Genomic diversity and antimicrobial resistance in clinical Klebsiella pneumoniae isolates from tertiary hospitals in Southern Ghana.

OBJECTIVES: Comprehensive data on the genomic epidemiology of hospital-associated Klebsiella pneumoniae in Ghana are scarce. This study investigated the genomic diversity, antimicrobial resistance patterns, and clonal relationships of 103 clinical K. pneumoniae isolates from five tertiary hospitals in Southern Ghana-predominantly from paediatric patients aged under 5 years (67/103; 65%), with the majority collected from urine (32/103; 31%) and blood (25/103; 24%) cultures. METHODS: We generated hybrid Nanopore-Illumina assemblies and employed Pathogenwatch for genotyping via Kaptive [capsular (K) locus and lipopolysaccharide (O) antigens] and Kleborate (antimicrobial resistance and hypervirulence) and determined clonal relationships using core-genome MLST (cgMLST). RESULTS: Of 44 distinct STs detected, ST133 was the most common, comprising 23% of isolates (n = 23/103). KL116 (28/103; 27%) and O1 (66/103; 64%) were the most prevalent K-locus and O-antigen types. Single-linkage clustering highlighted the global spread of MDR clones such as ST15, ST307, ST17, ST11, ST101 and ST48, with minimal allele differences (1-5) from publicly available genomes worldwide. Conversely, 17 isolates constituted novel clonal groups and lacked close relatives among publicly available genomes, displaying unique genetic diversity within our study population. A significant proportion of isolates (88/103; 85%) carried resistance genes for ≥3 antibiotic classes, with the blaCTX-M-15 gene present in 78% (n = 80/103). Carbapenem resistance, predominantly due to blaOXA-181 and blaNDM-1 genes, was found in 10% (n = 10/103) of the isolates. CONCLUSIONS: Our findings reveal a complex genomic landscape of K. pneumoniae in Southern Ghana, underscoring the critical need for ongoing genomic surveillance to manage the substantial burden of antimicrobial resistance.

Musculoskeletal injuries in real tennis.

Introduction: Real tennis is a growing, unique, and well-established sport. To date, there has been no epidemiological data on real tennis injuries. The primary aim of this retrospective study is to record the incidence and document any trends in real tennis musculoskeletal injuries, so as to improve injury awareness of common and possibly preventable injuries. Methods: A surveillance questionnaire e-mailed to 2,036 Tennis & Rackets Association members to retrospectively capture injuries sustained by amateur and professional real tennis players over their playing careers. Results: A total of 485 (438 males and 47 females) questionnaires were fully completed over 4 weeks. A total of 662 musculoskeletal injuries were recorded with a mean of 1.4 injuries per player (range 0-7). The incidence of sustaining an acute real tennis musculoskeletal injury is 0.4/1000 hrs. The three main anatomical locations reported injured were elbow 15.6% (103/662), knee 11.6% (77/662), and face 10.0% (66/662). The most common structures reported injured were muscle 24% (161/661), tendon 23.4% (155/661), ligament 7.0% (46/661), soft tissue bruising 6.5% (43/661), and eye 6.2% (41/661). The majority of the upper limb injuries were gradual onset (64.7%, 143/221), and the lower limb injuries were sudden onset (72.0%, 188/261). Conclusion: This study uniquely provides valuable preliminary data on the incidence and patterns of musculoskeletal injuries in real tennis players. In addition, it highlights a number of reported eye injuries. The study is also a benchmark for future prospective studies on academy and professional real tennis players.

The experiences of women receiving brachytherapy for cervical cancer: A systematic literature review.

OBJECTIVES: To determine women's experiences of brachytherapy for cervical cancer. KEY FINDINGS: Nineteen studies were included for data extraction/synthesis. Twelve studies focussed on psychological issues, seven on pharmacological aspects of women's experiences. Themes of anxiety, distress, pain, informational needs and non-pharmacological interventions were found. Nine out of ten psychological studies described brachytherapy as a distressing experience causing anxiety and distress for most women. Non-pharmacological interventions were found to be effective and inexpensive adjuncts. Peri and post-operative pharmacological management was variable, but duration of procedure was an important factor. CONCLUSION: Brachytherapy for gynaecological cancer causes varying levels of pain, anxiety and distress. To improve women's experiences there needs to be better pain management, patient information and the development of non-pharmacological interventions. Future recommendations are to develop clinical support guidelines, audit the quality of services and develop effective interventions to improve women's experiences of brachytherapy for locally advanced cervical cancer.

