Distinct mechanisms for cross-protection of the upper versus lower respiratory tract through intestinal priming

A main feature of the common mucosal immune system is that lymphocytes primed in one mucosal inductive site may home to distant mucosal effector sites. However, the mechanisms responsible for such cross-protection remain elusive. To address these we have used a model of local mucosal infection of mice with reovirus. In immunocompetent mice local duodenal priming protected against subsequent respiratory challenge. In the upper respiratory tract this protection appeared to be mainly mediated by specific IgA- and IgG2a-producing B cells, whereas ex vivo active effector memory CTL were found in the lower respiratory tract. In accordance with these findings, clearance of reovirus from the lower respiratory tract, but not from the upper respiratory tract, of infected SCID mice upon transfer of gut-primed lymphocytes depended on the presence of T cells. Taken together this study reveals that intestinal priming leads to protection of both the upper and lower respiratory tracts, however through distinct mechanisms. We suggest that cross-protection in the common mucosal immune system is mediated by trafficking of B cells and effector memory CTL.     

大气细颗粒物影响小鼠上、下呼吸道菌群结构

探讨影响人类健康的大气细颗粒物干扰小鼠上呼吸道和下呼吸道菌群定植及可能机制。

建立大气细颗粒物暴露的小鼠模型。BALB/c小鼠随机分为PM2.5暴露组和对照组, 每组10只。收集上呼吸道和下呼吸道灌洗液进行菌群测序分析, 并进行肺组织HE染色, 观察肺组织形态改变情况。

大气细颗粒物暴露小鼠, 破坏肺组织气血屏障结构。16S rRNA测序证实了上、下呼吸道微生态的组成因大气细颗粒物暴露而发生改变。明确了与细颗粒物暴露组相比较, 对照组的噬几丁质菌定植的丰度较高。

大气细颗粒物影响小鼠上、下呼吸道的微生态结构。研究发现的差异菌群改变将会成为新的肺损伤治疗的潜在菌群。

     

The neuronal control of the lower urinary tract: A model of architecture and control mechanisms

The human micturition cycle is controlled by central and peripheral nervous structures and connections. In literature, no complete or generally accepted model describes the principles of micturition control. In this paper, the integration of (neuro-)anatomy, (neuro-)physiology and control theory is used to describe and model the neuronal control of the lower urinary tract. Neuroanatomy supplies the most basic information necessary for the modellation of the peripheral pathways and central connections involved in the control of the uropoetic system. It is found that not all the nervous structures and connections have been identified as such yet. The linking up between several nervous structures (e.g., the presence of central and peripheral relay stations) is not completely clear. A s a consequence, each model to describe the micturition cycle from the perspective of control theory is yet of limited physiological value as it cannot exceed a rather general level of modellation. Adding functional considerations (neurophysiology and control theory) to the neuroanatomical skeleton completes the model. Some control mechanisms active during the micturition cycle can still not be revealed in detail. Crucial questions on the neuronal innervation of the human uropoetic system and the control mechanisms active during the micturition cycle remain, like how the supraspinal trigger mechanisms for micturition are organised, or how the voluntary cessation of voiding is realised. A simplified version of the model discussed in this paper can already be used for mathematical modelling, e.g., neural network simulations.     

Sex differences in lower urinary tract biology and physiology

Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review.     

The role of neutrophils in the upper and lower respiratory tract during influenza virus infection of mice

Background

Neutrophils have been shown to play a role in host defence against highly virulent and mouse-adapted strains of influenza virus, however it is not clear if an effective neutrophil response is an important factor moderating disease severity during infection with other virus strains. In this study, we have examined the role of neutrophils during infection of mice with influenza virus strain HKx31, a virus strain of the H3N2 subtype and of moderate virulence for mice, to determine the role of neutrophils in the early phase of infection and in clearance of influenza virus from the respiratory tract during the later phase of infection.

Methods

The anti-Gr-1 monoclonal antibody (mAb) RB6-8C5 was used to (i) identify neutrophils in the upper (nasal tissues) and lower (lung) respiratory tract of uninfected and influenza virus-infected mice, and (ii) deplete neutrophils prior to and during influenza virus infection of mice.

