Cytomegalovirus Serology and Replication Remain Associated With Solid Organ Graft Rejection and Graft Loss in the Era of Prophylactic Treatment

BACKGROUND Cytomegalovirus (CMV) replication has been associated with more risk for solid organ graft rejection. We wondered whether this association still holds when patients at risk receive prophylactic treatment for CMV. METHODS We correlated CMV infection, biopsy-proven graft rejection, and graft loss in 1,414 patients receiving heart (n=97), kidney (n=917), liver (n=237), or lung (n=163) allografts reported to the Swiss Transplant Cohort Study. RESULTS Recipients of all organs were at an increased risk for biopsy-proven graft rejection within 4 weeks after detection of CMV replication (hazard ratio [HR] after heart transplantation, 2.60; 95% confidence interval [CI], 1.34-4.94, P<0.001; HR after kidney transplantation, 1.58; 95% CI, 1.16-2.16, P=0.02; HR after liver transplantation, 2.21; 95% CI, 1.53-3.17, P<0.001; HR after lung transplantation, 5.83; 95% CI, 3.12-10.9, P<0.001. Relative hazards were comparable in patients with asymptomatic or symptomatic CMV infection. The CMV donor or recipient serological constellation also predicted the incidence of graft rejection after liver and lung transplantation, with significantly higher rates of rejection in transplants in which donor or recipient were CMV seropositive (non-D-/R-), compared with D- transplant or R- transplant (HR, 3.05; P=0.002 for liver and HR, 2.42; P=0.01 for lung transplants). Finally, graft loss occurred more frequently in non-D- or non-R- compared with D- transplant or R- transplant in all organs analyzed. Valganciclovir prophylactic treatment seemed to delay, but not prevent, graft loss in non-D- or non-R- transplants. CONCLUSION Cytomegalovirus replication and donor or recipient seroconstellation remains associated with graft rejection and graft loss in the era of prophylactic CMV treatment.

Organ donation in Switzerland - an analysis of factors associated with consent rate

BACKGROUND AND AIM Switzerland has a low post mortem organ donation rate. Here we examine variables that are associated with the consent of the deceased's next of kin (NOK) for organ donation, which is a prerequisite for donation in Switzerland. METHODS AND ANALYSIS During one year, we registered information from NOK of all deceased patients in Swiss intensive care units, who were approached for consent to organ donation. We collected data on patient demographics, characteristics of NOK, factors related to the request process and to the clinical setting. We analyzed the association of collected predictors with consent rate using univariable logistic regression models; predictors with p-values <0.2 were selected for a multivariable logistic regression. RESULTS Of 266 NOK approached for consent, consent was given in 137 (51.5%) cases. In multivariable analysis, we found associations of consent rates with Swiss nationality (OR 3.09, 95% CI: 1.46-6.54) and German language area (OR 0.31, 95% CI: 0.14-0.73). Consent rates tended to be higher if a parent was present during the request (OR 1.76, 95% CI: 0.93-3.33) and if the request was done before brain death was formally declared (OR 1.87, 95% CI: 0.90-3.87). CONCLUSION Establishing an atmosphere of trust between the medical staff putting forward a request and the NOK, allowing sufficient time for the NOK to consider donation, and respecting personal values and cultural differences, could be of importance for increasing donation rates. Additional measures are needed to address the pronounced differences in consent rates between language regions.

Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation

BACKGROUND  Polymorphisms in the interferon-λ (IFNL) 3/4 region have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of CMV infection in solid-organ transplant (SOT) recipients. METHODS  Caucasian patients participating in the Swiss Transplant Cohort Study in 2008-2011 were included. A novel functional TT/-G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated. RESULTS  A total of 840 SOT recipients at risk for CMV were included, among whom 373 (44%) received antiviral prophylaxis. The 12-months cumulative incidence of CMV replication and disease were 0.44 and 0.08, respectively. Patient homozygous for the minor rs368234815 allele (-G/-G) tended to have a higher cumulative incidence of CMV replication (SHR=1.30 [95%CI 0.97-1.74], P=0.07) compared to other patients (TT/TT or TT/-G). The association was significant among patients followed by a preemptive approach (SHR=1.46 [1.01-2.12], P=0.047), especially in patients receiving an organ from a seropositive donor (D+, SHR=1.92 [95%CI 1.30-2.85], P=0.001), but not among those who received antiviral prophylaxis (SHR=1.13 [95%CI 0.70-1.83], P=0.6). These associations remained significant in multivariate competing risk regression models. CONCLUSIONS  Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in SOT recipients, particularly in patients not receiving antiviral prophylaxis.

IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid Organ Transplantation.

BACKGROUND  Single nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell (HSCT) but not solid organ transplant (SOT) recipients. METHODS  24 SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidneys, 190 liver, 102 lungs, 79 hearts, 15 other) from the Swiss Transplant Cohort Study. Association between SNPs and the endpoint were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by ELISA in PBMCs from healthy volunteers and correlated with relevant genotypes. RESULTS  Mold colonization (N=45) and proven/probable IMI (N=26) were associated with polymorphisms in interleukin-1 beta (IL1B, rs16944; log-rank test, recessive mode, colonization P=0.001 and IMI P=0.00005), interleukin-1 receptor antagonist (IL1RN, rs419598; P=0.01 and P=0.02) and β-defensin-1 (DEFB1, rs1800972; P=0.001 and P=0.0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (IL1B rs16944 P=0.002; DEFB1 rs1800972 P=0.01). Presence of two copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced IL-1β and TNFα secretion by PBMCs. CONCLUSIONS  Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.

Anatomy, biology, physiology and basic pathology of the nail organ

The nail is the largest skin appendage. It grows continuously through life in a non-cyclical manner; its growth is not hormone-dependent. The nail of the middle finger of the dominant hand grows fastest with approximately 0.1 mm/day, whereas the big toe nail grows only 0.03-0.05 mm/d. The nails' size and shape vary characteristically from finger to finger and from toe to toe, for which the size and shape of the bone of the terminal phalanx is responsible. The nail apparatus consists of both epithelial and connective tissue components. The matrix epithelium is responsible for the production of the nail plate whereas the nail bed epithelium mediates firm attachment. The hyponychium is a specialized structure sealing the subungual space and allowing the nail plate to physiologically detach from the nail bed. The proximal nail fold covers most of the matrix. Its free end forms the cuticle which seals the nail pocket or cul-de-sac. The dermis of the matrix and nail bed is specialized with a morphogenetic potency. The proximal and lateral nail folds form a frame on three sides giving the nail stability and allowing it to grow out. The nail protects the distal phalanx, is an extremely versatile tool for defense and dexterity and increases the sensitivity of the tip of the finger. Nail apparatus, finger tip, tendons and ligaments of the distal interphalangeal joint form a functional unit and cannot be seen independently. The nail organ has only a certain number of reaction patterns that differ in many respects from hairy and palmoplantar skin.

CCL5/RANTES is a key chemoattractant released by degenerative intervertebral discs in organ culture.

Release of chemotactic factors in response to tissue damage has been described for different musculoskeletal tissues, including the intervertebral disc (IVD). This study investigated the chemoattractants that are released by induced degenerative IVDs and may be involved in recruiting mesenchymal stem cells (MSCs). Bovine caudal discs were cultured within a bioreactor and loaded under conditions that mimicked physiological or degenerative settings. Between days 4-6, medium was replaced by PBS, which was subsequently used for proteomic, ELISA and immunoprecipitation analyses of secreted chemokines and cytokines. A Boyden chamber assay was used to observe human MSC migration towards native and chemokine depleted media. Gene expression levels of chemokine receptors in human MSCs were analysed, and CCL5 was localised in bovine and human IVD by immunohistochemistry. Proteomic analysis revealed the presence of CCL5 and CXCL6 within conditioned media. Higher concentrations of CCL5 were found in the degenerative media, and a relationship was found between interleukin-1β and CCL5 concentration. Chemokine immunoprecipitation showed that MSCs had a significantly reduced chemotactic migration towards CCL5-immunoprecipitated and CCL5/CXCL6 co-immunoprecipitated media, whilst CXCL6 depletion did not change MSC chemotaxis. MSCs showed a significant increase in mRNA expression of the CCL5 receptors, CCR1 and CCR4, upon culture in degenerative media. Furthermore, CCL5 was identified in bovine and human disc tissue by immunohistochemistry. Hence, CCL5 may be a key chemoattractant that is produced and released by the intervertebral disc cells. Therefore, these factors could be used to enhance stem/progenitor cell mobilisation in regenerative therapies for early stages of disc degeneration.

The teleostean liver as an immunological organ: Intrahepatic immune cells (IHICs) in healthy and benzo[a]pyrene challenged rainbow trout (Oncorhynchus mykiss).