Heritable plant phenotypes track light and herbivory levels at fine spatial scales.

Organismal phenotypes often co-vary with environmental variables across broad geographic ranges. Less is known about the extent to which phenotypes match local conditions when multiple biotic and abiotic stressors vary at fine spatial scales. Bittercress (Brassicaceae: Cardamine cordifolia), a perennial forb, grows across a microgeographic mosaic of two contrasting herbivory regimes: high herbivory in meadows (sun habitats) and low herbivory in deeply shaded forest understories (shade habitats). We tested for local phenotypic differentiation in plant size, leaf morphology, and anti-herbivore defense (realized resistance and defensive chemicals, i.e., glucosinolates) across this habitat mosaic through reciprocal transplant-common garden experiments with clonally propagated rhizomes. We found habitat-specific divergence in morphological and defensive phenotypes that manifested as contrasting responses to growth in shade common gardens: weak petiole elongation and attenuated defenses in populations from shade habitats, and strong petiole elongation and elevated defenses in populations from sun habitats. These divergent phenotypes are generally consistent with reciprocal local adaptation: plants from shade habitats that naturally experience low herbivory show reduced investment in defense and an attenuated shade avoidance response, owing to its ineffectiveness within forest understories. By contrast, plants from sun habitats with high herbivory show shade-induced elongation, but no evidence of attenuated defenses canonically associated with elongation in shade-intolerant plant species. Finally, we observed differences in flowering phenology between habitat types that could potentially contribute to inter-habitat divergence by reducing gene flow. This study illuminates how clonally heritable plant phenotypes track a fine-grained mosaic of herbivore pressure and light availability in a native plant.

Spring Migration Stopover Ecology of Avian Influenza Virus Shorebird Hosts at Delaware Bay.

Although low pathogenicity avian influenza viruses (LPAIV) are detected in shorebirds at Delaware Bay annually, little is known about affected species habitat preferences or the movement patterns that might influence virus transmission and spread. During the 5-wk spring migration stopover period during 2007-2008, we conducted a radiotelemetry study of often-infected ruddy turnstones (Arenaria interpres morinella; n = 60) and rarely infected sanderlings (Calidris alba; n = 20) to identify locations and habitats important to these species (during daytime and nighttime), determine the extent of overlap with other AIV reservoir species or poultry production areas, reveal possible movements of AIV around the Bay, and assess whether long-distance movement of AIV is likely after shorebird departure. Ruddy turnstones and sanderlings both fed on Bay beaches during the daytime. However, sanderlings used remote sandy points and islands during the nighttime while ruddy turnstones primarily used salt marsh harboring waterfowl and gull breeding colonies, suggesting that this environment supports AIV circulation. Shorebird locations were farther from agricultural land and poultry operations than were random locations, suggesting selection away from poultry. Further, there was no areal overlap between shorebird home ranges and poultry production areas. Only 37% (22/60) of ruddy turnstones crossed into Delaware from capture sites in New Jersey, suggesting partial site fidelity and AIV gene pool separation between the states. Ruddy turnstones departed en masse around June 1 when AIV prevalence was low or declining, suggesting that a limited number of birds could disperse AIV onto the breeding grounds. This study provides needed insight into AIV and migratory host ecology, and results can inform both domestic animal AIV prevention and shorebird conservation efforts.

[The 2014 consensus conference of the ISUP on Gleason grading of prostatic carcinoma]. / Konsenskonferenz 2014 der ISUP zur Gleason-Graduierung des Prostatakarzinoms.

In 2005 the International Society of Urological Pathology (ISUP) held a concensus conference on Gleason grading in order to bring this grading system up to the current state of contemporary practice; however, it became clear that further modifications on the grading of prostatic carcinoma were necessary. The International Society of Urological Pathology therefore held a further consensus conference in 2014 to clarify these points. This article presents the essential results of the Chicago grading meeting.

NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence.

Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive owing to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found the upregulation of nuclear factor of activated T cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1ß, IL6 and SPP1 (osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten null-driven prostate tumorigenesis by overcoming the PTEN loss-induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa.

Evidence-Based Medicine as a Tool for Undergraduate Probability and Statistics Education.

Most students have difficulty reasoning about chance events, and misconceptions regarding probability can persist or even strengthen following traditional instruction. Many biostatistics classes sidestep this problem by prioritizing exploratory data analysis over probability. However, probability itself, in addition to statistics, is essential both to the biology curriculum and to informed decision making in daily life. One area in which probability is particularly important is medicine. Given the preponderance of pre health students, in addition to more general interest in medicine, we capitalized on students' intrinsic motivation in this area to teach both probability and statistics. We use the randomized controlled trial as the centerpiece of the course, because it exemplifies the most salient features of the scientific method, and the application of critical thinking to medicine. The other two pillars of the course are biomedical applications of Bayes' theorem and science and society content. Backward design from these three overarching aims was used to select appropriate probability and statistics content, with a focus on eliciting and countering previously documented misconceptions in their medical context. Pretest/posttest assessments using the Quantitative Reasoning Quotient and Attitudes Toward Statistics instruments are positive, bucking several negative trends previously reported in statistics education.

Feasibility of bioethanol production from tubers of Dioscorea sansibarensis and Pyrenacantha kaurabassana.

Inedible tubers from Dioscorea sansibarensis (DS) and Pyrenacantha kaurabassana (PK) were found to be suitable feedstock for bioethanol production. Important composition parameters for bioethanol production for DS and PK are dry matter (% fresh tubers) ca. 20 and 6, total carbohydrates % dry weight base (db) ca. 68 and 47 and total protein (% db) ca. 16 and 10, respectively. DS and PK were found to contain inulin and galactomannan as principal polysaccharides (% of total carbohydrate) ca. 90 and 70, respectively. Diluted acid hydrolysis yielded ca. 100% of total reducing sugars. Ethanol yield ca. 56 and 35g/L was obtained at high efficiency through batch fermentation of acid hydrolysate (25% w/v) of DS and PK, respectively. A simple technique of recording and monitoring ethanol through CO2 generated during fermentation correlated strongly with HPLC measurement R(2)=0.99. Thus, tubers from these plants are potential feedstocks for bioethanol production with no competing uses.

Vaginal vault brachytherapy in endometrial cancer: verifying target coverage with image-guided applicator placement.

OBJECTIVE: This quality assurance study assesses whether CT image-guided verification has led to improvements in the technique when compared with previous studies. METHODS: The CT images were studied from a cohort of 105 consecutive patients with endometrial cancer having adjuvant brachytherapy to the vaginal vault in 2010. Images were taken at first insertion, checked for air gaps and treatment delivered. Images were later transferred to the planning system and air gaps between vaginal mucosa and vaginal cylinder were measured. Comparisons were made with the 2008 results from this centre and the literature series. RESULTS: Images from two patients were not assessable owing to artefacts from hip replacements. Air gaps >2 mm were seen in 11/103 patients. Repositioning or use of a larger cylinder reduced air gaps to 7/103 patients. In total, 96/103 patients (over 93%) were able to achieve good vaginal contact throughout the treatment volume. This shows a significant improvement in applicator positioning in our centre since 2008 and also a significant improvement over the total data published in 2010 (Pearson χ(2) test=46.19; p<0.0001). CONCLUSION: The vaginal cylinder technique with CT imaging was proven to be effective for 96/103 patients. It is necessary to consider whether there is a better technique for the few patients with air gaps >2 mm. ADVANCES IN KNOWLEDGE: For the vast majority of patients, this technique is well tolerated, without the need for analgesia, and will continue to be the first choice technique in this centre.

Investigation into a new softening agent for use on formalin-fixed, paraffin wax-embedded tissue.

