiltrates containing B cells has also been described in the epicardial fat in transplants with advanced chronic rejection. B cells have been observed in endocardial and epicardial tertiary lymphoid nodules, but their impact on antigen presentation or antibody production remains to be determined. Experimental models in small and large animals suggest that B cells could be essential for the formation of lymphoid nodules through cytokine production. Similarly, the role of proinflammatory adipokines in the formation or function of epicardial lymphoid nodules has not been studied. These clinical observations provide critical questions to be addressed in experimental models.     

The voyage to healthy longevity: from experimental models to the ultimate goal

Understanding mechanisms underlying longevity, and endeavor towards the specific goals of alleviating frailty in old age, require a comprehensive approach that considers the various theoretical and experimental approaches, as well as compiling the data on humans. This logistic has underlined the program of the conference, and is reflected in the present special issue. Considerable volume of data now point to distinct genes that are associated with exceptional longevity in humans, as reflected from the articles in this volume. However, this symposium also highlighted non-genetic effects, including physical, mental and social activities, and elucidate the relevant underlying mechanisms. The symposium focused on understanding the basis of human longevity coupled to extended health-span and function into old age.     

GW bodies: from RNA biology to clinical implications in autoimmunity

Evaluation of: Lian S, Fritzler M, Katz J et al. Small interfering RNA-mediated silencing induces target-dependent assembly of GW/P bodies. Mol. Biol. Cell 18, 3375–3387 (2007).

GW bodies (GWBs) are also known as mammalian processing bodies and are involved in 5´–3´ mRNA degradation. Conversely, siRNA is a powerful tool for silencing genes. Recently, components of RNAi have been associated with GWBs, but as more components of this complex pathway become known, such relationships remain to be clarified. This paper evaluates the induction of GWBs by siRNA transfection. The main results of these studies indicate that siRNA increased the GWBs, such an increase is also dependent on the endogenous expression of the target mRNA; siRNA increases require GW182 or Ago-2 proteins, but not rck/p54 or LSm1. Results of the present studies propose a regulatory function of RNAi in GWB assembly; therefore, cell biology implications of GWBs may open a new area in pathogenic mechanisms of autoimmunity.     

Chronic infections with viruses or parasites: breaking bad to make good

Eukaryotic forms of life have been continually invaded by microbes and larger multicellular parasites, such as helminths. Over a billion years ago bacterial endosymbionts permanently colonized eukaryotic cells leading to recognized organelles with a distinct genetic lineage, such as mitochondria and chloroplasts. Colonization of our skin and mucosal surfaces with bacterial commensals is now known to be important for host health. However, the contribution of chronic virus and parasitic infections to immune homeostasis is being increasingly questioned. Persistent infection does not necessarily equate to exhibiting a chronic illness: healthy hosts (e.g. humans) have chronic viral and parasitic infections with no evidence of disease. Indeed, there are now examples of complex interactions between these microbes and hosts that seem to confer an advantage to the host at a particular time, suggesting that the relationship has progressed along an axis from parasitic to commensal to one of a mutualistic symbiosis. This concept is explored using examples from viruses and parasites, considering how the relationships may be not only detrimental but also beneficial to the human host.     

The mechanisms of coronary restenosis: insights from experimental models

Since its introduction into clinical practice, more than 20 years ago, percutaneous transluminal coronary angioplasty (PTCA) has proven to be an effective, minimally invasive alternative to coronary artery bypass grafting (CABG). During this time there have been great improvements in the design of balloon catheters, operative procedures and adjuvant drug therapy, and this has resulted in low rates of primary failure and short-term complications. However, the potential benefits of angioplasty are diminished by the high rate of recurrent disease. Up to 40% of patients undergoing angioplasty develop clinically significant restenosis within a year of the procedure. Although the deployment of endovascular stents at the time of angioplasty improves the short-term outcome, 'in-stent' stenosis remains an enduring problem. In order to gain an insight into the mechanisms of restenosis, several experimental models of angioplasty have been developed. These have been used together with the tools provided by recent advances in molecular biology and catheter design to investigate restenosis in detail. It is now possible to deliver highly specific molecular antagonists, such as antisense gene sequences, to the site of injury. The knowledge provided by these studies may ultimately lead to novel forms of intervention. The present review is a synopsis of our current understanding of the pathological mechanisms of restenosis.     

Immunomagnetic depletion of malignant cells from autologous bone marrow graft: from experimental models to clinical trials

Using experimental modes with normal allogeneic bone marrow (BM) contaminated with Burkitt or neuroblastoma cell lines, and a liquid culture assay, we demonstrated that, when used in optimal conditions, the immunomagnetic depletion technique permitted a reproducible elimination of 3-4 log malignant cells. Results were very similar to those obtained with the complement lysis procedure in Burkitt lymphoma. This immunomagnetic procedure was used in 123 cases of autologous bone marrow transplantation (ABMT) in children with neuroblastoma. The analysis of the cases demonstrated, first, that the procedure induced a significant loss of mononuclear cells but was not toxic for BM precursors. Delays to engraftment observed in a few patients were probably due to the combination of pejorative factors, especially the damage caused to the micro-environment by previous heavy and prolonged chemotherapy or the double ABMT programme. Second, patients presented with profound T-cell defect with undetectable IL2 secretion up to 1 year post-graft but they all had normal NK functions from the first month post-graft, these functions exceeding normal values on the second and third months post-graft. Finally, in 20 cases, dual-immunofluorescence staining permitted the demonstration that the autograft contained malignant cells before purging that were eliminated by the immunomagnetic depletion.