An evolved AAV variant enables efficient genetic engineering of murine T cells.

Precise targeting of large transgenes to T cells using homology-directed repair has been transformative for adoptive cell therapies and T cell biology. Delivery of DNA templates via adeno-associated virus (AAV) has greatly improved knockin efficiencies, but the tropism of current AAV serotypes restricts their use to human T cells employed in immunodeficient mouse models. To enable targeted knockins in murine T cells, we evolved Ark313, a synthetic AAV that exhibits high transduction efficiency in murine T cells.

Increased frequency of proangiogenic tunica intima endothelial kinase 2 (Tie2) expressing monocytes in individuals with type 2 diabetes mellitus.

Background: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk for developing macrovascular disease (MVD) manifested by atherosclerosis. Phenotypically and functionally different monocyte subsets (classical; CD14CD16, non-classical; CD14CD16, and intermediate; CD14CD16) including pro-angiogenic monocytes expressing Tie2 (TEMs) can be identified. Here we investigated monocyte heterogeneity and its association with T2DM and MVD.

Receptor Switching in Newly Evolved Adeno-associated Viruses.

Adeno-associated viruses utilize different glycans and the AAV receptor (AAVR) for cellular attachment and entry. Directed evolution has yielded new AAV variants; however, structure-function correlates underlying their improved transduction are generally overlooked. Here, we report that infectious cycling of structurally diverse AAV surface loop libraries yields functionally distinct variants.

The Golgi Calcium ATPase Pump Plays an Essential Role in Adeno-associated Virus Trafficking and Transduction.

Adeno-associated viruses (AAVs) are dependoparvoviruses that have proven useful for therapeutic gene transfer; however, our understanding of host factors that influence AAV trafficking and transduction is still evolving. Here, we investigated the role of cellular calcium in the AAV infectious pathway. First, we demonstrated a critical role for the host Golgi compartment-resident ATP-powered calcium pump (secretory pathway calcium ATPase 1 [SPCA1]) encoded by the gene in AAV infection.

Variation in the Diagnostic Evaluation among Persons with Hematuria: Influence of Gender, Race and Risk Factors for Bladder Cancer.

Purpose: We sought to determine whether race, gender and number of bladder cancer risk factors are significant predictors of hematuria evaluation.

Materials And Methods: We used self-reported data from SCCS (Southern Community Cohort Study) linked to Medicare claims data. Evaluation of subjects diagnosed with incident hematuria was considered complete if imaging and cystoscopy were performed within 180 days of diagnosis.

The Null Effect of Bladder Neck Size on Incontinence Outcomes after Radical Prostatectomy.

Purpose: We sought to determine whether bladder neck size is associated with incontinence scores after robot-assisted laparoscopic radical prostatectomy.

Materials And Methods: Consecutive eligible patients undergoing robot-assisted laparoscopic radical prostatectomy between July 19 and December 28, 2016 were enrolled in a prospective, longitudinal, observational cohort study. The primary outcome was patient reported urinary incontinence on the EPIC (Expanded Prostate Cancer Index Composite) scale 6 and 12 weeks postoperatively.

Distinct Differences on Neointima Formation in Immunodeficient and Humanized Mice after Carotid or Femoral Arterial Injury.

Percutaneous coronary intervention is widely adopted to treat patients with coronary artery disease. However, restenosis remains an unsolved clinical problem after vascular interventions. The role of the systemic and local immune response in the development of restenosis is not fully understood.

Operative considerations for late-presenting persistent Müllerian duct syndrome.

Persistent Müllerian duct syndrome (PMDS) is a condition in which a 46, XY male displays masculine external genitalia, but internally retains developed Müllerian duct structures (uterus, fallopian tubes, and upper two-thirds vagina). Thoughtful operative consideration is needed to maximize the therapeutic benefit while minimizing the risk of hypogonadism, infertility, and erectile dysfunction. We report a 53-year-old male with a pelvic mass incidentally discovered on routine ultrasound, intra-operatively discovered to be PMDS.

Use of Contrasted Computerized Tomography as a Surrogate for Nuclear Medicine Renogram to Categorize Renal Function in the Setting of Ureteropelvic Junction Obstruction.

Objective: To use basic measurements on contrasted computerized tomography (CT) to reliably determine whether a kidney with ureteropelvic junction obstruction (UPJO) is definitively functional (≥30% differential renal function [DRF]) or nonfunctional (≤10% DRF), obviating the need for nuclear medicine renogram (RG) to determine DRF.

Methods: This is a single institution, retrospective cohort of patients diagnosed with UPJO who underwent either pyeloplasty or nephrectomy between December 2004 and December 2014. Included patients had both preoperative mercaptoacetyltriglycine RG and contrasted CT within 180 days of each other.

Membrane-bound Klotho is not expressed endogenously in healthy or uraemic human vascular tissue.

Aims: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD), a disease state that is strongly associated with loss of renal and systemic (alpha-)Klotho. Reversely, murine Klotho deficiency causes marked medial calcification. It is therefore thought that Klotho conveys a vasculoprotective effect.

CD16⁺ monocytes with smooth muscle cell characteristics are reduced in human renal chronic transplant dysfunction.

In chronic transplant dysfunction (CTD), persistent (allo)immune-mediated inflammation eventually leads to tissue remodeling including neointima formation in intragraft arteries. We previously showed that recipient-derived neointimal α-SMA(+) smooth muscle-like cells are present in human renal allografts with CTD. Human PBMC contain myeloid cells capable of differentiating into α-SMA(+) cells in vitro; the phenotype of the ancestral subset is as yet unknown.

Incidence and predictors of understaging in patients with clinical T1 urothelial carcinoma undergoing radical cystectomy.