The use of tissue softening agents to improve microtomy of keratotic tissues is employed widely. Many of these softeners contain hazardous constituents such as phenol. In this study, the use of non-ionic surfactants or non-toxic ingredients are investigated with the aim of creating a new softening agent. The new agent should be more effective in facilitating the sectioning of hardened tissue while reducing toxicity and complications associated with sectioning hard tissue compared to a commercially available phenol-based formulation. Four formulations are compared against the commercial product for their capability to section routinely processed paraffin-embedded tissue under standard operating procedure parameters. The trial formulations were shown to be fast acting and enabled improved serial sectioning of hard keratotic tissue in nearly all the cases tested. There was no evidence of adverse staining using either tinctorial or immunohistochemical methods. The new formulations had advantages over the commercially available solutions, improving on the number and quality of sections attainable from the tissue blocks, as well as offering a composition less toxic than phenol-based products.

Loss of Nkx3.1 leads to the activation of discrete downstream target genes during prostate tumorigenesis.

The expression of NKX3.1, a transcriptional regulator and tumor suppressor gene in prostate cancer, is downregulated during early stages of prostate tumorigenesis. However, little is known of the alterations in gene expression that occur as a result of this event. We combined laser capture microdissection and gene expression profiling to analyse the molecular consequences of Nkx3.1 loss during prostate cancer initiation using Nkx3.1-deficient mice. This analysis identified a cohort of genes (loss-of-Nkx3.1 signature) that are aberrantly overexpressed during loss-of-Nkx3.1-driven tumor initiation. We studied the expression of these genes in independent loss-of-Pten and c-myc overexpression prostate adenocarcinoma mouse models. Nkx3.1 expression is lost in prostate epithelial proliferation in both of these mouse models. However, Nkx3.1 loss is an early event of tumor development in the loss-of-Pten model, whereas it occurs at later stages in c-myc transgenic mice. A number of genes of the loss-of-Nkx3.1 signature, such as clusterin and quiescin Q6, are highly expressed in prostatic hyperplasia and intraepithelial neoplasia (PIN) lesions that also lack Nkx3.1 in the Pten-deficient prostate, but not in similar lesions in the c-myc transgenic model. Meta-analysis of multiple prostate cancer gene expression data sets, including those from loss-of-Nkx3.1, loss-of-Pten, c-myc overexpression and constitutively active Akt prostate cancer models, further confirmed that genes associated with the loss-of-Nkx3.1 signature integrate with PTEN-AKT signaling pathways, but do not overlap with molecular changes associated with the c-myc signaling pathway. In human prostate tissue samples, loss of NKX3.1 expression and corresponding clusterin overexpression are co-localized at sites of prostatic inflammatory atrophy, a possible very early stage of human prostate tumorigenesis. Collectively, these results suggest that the molecular consequences of NKX3.1 loss depend on the epithelial proliferative stage at which its expression is lost, and that alterations in the PTEN-AKT-NKX3.1 axis are important for prostate cancer initiation.

Prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue.

AIMS: Predicting prostatic cancer patients' outcome is a major objective for clinicians and patients. Several nomograms are currently implemented prior to treatment to help predict clinical and pathological outcome. The aim of this study was to investigate the prognostic significance of morphometric measurements of cancer on the needle biopsy specimen in relation to the final pathological stage or the biochemical failure status following radical prostatectomy, and to determine which measurement of tumour length in cases with discontinuous foci of cancer (DFC) is most reliably reflective of the pathological stage. METHODS AND RESULTS: Of the 100 patients included in this study, 34% had high-stage disease (pT >or= 3 and/or pN1) and 16% experienced biochemical recurrence. The analysis showed that fraction of positive cores, total percentage of cancer and both total and greatest millimetric cancer lengths were the variables most closely associated with pathological stage and biochemical failure status. CONCLUSIONS: This study confirms the prognostic value of recording tumour extent in prostatic needle biopsy reporting. However, the results are inconclusive in determining the best method to record tumour length in cores with DFC and larger studies are needed to answer this question fully.

The in vivo gastrointestinal activity of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity.

The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal pro-kinetic agents, tegaserod, cisapride and mosapride. The activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT(4) receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.

The in vitro pharmacological profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity.

