Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate ligament rupture in mice.

IntroductionPrevious studies in animal models of osteoarthritis suggest that alendronate (ALN) has antiresorptive and chondroprotective effects, and can reduce osteophyte formation. However, these studies used non-physiologic injury methods, and did not investigate early time points during which bone is rapidly remodeled prior to cartilage degeneration. The current study utilized a non-invasive model of knee injury in mice to investigate the effect of ALN treatment on subchondral bone changes, articular cartilage degeneration, and osteophyte formation following injury.MethodsNon-invasive knee injury via tibial compression overload or sham injury was performed on a total of 90 mice. Mice were treated with twice weekly subcutaneous injections of low-dose ALN (40 μg/kg/dose), high-dose ALN (1,000 μg/kg/dose), or vehicle, starting immediately after injury until sacrifice at 7, 14 or 56 days. Trabecular bone of the femoral epiphysis, subchondral cortical bone, and osteophyte volume were quantified using micro-computed tomography (μCT). Whole-joint histology was performed at all time points to analyze articular cartilage and joint degeneration. Blood was collected at sacrifice, and serum was analyzed for biomarkers of bone formation and resorption.ResultsμCT analysis revealed significant loss of trabecular bone from the femoral epiphysis 7 and 14 days post-injury, which was effectively prevented by high-dose ALN treatment. High-dose ALN treatment was also able to reduce subchondral bone thickening 56 days post-injury, and was able to partially preserve articular cartilage 14 days post-injury. However, ALN treatment was not able to reduce osteophyte formation at 56 days post-injury, nor was it able to prevent articular cartilage and joint degeneration at this time point. Analysis of serum biomarkers revealed an increase in bone resorption at 7 and 14 days post-injury, with no change in bone formation at any time points.ConclusionsHigh-dose ALN treatment was able to prevent early trabecular bone loss and cartilage degeneration following non-invasive knee injury, but was not able to mitigate long-term joint degeneration. These data contribute to understanding the effect of bisphosphonates on the development of osteoarthritis, and may support the use of anti-resorptive drugs to prevent joint degeneration following injury, although further investigation is warranted

New modelling technique for aperiodic-sampling linear systems

A general input-output modelling technique for aperiodic-sampling linear systems has been developed. The procedure describes the dynamics of the system and includes the sequence of sampling periods among the variables to be handled. Some restrictive conditions on the sampling sequence are imposed in order to guarantee the validity of the model. The particularization to the periodic case represents an alternative to the classic methods of discretization of continuous systems without using the Z-transform. This kind of representation can be used largely for identification and control purposes.Comment: 19 pages, 0 figure

Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification

<p>Abstract</p> <p>Background</p> <p>During primary infection of its human host, Herpes Simplex Virus Type-1 (HSV-1) establishes latency in neurons where the viral genome is maintained in a circular form associated with nucleosomes in a chromatin configration. During latency, most viral genes are silenced, although the molecular mechanisms responsible for this are unclear. We hypothesized that neuronal factors repress HSV-1 gene expression during latency. A search of the HSV-1 DNA sequence for potential regulatory elements identified a Repressor Element-1/Neuronal Restrictive Silencer Element (RE-1/NRSE) located between HSV-1 genes ICP22 and ICP4. We predicted that the Repressor Element Silencing Transcription Factor/Neuronal Restrictive Silencer Factor (REST/NRSF) regulates expression of ICP22 and ICP4.</p> <p>Results</p> <p>Transient cotransfection indicated that REST/NRSF inhibited the activity of both promoters. In contrast, cotransfection of a mutant form of REST/NRSF encoding only the DNA-binding domain of the protein resulted in less inhibition. Stably transformed cell lines containing episomal reporter plasmids with a chromatin structure showed that REST/NRSF specifically inhibited the ICP4 promoter, but not the ICP22 promoter. REST/NRSF inhibition of the ICP4 promoter was reversed by histone deacetylase (HDAC) inhibitor Trichostatin A (TSA). Additionally, chromatin immuno-precipitation (ChIP) assays indicated that the corepressor CoREST was recruited to the proximity of ICP4 promoter and that acetylation of histone H4 was reduced in the presence of REST/NRSF.</p> <p>Conclusion</p> <p>Since the ICP4 protein is a key transactivator of HSV-1 lytic cycle genes, these results suggest that REST/NRSF may have an important role in the establishment and/or maintenance of HSV-1 gene silencing during latency by targeting ICP4 expression.</p

Referral Center Experience With Nonpalpable Contraceptive Implant Removals.