Results

Neutrophils were rapidly recruited to the upper and lower airways following influenza virus infection. We demonstrated that use of mAb RB6-8C5 to deplete C57BL/6 (B6) mice of neutrophils is complicated by the ability of this mAb to bind directly to virus-specific CD8⁺ T cells. Thus, we investigated the role of neutrophils in both the early and later phases of infection using CD8⁺ T cell-deficient B6.TAP^-/- mice. Infection of B6.TAP^-/- mice with a low dose of influenza virus did not induce clinical disease in control animals, however RB6-8C5 treatment led to profound weight loss, severe clinical disease and enhanced virus replication throughout the respiratory tract.

Conclusion

Neutrophils play a critical role in limiting influenza virus replication during the early and later phases of infection. Furthermore, a virus strain of moderate virulence can induce severe clinical disease in the absence of an effective neutrophil response.     

Adrenergic innervation of the lower urinary tract in cattle

Studies were carried out on 8 sexually immature male calves. Sections of the ureters, urinary bladder, and urethra were cut with a freezing microtome and the method of Ky?s?la et al. (1980) was used to visualize the adrenergic nerve fibres. It was found that bovine ureters possessed weak innervation; most of the nerves was located in the muscular membrane, and only in the paravesical part, sparse nerve fibres were found in the submucosa of this one. Apex of the urinary bladder was more weakly supplied with the adrenergic nerves than the corpus, whereas bladder's trigonum and cervix possessed numerous nerve fibres in both muscular and submucosal membranes. The distribution pattern of adrenergic nerves in the urethra was similar to that of urinary bladder's cervix. The presence of adregeneric nerve fibres was found in submucosal layer of both the urinary bladder and the urethra. Part of the nerves was connected with blood vessels of the organs under study.     

Interstitial cell of Cajal-like cells in the upper urinary tract

Autorhythmicity in the upper urinary tract (UUT) has long been considered to arise in specialized atypical smooth muscle cells (SMC) predominately situated in the most proximal regions of the pyeloureteric system. These atypical SMC pacemakers have been thought to trigger adjacent electrically-quiescent typical SMC to fire action potentials which allow an influx of Ca2+ and the generation of muscle contraction. More recently, the presence of cells with many of the morphological, electrical and immunohistochemical characteristics of interstitial cells of Cajal (ICC), the pacemaker cells of the gastrointestinal tract, have been located in many regions of both the upper and lower urinary tract. This article reviews the evidence from the literature and from our laboratory supporting a role of both atypical SMC and ICC-like cells in the initiation and propagation of pyeloureteric peristalsis in the UUT. We propose a new model in which there are 2 populations of pacemaker cells, high frequency atypical SMC and lower frequency ICC-like cells, both of which can drive electrically-quiescent typical SMC. The relative presence of these 2 populations of pacemaker cells and the relatively-long refractoriness of typical SMC determines the decreasing frequency of contraction with distance from the renal fornix. In the absence of the proximal pacemaker drive from atypical SMC after pyeloureteral/ureteral obstruction or surgery, ICC-like cell pacemaking provides a compensatory mechanism allowing the ureter to maintain rudimentary peristaltic waves and movement of urine from the pyelon towards the bladder.     

Sex-related differences in activity of lower urinary tract in response to intravesical acid irritation in decerebrate unanesthetized mice

Sex-related differences in lower urinary tract (LUT) activity responding to intravesical infusion of diluted acetic acid (A/A, pH 3.0) were investigated during cystometrograms in decerebrate unanesthetized mice. A/A produced a decrease of intercontraction intervals in both female and male animals, and the extent of the decrease in male mice was much less than in female mice [19 +/- 5% (P = 0.03) vs. 65 +/- 5% (P = 0.03); n = 6 for each], exhibiting a marked difference between the two groups in response to acid irritation of the LUT (P = 0.002). A/A reduced maximal voiding pressure (MVP) (19 +/- 4%, P = 0.03) but had no effect on pressure threshold for inducing voiding contraction (PT) (P = 0.56) in females, whereas A/A did not change MVP (P = 1.00) but increased PT (16 +/- 4%, P = 0.03) in males. A/A decreased bladder compliances of female and male mice in a similar fashion (44 +/- 10% vs. 24 +/- 7%, P = 0.03 for each). In male mice, A/A produced persistent dribbling of fluid after voiding contraction phase, which was virtually not seen in females. The present study demonstrates the differences between female and male mice in response to noxious stimulation in the LUT: the female bladder is more sensitive to the acid irritation, while the male urethra is more irritable to the noxious stimulus. Identification of mechanisms underlying sex-specific characteristics might be helpful for elucidating pathogenesis of painful bladder syndrome.     