The in vitro pharmacological profile of TD-5108, a novel, selective 5-HT(4) receptor agonist, was compared to that of clinically efficacious gastroprokinetic 5-HT(4) receptor agonists. TD-5108 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptor (pEC(50) = 8.3) and 5-HT(4) receptor-mediated relaxation of the rat esophagus (pEC(50) = 7.9) and contraction of the guinea pig colon (pEC(50) = 7.9). In all in vitro assays, TD-5108 was a high intrinsic activity agonist, unlike tegaserod, mosapride, and cisapride which, in the majority of test systems, had lower intrinsic activity. TD-5108 had high affinity (pK (i) = 7.7) and selectivity (> or =25-fold) for h5-HT(4(c)) receptors over other biogenic amine receptors. TD-5108 was >500-fold selective over other 5-HT receptors (including h5-HT(2B) and h5-HT(3A)) and, at 3 microM, had no effect on human ether-à-go-go-related gene K+ channels. In conclusion, TD-5108 is a selective 5-HT(4) receptor agonist in vitro. The high intrinsic activity and preferential binding of TD-5108 to 5-HT4 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility.

Safety of an attenuated West Nile virus vaccine, live Flavivirus chimera in horses.

REASON FOR PERFORMING STUDY: West Nile virus (WNV) infection is endemic and able to cause disease in naive hosts. It is necessary therefore to evaluate the safety of new vaccines. OBJECTIVES: To establish: 1) the safety of a modified live Flavivirus/West Nile virus (WN-FV) chimera by administration of an overdose and testing for shed of vaccine virus and spread to uninoculated sentinel horses; 2) that this vaccine did not become pathogenic once passaged in horses; and 3) vaccine safety under field conditions. METHODS: There were 3 protocols: 1) In the overdose/shed and spread study, horses were vaccinated with a 100x immunogenicity overdose of WN-FV chimera vaccine and housed with sentinel horses. 2) A reversion to virulence study, where horses were vaccinated with a 20x immunogenicity overdose of WN-FV chimera vaccine. Horses in both studies were evaluated for abnormal health conditions and samples obtained to detect virus, seroconversion and dissemination into tissues. 3) In a field safety test 919 healthy horses of various ages, breeds and sex were used. RESULTS: Vaccination did not result in site or systemic reactions in either experimental or field-injected horses. There was no shed of vaccine virus, no detection of vaccine virus into tissue and no reversion to virulence with passage. CONCLUSIONS: WN-FV chimera vaccine is safe to use in horses with no evidence of ill effects from very high doses of vaccine. There was no evidence of reversion to virulence. In addition, administration of this vaccine to several hundred horses that may have been previously exposed to WNV or WNV vaccine resulted in no untoward reactions. POTENTIAL RELEVANCE: These studies establish that this live attenuated Flavivirus chimera is safe to use for immunoprophylaxis against WNV disease in horses.

Efficacy, duration, and onset of immunogenicity of a West Nile virus vaccine, live Flavivirus chimera, in horses with a clinical disease challenge model.

REASON FOR PERFORMING STUDY: West Nile virus (WNF) is a Flavivirus responsible for a life-threatening neurological disease in man and horses. Development of improved vaccines against Flavivirus infections is therefore important. OBJECTIVES: To establish that a single immunogenicity dose of live Flavivirus chimera (WN-FV) vaccine protects horses from the disease and it induces a protective immune response, and to determine the duration of the protective immunity. METHODS: Clinical signs were compared between vaccinated (VACC) and control (CTRL) horses after an intrathecal WNV challenge given at 10 or 28 days, or 12 months post vaccination. RESULTS: Challenge of horses in the immunogenicity study at Day 28 post vaccination resulted in severe clinical signs of WNV infection in 10/10 control (CTRL) compared to 1/20 vaccinated (VACC) horses (P<0.01). None of the VACC horses developed viraemia and minimal histopathology was noted. Duration of immunity (DPI) was established at 12 months post vaccination. Eight of 10 CTRL exhibited severe clinical signs of infection compared to 1 of 9 VACC horses (P<0.05). There was a significant reduction in the occurrence of viraemia and histopathology lesion in VACC horses relative to CTRL horses. Horses challenged at Day 10 post vaccination experienced moderate or severe clinical signs of WNV infection in 3/3 CTRL compared to 5/6 VACC horses (P<0.05). CONCLUSIONS: This novel WN-FV chimera vaccine generates a protective immune response to WNV infection in horses that is demonstrated 10 days after a single vaccination and lasts for up to one year. POTENTIAL RELEVANCE: This is the first USDA licensed equine WNV vaccine to utilise a severe challenge model that produces the same WNV disease observed under field conditions to obtain a label claim for prevention of viraemia and aid in the prevention of WNV disease and encephalitis with a duration of immunity of 12 months.

