Efficacy and safety of COVID-19 vaccination in solid organ transplant recipients: A systematic review and network meta-analysis.

The impact of COVID-19 vaccination on clinical outcomes in solid organ transplant (SOT) recipients remains unclear. This systematic review and network meta-analysis sought to assess the efficacy and safety of COVID-19 vaccination in SOT recipients. We searched 6 databases from inception to March 1, 2024 for randomized controlled trials (RCTs) and observational studies evaluating different COVID-19 vaccination strategies in SOT recipients. Based on patient-important outcomes, we performed frequentist random-effects pairwise meta-analyses and network meta-analyses, separating RCTs and nonrandomized evidence, and used the Grading of Recommendation, Assessment, Development, and Evaluation approach to assess our certainty in the evidence. We included 6 RCTs (N = 814) and 43 observational studies (N = 125 199). Overall, there is a paucity of randomized evidence evaluating COVID-19 vaccines in SOT recipients. The nonrandomized evidence evaluating COVID-19 vaccination strategies patient-important outcomes, including COVID-19 infection, mortality, hospitalization, ICU admission, and rejection, demonstrated low to very low certainty due to the included studies' risk of bias. Throughout the COVID-19 pandemic, clinicians and SOT recipients worked with minimal, very low-quality evidence in relation to COVID-19 vaccines in this population. In the instance of future public health emergencies, clinicians and researchers should collaborate closely with patient partners to ensure there is sufficient evidence in the transplant population on patient-important outcomes.

The rise of Telecardiology in developing countries.

Telecardiology, the remote diagnosis and treatment of cardiac conditions, is experiencing a significant increase in developing nations. This article explores the driving forces behind this trend and its implications. Limited access to healthcare facilities, especially in rural, isolated, and underdeveloped regions, has propelled the adoption of telecardiology as a cost-effective solution to bridge the gap in cardiac care provision. Technological advancements, such as portable diagnostic devices and improvements in telecommunication infrastructure, have facilitated the expansion of telecardiology services. Moreover, the COVID-19 pandemic has accelerated the acceptance and deployment of telehealth solutions worldwide. Nevertheless, challenges persist, including regulatory hurdles, data privacy concerns, and disparities in digital literacy. Despite these obstacles, the rise of telecardiology in developing countries presents a promising opportunity to enhance access to cardiac care and improve health outcomes among underserved populations.

Clinical Features and Management of Patients Assessed by Cardiology Teleconsultation in the Brazilian Region with the Highest Number of Isolated Cities. / Características Clínicas e Manejo de Pacientes Avaliados por Teleconsulta Cardiológica na Região Brasileira com Maior Número de Cidades Isoladas.

BACKGROUND: Cardiovascular diseases are the leading cause of adult mortality. Geographically remote and low-income Brazilian regions lack specialized consultations. The telemedicine management of this population by cardiologists is not fully known. OBJECTIVES: To analyze cardiology teleconsultation in the Brazilian region with the highest number of isolated cities. METHODS: From February 2020 to October 2021, patients from the North Region of Brazil evaluated by local general practitioners were referred for cardiological evaluation by telemedicine. Referral reasons, demographics, clinical history, physical examinations, tests, medications, and prescriptions pre- and post-telemedicine were analyzed (p<0.05 was considered statistically significant). RESULTS: We analyzed 653 patients. The attendance rate was 85.7% (53.1% female, mean age: 54.2±6.5 years). The main reasons for referral were cardiovascular symptoms (58.1%) and risk factors among asymptomatic patients (13.3%). Only 12.6% had a diagnosed disease. Most patients had regular physical examinations and electrocardiograms. Few had recent complementary tests. The prescription of angiotensin receptor blockers (ARBs), calcium channel blockers and statins was significantly increased, while that of digoxin, noncardiac beta-blockers and acetylsalicylic acid (ASA) was decreased at the first teleconsultation. Most of the tests requested were of low complexity and cost: electrocardiogram (28.2%), chest X-ray (14%), echocardiogram (64.5%) and blood tests (71.8%). For 2.1% of patients, interventions were indicated, and 8% were discharged after the first consultation. CONCLUSION: On-demand cardiology teleconsultation contributes to heart disease treatment optimization. Most patients were referred with syndromic diagnoses without previous complementary tests. The specialist workup requested was usually available locally and at a low cost but precluded early discharge. Local training could optimize the referral.

