Predictors of Intraspinal Pressure and Optimal Cord Perfusion Pressure After Traumatic Spinal Cord Injury.

BACKGROUND/OBJECTIVES: We recently developed techniques to monitor intraspinal pressure (ISP) and spinal cord perfusion pressure (SCPP) from the injury site to compute the optimum SCPP (SCPPopt) in patients with acute traumatic spinal cord injury (TSCI). We hypothesized that ISP and SCPPopt can be predicted using clinical factors instead of ISP monitoring. METHODS: Sixty-four TSCI patients, grades A-C (American spinal injuries association Impairment Scale, AIS), were analyzed. For 24 h after surgery, we monitored ISP and SCPP and computed SCPPopt (SCPP that optimizes pressure reactivity). We studied how well 28 factors correlate with mean ISP or SCPPopt including 7 patient-related, 3 injury-related, 6 management-related, and 12 preoperative MRI-related factors. RESULTS: All patients underwent surgery to restore normal spinal alignment within 72 h of injury. Fifty-one percentage had U-shaped sPRx versus SCPP curves, thus allowing SCPPopt to be computed. Thirteen percentage, all AIS grade A or B, had no U-shaped sPRx versus SCPP curves. Thirty-six percentage (22/64) had U-shaped sPRx versus SCPP curves, but the SCPP did not reach the minimum of the curve, and thus, an exact SCPPopt could not be calculated. In total 5/28 factors were associated with lower ISP: older age, excess alcohol consumption, nonconus medullaris injury, expansion duroplasty, and less intraoperative bleeding. In a multivariate logistic regression model, these 5 factors predicted ISP as normal or high with 73% accuracy. Only 2/28 factors correlated with lower SCPPopt: higher mean ISP and conus medullaris injury. In an ordinal multivariate logistic regression model, these 2 factors predicted SCPPopt as low, medium-low, medium-high, or high with only 42% accuracy. No MRI factors correlated with ISP or SCPPopt. CONCLUSIONS: Elevated ISP can be predicted by clinical factors. Modifiable factors that may lower ISP are: reducing surgical bleeding and performing expansion duroplasty. No factors accurately predict SCPPopt; thus, invasive monitoring remains the only way to estimate SCPPopt

Fitting the HIV Epidemic in Zambia: A Two-Sex Micro-Simulation Model

BACKGROUND: In describing and understanding how the HIV epidemic spreads in African countries, previous studies have not taken into account the detailed periods at risk. This study is based on a micro-simulation model (individual-based) of the spread of the HIV epidemic in the population of Zambia, where women tend to marry early and where divorces are not frequent. The main target of the model was to fit the HIV seroprevalence profiles by age and sex observed at the Demographic and Health Survey conducted in 2001. METHODS AND FINDINGS: A two-sex micro-simulation model of HIV transmission was developed. Particular attention was paid to precise age-specific estimates of exposure to risk through the modelling of the formation and dissolution of relationships: marriage (stable union), casual partnership, and commercial sex. HIV transmission was exclusively heterosexual for adults or vertical (mother-to-child) for children. Three stages of HIV infection were taken into account. All parameters were derived from empirical population-based data. Results show that basic parameters could not explain the dynamics of the HIV epidemic in Zambia. In order to fit the age and sex patterns, several assumptions were made: differential susceptibility of young women to HIV infection, differential susceptibility or larger number of encounters for male clients of commercial sex workers, and higher transmission rate. The model allowed to quantify the role of each type of relationship in HIV transmission, the proportion of infections occurring at each stage of disease progression, and the net reproduction rate of the epidemic (R(0) = 1.95). CONCLUSIONS: The simulation model reproduced the dynamics of the HIV epidemic in Zambia, and fitted the age and sex pattern of HIV seroprevalence in 2001. The same model could be used to measure the effect of changing behaviour in the future

A Template-Dependent Dislocation Mechanism Potentiates K65R Reverse Transcriptase Mutation Development in Subtype C Variants of HIV-1