ObjectiveTo describe our experience with office removal of nonpalpable contraceptive implants at our referral center.MethodsWe performed a retrospective cohort study by reviewing the charts of patients referred to our family planning specialty center for nonpalpable or complex contraceptive implant removal from January 2015 through December 2018. We localized nonpalpable implants using high-frequency ultrasonography and skin mapping in radiology, followed by attempted removal in the office using local anesthesia and a modified vasectomy clamp. We abstracted information on demographics, implant location, and outcomes.ResultsOf 61 referrals, 55 patients attended their scheduled appointments. Seven patients had palpable implants; six elected removal. The other 48 patients had ultrasound localization, which identified 47 (98%) of the implants; the remaining patient had successful localization with computed tomography imaging. Nonpalpable implants were suprafascial (n=22), subfascial (n=25) and intrafascial (n=1); four of these patients opted to delay removal. Of 50 attempted office removals, all palpable (n=6), all nonpalpable suprafascial (n=21 [100%, 95% CI 83-100%]), and 19 out of 23 (83%, 95% CI 67-98%) subfascial implants were successful. Three of the four patients with failed subfascial implant office removal had successful operating room removal with a collaborative orthopedic surgeon; the other patient sought removal elsewhere. Transient postprocedure neuropathic complaints were noted in 7 out of 23 (30%, 95% CI 12-49%) subfascial and 1 out of 21 (5%, 95% CI 0-13%) suprafascial removals (P=.048). Nonpalpable implants were more likely to be subfascial in nonobese patients (24/34, 71%) as compared with obese (1/13, 8%) patients (P&lt;.001). Seven (28%) of the 25 subfascially located implants had been inserted during a removal-reinsertion procedure through the same incision.ConclusionMost nonpalpable contraceptive implants can be removed in the office by an experienced subspecialty health care provider after ultrasound localization. Some patients may experience transient postprocedure neuropathic pain. Nonpalpable implants in thinner women are more likely to be in a subfascial location

Multiscale Modeling of Superior Cavopulmonary Circulation: Hemi-Fontan and Bidirectional Glenn Are Equivalent

Superior cavopulmonary circulation (SCPC) can be achieved by either the Hemi-Fontan (hF) or Bidirectional Glenn (bG) connection. Debate remains as to which results in best hemodynamic results. Adopting patient-specific multiscale computational modeling, we examined both the local dynamics and global physiology to determine if surgical choice can lead to different hemodynamic outcomes. Six patients (age: 3-6 months) underwent cardiac magnetic resonance imaging and catheterization prior to SCPC surgery. For each patient: (1) a finite 3-dimensional (3D) volume model of the preoperative anatomy was constructed to include detailed definition of the distal branch pulmonary arteries, (2) virtual hF and bG operations were performed to create 2 SCPC 3D models, and (3) a specific lumped network representing each patient's entire cardiovascular circulation was developed from clinical data. Using a previously validated multiscale algorithm that couples the 3D models with lumped network, both local flow dynamics, that is, power loss, and global systemic physiology can be quantified. In 2 patients whose preoperative imaging demonstrated significant left pulmonary artery (LPA) stenosis, we performed virtual pulmonary arterioplasty to assess its effect. In one patient, the hF model showed higher power loss (107%) than the bG, while in 3, the power losses were higher in the bG models (18-35%). In the remaining 2 patients, the power loss differences were minor. Despite these variations, for all patients, there were no significant differences between the hF and bG models in hemodynamic or physiological outcomes, including cardiac output, superior vena cava pressure, right-left pulmonary flow distribution, and systemic oxygen delivery. In the 2 patients with LPA stenosis, arterioplasty led to better LPA flow (5-8%) while halving the power loss, but without important improvements in SVC pressure or cardiac output. Despite power loss differences, both hF and bG result in similar SCPC hemodynamics and physiology outcome. This suggests that for SCPC, the pre-existing patient-specific physiology and condition, such as pulmonary vascular resistance, are more deterministic in the hemodynamic performance than the type of surgical palliation. Multiscale modeling can be a decision-assist tool to assess whether an extensive LPA reconstruction is needed at the time of SCPC for LPA stenosis

Applied Plasma Research

Contains research objectives and reports on three research projects.National Science Foundation (Grant GK-18185)Lincoln Laboratory Purchase Order No. CC-554U. S. Navy (Office of Naval Research) under Contract N00014-67-A-0204-0019Air Force Office of Scientific Researc

Rising Rates of All Types of Diabetes in South Asian and Non-South Asian Children and Young People Aged 0–29 Years in West Yorkshire, U.K., 1991–2006

OBJECTIVE: To investigate incidence trends of all diabetes types in all children and young people and in the south Asian subpopulation. RESEARCH DESIGN AND METHODS: Annual incidence per 100,000 and time trends (1991-2006) were analyzed for 2,889 individuals aged 0-29 years diagnosed with diabetes while resident in West Yorkshire, U.K. RESULTS: Diagnoses comprised type 1 (83%), type 2 (12%), maturity-onset diabetes of the young (0.7%), "J"-type/other (0.1%), and uncertain/unclassified (4%). There was a lower incidence of type 1 and a threefold excess of type 2 in south Asians compared with non-south Asians. Type 1 incidence leveled out and type 2 increased after the first south Asian case of type 2 was diagnosed in 1999. Type 2 and unclassified diabetes incidence rose in all population subgroups. CONCLUSIONS: The burden of diabetes increased over time for both ethnic groups, with a significant excess of type 2 diabetes in south Asians. The rising incidence of type 1 diabetes in south Asians attenuated as type 2 diabetes increased after 1999

Applied Plasma Research

Contains research objectives, summary of research and reports on three research projects.National Science Foundation (Grant GK-28282X)M.I.T. Lincoln Laboratory Purchase Order No. CC-54