The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9^Q152H) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9^Q152H variation. We report that PCSK9^Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9^Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress-response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than inducing them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress–driven conditions of the liver. In summary, we have uncovered a cochaperone function for PCSK9^Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.     

Importance of measurement site on assessment of lesion-specific ischemia and diagnostic performance by coronary computed tomography Angiography-Derived Fractional Flow Reserve

BackgroundValues of fractional flow reserve (FFR_CT) by coronary computed tomography angiography (CTA) decline from the ostium to the terminal vessel, irrespective of stenosis severity. The purpose of this study is to determine if the site of measurement of FFR_CT impacts assessment of ischemia and its diagnostic performance relative to invasive FFR (FFR_INV).Methods1484 patients underwent FFR_CT; 1910 vessels were stratified by stenosis severity (normal; <25%, 25–50%, 50–70%, and >70% stenosis). The rates of positive FFR_CT (≤0.8) were determined by measuring FFR_CT from the terminal vessel and from distal-to-the-lesion. Reclassification rates from positive to negative FFR_CT were calculated. Diagnostic performance of FFR_CT relative to FFR_INV was evaluated in 182 vessels using linear regression, Bland Altman analysis, and receiver operating characteristic (ROC) curves.ResultsPositive FFR_CT was identified in 24.9% of vessels using terminal vessel FFR_CT and 10.1% using FFR_CT distal-to-the-lesion (p ?< ?0.001). FFR_CT obtained distal-to-the-lesion resulted in reclassification of 59.6% of positive terminal FFR_CT to negative FFR_CT. Relative to FFR_INV, there were improvements in specificity (50% to 86%, p ?< ?0.001), diagnostic accuracy (65% to 88%, p ?< ?0.001), positive predictive value (50% to 78%, p ?< ?0.001), and area-under-the-curve (AUC, 0.83 to 0.91, p ?< ?0.001) when FFR_CT was measured distal-to-the-lesion.ConclusionFFR_CT values from the terminal vessel should not be used to assess lesion-specific ischemia due to high rates of false positive results. FFR_CT measured distal-to-the-lesion improves the diagnostic performance of FFR_CT relative to FFR_INV, ensures that FFR_CT values are due to lesion-specific ischemia, and could reduce the rate of unnecessary invasive procedures.     

Can exercise-related improvements in immunity influence cancer prevention and prognosis in the elderly?

Cancer incidence increases with advancing age. Over 60% of new cancers and 70% of cancer deaths occur in individuals aged 65 years or older. One factor that may contribute to this is immunosenescence – a canopy term that is used to describe age-related declines in the normal functioning of the immune system. There are multiple age-related deficits in both the innate and adaptive systems that may play a role in the increased incidence of cancer. These include decreased NK-cell function, impaired antigen uptake and presentation by monocytes and dendritic cells, an increase in ‘inflammaging’, a decline in the number of naïve T-cells able to respond to evolving tumor cells, and an increase in functionally exhausted senescent cells. There is consensus that habitual physical exercise can offer protection against certain types of cancer; however the evidence linking immunological mechanisms, exercise, and reduced cancer risk remain tentative. Multiple studies published over the last two decades suggest that exercise can mitigate the deleterious effects of age on immune function, thus increasing anti-cancer immunity. The potential ameliorative effect of exercise on these mechanisms include evidence that physical activity is able to stimulate greater NK-cell activity, enhance antigen-presentation, reduce inflammation, and prevent senescent cell accumulation in the elderly. Here we discuss the role played by the immune system in preventing and controlling cancer and how aging may retard these anti-cancer mechanisms. We also propose a pathway by which exercise-induced alterations in immunosenescence may decrease the incidence of cancer and help improve prognosis in cancer patients.     

Tetracycline use in treating osteoarthritis: a systematic review

Inflammation Research - The purpose of the review was to synthesize the current literature regarding tetracyclines in the treatment of osteoarthritis. Using multiple databases, a systematic review...     

What is the Utility Of a Limb Lengthening and Reconstruction Service in an Academic Department of Orthopaedic Surgery?

Background

Limb lengthening and reconstruction surgery is a relatively new subspecialty of orthopaedic surgery in the United States. Despite increased awareness and practice of the specialty, it is rarely vested as a separate clinical service in an academic department of orthopaedic surgery. We have had experience growing such a dedicated service within an academic department of orthopaedic surgery over the past 9 years.

Questions/purposes

We explored (1) the use of a limb deformity service (LDS) in an academic department of orthopaedic surgery by examining data on referral patterns, our clinical volume, and academic productivity; and (2) the surgical breadth of cases comprising the patients of the LDS in an academic department of orthopaedic surgery by examining data on caseload by anatomic sites, category, and surgical techniques/tools.

Methods

We (SRR, ATF, EWB) retrospectively examined data on numbers of surgical cases and outpatient visits from the limb lengthening and complex reconstruction service at the Hospital for Special Surgery from 2005 to 2013 to evaluate growth. We studied 672 consecutive surgical cases performed by our service for a sample period of 1 year, assessing referral patterns within and outside our medical center, anatomic region, surgical category, and surgical technique/tool. Academic productivity was measured by review of our service’s publications.

Results

During the time period studied (2005–2013), outpatient and surgical volume significantly increased by 120% (1530 to 3372) and 105% (346 to 708), respectively, on our LDS. Surgical volume growth was similar to the overall growth of the department of orthopaedic surgery. Referrals were primarily from orthopaedic surgeons (56%) and self/Internet research (25%). Physician referrals were predominantly from our own medical center (83%). Referrals from within our institution came from a variety of clinical services. Forty-nine peer-reviewed articles and 23 book chapters were published by staff members of our service. Anatomic surgical sites, surgical categories, and technique/tools used on our LDS were diverse, yet procedures were specialized to the discipline of limb deformity.

Conclusions

There is a substantial role for an LDS within an academic department of orthopaedic surgery. With establishment of a dedicated service comes focus and resources that establish an environment for growth in volume, intramural and extramural referral, and purposeful research and education. The majority of referrals were from orthopaedic surgeons from our own medical center, suggesting needfulness. The LDS provides patients access to specialized surgery. The number of intramural referrals suggests that the specialty service helps retain patients within our academic orthopaedic department. Future research will try to determine if such a dedicated service leads to improved outcomes, efficiency, and value.

Level of Evidence

Level IV, retrospective study.