The existence of a resident population of intrahepatic immune cells (IHICs) is well documented for mammalian vertebrates, however, it is uncertain whether IHICs are present in the liver of teleostean fish. In the present study we investigated whether trout liver contains an IHIC population, and if so, what the relative cellular composition of this population is. The results provide clear evidence for the existence of an IHIC population in trout liver, which constitutes 15-29% of the non-hepatocytes in the liver, and with a cellular composition different to that of the blood leukocyte population. We also analyzed the response of IHICs to a non-infectious liver challenge with the hepatotoxic and immunotoxic chemical, benzo[a]pyrene (BaP). Juvenile trout were treated with BaP (25 or 100mg/kgbw) at levels sufficient to induce the molecular pathway of BaP metabolism while not causing pathological and inflammatory liver changes. The IHIC population responded to the BaP treatments in a way that differed from the responses of the leukocyte populations in trout blood and spleen, suggesting that IHICs are an independently regulated immune cell population.

Organ Culture Bioreactors - Platforms to Study Human Intervertebral Disc Degeneration and Regenerative Therapy.

In recent decades the application of bioreactors has revolutionized the concept of culturing tissues and organs that require mechanical loading. In intervertebral disc (IVD) research, collaborative efforts of biomedical engineering, biology and mechatronics have led to the innovation of new loading devices that can maintain viable IVD organ explants from large animals and human cadavers in precisely defined nutritional and mechanical environments over extended culture periods. Particularly in spine and IVD research, these organ culture models offer appealing alternatives, as large bipedal animal models with naturally occurring IVD degeneration and a genetic background similar to the human condition do not exist. Latest research has demonstrated important concepts including the potential of homing of mesenchymal stem cells to nutritionally or mechanically stressed IVDs, and the regenerative potential of "smart" biomaterials for nucleus pulposus or annulus fibrosus repair. In this review, we summarize the current knowledge about cell therapy, injection of cytokines and short peptides to rescue the degenerating IVD. We further stress that most bioreactor systems simplify the real in vivo conditions providing a useful proof of concept. Limitations are that certain aspects of the immune host response and pain assessments cannot be addressed with ex vivo systems. Coccygeal animal disc models are commonly used because of their availability and similarity to human IVDs. Although in vitro loading environments are not identical to the human in vivo situation, 3D ex vivo organ culture models of large animal coccygeal and human lumbar IVDs should be seen as valid alternatives for screening and feasibility testing to augment existing small animal, large animal, and human clinical trial experiments.

PTX3 Polymorphisms and Invasive Mold Infections after Solid Organ Transplantation

Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infection among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patient's risk stratification.

Comparative histology of the adult electric organ among four species of the genus Campylomormyrus (Teleostei: Mormyridae)

The electric organ (EO) of weakly electric mormyrids consists of flat, disk-shaped electrocytes with distinct anterior and posterior faces. There are multiple species-characteristic patterns in the geometry of the electrocytes and their innervation. To further correlate electric organ discharge (EOD) with EO anatomy, we examined four species of the mormyrid genus Campylomormyrus possessing clearly distinct EODs. In C. compressirostris, C. numenius, and C. tshokwe, all of which display biphasic EODs, the posterior face of the electrocytes forms evaginations merging to a stalk system receiving the innervation. In C. tamandua that emits a triphasic EOD, the small stalks of the electrocyte penetrate the electrocyte anteriorly before merging on the anterior side to receive the innervation. Additional differences in electrocyte anatomy among the former three species with the same EO geometry could be associated with further characteristics of their EODs. Furthermore, in C. numenius, ontogenetic changes in EO anatomy correlate with profound changes in the EOD. In the juvenile the anterior face of the electrocyte is smooth, whereas in the adult it exhibits pronounced surface foldings. This anatomical difference, together with disparities in the degree of stalk furcation, probably contributes to the about 12 times longer EOD in the adult.

Light stops, blind spots, and isospin violation in the MSSM

In the framework of the MSSM, we examine several simplified models where only a few superpartners are light. This allows us to study WIMP-nucleus scattering in terms of a handful of MSSM parameters and thereby scrutinize their impact on dark matter direct-detection experiments. Focusing on spin-independent WIMP-nucleon scattering, we derive simplified, analytic expressions for the Wilson coefficients associated with Higgs and squark exchange. We utilize these results to study the complementarity of constraints due to direct-detection, flavor, and collider experiments. We also identify parameter configurations that produce (almost) vanishing cross sections. In the proximity of these so-called blind spots, we find that the amount of isospin violation may be much larger than typically expected in the MSSM. This feature is a generic property of parameter regions where cross sections are suppressed, and highlights the importance of a careful analysis of the nucleon matrix elements and the associated hadronic uncertainties. This becomes especially relevant once the increased sensitivity of future direct-detection experiments corners the MSSM into these regions of parameter space.