FUNDAMENTO: As doenças cardiovasculares são a principal causa de morte no mundo. Regiões brasileiras geograficamente remotas e de baixa renda carecem de consultas especializadas. Não se tem conhecimento total acerca do manejo por telemedicina dessa população por parte de cardiologistas. OBJETIVOS: Analisar a teleconsulta cardiológica na região brasileira com maior número de municípios isolados. MÉTODOS: Entre fevereiro de 2020 e outubro de 2021, pacientes da Região Norte do Brasil avaliados por médicos generalistas locais foram encaminhados para avaliação cardiológica por telemedicina. Foram analisados os motivos do encaminhamento, dados demográficos, histórico clínico, exames físicos, exames complementares, medicamentos e prescrições pré e pós-telemedicina (considerou-se p<0,05 como estatisticamente significativo). RESULTADOS: Analisamos 653 pacientes. A taxa de frequência foi de 85,7% (53,1% do sexo feminino, idade média: 54,2±6,5 anos). Os principais motivos de encaminhamento foram sintomas cardiovasculares (58,1%) e fatores de risco entre pacientes assintomáticos (13,3%). Apenas 12,6% apresentava alguma doença diagnosticada. A maioria dos pacientes havia passado por exame físico e eletrocardiogramas regulares. Poucos tinham exames complementares recentes. A prescrição de bloqueadores dos receptores da angiotensina (BRA), bloqueadores dos canais de cálcio e estatinas aumentou significativamente, enquanto a de digoxina, betabloqueadores não cardíacos e ácido acetilsalicílico (AAS) diminuiu na primeira teleconsulta. A maioria dos exames complementares solicitados era de baixa complexidade e custo: eletrocardiograma (28,2%), radiografia de tórax (14%), ecocardiograma (64,5%) e exames de sangue (71,8%). Para 2,1% dos pacientes, foram indicadas intervenções, e 8% recebeu alta após a primeira consulta. CONCLUSÃO: A teleconsulta cardiológica sob demanda contribui para a otimização do tratamento das doenças cardíacas. A maioria dos pacientes foi encaminhada com diagnósticos sindrômicos sem exames complementares prévios. A avaliação especializada solicitada geralmente estava disponível localmente e com baixo custo, mas impedia a alta precoce. Capacitação local poderia otimizar o encaminhamento.

Assessment of a 3D neural spheroid model to detect pharmaceutical-induced neurotoxicity.

Drug-induced neurotoxicity is a leading cause of safety-related attrition for therapeutics in clinical trials, often driven by poor predictivity of preclinical in vitro and in vivo models of neurotoxicity. Over a dozen different iPSC-derived 3D spheroids have been described in recent years, but their ability to predict neurotoxicity in patients has not been evaluated nor compared with the predictive power of nonclinical species. To assess the predictive capabilities of human iPSC-derived neural spheroids (microBrains), we used 84 structurally diverse pharmaceuticals with robust clinical and pre-clinical datasets with varying degrees of seizurogenic and neurodegenerative liability. Drug-induced changes in neural viability and phenotypic calcium bursts were assessed using 7 endpoints based on calcium oscillation profiles and cel-lular ATP levels. These endpoints, normalized by therapeutic exposure, were used to build logistic regression models to establish endpoint cutoffs and evaluate probability for clinical neurotoxicity. The neurotoxicity score calculated from the logistic regression model could distinguish neurotoxic from non-neurotoxic clinical molecules with a specificity as high as 93.33% and a sensitivity of 53.49%, demonstrating a very low false positive rate for the prediction of seizures, convulsions, and neurodegeneration. In contrast, nonclinical species showed a higher sensitivity (75%) but much lower specificity (30.4%). The neural spheroids demonstrated higher likelihood ratio positive and inverse likelihood ratio neg-ative values compared with nonclinical safety studies. This assay has the potential to be used as a predictive assay to detect neurotoxicity in early drug discovery, aiding in the early identification of compounds that eventually may fail due to neurotoxicity.