Psychological aspects of lower urinary tract infections in women.

OBJECTIVE--To determine whether women with the urethral syndrome can be distinguished from those with urinary tract infection by case notes, clinical symptoms, or psychiatric state. DESIGN--Longitudinal survey of consecutive women presenting with dysuria and frequency. SETTING--General practice and community. SUBJECTS--58 patients with the urethral syndrome and 44 patients with a urinary tract infection, mean age 39.9 years. MAIN OUTCOME MEASURES--Results of analysis of serial midstream urine specimens, patients'' self rated physical symptoms and responses to 60 item general health questionnaire at presentation and after resolution of symptoms, and results of psychiatric assessment with the clinical psychiatric interview. RESULTS--4 of 42 patients with a urinary tract infection had recently changed sexual partner compared with none of 58 with the urethral syndrome. Dysuria and nocturia were more common in patients with urinary tract infections than those with the urethral syndrome (mean (SD) score for dysuria 5.37 (2.39) v 4.57 (2.13), p less than 0.05; nocturia in 39/44 (88%) patients v 40/58 (69%), chi 2 = 5.5, p less than 0.02). Both groups showed transient high levels of distress which resolved with the physical symptoms, but no psychiatric difference distinguished them. CONCLUSION--The urethral syndrome is not associated with increased psychiatric morbidity.     

Modelling crystal aggregation and deposition in the catheterised lower urinary tract

Urethral catheters often become encrusted with crystals of magnesium struvite and calcium phosphate. The encrustation can block the catheter, which can cause urine retention in the bladder and reflux into the kidneys. We develop a mathematical model to investigate crystal deposition on the catheter surface, modelling the bladder as a reservoir of fluid and the urethral catheter as a rigid channel. At a constant rate, fluid containing crystal particles of unit size enters the reservoir, and flows from the reservoir through the channel and out of the system. The crystal particles aggregate, which we model using Becker–Döring coagulation theory, and are advected through the channel, where they continue to aggregate and are deposited on the channel’s walls. Inhibitor particles also enter the reservoir, and can bind to the crystals, preventing further aggregation and deposition. The crystal concentrations are spatially homogeneous in the reservoir, whereas the channel concentrations vary spatially as a result of advection, diffusion and deposition. We investigate the effect of inhibitor particles on the amount of deposition. For all parameter values, we find that crystals deposit along the full length of the channel, with maximum deposition close to the channel’s entrance.     

Distribution of serotonin-immunoreactive paraneurons in the lower urinary tract of dogs

Morphological and quantitative studies were made on serotonin-containing paraneurons throughout the lower urinary tract in male and female dogs. Using an anti-serotonin antiserum, the cells were consistently demonstrated to be dispersed in the epithelium from the vesico-urethral junction to the external urethral ostium. They occurred most frequently in the urethra proximal to the urogenital diaphragm in both sexes. The total number of the serotonin-immunoreactive cells in the urethra was estimated to be 36.2 X 10(4) (SD 9.9 X 10(4] in the male (n = 3) and 15.6 X 10(4) (SD 2.1 X 10(4] in the female (n = 3). Besides the urethra, the prostate and vaginal vestibule contained several serotonin-immunoreactive cells. The urethral serotonin cells were basically bipolar basal-granulated cells that extended the basal cytoplasm to the basement membrane and reached the lumen with an apical process. Modified cell shapes were, however, also frequent, and included bifurcated apical and/or basal processes or a laterally directed basal process. Occasional serotonin cells possessed a threadlike basal process with varicosities and a terminal bouton, reminiscent of a neuronal process. Immunoreactivity for chromogranin A, a carrier protein common to endocrine paraneurons, was demonstrated in all of the urethral serotonin cells. The chromogranin A-immunoreactive granules accumulated more densely in the basal and perinuclear regions of the cell. It is hypothesized that the serotonin-immunopositive paraneurons may receive chemical and/or physical information from urine and, in response to it, secrete serotonin which presumably causes the contraction of the musculature of the urethra.     

Spinning top urethra and lower urinary tract dysfunction in a young female

Spinning top urethra (STU) denotes a particular urethral configuration that is a dilated posterior urethra mainly seen in young girls or women. STU deformity arises secondary to detrusor instability, leading to a rise the intravesical pressure against a closed sphincter. We describe a case of spinning top urethra in a 30-year-old woman who presented with lower urinary tract symptoms and left flank pain.     