Objective: To evaluate predictors of understaging in patients with presumed non-muscle-invasive bladder cancer (NMIBC) identified on transurethral resection of bladder tumour (TURBT) who underwent radical cystectomy (RC) with attention to the role of a restaging TURBT.

Patients And Methods: We retrospectively evaluated 279 consecutive patients with clinically staged T1 (cT1) disease after TURBT who underwent RC at our institution from April 2000 to July 2011. In all, 60 of these cT1 patients had undergone a restaging TURBT before RC.

Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy.

Background: Diabetes is associated with a high incidence of macrovascular disease (MVD), including peripheral and coronary artery disease. Circulating soluble-Klotho (sKlotho) is produced in the kidney and is a putative anti-aging and vasculoprotective hormone. Reduced Klotho levels may therefore increase cardiovascular risk in diabetes.

Type 2 diabetes mellitus is associated with an imbalance in circulating endothelial and smooth muscle progenitor cell numbers.

Aims/hypothesis: Individuals with type 2 diabetes mellitus have increased rates of macrovascular disease (MVD). Endothelial progenitor cells (EPCs), circulating angiogenic cells (CACs) and smooth muscle progenitor cells (SMPCs) are suggested to play a role in the pathogenesis of MVD. The relationship between vasoregenerative EPCs or CACs and damaging SMPCs and the development of accelerated MVD in diabetes is still unknown.

Failure by engorged stages of the lone star tick, Amblyomma americanum, to react to assembly pheromone, guanine and uric acid.

Response to tick-exposed filter paper discs (tick excreta) by fed and non-fed stages of the lone star tick Amblyomma americanum (L.) (Acari: Ixodidae) was examined from larva to adult. By contrast with engorged stages, each non-fed stage exhibited a classic arrestment response to assembly pheromone, characterized by lack of movement, retraction of legs and formation of small groups; this response was seen in approximately 75% of ticks that made contact with pheromone-treated surfaces.

Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction.

Myofibroblasts play a major role in scar formation during wound healing after myocardial infarction (MI). Their origin has been thought to be interstitial cardiac fibroblasts. However, the bone marrow (BM) can be a source of myofibroblasts in a number of organs after injury.

Prolonged maintenance of water balance by adult females of the American spider beetle, Mezium affine Boieldieu, in the absence of food and water resources.

Moisture requirements were evaluated for female adults of spider beetles Mezium affine Boieldieu and Gibbium aequinoctiale Boieldieu to determine how they are differentially adapted for life in a dry environment. Features showing extreme desiccation resistance of M. affine were an impermeable cuticle wherein activation energies (43kJ/mol) were suppressed, daily water losses as little as 0.

Contact areas in the thumb carpometacarpal joint.

The thumb carpometacarpal joint is a common site of osteoarthritis. It has been hypothesized that peaks of localized stress on the dorsoradial or volar-ulnar regions, or both, of the articular surfaces of the trapezium and metacarpal lead to erosion of cartilage and may be responsible for the progression of the disease. The objective of this study was to determine the contact areas in this joint under the functional position of lateral (key) pinch and in the extremes of range of motion of the joint.

Excursion of the rotator cuff under the acromion. Patterns of subacromial contact.

Nine fresh-frozen, human cadaveric shoulders were elevated in the scapular plane in two different humeral rotations by applying forces along action lines of rotator cuff and deltoid muscles. Stereophotogrammetry determined possible regions of subacromial contact using a proximity criterion; radiographs measured acromiohumeral interval and position of greater tuberosity. Contact starts at the anterolateral edge of the acromion at 0 degrees of elevation; it shifts medially with arm elevation.

Cellular survival and proliferation in autogenous flexor tendon grafts.

In order to investigate fibroblast survival and proliferation in autogenous flexor tendon grafts, hindlimb intrasynovial and extrasynovial donor tendons were placed within the synovial sheaths of the medial and lateral forepaw digits of 21 dogs (42 tendons) and treated with controlled early passive motion. Intravital histologic evaluations with confocal microscopy and biochemical determinations of total DNA content and DNA synthesis were carried out at 10 days, 3 weeks, and 6 weeks. Intravital staining of the extrasynovial tendon grafts demonstrated variable degrees of cellular necrosis at the earliest intervals followed by cellular repopulation with fibroblasts and neovascularization from surface vessels.

The rationale for precise management of distal radius fractures.

Fractures of the distal radius continue to be one of the most common skeletal injuries treated by orthopedic or trauma surgeons. These injuries account for one sixth of all fractures seen and treated in emergency rooms. The rapid expansion of knowledge regarding the functional anatomy of the hand and wrist, the recognition by treating physicians of the ever increasing functional demands of senior citizens, and improved methodologies of achieving and maintaining anatomic restoration of these fractures have generated a renewed interest in addressing these fractures in a more precise manner.

Arthroscopic treatment of calcific tendinitis of the shoulder.

The results of arthroscopic treatment of chronic resistant calcific tendinitis of the shoulder in twenty-three patients were evaluated. Each patient had greater than 1 year of unsuccessful nonoperative management prior to arthroscopic surgery. The average age was 49 years (range 33-60) and average follow up was 26 months (range 12-47).

A simulation model of AIDS in San Francisco: I. Model formulation and parameter estimation.

A model is formulated for the spread of the human immunodeficiency virus (HIV) and the subsequent development of acquired immunodeficiency syndrome (AIDS) in the population of homosexual men in San Francisco. The dynamic simulation model includes sexually very active and active subpopulations, migration, and a staged progression of HIV-infected persons to AIDS and death. Numerous data sources are used to estimate parameter values in the model.