Incidental Carcinoid Tumor Arising in a Meckel's Diverticulum.

This case report describes a patient who presented with concern for a closed-loop small bowel obstruction (SBO). During exploratory laparotomy, an area of ischemic bowel due to closed loop obstruction was resected, along with an incidentally discovered inflamed-appearing Meckel's diverticulum (MD). The resected specimen contained a well-differentiated carcinoid tumor of benign behavior with a maximum diameter of 0.

Using Dynamic Oral Dosing of Rifapentine and Rifabutin to Simulate Exposure Profiles of Long-Acting Formulations in a Mouse Model of Tuberculosis Preventive Therapy.

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have antituberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens.

Using dynamic oral dosing of rifapentine and rifabutin to simulate exposure profiles of long-acting formulations in a mouse model of tuberculosis preventive therapy.

Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have anti-tuberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens.

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described.

Preserved Efficacy and Reduced Toxicity with Intermittent Linezolid Dosing in Combination with Bedaquiline and Pretomanid in a Murine Tuberculosis Model.

The novel regimen of bedaquiline, pretomanid, and linezolid (BPaL) is highly effective against drug-resistant tuberculosis, but linezolid toxicities are frequent. We hypothesized that, for a similar total weekly cumulative dose, thrice-weekly administration of linezolid would preserve efficacy while reducing toxicity compared with daily dosing, in the context of the BPaL regimen. Using C3HeB/FeJ and BALB/c mouse models of tuberculosis disease, thrice-weekly linezolid dosing was compared with daily dosing, with intermittent dosing introduced (i) from treatment initiation or (ii) after an initial period of daily dosing.

Treatment-Shortening Effect of a Novel Regimen Combining Clofazimine and High-Dose Rifapentine in Pathologically Distinct Mouse Models of Tuberculosis.

Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e.

Noninvasive C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis.

Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Current methods to measure intralesional drug distribution rely on tissue resection, which is difficult in humans and generally limited to a single time point even in animals.

Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas.

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M.

Impact of Clofazimine Dosing on Treatment Shortening of the First-Line Regimen in a Mouse Model of Tuberculosis.

The antileprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown.

Where is the Target Point to Prevent Cortical Hinge Fracture in Medial Closing-Wedge Distal Femoral Varus Osteotomy?

The purpose of this study was to investigate whether the location of the hinge affects the incidence of hinge fracture during medial closing-wedge distal femoral varus osteotomy (DFVO). Twenty knees from 10 fresh-frozen human cadavers (mean age, 75 ± 17 years) were used to perform uniplanar medial closing-wedge DFVO with a 7-mm wedge. Each specimen was randomly assigned to either group A (supracondylar hinge) or group B (lateral condylar hinge).

Distal Femoral Varus Osteotomy for Valgus Arthritis of the Knees: Systematic Review of Open versus Closed Wedge Osteotomy.

Purpose: The purpose of this review is to compare the clinical and radiological outcomes between open and closed wedge distal femoral varus osteotomy (DFO).

Methods: A literature search of online databases (MEDLINE, EMBASE, and Cochrane Library database) was made in addition to manual search of major orthopedic journals. Data were searched from the time period of January 1990 to October 2016.

Open-wedge high tibial osteotomy versus unicompartmental knee arthroplasty: no difference in progression of patellofemoral joint arthritis.

Purpose: The purpose of this retrospective comparative study was to evaluate and compare, radiographically and clinically, progression of osteoarthritis (OA) in the patellofemoral (PF) compartment after open-wedge high tibial osteotomy (OWHTO), and unicompartmental knee arthroplasty (UKA) over a minimum follow-up of 5 years.

Methods: In this study, 42 knees in an OWHTO group were compared with 59 knees in a UKA group in terms of radiographic parameters, such as the grading system for OA progression in the PF compartment, and clinical parameters, such as the PF pain and function scores over a minimum follow-up of 5 years.

Results: There was no significant difference of OA progression in the PF compartment between the two groups on knee radiography.

The biodistribution of 5-[18F]fluoropyrazinamide in Mycobacterium tuberculosis-infected mice determined by positron emission tomography.

5-[18F]F-pyrazinamide (5-[18F]F-PZA), a radiotracer analog of the first-line tuberculosis drug pyrazinamide (PZA), was employed to determine the biodistribution of PZA using PET imaging and ex vivo analysis. 5-[18F]F-PZA was synthesized in 60 min using a halide exchange reaction. The overall decay-corrected yield of the reaction was 25% and average specific activity was 2.