Decision making by general practitioners in diagnosis and management of lower urinary tract symptoms in women.

OBJECTIVE--To identify factors influencing decision making by general practitioners in the diagnosis and treatment of lower urinary tract symptoms in women. SETTING--Two suburban London general practices. SUBJECTS--Women presenting to their family doctor with lower urinary tract symptoms. DESIGN--After each consultation the doctor completed a questionnaire on presenting symptoms; clinical examination; investigations undertaken; presence of psychological, social, and menstrual problems; patients'' requests for antibiotics; antibiotic prescribing; knowledge of the patient; attitude towards the consultation; and any other factors assisting in diagnosis and management. Finally, doctors predicted the presence or absence of clinically important bacteriuria. Each woman completed a demographic questionnaire, the 12 item general health questionnaire, and the modified menstrual distress questionnaire, after which each provided a clean catch midstream urine sample. Case notes were examined for information on previous reports of results of urine analysis. RESULTS--When the general practitioners did not know the patients well they were 4.5 times more likely to assume that there was a clinically important infection. When they knew the patient well, they were four times more likely to make a correct prediction of the test result and 12 times less likely to prescribe antibiotics. Doctors were five times more likely to predict the test result correctly in patients from social classes 1 and 2 and were six times more likely to prescribe antibiotics for the older women in the sample. CONCLUSIONS--In women presenting with urinary tract symptoms, these family practitioners seemed to take no particular regard of physical, psychological, or menstrual factors in making their assessments. They were most accurate in their prediction of the result of urine analysis and least likely to prescribe antibiotics when they had a good general knowledge of the patient. Which came first, the diagnosis or prescribing, is difficult to say and probably differed in individual cases. Doctors tended to be more conservative in their management of older women and those whom they knew less well.     

Cytodiagnosis of in situ and early carcinoma of the upper gastrointestinal tract

Three cases of adenocarcinoma of the stomach, two in situ and one superficially invasive, and one of superficially invasive squamous-cell carcinoma of the esophagus are presented to illustrate the problems encountered in the diagnosis of early lesions of the upper gastrointestinal (GI) tract and the contribution that cytodiagnosis can make. The symptomology and roentgenographic findings in these cases were largely nonspecific. While endoscopic biopsies were repeatedly negative in three of the four cases, endoscopic brushing cytology consistently indicated the presence of a malignancy. Surgery was finally performed on the basis of the cytologic findings, confirming the presence of early malignancy. The cytologic findings, with histologic correlations, are presented in an effort to define some specific criteria for the diagnosis of early malignancy of the upper GI tract.     

Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice

Urinary tract development depends on a complex series of events in which the ureter moves from its initial branch point on the nephric duct (ND) to its final insertion site in the cloaca (the primitive bladder and urethra). Defects in this maturation process can result in malpositioned ureters and hydronephrosis, a common cause of renal disease in children. Here, we report that insertion of the ND into the cloaca is an unrecognized but crucial step that is required for proper positioning of the ureter and that depends on Ret signaling. Analysis of Ret mutant mice at birth reveals hydronephrosis and defective ureter maturation, abnormalities that our results suggest are caused, at least in part, by delayed insertion of the ND. We find a similar set of malformations in mutants lacking either Gata3 or Raldh2. We show that these factors act in parallel to regulate ND insertion via Ret. Morphological analysis of ND extension in wild-type embryos reveals elaborate cellular protrusions at ND tips that are not detected in Ret, Gata3 or Raldh2 mutant embryos, suggesting that these protrusions may normally be important for fusion with the cloaca. Together, our studies reveal a novel Ret-dependent event, ND insertion, that, when abnormal, can cause obstruction and hydronephrosis at birth; whether ND defects underlie similar types of urinary tract abnormalities in humans is an interesting possibility.     

State of the art in intravesical therapy for lower urinary tract symptoms

Intravesical therapy is the routine first-line treatment for effectively delaying or preventing the recurrence of bladder cancer. This route of drug administration has also shown tremendous promise in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS) and potentially overactive bladder to justify investments for further improvements. This review takes a bird's eye view into the current status of intravesical therapy, with emphasis on liposomal nanoparticles, in diseases associated with lower urinary tract symptoms (LUTS). Ongoing efforts to advance the field of intravesical drug delivery include development of sustained-release drug implants and efforts to improve delivery of biotechnological products including large protein acting as neurotoxins and small interfering RNAs.