Predicting outbreaks: a spatial risk assessment of West Nile virus in British Columbia

Background  

West Nile virus (WNv) has recently emerged as a health threat to the North American population. After the initial disease outbreak in New York City in 1999, WNv has spread widely and quickly across North America to every contiguous American state and Canadian province, with the exceptions of British Columbia (BC), Prince Edward Island and Newfoundland. In this study we develop models of mosquito population dynamics for Culex tarsalis and C. pipiens, and create a spatial risk assessment of WNv prior to its arrival in BC by creating a raster-based mosquito abundance model using basic geographic and temperature data. Among the parameters included in the model are spatial factors determined from the locations of BC Centre for Disease Control mosquito traps (e.g., distance of the trap from the closest wetland or lake), while other parameters were obtained from the literature. Factors not considered in the current assessment but which could influence the results are also discussed.     

Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection

BackgroundDeveloping a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.MethodsUsing 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.ResultsAn exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell–mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature’s negative predictive value was 90.6% and its positive predictive value was 77.8%.ConclusionsOur findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.     

Impact of acute rejection therapy on infections and malignancies in renal transplant recipients

BACKGROUND: Infections and malignancies are important causes of mortality and morbidity in renal allograft recipients. Their risk increases with increasing immunosuppression. METHODS: In an attempt to quantitate the increase in the risk of these complications in association with antirejection therapy, we reviewed the records of all renal allograft recipients of our center transplanted during the cyclosporin era. We sub-divided the patients into three groups based on acute rejection episodes during the first 6 months posttransplant, and the treatment for acute rejection: those who did not develop AR--group 1 (n=168); those who had one or more episodes of acute rejection and were treated with high dose corticosteroids --group 2 (n=169); those who in addition to corticosteroids required cytolytics (OKT3) and/or other drugs--group 3 (n=141). RESULTS: 52% patients in group 1, 71% patients in group 2 and 86% patients in group 3 had one or more episodes of infection during the first 6 months posttransplantation. Relative risk for group 2 and 3 were 1.56 (P=0.0002) and 2.98 (P<0.00001), respectively. Infection/patient rates at 6 months were 0.67, 1.23, and 2.79 in groups 1, 2, and 3 respectively. Groups 1 and 2 had a similar number of cases with squamous and basal cell carcinoma, however, there were few cases with these malignancies in group 3. No case of lymphoma was seen in group 1; there were four cases in group 2 and nine in group 3. There was no significant difference in patient survival in group 1 and 2, however, patients in group 3 had a reduced patient survival (1 vs. 3 P<0.001, 2 vs. 3 P=0.067). Graft survival was best in group 1 and worst in group 3 (1 vs. 2 P<0.05; 1 vs. 3 P<0.00001; 2 vs. 3 P<0.01). CONCLUSIONS: In renal transplant recipients the risk of infections and lymphoma increases with increasing immunosuppression and hence mortality and morbidity associated with it. When adding a potent immunosuppressive agent to rescue a kidney one needs to consider the serious and at times fatal side effects given the modest beneficial effect on long-term outcome.     

The Correlation Between the New Rigiscan Plus Software and the Final Diagnosis in the Evaluation of Erectile Dysfunction

Purpose

The computer generated recordings for 2 nights in 40 patients studied with the RigiScan^† device were reevaluated using the new RigiScan Plus software to test its value in improving the discrimination between psychogenic and organic erectile dysfunction.

Materials and Methods

Each man was evaluated for erectile dysfunction with a detailed medical and sexual history, physical examination, biothesiometry, plethysmography, 2 nights of ambulatory RigiScan monitoring and a psychological evaluation that usually included a private interview with the sexual partner. At the conclusion of evaluation each patient was broadly classified as having organic or psychogenic erectile dysfunction. The RigiScan reports were initially independently analyzed without the investigator's knowledge of the final diagnosis by determining the single best erectile event, with a minimal cutoff value of 60 percent erection for 5 minutes as necessary to be considered normal and the sum of measurements from the 2 nights. The original reading and final diagnosis were correlated. At this point the data were processed with the new RigiScan Plus software using 2 new measurements: 1) rigidity activity units and 2) tumescence activity units at the base and tip of the penis, and the results were correlated with the final diagnosis.

Results

Evaluation of the single best event again showed that tip rigidity was the best single predictor if the diagnostic criteria were modified to 70 percent tip rigidity for 5 minutes with an estimate of correct classification of 92.5 percent. Nearly the same accuracy was obtained by base single event rigidity, tip rigidity and base tumescence activity units (each 90 percent). The summary analysis of all erectile events during the 2 nights of evaluation that had a low correlation with the final diagnosis using the original software showed that the best overall predictor of final diagnosis was tip tumescence activity units (92.5 percent), followed by base rigidity and tumescence activity units (each 90 percent).

Conclusions

The RigiScan Plus software introduced 4 new parameters that facilitate interpretation of the RigiScan data. The new software did not improve the correlation with the final diagnosis compared to the subjective single best event analysis but added new objective parameters, measured and displayed by the software, that facilitate use of the data by the physician.     