Numerous studies have suggested that the K65R reverse transcriptase (RT) mutation develops more readily in subtype C than subtype B HIV-1. We recently showed that this discrepancy lies partly in the subtype C template coding sequence that predisposes RT to pause at the site of K65R mutagenesis. However, the mechanism underlying this observation and the elevated rates of K65R development remained unknown. Here, we report that DNA synthesis performed with subtype C templates consistently produced more K65R-containing transcripts than subtype B templates, regardless of the subtype-origin of the RT enzymes employed. These findings confirm that the mechanism involved is template-specific and RT-independent. In addition, a pattern of DNA synthesis characteristic of site-specific primer/template slippage and dislocation was only observed with the subtype C sequence. Analysis of RNA secondary structure suggested that the latter was unlikely to impact on K65R development between subtypes and that Streisinger strand slippage during DNA synthesis at the homopolymeric nucleotide stretch of the subtype C K65 region might occur, resulting in misalignment of the primer and template. Consequently, slippage would lead to a deletion of the middle adenine of codon K65 and the production of a -1 frameshift mutation, which upon dislocation and realignment of the primer and template, would lead to development of the K65R mutation. These findings provide additional mechanistic evidence for the facilitated development of the K65R mutation in subtype C HIV-1

The role of unintegrated DNA in HIV infection

Integration of the reverse transcribed viral genome into host chromatin is the hallmark of retroviral replication. Yet, during natural HIV infection, various unintegrated viral DNA forms exist in abundance. Though linear viral cDNA is the precursor to an integrated provirus, increasing evidence suggests that transcription and translation of unintegrated DNAs prior to integration may aid productive infection through the expression of early viral genes. Additionally, unintegrated DNA has the capacity to result in preintegration latency, or to be rescued and yield productive infection and so unintegrated DNA, in some circumstances, may be considered to be a viral reservoir. Recently, there has been interest in further defining the role and function of unintegrated viral DNAs, in part because the use of anti-HIV integrase inhibitors leads to an abundance of unintegrated DNA, but also because of the potential use of non-integrating lentiviral vectors in gene therapy and vaccines. There is now increased understanding that unintegrated viral DNA can either arise from, or be degraded through, interactions with host DNA repair enzymes that may represent a form of host antiviral defence. This review focuses on the role of unintegrated DNA in HIV infection and additionally considers the potential implications for antiviral therapy

Pemphigus autoimmunity: Hypotheses and realities

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients

Ex-PRESS glaucoma filter: an MRI compatible metallic orbital foreign body imaged at 1.5 and 3T

AimTo report on the MRI compatibility of the Ex-PRESS glaucoma filtration device, a tiny metallic implant placed into the anterior chamber of the eye that is much smaller than traditional glaucoma shunts, and to educate the radiology community regarding its appearance.Materials and methodsSeven patients with Ex-PRESS glaucoma filtration devices were identified that had undergone MRI at San Francisco General Hospital/University of California San Francisco Medical Center by searching and cross-referencing the radiology reporting system and the electronic medical record. MRI images were reviewed for artefact interfering with interpretation. Ophthalmology examinations were reviewed for evidence of complications.ResultsEighteen individual MRI examinations were performed during 12 unique MRI events on these 7 patients. 13/18 individual MRI examinations and 7/12 MRI events were performed at 3 T with the others performed at 1.5 T. Mean time from Ex-PRESS implantation to MRI was 17.5 months. Mean time from MRI to first ophthalmology examination was 1.1 months and from MRI to latest ophthalmology examination was 6.6 months. Susceptibility artefact did not interfere with image interpretation and no complications related to MRI were encountered.ConclusionThe Ex-PRESS glaucoma filtration device appears to be safe for MRI at 1.5 and 3 T and does not produce significant susceptibility artefact to affect diagnostic interpretation adversely

Utility of Repeat Head CT in Patients with Blunt Traumatic Brain Injury Presenting with Small Isolated Falcine or Tentorial Subdural Hematomas.

