APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy

A chromosome 22q13 locus strongly associates with increased risk for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-1-associated nephropathy (HIVAN), and hypertensive ESRD among individuals of African descent. Although initial studies implicated MYH9, more recent analyses localized the strongest association within the neighboring APOL1 gene. In this replication study, we examined the six top-most associated variants in APOL1 and MYH9 in an independent cohort of African Americans with various nephropathies (44 with FSGS, 21 with HIVAN, 32 with IgA nephropathy, and 74 healthy controls). All six variants associated with FSGS and HIVAN (additive ORs, 1.8 to 3.0; P values 3 × 10(-2) to 5 × 10(-5)) but not with IgA nephropathy. In conditional and haplotype analyses, two APOL1 haplotypes accounted for virtually all of the association with FSGS and HIVAN on chromosome 22q13 (haplotype P value = 5.6 × 10(-8)). To assess the role of MYH9 deficiency in nephropathy, we crossbred Myh9-haploinsufficient mice (Myh9(+/-)) with HIV-1 transgenic mice. Myh9(+/-) mice were healthy and did not demonstrate overt proteinuria or nephropathy, irrespective of the presence of the HIV-1 transgene. These data further support the strong association of genetic variants in APOL1 with susceptibility to FSGS and HIVAN among African Americans.     

Photo Essay: Retinal Changes in Type 3 Gaucher Disease

Ocular features of Gaucher disease include gaze abnormalities, corneal clouding, ocular deposits and pigmentary changes in the macula. We report the presence of bilateral fovea sparing macular deposits in a 21-year-old woman with type 3 Gaucher disease. Macular deposits occur due to glucocerebroside accumulation within histiocytes and retinal deposits might correlate with the degree of systemic infiltration.     

Impact of pre‐existing elastic matrix on TGFβ1 and HA oligomer‐induced regenerative elastin repair by rat aortic smooth muscle cells

Regenerating elastic matrices lost to disease (e.g. in aneurysms) is vital to re‐establishing vascular homeostasis but is challenged by the poor elastogenicity of post‐neonatal cells. We previously showed that exogenous hyaluronan oligomers (HA‐o) and TGFβ1 synergistically enhance tropo‐ and matrix elastin deposition by healthy adult rat aortic SMCs (RASMCs). Towards treating aortic aneurysms (AAs), which exhibit cause‐ and site‐specific heterogeneity in matrix content/structure and contain proteolytically‐injured SMCs, we investigated the impact of pre‐existing elastic matrix degeneration on elastogenic induction of injured RASMCs. Elastin‐rich RASMC layers at 21 days of culture were treated with 0.15 U/ml (PPE15) and 0.75 U/ml (PPE75) porcine pancreatic elastase to degrade the elastic matrix variably, or left uninjured (control). One set of cultures was harvested at 21 days, before and after injury, to quantify viable cell count, matrix elastin loss. Other injured cell layers were cultured to 42 days with or without factors (0.2 µg/ml HA oligomers, 1 ng/ml TGFβ1). We showed that: (a) the ability of cultures to self‐repair and regenerate elastic matrices following proteolysis is limited when elastolysis is severe; (b) HA oligomers and TGFβ1 elastogenically stimulate RASMCs in mildly‐injured (i.e. PPE15) cultures to restore both elastic matrix amounts and elastic fibre deposition to levels in healthy cultures; and (c) in severely injured (i.e. PPE75) cultures, the factors stimulate matrix elastin synthesis and crosslinking, although not to control levels. The outcomes underscore the need to enhance elastogenic factor doses based on the severity of elastin loss. This study will help in customizing therapies for elastin regeneration within AAs, based on cause and location. Copyright © 2010 John Wiley & Sons, Ltd.     

Kinematics of medial osteoarthritic knees before and after posterior cruciate ligament retaining total knee arthroplasty

Total knee arthroplasty (TKA) is a widely accepted surgical procedure for the treatment of patients with end‐stage osteoarthritis (OA). However, the function of the knee is not always fully recovered after TKA. We used a dual fluoroscopic imaging system to evaluate the in vivo kinematics of the knee with medial compartment OA before and after a posterior cruciate ligament‐retaining TKA (PCR‐TKA) during weight‐bearing knee flexion, and compared the results to those of normal knees. The OA knees displayed similar internal/external tibial rotation to normal knees. However, the OA knees had less overall posterior femoral translation relative to the tibia between 0° and 105° flexion and more varus knee rotation between 0° and 45° flexion, than in the normal knees. Additionally, in the OA knees the femur was located more medially than in the normal knees, particularly between 30° and 60° flexion. After PCR‐TKA, the knee kinematics were not restored to normal. The overall internal tibial rotation and posterior femoral translation between 0° and 105° knee flexion were dramatically reduced. Additionally, PCR‐TKA introduced an abnormal anterior femoral translation during early knee flexion, and the femur was located lateral to the tibia throughout weight‐bearing flexion. The data help understand the biomechanical functions of the knee with medial compartment OA before and after contemporary PCR‐TKA. They may also be useful for improvement of future prostheses designs and surgical techniques in treatment of knees with end‐stage OA. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:40–46, 2011