A cervical ectopic masquerading as a molar pregnancy

We report a case of cervical pregnancy complicated by life threatening hemorrhage. An initial diagnosis of molar pregnancy was made preoperatively. During uterine evacuation she developed profuse hemorrhage which required an emergency hysterectomy for uncontrolled bleeding. Histopathological examination confirmed a cervical pregnancy. The clinical and pathological criteria for the diagnosis and the etiology of cervical pregnancy are discussed.     

Trio engagement via plasma membrane phospholipids and the myristoyl moiety governs HIV-1 matrix binding to bilayers

Localization of the HIV type-1 (HIV-1) Gag protein on the plasma membrane (PM) for virus assembly is mediated by specific interactions between the N-terminal myristoylated matrix (MA) domain and phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P₂]. The PM bilayer is highly asymmetric, and this asymmetry is considered crucial in cell function. In a typical mammalian cell, the inner leaflet of the PM is enriched in phosphatidylserine (PS) and phosphatidylethanolamine (PE) and contains minor populations of phosphatidylcholine (PC) and PI(4,5)P₂. There is strong evidence that efficient binding of HIV-1 Gag to membranes is sensitive not only to lipid composition and net negative charge, but also to the hydrophobic character of the acyl chains. Here, we show that PS, PE, and PC interact directly with MA via a region that is distinct from the PI(4,5)P₂ binding site. Our NMR data also show that the myristoyl group is readily exposed when MA is bound to micelles or bicelles. Strikingly, our structural data reveal a unique binding mode by which the 2′-acyl chain of PS, PE, and PC lipids is buried in a hydrophobic pocket whereas the 1′-acyl chain is exposed. Sphingomyelin, a major lipid localized exclusively on the outer layer of the PM, does not bind to MA. Our findings led us to propose a trio engagement model by which HIV-1 Gag is anchored to the PM via the 1′-acyl chains of PI(4,5)P₂ and PS/PE/PC and the myristoyl group, which collectively bracket a basic patch projecting toward the polar leaflet of the membrane.     

Pneumonia‐induced sepsis in mice: temporal study of inflammatory and cardiovascular parameters

The aim of the present work is to provide a better comprehension of the pneumonia‐induced sepsis model through temporal evaluation of several parameters, and thus identify the main factors that determine mortality in this model. Klebsiella pneumoniae was inoculated intratracheally in anesthetized Swiss male mice. Inflammatory and cardiovascular parameters were evaluated 6, 24 and 48 h after the insult. The results show that severity of infection and the mortality correlated with the amount of bacteria. Six, 24 and 48 h after inoculation, animals presented pathological changes in lungs, increase in cell number in the bronchoalveolar lavage, leukopenia, increase in TNF‐α and IL‐1β levels, hypotension and hyporesponsiveness to vasoconstrictors, the two latter characteristics of severe sepsis and septic shock. Significant numbers of bacteria in spleen and heart homogenates indicated infection spreading. Interestingly, NOS‐2 expression appeared late after bacteria inoculation, whereas levels of NOS‐1 and NOS‐3 were unchanged. The high NOS‐2 expression coincided with an exacerbated NO production in the infection focus and in plasma, as judging by nitrate + nitrite levels. This study shows that K. pneumoniae inoculation induces a systemic inflammatory response and cardiovascular alterations, which endures at least until 48 h. K. pneumoniae‐induced lung infection is a clinically relevant animal model of sepsis and a better understanding of this model may help to increase the knowledge about sepsis pathophysiology.     

Articular Ultrasound in Asymptomatic Volunteers: Identification of the Worst Measures of Synovial Hypertrophy,Synovial Blood Flow and Joint Damage Among Small-, Medium- and Large-Sized Joints

Articular ultrasound of 6500 joint recesses was performed for the purpose of identifying which joint had the highest measurements among small-sized (SSJ), medium-sized (MSJ) and large-sized (LSJ) joints. Quantitative measurements of synovial hypertrophy (QSR) and semiquantitative measurements of synovial hypertrophy (SSH), power Doppler (SPD) and bone erosion (SBE) (score: 0–3) were made. Higher measurements (p < 0.01) of QSR were obtained in the second metatarsophalangeal joint (MTP), talonavicular joint, and hip. The highest SSH scores (2/3) were obtained in the second MTP, talonavicular joint, hip and knee; the highest SPD scores (1/2/3) in the first MTP, second MTP, dorsal second metacarpophalangeal (MCP) and radiocarpal recesses; and the highest SBE scores (2/3) in the radiocarpal, ulnocarpal and posterior recesses of the glenohumeral joint. In conclusion, higher measurements of synovial hypertrophy were found in the first and second MTPs (SSJ), talonavicular recess (MSJ) and hip (LSJ). Synovial blood flow was frequent in the first MTP and radiocarpal recess. Bone erosion stood out only in the glenohumeral joint.