AAV Vectors Avoid Inflammatory Signals Necessary to Render Transduced Hepatocyte Targets for Destructive T Cells

Studies in mice indicate that gene transfer to liver with vectors based on adeno-associated viruses (AAVs) is characterized by immunological tolerance to antigenic transgene products. Mechanisms to explain host nonresponsiveness have focused on aberrant T-cell responses. We propose a distinct mechanism for conferring tolerance to AAV-transduced hepatocytes that relates to diminished sensitivity of the target organ to T cell–mediated effects. T cells to β-galactosidase (β-gal) were adoptively transferred into RAG^−/− mice expressing β-gal in hepatocytes due to prior administration of either Ad or AAV vectors. Adoptive transfer was associated with extinction of LacZ expression in Ad-LacZ-transduced RAG^−/− mice and had no effect on liver LacZ expression in AAV-LacZ-transduced RAG^−/− mice. Systemic administration of TLR ligands lipopolysaccharide (LPS) and CpG at the time of adoptive transfer did lead to extinction of LacZ expression. Systemic TLR ligands were associated with upregulation of major histocompatibility complex (MHC) class I and the cell adhesion molecules ICAM and VCAM as was seen with Ad-LacZ alone. These data indicate that AAV transduction lacks the inflammatory signals necessary to render hepatocyte targets for cytotoxic T lymphocytes (CTLs). Underlying liver pathology may confound vector performance and should be considered in the design of clinical trials.     

Exploring the potential of minoxidil tretinoin liposomal based hydrogel for topical delivery in the treatment of androgenic alopecia

Abstract

Purpose: Androgenic alopecia (AGA) is a condition of progressive hair loss and involves follicular miniaturization triggered mainly due to varying levels of androgen besides environmental and genetic factors, which may also play some role. Minoxidil (MXD) has been considered as most effective therapeutic moiety to treat this disorder. Another drug Tretinoin (TRET) is known for its comedolytic activity and is reported to enhance percutaneous absorption of MXD. Presently both these drugs are being utilized for treatment of androgenic alopecia (AGA) in solution form which poses several problems in terms of poor solubility of drug, frequency of application and side effects.

Materials and methods: Current work investigates liposomal hydrogel system for simultaneous delivery of MXD and TRET to overcome the limitations of existing formulation. Successful development of liposomes was commenced by thin film hydration method and various parameters affecting desired characteristics like size, morphology, entrapment efficiency; stability and ex vivo permeation were optimized. The formulated liposomes were further characterized for various physicochemical properties and evaluated for in vivo irritancy study in animals.

Results and discussion: Results suggested prepared liposomes to be stable, homogenous and capable to hold both the drugs within. Association with hydrogel enhanced the permeation of MXD through skin ex vivo but TRET retained on the skin. Liposome loaded hydrogel was found to be non-irritant to skin.

Conclusion: Overall developed system showed potential for effective and simultaneous delivery of both the drugs.     

Is the Revision Rate Higher After Hip Arthroplasty in Teenage Patients? A Prospective Study with Long-Term Follow-Up of More Than 10 Years