Background and purposeIn blunt traumatic brain injury with isolated falcotentorial subdural hematoma not amenable to neurosurgical intervention, the routinely performed, nonvalidated practice of serial head CT scans frequently necessitates increased hospital resources and exposure to ionizing radiation. The study goal was to evaluate clinical and imaging features of isolated falcotentorial subdural hematoma at presentation and short-term follow-up.Materials and methodsWe performed a retrospective analysis of patients presenting to a level 1 trauma center from January 2013 to March 2015 undergoing initial and short-term follow-up CT with initial findings positive for isolated subdural hematoma along the falx and/or tentorium. Patients with penetrating trauma, other sites of intracranial hemorrhage, or depressed skull fractures were excluded. Patient sex, age, Glasgow Coma Scale score, and anticoagulation history were obtained through review of the electronic medical records.ResultsEighty patients met the inclusion criteria (53 males; 27 females; median age, 61 years). Of subdural hematomas, 57.1% were falcine, 33.8% were tentorial, and 9.1% were mixed. The mean initial Glasgow Coma Scale score was 14.2 (range, 6-15). Isolated falcotentorial subdural hematomas were small (mean, 2.8 mm; range, 1-8 mm) without mass effect and significant change on follow-up CT (mean, 2.7 mm; range, 0-8 mm; P = .06), with an average follow-up time of 10.3 hours (range, 3.9-192 hours). All repeat CTs demonstrated no change or decreased size of the initial subdural hematoma. No new intracranial hemorrhages were seen on follow-up CT.ConclusionsIsolated falcotentorial subdural hematomas in blunt traumatic brain injury average 2.8 mm in thickness and do not increase in size on short-term follow-up CT. Present data suggest that repeat CT in patients with mild traumatic brain injury with isolated falcotentorial subdural hematoma may not be necessary

Utility of Repeat Head CT in Patients with Blunt Traumatic Brain Injury Presenting with Small Isolated Falcine or Tentorial Subdural Hematomas

Background and purposeIn blunt traumatic brain injury with isolated falcotentorial subdural hematoma not amenable to neurosurgical intervention, the routinely performed, nonvalidated practice of serial head CT scans frequently necessitates increased hospital resources and exposure to ionizing radiation. The study goal was to evaluate clinical and imaging features of isolated falcotentorial subdural hematoma at presentation and short-term follow-up.Materials and methodsWe performed a retrospective analysis of patients presenting to a level 1 trauma center from January 2013 to March 2015 undergoing initial and short-term follow-up CT with initial findings positive for isolated subdural hematoma along the falx and/or tentorium. Patients with penetrating trauma, other sites of intracranial hemorrhage, or depressed skull fractures were excluded. Patient sex, age, Glasgow Coma Scale score, and anticoagulation history were obtained through review of the electronic medical records.ResultsEighty patients met the inclusion criteria (53 males; 27 females; median age, 61 years). Of subdural hematomas, 57.1% were falcine, 33.8% were tentorial, and 9.1% were mixed. The mean initial Glasgow Coma Scale score was 14.2 (range, 6-15). Isolated falcotentorial subdural hematomas were small (mean, 2.8 mm; range, 1-8 mm) without mass effect and significant change on follow-up CT (mean, 2.7 mm; range, 0-8 mm; P = .06), with an average follow-up time of 10.3 hours (range, 3.9-192 hours). All repeat CTs demonstrated no change or decreased size of the initial subdural hematoma. No new intracranial hemorrhages were seen on follow-up CT.ConclusionsIsolated falcotentorial subdural hematomas in blunt traumatic brain injury average 2.8 mm in thickness and do not increase in size on short-term follow-up CT. Present data suggest that repeat CT in patients with mild traumatic brain injury with isolated falcotentorial subdural hematoma may not be necessary