Características Clínicas e Manejo de Pacientes Avaliados por Teleconsulta Cardiológica na Região Brasileira com Maior Número de Cidades Isoladas / Clinical Features and Management of Patients Assessed by Cardiology Teleconsultation in the Brazilian Region with the Highest Number of Isolated Cities

Resumo Fundamento As doenças cardiovasculares são a principal causa de morte no mundo. Regiões brasileiras geograficamente remotas e de baixa renda carecem de consultas especializadas. Não se tem conhecimento total acerca do manejo por telemedicina dessa população por parte de cardiologistas. Objetivos Analisar a teleconsulta cardiológica na região brasileira com maior número de municípios isolados. Métodos Entre fevereiro de 2020 e outubro de 2021, pacientes da Região Norte do Brasil avaliados por médicos generalistas locais foram encaminhados para avaliação cardiológica por telemedicina. Foram analisados os motivos do encaminhamento, dados demográficos, histórico clínico, exames físicos, exames complementares, medicamentos e prescrições pré e pós-telemedicina (considerou-se p<0,05 como estatisticamente significativo). Resultados Analisamos 653 pacientes. A taxa de frequência foi de 85,7% (53,1% do sexo feminino, idade média: 54,2±6,5 anos). Os principais motivos de encaminhamento foram sintomas cardiovasculares (58,1%) e fatores de risco entre pacientes assintomáticos (13,3%). Apenas 12,6% apresentava alguma doença diagnosticada. A maioria dos pacientes havia passado por exame físico e eletrocardiogramas regulares. Poucos tinham exames complementares recentes. A prescrição de bloqueadores dos receptores da angiotensina (BRA), bloqueadores dos canais de cálcio e estatinas aumentou significativamente, enquanto a de digoxina, betabloqueadores não cardíacos e ácido acetilsalicílico (AAS) diminuiu na primeira teleconsulta. A maioria dos exames complementares solicitados era de baixa complexidade e custo: eletrocardiograma (28,2%), radiografia de tórax (14%), ecocardiograma (64,5%) e exames de sangue (71,8%). Para 2,1% dos pacientes, foram indicadas intervenções, e 8% recebeu alta após a primeira consulta. Conclusão A teleconsulta cardiológica sob demanda contribui para a otimização do tratamento das doenças cardíacas. A maioria dos pacientes foi encaminhada com diagnósticos sindrômicos sem exames complementares prévios. A avaliação especializada solicitada geralmente estava disponível localmente e com baixo custo, mas impedia a alta precoce. Capacitação local poderia otimizar o encaminhamento.

Abstract Background Cardiovascular diseases are the leading cause of adult mortality. Geographically remote and low-income Brazilian regions lack specialized consultations. The telemedicine management of this population by cardiologists is not fully known. Objectives To analyze cardiology teleconsultation in the Brazilian region with the highest number of isolated cities. Methods From February 2020 to October 2021, patients from the North Region of Brazil evaluated by local general practitioners were referred for cardiological evaluation by telemedicine. Referral reasons, demographics, clinical history, physical examinations, tests, medications, and prescriptions pre- and post-telemedicine were analyzed (p<0.05 was considered statistically significant). Results We analyzed 653 patients. The attendance rate was 85.7% (53.1% female, mean age: 54.2±6.5 years). The main reasons for referral were cardiovascular symptoms (58.1%) and risk factors among asymptomatic patients (13.3%). Only 12.6% had a diagnosed disease. Most patients had regular physical examinations and electrocardiograms. Few had recent complementary tests. The prescription of angiotensin receptor blockers (ARBs), calcium channel blockers and statins was significantly increased, while that of digoxin, noncardiac beta-blockers and acetylsalicylic acid (ASA) was decreased at the first teleconsultation. Most of the tests requested were of low complexity and cost: electrocardiogram (28.2%), chest X-ray (14%), echocardiogram (64.5%) and blood tests (71.8%). For 2.1% of patients, interventions were indicated, and 8% were discharged after the first consultation. Conclusion On-demand cardiology teleconsultation contributes to heart disease treatment optimization. Most patients were referred with syndromic diagnoses without previous complementary tests. The specialist workup requested was usually available locally and at a low cost but precluded early discharge. Local training could optimize the referral.

Systems Biology Analysis of Temporal In vivo Brucella melitensis and Bovine Transcriptomes Predicts host:Pathogen Protein-Protein Interactions.

