Early response to erythropoiesis-stimulating agents in non-dialysis chronic kidney disease patients

Background

Renal anemia complicated with chronic kidney disease is usually treated with erythropoiesis-stimulating agents (ESAs). However, few studies have compared the early response of hemoglobin (Hb) to different kinds of ESAs.

Methods

The effects of three types of ESAs—epoetin alfa or beta (EPO), darbepoetin alfa (DPO), and epoetin beta pegol (EPObp)—on renal anemia were followed in 416 pre-dialysis chronic kidney disease (CKD) patients. After the initial 12-week administration of ESAs, ΔHb/ESA dose/kg was calculated as an index of efficacy of each ESA. Furthermore, independent variables associated with ΔHb/ESA dose/kg (dependent variable) were determined using multiple linear regression analysis. The ten independent variables selected for analysis were: presence of diabetic nephropathy, estimated glomerular filtration rate (eGFR), Hb, albumin, iron (Fe), transferrin saturation (TSAT), ferritin, phosphate (P), intact parathyroid hormone (iPTH), and C-reactive protein.

Results

The efficacy of DPO and EPObp were similar and higher than EPO. TSAT was most strongly correlated with ΔHb/EPO dose/kg in all three types of ESAs. Other significant independent factors were Hb, albumin, P, iPTH, and diabetic nephropathy in the EPO group, eGFR in the DPO group, and Fe in the EPObp group. The adjusted coefficient of determination (R ²) ranged from 0.415 to 0.520 in the three ESA groups.

Conclusions

The study results suggest that TSAT is the best predictor of the initial 12-week responsiveness to ESA, irrespective of the type. Variables not investigated in this study also affect responsiveness to ESA in Japanese pre-dialysis CKD patients.

     

Hypoxia augments MHC class I antigen presentation via facilitation of ERO1‐α‐mediated oxidative folding in murine tumor cells

To establish an effective cancer immunotherapy, it is crucial that cancer cells present a cancer‐specific antigen in a hypoxic area, a hallmark of the tumor microenvironment. Here, we show the impact of hypoxia on MHC class I antigen presentation in vitro and in vivo in murine tumors. Activation of antigen‐specific CTLs by tumor cells that had been pre‐incubated under a condition of hypoxia was enhanced compared with that by tumor cells pre‐incubated under a condition of normoxia. Cell surface expression of MHC class I‐peptide complex on the tumor cells was increased under a condition of hypoxia, thereby leading to higher susceptibility to specific CTLs. We show that the hypoxia‐inducible ER‐resident oxidase ERO1‐α plays an important role in the hypoxia‐induced augmentation of MHC class I‐peptide complex expression. ERO1‐α facilitated oxidative folding of MHC class I heavy chains, thereby resulting in the augmentation of cell surface expression of MHC class I‐peptide complex under hypoxic conditions. These results suggest that since the expression of MHC class I‐peptide complex is augmented in a hypoxic tumor microenvironment, strategies for inhibiting the function of regulatory T cells and myeloid‐derived suppressor cells and/or immunotherapy with immune checkpoint inhibitors are promising for improving cancer immunotherapy.     

The Role of Patient–Provider Communication in Engagement and Re-engagement in HIV Treatment in Bamako,Mali: A Qualitative Study

Mounting evidence in sub-Saharan Africa suggests poor patient-provider communication (PPC) negatively impacts patient engagement (retention in care and adherence to medication) in antiretroviral therapy (ART) programs. In Bamako, Mali, where 36% of ART patients are lost to follow-up within 12 months of initiating treatment, we aimed to define features of positive PPC according to patient values and explore the mechanisms by which these features may sustain engagement and re-engagement according to patient and provider experiences. We conducted 33 in-depth interviews and 7 focus groups with 69 patients and 17 providers in five ART clinics. Regarding sustaining engagement, participants highlighted “establishing rapport” as a foundational feature of effective PPC, but also described how “responding to emotional needs”, “eliciting patient conflicts and perspective” and “partnering to mitigate conflicts” functioned to address barriers to engagement and increase connectedness to care. Patients who had disengaged felt that “communicating reacceptance” may have prompted them re-engage sooner and that tailored “partnering to mitigate conflicts” would be more effective in sustaining re-engagement than the standard adherence education providers typically offer. Optimizing provider skills related to these key PPC features may help maximize ART patient engagement, ultimately improving health outcomes and decreasing HIV transmission in sub-Saharan Africa.     

Orbital seeding of mesenchymal stromal cells increases osteogenic differentiation and bone-like tissue formation

In bone tissue engineering (TE), an efficient seeding and homogenous distribution of cells is needed to avoid cell loss and damage as well as to facilitate tissue development. Dynamic seeding methods seem to be superior to the static ones because they tend to result in a more homogeneous cell distribution by using kinetic forces. However, most dynamic seeding techniques are elaborate or require special equipment and its influence on the final bone tissue-engineered construct is not clear. In this study, we applied a simple, dynamic seeding method using an orbital shaker to seed human bone marrow–derived mesenchymal stromal cells (hBMSCs) on silk fibroin scaffolds. Significantly higher cell numbers with a more homogenous cell distribution, increased osteogenic differentiation, and mineral deposition were observed using the dynamic approach both for 4 and 6 hours as compared to the static seeding method. The positive influence of dynamic seeding could be attributed to both cell density and distribution but also nutrient supply during seeding and shear stresses (0.0-3.0 mPa) as determined by computational simulations. The influence of relevant mechanical stimuli during seeding should be investigated in the future, especially regarding the importance of mechanical cues for bone TE applications. Our results highlight the importance of adequate choice of seeding method and its impact on developing tissue-engineered constructs. The application of this simple seeding technique is not only recommended for bone TE but can also be used for seeding similar porous scaffolds with hBMSCs in other TE fields.     