BackgroundTotal hip arthroplasty (THA) and hip resurfacing arthroplasty (HRA) are already proven good for end-stage arthritis in the older populations but it is challenging in young teenage patients. The primary aim was to assess Hip Disability and Osteoarthritis Outcome Score (HOSS), Harris Hip Score (HHS) and secondary aim for implant survival rate.Materials and MethodsThe details of 33 teenage patients (forty hips) who underwent HRA (21) and THA (19) at our institution (January 2002 to December 2013) with a mean follow-up period of 11.00 years (range 7.00–18.40) were included. The study group had 25 males and eight females.ResultsThe overall median HOOSs with interquartile range were 89.00 (87.63–0.00). The median HOOSs at follow-up were as follows: 95.00 (90.00–95.00) for symptoms, 92.00 (90.00–95.00) pain, 87.00 (85.00–90.00) for functions, 81.00 (75.00–85.00) for sports and 94.00 (88.00–95.00) for QOL. HHS improved significantly from 36.88 ± 6.14 to 90.12 ± 6.56 (p < 0.001). The HHS of HRA group improved from 36.29 ± 5.83 to 89.38 ± 5.23 and THA group improved from 37.26 ± 6.22 to 90.94 ± 7.84. The 5-year radiological follow-up X-rays did not show any radiolucent line wider than 2 mm in all three zones of the acetabulum and no progressive subsidence or migration of > 1 mm and divergent radiopaque line in femur. The Implant survival rate for HRA was 100% at 5 years, 100% at 10 years, 92% at 15 years and THA group was 100% at 5 years and 90% at 10 years.ConclusionOur study showed a disability rate of zero with improved HOSS and HHS. The overall implant survival rate was good with 100% at 5 years, 97% at 10 years and 89.9% at 15 years in contrast to the previous studies with the use of modern implants and newer standard surgical techniques.Level of EvidenceA Level II study http://www.spine.org/Documents/LevelsofEvidenceFinal.pdf.     

Modified cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone therapy for posttransplantation lymphoproliferative disease in pediatric patients undergoing solid organ transplantation

PURPOSE: The authors report the use of a cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP)-based chemotherapy regimen in treating six children with posttransplantation lymphoproliferative disorder (PTLD) that developed after solid organ transplantation. MATERIALS AND METHODS: The chemotherapy regimen consisted of a 29-day induction with CHOP and then as many as 15 cycles of maintenance therapy using methotrexate and cytarabine alternating with vincristine, adriamycin, mercaptopurine, and prednisone. RESULTS: All patients attained remission. One patient died of sepsis while in remission. Four of the five remaining patients have been followed-up in remission for as long as 8 years without losing the graft. One of the patients experienced relapse after completing therapy and subsequently died with disease. CONCLUSIONS: The authors conclude that pediatric patients with PTLD after solid organ transplantation that fails conservative management can be treated successfully with CHOP-based chemotherapy.     

Clinical presentation and endoscopic management of Dieulafoy''''s lesions in an urban community hospital

AIM:To identify rates of occurrence,common clinical and endoscopic features,and to review the outcome of endoscopic management of Dieulafoy's lesions in the upper gastrointestinal (GI) tract in an urban community hospital setting. METHODS:Endoscopic data from esophagogastroduo denoscopies (EGDs),done at Wyckoff Heights Medical Center,Brooklyn,NY between 2000 and 2006 were reviewed to identify patients with Dieulafoy's lesions. Demographic data,medical history,examination findings,lab data,endoscopic findings and details of therapy for patients treated for Dieulafoy's lesions were reviewed retrospectively. RESULTS:Dieulafoy's lesions were documented to be the cause of bleeding in approximately 1% of patients presenting with upper gastrointestinal bleeding,while they were detected in only 2 patients when the indications for EGDs were different from active GI bleeding. When we analyzed EGDs performed in patients above age 65 years presenting with gastrointestinal bleeding,prevalence of Dieulafoy's lesions approached 10 percent. The most common location of the lesion was the body of stomach (7),followed by the cardia (4) and the esophagus (2). One patient had this lesion in the fundus and one patient in the duodenal apex. All patients were initially treated endoscopically with epinephrine injection,in eight cases heater probe was applied following epinephrine and endoscopic clips were applied in two cases. All but one of the patients did well in near and intermediate term follow-up (average follow-up period of 18 mo). One patient died of multi-organ failure during the same hospital stay. Average length hospital stay was 7 d.CONCLUSION:Community hospital gastroenterologists and endoscopists should be aware that Dieulafoy's lesions are an uncommon cause of upper GI bleeding among elderly patients. Early accurate diagnosis through emergent endoscopy and endoscopic therapy,especially in patients with multiple co-morbid conditions,can be very effective and life saving.