To date, fewer than 200 gene-products have been identified as Brucella virulence factors, and most were characterized individually without considering how they are temporally and coordinately expressed or secreted during the infection process. Here, we describe and analyze the in vivo temporal transcriptional profile of Brucella melitensis during the initial 4 h interaction with cattle. Pathway analysis revealed an activation of the "Two component system" providing evidence that the in vivo Brucella sense and actively regulate their metabolism through the transition to an intracellular lifestyle. Contrarily, other Brucella pathways involved in virulence such as "ABC transporters" and "T4SS system" were repressed suggesting a silencing strategy to avoid stimulation of the host innate immune response very early in the infection process. Also, three flagellum-encoded loci (BMEII0150-0168, BMEII1080-1089, and BMEII1105-1114), the "flagellar assembly" pathway and the cell components "bacterial-type flagellum hook" and "bacterial-type flagellum" were repressed in the tissue-associated B. melitensis, while RopE1 sigma factor, a flagellar repressor, was activated throughout the experiment. These results support the idea that Brucella employ a stealthy strategy at the onset of the infection of susceptible hosts. Further, through systems-level in silico host:pathogen protein-protein interactions simulation and correlation of pathogen gene expression with the host gene perturbations, we identified unanticipated interactions such as VirB11::MAPK8IP1; BtaE::NFKBIA, and 22 kDa OMP precursor::BAD and MAP2K3. These findings are suggestive of new virulence factors and mechanisms responsible for Brucella evasion of the host's protective immune response and the capability to maintain a dormant state. The predicted protein-protein interactions and the points of disruption provide novel insights that will stimulate advanced hypothesis-driven approaches toward revealing a clearer understanding of new virulence factors and mechanisms influencing the pathogenesis of brucellosis.

Equine histoplasmosis presenting as a tumor in the abdominal cavity.

A 3.5-year-old Thoroughbred mare presented at necropsy with a large mass at the root of the mesentery and multiple smaller mesenteric masses. The mucosa of the small intestine contained numerous raised nodules. Histologic examination revealed severe granulomatous mesenteric lymphadenitis and enteritis. Epithelioid macrophages and multinucleated giant cells frequently contained numerous intracytoplasmic yeast organisms, which were strongly positive on immunohistochemical staining when using a polyclonal antibody against Histoplasma spp. A diagnosis of abdominal histoplasmosis was made based on the gross, microscopic, and immunohistochemical findings.

Simultaneous genital ulcer and meningitis: a case of EBV infection.

The Epstein-Barr virus (EBV) is associated with a broad spectrum of diseases, mainly because of its genomic characteristics, which result in different latency patterns in immune cells and infective mechanisms. The patient described in this report is a previously healthy young man who presented to the emergency department with clinical features consistent with meningitis and genital ulcers, which raised concern that the herpes simplex virus was the causative agent. However, the polymerase chain reaction of cerebral spinal fluid was positive for EBV. The authors highlight the importance of this infection among the differential diagnosis of central nervous system involvement and genital ulceration.

Systems Analysis of Early Host Gene Expression Provides Clues for Transient Mycobacterium avium ssp avium vs. Persistent Mycobacterium avium ssp paratuberculosis Intestinal Infections.

It has long been a quest in ruminants to understand how two very similar mycobacterial species, Mycobacterium avium ssp. paratuberculosis (MAP) and Mycobacterium avium ssp. avium (MAA) lead to either a chronic persistent infection or a rapid-transient infection, respectively. Here, we hypothesized that when the host immune response is activated by MAP or MAA, the outcome of the infection depends on the early activation of signaling molecules and host temporal gene expression. To test our hypothesis, ligated jejuno-ileal loops including Peyer's patches in neonatal calves were inoculated with PBS, MAP, or MAA. A temporal analysis of the host transcriptome profile was conducted at several times post-infection (0.5, 1, 2, 4, 8 and 12 hours). When comparing the transcriptional responses of calves infected with the MAA versus MAP, discordant patterns of mucosal expression were clearly evident, and the numbers of unique transcripts altered were moderately less for MAA-infected tissue than were mucosal tissues infected with the MAP. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis. Bayesian network modeling identified mechanistic genes, gene-to-gene relationships, pathways and Gene Ontologies (GO) biological processes that are involved in specific cell activation during infection. MAP and MAA had significant different pathway perturbation at 0.5 and 12 hours post inoculation. Inverse processes were observed between MAP and MAA response for epithelial cell proliferation, negative regulation of chemotaxis, cell-cell adhesion mediated by integrin and regulation of cytokine-mediated signaling. MAP inoculated tissue had significantly lower expression of phagocytosis receptors such as mannose receptor and complement receptors. This study reveals that perturbation of genes and cellular pathways during MAP infection resulted in host evasion by mucosal membrane barrier weakening to access entry in the ileum, inhibition of Ca signaling associated with decreased phagosome-lysosome fusion as well as phagocytosis inhibition, bias toward Th2 cell immune response accompanied by cell recruitment, cell proliferation and cell differentiation; leading to persistent infection. Contrarily, MAA infection was related to cellular responses associated with activation of molecular pathways that release chemicals and cytokines involved with containment of infection and a strong bias toward Th1 immune response, resulting in a transient infection.

