Hip geometry in diabetic women: Implications for fracture risk

ObjectiveWomen with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD) as compared to women without diabetes. We hypothesized that bone strength is diminished in women with T2DM after accounting for lean body mass, which may contribute to their increased fracture risk.MethodsParticipants from Women's Health Initiative Observational Study were included in this cross-sectional study. These analyses include 3 groups of women: 1) T2DM women on diet or oral hypoglycemic agents (n = 299); 2) T2DM women on insulin therapy (with or without oral agents) (n = 128); and 3) Non-diabetic control women (n = 5497). Hip structural analyses were done using the validated Beck's method on hip scans from dual energy x-ray absorptiometry (DXA). We compared BMD and section modulus (bending strength) at the narrow neck with and without correcting for total body DXA lean body mass.ResultsWomen in all three groups were of similar ages (63.7, 64.6 and 64.2 years, respectively) and heights, but those with T2DM were heavier, with greater lean body weight vs controls (P < .001). In both diabetic groups, absolute BMD and section modulus were higher compared with controls. However, after adjusting for total lean body weight, diabetic women on insulin had significantly lower BMD and section modulus.ConclusionAdjusted for lean body weight, the BMD and bending strength in the femoral neck are significantly lower in insulin-treated diabetic women vs controls. This may represent altered adaptation of bone modeling and explain the higher fracture risk in patients with T2DM.     

Targeting protein-trafficking pathways alters melanoma treatment sensitivity

Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the protein-trafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocyte-stimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents.     

The ABO blood group is a trans-species polymorphism in primates

The ABO histo-blood group, the critical determinant of transfusion incompatibility, was the first genetic polymorphism discovered in humans. Remarkably, ABO antigens are also polymorphic in many other primates, with the same two amino acid changes responsible for A and B specificity in all species sequenced to date. Whether this recurrence of A and B antigens is the result of an ancient polymorphism maintained across species or due to numerous, more recent instances of convergent evolution has been debated for decades, with a current consensus in support of convergent evolution. We show instead that genetic variation data in humans and gibbons as well as in Old World monkeys are inconsistent with a model of convergent evolution and support the hypothesis of an ancient, multiallelic polymorphism of which some alleles are shared by descent among species. These results demonstrate that the A and B blood groups result from a trans-species polymorphism among distantly related species and has remained under balancing selection for tens of millions of years—to date, the only such example in hominoids and Old World monkeys outside of the major histocompatibility complex.     

After treat-to-target: can a targeted ultrasound initiative improve RA outcomes?

For patients with rheumatoid arthritis (RA), remission can be achieved with tight control of inflammation and early use of disease modifying agents. The importance of remission as an outcome has been recently highlighted by European League Against Rheumatism recommendations. However, remission when defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US) . There is evidence that imaging synovitis is frequently found in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who have recently formed a research network--the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted ultrasound in RA.     

Porous polyethylene implant reconstruction of the orbit after resection of spheno-orbital meningiomas: A novel technique

Background

Spheno-orbital meningiomas (SOM) are complex tumors involving the middle cranial fossa and orbit. Following resection of these tumors, reconstruction of the orbit can be challenging. Inadequate reconstruction may lead to cosmetic deformities and functional complications.

Objective

The development of a technique for orbital reconstruction which is technically straightforward, cost-effective, with an excellent functional and cosmetic outcome.

Technique

Twelve patients with SOM each underwent a modified orbital-zygomatic craniotomy with osteotomies based on individual tumor location. After tumor resection, the lateral orbit and orbital roof, where necessary, were reconstructed using a 1 mm porous polyethylene sheet, customized to reconstruct the bony anatomy of the lateral and superior orbit and secured with 1.5 × 4 mm titanium screws into the orbital roof and rim.

Results

All patients demonstrated stabilization or improvement of vision and satisfactory cosmetic outcomes. One complication (surgical site infection) was noted. Follow-up imaging was obtained at regular intervals. The resection cavity was easily visualized without interference from the implant in each case. One patient developed tumor recurrence requiring re-operation 20 months after the initial procedure.

Conclusions

Use of a 1 mm porous polyethylene sheet for reconstruction of the lateral orbit offers an excellent functional and cosmetic outcome, does not interfere with postoperative imaging, is technically straightforward, and is cost-effective.