In situ label‐free cell viability assessment of nucleus pulposus tissue

Regenerative medicine approaches aiming at treating degenerating intervertebral discs, a major cause of back pain, are increasingly tested in ex‐vivo disc explant models mimicking in‐vivo conditions. For assessing the efficacy of regenerative therapies, cell viability is commonly measured requiring specific labels to stain cells. Here, we demonstrate and evaluate how cellular auto‐fluorescence can be utilized to non‐invasively assess viability in disc tissue in‐situ using label‐free two‐photon microscopy. Live and dead bovine disc cells (0% and 100% cell viability) from the nucleus pulposus were seeded into collagen gels and auto‐fluorescence was characterized. Subsequently, nucleus pulposus explants were cultured for 6 days in media with different glucose supplementation (0, 0.25, 0.5, and 1 g/L) to induce different degrees of cell death. Then, samples were split and viability was assessed using label‐free two‐photon microscopy and conventional staining. Results show that live and dead nucleus pulposus cells systematically emit auto‐fluorescent light with distinct characteristics. Cell viability values obtained with label‐free microscopy did not significantly differ from those acquired with staining. In summary, monitoring auto‐fluorescence facilitates accurate cell viability assessment in nucleus tissue requiring no additional dyes. Thus, this technique may be suitable for pre‐clinical testing of regenerative therapies in nucleus pulposus cultures. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:545–550, 2014.     

Risk factors for incisional surgical site infections in elective surgery for colorectal cancer: focus on intraoperative meticulous wound management

Purpose

An incisional surgical site infection (I-SSI) is a frequently observed complication following colorectal surgery. Intraoperative wound management is one of the most important factors that determine the incidence of postoperative I-SSI. The purpose of this study was to assess the impact of the methods used for intraoperative wound management on the incidence of I-SSI following elective surgery for colorectal cancer.

Methods

Between November 2009 and February 2011, the data of 1,980 consecutive patients who underwent elective colorectal resection for colorectal cancer were prospectively collected from 19 affiliated hospitals. The incidence of and risk factors for I-SSI were investigated.

Results

Overall, 233 I-SSIs were identified (11.7 %). Forty-two possible risk factors were analyzed. Using a multivariate analysis, the independent risk factors for I-SSI were identified to be a high body mass index, previous laparotomy, chronic liver disease, wound length, contaminated wound class, creation or closure of an ostomy, right hemicolectomy procedure, the suture material used for fascial closure and the incidence of organ/space SSI.

Conclusion

To prevent I-SSI following elective colorectal surgery, it is crucial to avoid making large incisions and reduce fecal contamination whenever possible. A high quality randomized control trial is necessary to confirm the definitive intraoperative procedure(s) that can minimize the incidence of I-SSI.     

Anatomic Versus Nonanatomic Hepatectomy for a Solitary Hepatocellular Carcinoma

Background

It remains controversial whether anatomical resection (AR) improves the prognosis for hepatocellular carcinoma (HCC) or not. To our knowledge, there have been a few well-matched studies about this issue. The aim of the present study was to compare the recurrence-free survival of AR versus nonanatomical resection (NAR) for a solitary HCC using propensity score matching.

Methods

The present study included 236 patients who had a solitary HCC without macroscopic vessel thrombosis. Those patients were divided into AR (n?=?139) and NAR (n?=?97) groups. A propensity score matching was performed to minimize the effect of potential confounders.

Results

Sixty-four patients from each group were matched. Preoperative confounding factors were balanced between the two groups. The median recurrence-free survival times in the AR and NAR groups were 33.8 and 30.8 months, respectively (P?=?0.520). There were no significant differences in the intrahepatic recurrence pattern (P?=?0.097). Operative procedure was not a significant risk factor for recurrence in both uni- and multivariate analyses.

Conclusions

This case-matching study using a propensity score shows that there is no superiority of AR to NAR relevant to the recurrence-free survival in patients with a single HCC.     

Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization

A missense mutation R141W in the strong tropomyosin-binding region of cardiac troponin T (cTnT) has recently been reported to cause dilated cardiomyopathy (DCM), following the first report of a DCM-causing deletion mutation DeltaK210. To clarify the molecular mechanism for the pathogenesis of DCM caused by this novel mutation in cTnT gene, functional analyses were made on the recombinant human cTnT mutant proteins. Exchanging human wild-type and mutant cTnTs into rabbit skinned cardiac muscle fibers revealed that R141W mutation resulted in a decrease in the Ca(2+) sensitivity of force generation, as in the case of DeltaK210 mutation lying outside the strong tropomyosin-binding region. In contrast, a missense mutation R94L in the vicinity of the strong tropomyosin-binding region associated with hypertrophic cardiomyopathy (HCM) resulted in an increase in the Ca(2+) sensitivity of force generation, as in the case of the other HCM-causing mutations in cTnT reported previously. An assay using a quartz-crystal microbalance (a very sensitive mass-measuring device) revealed that R141W mutation increased the affinity of cTnT for alpha-tropomyosin by approximately three times, whereas an HCM-causing mutation DeltaE160 in the strong tropomyosin-binding region, as well as DeltaK210 and R94L mutations, had no effects on the interaction between cTnT and alpha-tropomyosin. Since cTnT has an important role in structurally integrating cardiac troponin I (cTnI) into the thin filaments via its two-way interactions with cTnI and tropomyosin, the present results suggest that R141W mutation in the strong tropomyosin-binding region in cTnT strengthens the integrity of cTnI in the thin filament by stabilizing the interaction between cTnT and tropomyosin, which might allow cTnI to inhibit the thin filament more effectively, leading to a Ca(2+) desensitization.