Concordant changes of plasma and kidney microRNA in the early stages of acute kidney injury: time course in a mouse model of bilateral renal ischemia-reperfusion.

BACKGROUND: Acute kidney injury (AKI) is a syndrome characterized by the rapid loss of the kidney excretory function and is strongly associated with increased early and long-term patient morbidity and mortality. Early diagnosis of AKI is challenging; therefore we profiled plasma microRNA in an effort to identify potential diagnostic circulating markers of renal failure. The goal of the present study was to investigate the dynamic relationship of circulating and renal microRNA profiles within the first 24 hours after bilateral ischemia-reperfusion kidney injury in mice. METHODOLOGY/PRINCIPAL FINDINGS: Bilateral renal ischemia was induced in C57Bl/6 mice (n = 10 per group) by clamping the renal pedicle for 27 min. Ischemia-reperfusion caused highly reproducible, progressive, concordant elevation of miR-714, miR-1188, miR-1897-3p, miR-877*, and miR-1224 in plasma and kidneys at 3, 6 and 24 hours after acute kidney injury compared to the sham-operated mice (n = 5). These dynamics correlated with histologic findings of kidney injury and with a conventional plasma marker of renal dysfunction (creatinine). Pathway analysis revealed close association between miR-1897-3p and Nucks1 gene expression, which putative downstream targets include genes linked to renal injury, inflammation and apoptosis. CONCLUSIONS/SIGNIFICANCE: Systematic profiling of renal and plasma microRNAs in the early stages of experimental AKI provides the first step in advancing circulating microRNAs to the level of promising novel biomarkers.

Systems biology analysis of Brucella infected Peyer's patch reveals rapid invasion with modest transient perturbations of the host transcriptome.

Brucella melitensis causes the most severe and acute symptoms of all Brucella species in human beings and infects hosts primarily through the oral route. The epithelium covering domed villi of jejunal-ileal Peyer's patches is an important site of entry for several pathogens, including Brucella. Here, we use the calf ligated ileal loop model to study temporal in vivo Brucella-infected host molecular and morphological responses. Our results document Brucella bacteremia occurring within 30 min after intraluminal inoculation of the ileum without histopathologic traces of lesions. Based on a system biology Dynamic Bayesian Network modeling approach (DBN) of microarray data, a very early transient perturbation of the host enteric transcriptome was associated with the initial host response to Brucella contact that is rapidly averted allowing invasion and dissemination. A detailed analysis revealed active expression of Syndecan 2, Integrin alpha L and Integrin beta 2 genes, which may favor initial Brucella adhesion. Also, two intestinal barrier-related pathways (Tight Junction and Trefoil Factors Initiated Mucosal Healing) were significantly repressed in the early stage of infection, suggesting subversion of mucosal epithelial barrier function to facilitate Brucella transepithelial migration. Simultaneously, the strong activation of the innate immune response pathways would suggest that the host mounts an appropriate protective immune response; however, the expression of the two key genes that encode innate immunity anti-Brucella cytokines such as TNF-α and IL12p40 were not significantly changed throughout the study. Furthermore, the defective expression of Toll-Like Receptor Signaling pathways may partially explain the lack of proinflammatory cytokine production and consequently the absence of morphologically detectable inflammation at the site of infection. Cumulatively, our results indicate that the in vivo pathogenesis of the early infectious process of Brucella is primarily accomplished by compromising the mucosal immune barrier and subverting critical immune response mechanisms.