Comparative efficacies of three commercially available vaccines against West Nile Virus (WNV) in a short-duration challenge trial involving an equine WNV encephalitis model.

We used a severe challenge model that produces clinical West Nile virus (WNV) disease to test the efficacy of three commercially available equine WNV vaccines in horses. Twenty-four healthy, WNV-seronegative horses of varying ages and genders were placed, in random and blind manner, into three trial groups consisting of eight horses each; two horses in each group received (i) an inactivated WNV vaccine (K-WN), (ii) a modified-live vaccine (CP-WN) containing the WNV prM and E proteins expressed by a canarypox vector, (iii) a live-chimera vaccine (WN-FV) containing WNV prM and E proteins expressed in a YF17D vector, or (iv) a diluent control. Challenge by this model caused grave neurological signs, viremia, moderate to severe histopathologic lesions in the brain and spinal cord, and an outcome of 0% survivorship in all six control horses. In contrast, challenge in horses at between 28 days postvaccination with the chimera vaccine and 56 days postvaccination with the commercial inactivated or modified-live vaccine resulted in 100% survivorship (protection from the onset of WNV encephalitis and viremia). Horses vaccinated with the live-chimera vaccine showed significantly fewer clinical signs than did the control horses (P

Segmental disorders of the nephron: histopathological and imaging perspective.

Recent advances in molecular genetics and immunocytochemistry have clarified the cell of origin in many renal disorders. Several renal disorders are thought to involve specific segments of the nephron. Renin-secreting tumours arise from juxtaglomerular cells. Clear cell and papillary renal cell carcinoma (RCC) recapitulate the epithelium of the proximal tubules. Oncocytoma and chromophobe RCC differentiate towards Type A and Type B intercalated cells of the cortical collecting duct, respectively. Medullary collecting ducts are the target sites for the development of autosomal recessive polycystic kidney disease, collecting duct carcinoma and medullary carcinoma. Renal papillae are susceptible to unique changes such as necrosis or papillitis. The purpose of our article is threefold: to illustrate the imaging findings of renal disorders that show segmental involvement of the nephron, to describe proximal and distal nephron disorders and to correlate imaging findings of some entities with histopathological features.

A comparison of the pharmacological properties of guinea-pig and human recombinant 5-HT4 receptors.

BACKGROUND AND PURPOSE: 5-HT(4) receptor agonists are used therapeutically to treat disorders of reduced gastrointestinal motility. Since such compounds are evaluated in guinea-pigs, we cloned, expressed and pharmacologically characterized the guinea-pig 5-HT(4) and human 5-HT(4(b)) splice variant, which share 95% homology. The functional properties of guinea-pig 5-HT(4(b)) receptors were compared with native receptors in guinea-pig colon. EXPERIMENTAL APPROACH: Membrane radioligand binding and whole cell cAMP accumulation assays were used to determine the affinities, potencies and intrinsic activities (IA). Contraction of the guinea-pig distal colon longitudinal muscle myenteric plexus preparation (LMMP) was monitored to evaluate functional activity. KEY RESULTS: pK(i) values for guinea-pig and human recombinant receptors, and guinea-pig striatum 5-HT(4) receptors, were in agreement, as were the potency and IA values for guinea-pig and human 5-HT(4) receptors expressed at a similar density ( approximately 0.2 pmol mg(-1) protein). Tegaserod was a potent (pEC(50)=8.4 and 8.7, respectively), full agonist at both guinea-pig and human 5-HT(4) receptors. In contrast, in the LMMP preparation, tegaserod was a potent, partial agonist (pEC(50)=8.2; IA=66%). CONCLUSIONS AND IMPLICATIONS: Close agreement between the pharmacological properties of guinea-pig and human 5-HT(4) receptors support the use of guinea-pig model systems for the identification of 5-HT(4) receptor therapeutics. However, the mechanisms underlying the different agonist properties of tegaserod in recombinant and isolated tissue preparations, and the extent to which these impact the clinical efficacy of tegaserod as a prokinetic agent, remain to be determined.