Modified Iliac Crest Reconstruction with Bone Cement for Reduction of Donor Site Pain and Morbidity after Open Wedge High Tibial Osteotomy: A Prospective Study.

Purpose: This study was to determine the efficacy of iliac crest reconstruction using bone cement in reducing pain and morbidity at the donor site in patients undergoing open wedge high tibial osteotomy (OWHTO) with tricortical iliac crest autologous graft.

Materials And Methods: Thirty-three patients who underwent iliac crest reconstruction using polymethyl methacrylate (PMMA) bone cement (group A) and thirty patients who had no iliac crest reconstruction (group B) were enrolled in this study. All patients were evaluated for pain and functional disability related to graft harvesting using the pain and functional visual analogue scale (VAS) score during hospital stay and at 6 weeks, 3 months, and 6 months postoperatively.

Polymeric nanofiber coating with tunable combinatorial antibiotic delivery prevents biofilm-associated infection in vivo.

Bacterial biofilm formation is a major complication of implantable medical devices that results in therapeutically challenging chronic infections, especially in cases involving antibiotic-resistant bacteria. As an approach to prevent these infections, an electrospun composite coating comprised of poly(lactic-coglycolic acid) (PLGA) nanofibers embedded in a poly(ε-caprolactone) (PCL) film was developed to locally codeliver combinatorial antibiotics from the implant surface. The release of each antibiotic could be adjusted by loading each drug into the different polymers or by varying PLGA:PCL polymer ratios.

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers.

Unlabelled: The modern patient is increasingly susceptible to bacterial infections including those due to multidrug-resistant organisms (MDROs). Noninvasive whole-body analysis with pathogen-specific imaging technologies can significantly improve patient outcomes by rapidly identifying a source of infection and monitoring the response to treatment, but no such technology exists clinically.

Methods: We systematically screened 961 random radiolabeled molecules in silico as substrates for essential metabolic pathways in bacteria, followed by in vitro uptake in representative bacteria-Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and mycobacteria.

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors.

Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity.

Total knee arthroplasty after failed high tibial osteotomy: a systematic review of open versus closed wedge osteotomy.

Purpose: Medial opening wedge high tibial osteotomy (HTO) has become increasingly popular as an alternative to lateral closing wedge osteotomy for the treatment of medial compartment knee osteoarthritis with varus deformity. The present systematic review was conducted to provide an objective analysis of total knee arthroplasty (TKA) outcomes following previous knee osteotomy (medial opening wedge vs. lateral closing wedge).

Arthroscopy during ulnar shortening for idiopathic ulnar impaction syndrome.

Arthroscopy during ulnar shortening osteotomy for ulnar impaction syndrome is subject to debate regarding its clinical usefulness. The purposes of this study were to analyze the arthroscopic findings in patients who underwent ulnar shortening osteotomy and to assess the role of arthroscopic evaluation during osteotomy. Medical records and arthroscopic findings of 50 consecutive patients who had been diagnosed with idiopathic ulnar impaction syndrome were retrospectively evaluated.

Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy.

Stapled α-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action.

Targeting the insulin-like growth factor axis for the development of novel therapeutics in oncology.

Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic effects that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. As a result, compounds targeting the IGF axis have become an area of intense preclinical and clinical research for cancer therapeutics.

Therapeutic mechanism and efficacy of the antibody-drug conjugate BAY 79-4620 targeting human carbonic anhydrase 9.

Carbonic anhydrase IX (CAIX) is a cell surface glycoprotein that is expressed in many different tumors and yet restricted in normal tissues to the gastrointestinal tract. It is upregulated by hypoxia and correlates with tumor grade and poor survival in several tumor indications. Monoclonal antibodies (mAb) with single digit nanomolar binding affinity for CAIX were derived by panning with the recombinant ectodomain of CAIX against the MorphoSys HUCAL Gold library of human Fabs.

Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth.

Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented.

A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.

This paper reviews the body of evidence that major depression is accompanied by a decreased antioxidant status and by induction of oxidative and nitrosative (IO&NS) pathways. Major depression is characterized by significantly lower plasma concentrations of a number of key antioxidants, such as vitamin E, zinc and coenzyme Q10, and a lowered total antioxidant status. Lowered antioxidant enzyme activity, e.