Systems biology analysis of gene expression during in vivo Mycobacterium avium paratuberculosis enteric colonization reveals role for immune tolerance.

Survival and persistence of Mycobacterium avium subsp. paratuberculosis (MAP) in the intestinal mucosa is associated with host immune tolerance. However, the initial events during MAP interaction with its host that lead to pathogen survival, granulomatous inflammation, and clinical disease progression are poorly defined. We hypothesize that immune tolerance is initiated upon initial contact of MAP with the intestinal Peyer's patch. To test our hypothesis, ligated ileal loops in neonatal calves were infected with MAP. Intestinal tissue RNAs were collected (0.5, 1, 2, 4, 8 and 12 hrs post-infection), processed, and hybridized to bovine gene expression microarrays. By comparing the gene transcription responses of calves infected with the MAP, informative complex patterns of expression were clearly visible. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis, and genes were grouped into the specific pathways and gene ontology categories to create a holistic model. This model revealed three different phases of responses: i) early (30 min and 1 hr post-infection), ii) intermediate (2, 4 and 8 hrs post-infection), and iii) late (12 hrs post-infection). We describe here the data that include expression profiles for perturbed pathways, as well as, mechanistic genes (genes predicted to have regulatory influence) that are associated with immune tolerance. In the Early Phase of MAP infection, multiple pathways were initiated in response to MAP invasion via receptor mediated endocytosis and changes in intestinal permeability. During the Intermediate Phase, perturbed pathways involved the inflammatory responses, cytokine-cytokine receptor interaction, and cell-cell signaling. During the Late Phase of infection, gene responses associated with immune tolerance were initiated at the level of T-cell signaling. Our study provides evidence that MAP infection resulted in differentially regulated genes, perturbed pathways and specifically modified mechanistic genes contributing to the colonization of Peyer's patch.

Role of SPI-1 secreted effectors in acute bovine response to Salmonella enterica Serovar Typhimurium: a systems biology analysis approach.

Salmonella enterica Serovar Typhimurium (S. Typhimurium) causes enterocolitis with diarrhea and polymorphonuclear cell (PMN) influx into the intestinal mucosa in humans and calves. The Salmonella Type III Secretion System (T3SS) encoded at Pathogenicity Island I translocates Salmonella effector proteins SipA, SopA, SopB, SopD, and SopE2 into epithelial cells and is required for induction of diarrhea. These effector proteins act together to induce intestinal fluid secretion and transcription of C-X-C chemokines, recruiting PMNs to the infection site. While individual molecular interactions of the effectors with cultured host cells have been characterized, their combined role in intestinal fluid secretion and inflammation is less understood. We hypothesized that comparison of the bovine intestinal mucosal response to wild type Salmonella and a SipA, SopABDE2 effector mutant relative to uninfected bovine ileum would reveal heretofore unidentified diarrhea-associated host cellular pathways. To determine the coordinated effects of these virulence factors, a bovine ligated ileal loop model was used to measure responses to wild type S. Typhimurium (WT) and a ΔsipA, sopABDE2 mutant (MUT) across 12 hours of infection using a bovine microarray. Data were analyzed using standard microarray analysis and a dynamic bayesian network modeling approach (DBN). Both analytical methods confirmed increased expression of immune response genes to Salmonella infection and novel gene expression. Gene expression changes mapped to 219 molecular interaction pathways and 1620 gene ontology groups. Bayesian network modeling identified effects of infection on several interrelated signaling pathways including MAPK, Phosphatidylinositol, mTOR, Calcium, Toll-like Receptor, CCR3, Wnt, TGF-ß, and Regulation of Actin Cytoskeleton and Apoptosis that were used to model of host-pathogen interactions. Comparison of WT and MUT demonstrated significantly different patterns of host response at early time points of infection (15 minutes, 30 minutes and one hour) within phosphatidylinositol, CCR3, Wnt, and TGF-ß signaling pathways and the regulation of actin cytoskeleton pathway.

Longitudinal in vivo analysis of the region-specific efficacy of parathyroid hormone in a rat cortical defect model.

PTH has been shown to enhance fracture repair; however, exactly when and where PTH acts in this process remains to be elucidated. Therefore, we conducted a longitudinal, region-specific analysis of bone regeneration in mature, osteopenic rats using a cortical defect model. Six-month-old rats were ovariectomized, and allowed to lose bone for 2 months, before being subjected to bilateral 2-mm circular defects in their femoral diaphyses. They were then treated for 5 wk with hPTH1-38 at doses of 0, 3, 10, or 30 microg/kg . d and scanned weekly by in vivo quantitative computed tomography. Quantitative computed tomography analyses showed temporal, dose-dependent increases in mineralization in the defects, intramedullary (IM) spaces, and whole diaphyses at the defect sites. Histomorphometry confirmed PTH stimulation of primarily woven bone in the defects and IM spaces, but not the periosteum. After necropsy, biomechanical testing identified an increase in strength at the highest PTH dose. Serum procollagen type I N-terminal propeptide concentration showed a transient increase due to drilling, but procollagen type I N-terminal propeptide also increased with PTH treatment, whereas tartrate-resistant acid phosphatase unexpectedly decreased. Analyses of lumber vertebra confirmed systemic efficacy of PTH at a nonfracture site. In summary, PTH dose dependently induced new bone formation within defects, at endocortical surfaces, and in IM spaces, resulting in faster and greater bone healing, as well as efficacy at other skeletal sites. The effects of PTH were kinetic, region specific, and most apparent at high doses that may not be entirely clinically relevant; therefore, clinical studies are necessary to clarify the therapeutic utility of PTH in bone healing.

Mycobacterium bovis DeltaleuD auxotroph-induced protective immunity against tissue colonization, burden and distribution in cattle intranasally challenged with Mycobacterium bovis Ravenel S.

Bovine tuberculosis is a chronic granulomatous disease caused by Mycobacterium bovis. Lack of definitive diagnostics and effective vaccines for domestic animals are major obstacles to the control and eradication of bovine tuberculosis. Auxotrophic mutants of Mycobacterium tuberculosis have shown promise as vaccine candidates for preventing human tuberculosis. Similarly, we constructed a leucine auxotroph of M. bovis, by using allelic exchange to delete leuD (encoding isopropyl malate isomerase), creating a strain requiring exogenous leucine for growth in vitro. We vaccinated 10 cattle subcutaneously with 10(9)CFU of M. bovis DeltaleuD and 10 age-matched, gender-matched controls were injected with phosphate-buffered saline. Vaccinated cattle had significantly increased in vitro antigen-specific T-cell-mediated responses. All cattle were challenged intranasally on day 160 post-immunization with 10(6)CFU of virulent M. bovis Ravenel S. On day 160 post-challenge vaccinated cattle had significantly reduced tissue mycobacterial burdens and 6 of 10 had complete clearance of the challenge strain and histopathological lesions were dramatically less severe in the vaccinated group. Thus, a single subcutaneous immunization of the M. bovis DeltaleuD mutant produced highly significantly protective immunity as measured by a reduction in tissue colonization, burden, bacilli dissemination, and histopathology caused by virulent M. bovis Ravenel S challenge.

Imaging diagnosis--bacterial diskospondylitis in a goat.

A 3-year-old intact male Boer goat was evaluated for paraplegia. Computed tomography (CT) indicated the presence of diskospondylitis, which had previously not been reported in this species, and significant compressive myelopathy. Chronic bacterial pneumonia, epididymitis, nephritis, and soft-tissue abscesses were believed to result in hematogenous spread of bacteria to the affected disk spaces. Staphylococcus spp. and Archanobacterium pyogenes were both identified from postmortem cultures of the vertebral column.

Secreted effector proteins of Salmonella enterica serotype typhimurium elicit host-specific chemokine profiles in animal models of typhoid fever and enterocolitis.

Infection of bovine ligated loops with the Salmonella enterica serotype Typhimurium wild type but not a sipA sopABDE2 mutant resulted in fluid accumulation, polymorphonuclear cell infiltration, and expression of CXC chemokines, particularly GRO alpha. None of these sipA sopABDE2-dependent responses was observed in murine-ligated loops. The majority of GRO alpha transcripts localized to bovine intestinal epithelium. Thus, different disease outcomes between mice (i.e., no diarrhea) and calves (i.e., diarrhea) may be due to differences in sipA sopABDE2-dependent CXC chemokine gene expression in epithelial cells.