Chronic rejection: insights from a novel immunosuppressive-free model of kidney transplantation

The use of immunosuppressive drugs in models of chronic rejection may limit their usefulness for mechanistic studies. We have developed a new minor histocompatibility-mismatched rat kidney transplant model without the need for immunosuppression. Kidneys from LEW (RT1(l)) donors were transplanted to congenic WF.1L (RT1(l)) recipients and compared with the reversed strain combination and isogenic controls. Urinary protein excretion was measured serially in all recipients; kidneys were harvested 90, 120, and 180 d after transplantation for morphologic analysis and cytokine gene expression. In vitro lymphocytic reactivity and cytokine analysis of mixed lymphocyte reaction (MLR) culture supernatants by ELISA was also carried out. LEW into WF.1L kidney grafts developed proteinuria starting 120 d after transplantation and were associated with morphologic changes of focal segmental glomerulosclerosis together with interstitial cell infiltrates, upregulated gene expression of IL-1beta, IL-2, and TNF-alpha/-beta, as well as IL-2, IFN-gamma, and TNF-alpha production by lymphocytes in MLR culture supernatants. WF.1L kidneys transplanted into LEW recipients did not develop chronic rejection and had upregulation of Th2 cytokines, both within the allograft and in MLR supernatant of recipient lymphocytes cultured with WF.1L cells. Furthermore, these lymphocytes produced both Th1 and Th2 cytokines when cultured with WF cells, unlike lymphocytes from the LEW isografts, which produced Th1 cytokines when challenged with WF cells. These studies show that indirect allorecognition can cause strain-dependent chronic rejection associated with Th1-like cytokine production, whereas production of Th2 cytokines is associated with protection from the development of chronic rejection.     

A chronic-constriction injury of the sciatic nerve reduces bilaterally the responsiveness to formalin in rats: a behavioral and hormonal evaluation

Application of four loose ligatures to the sciatic nerve of a rat (chronic constriction injury [CCI]) induces clear hypersensitivity to non-noxious stimulation and chemical irritants. However, in this study, an injection of formalin in the hind paw of a rat with CCI-induced mononeuropathy resulted in an ipsilateral decreased flinching and licking or biting behavior in both phases of the formalin testing. The effect was independent of the formalin concentration used. This altered behavior was accompanied with smaller plasma levels of adrenocorticotrope hormone and corticosterone compared with sham and non-operated animals. Formalin injection in the contralateral nonligated hind paw of CCI rats also reduced the licking or biting behavior as compared with sham-operated and non-operated control animals only in the second phase of the formalin test. Thus, CCI reduces the pain reactivity and hypothalamic-pituitary-adrenal-axis activation to ipsilateral and contralateral formalin injection. Further research should investigate whether the decreased pain reactivity by CCI is situated at the peripheral, spinal, or supraspinal level or is result of changes in the stress reactivity and coping strategies. IMPLICATIONS: We evaluated the changes in the behavioral reactions and the hormonal effects of a noxious chemical stimulus, i.e., formalin injection in animals with previously induced chronic constriction injury to the sciatic nerve. The effect in animals injected at the ipsilateral and contralateral site, sham-operated and controls, were compared.     

Causes of frequency and nocturia after renal transplantation

OBJECTIVE

To explore the role of bladder capacity, bladder pain, dysfunctional voiding, urgency, urinary tract infections (UTIs), and urinary output as potential causes of frequency and nocturia after renal transplantation.

PATIENTS AND METHODS

Data were gathered from 52 adult renal transplant patients (35 men and 17 women, mean age 49 years), using a written questionnaire, medical records, frequency/volume charts, and urinary cultures. The mean time between transplantation and data collection was 5 months. Structural equation modelling (SEM) was used for the simultaneous assessment of direct and indirect relationships between explanatory variables and voiding frequency.

RESULTS

Frequency and nocturia were found in 54% and 60% of the study population, respectively. Frequency was directly associated with a small bladder capacity, bladder pain, urgency, and a high daytime urine volume, and indirectly by UTIs (via urgency and bladder pain). Nocturia was associated with high nocturnal urine volume, small bladder capacity and dysfunctional voiding. A quarter of the patients had small bladders and another quarter had large bladders, the latter being associated with nocturnal polyuria.

CONCLUSIONS

The presence of frequency, especially when accompanied by bladder pain, might aid the physician to identify patients with small bladders. The presence of nocturia can be the result of a high nocturnal urine volume, which increases the risk of bladder enlargement. Because both abnormal bladder conditions can contribute to graft dysfunction, we recommend a urological follow‐up after renal transplantation, using frequency/volume charts.     

Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood

The platelet glycoproteins (GPs) Ib, integrin alpha(2)beta(1), and GPVI are considered central to thrombus formation. Recently, their relative importance has been re-evaluated based on data from murine knockout models. To examine their relationship during human thrombus formation on collagen type I fibers at high shear (1000 s(-1)), we tested a novel antibody against GPVI, an immunoglobulin single-chain variable fragment, 10B12, together with specific antagonists for GPIb alpha (12G1 Fab(2)) and alpha(2)beta(1) (6F1 mAb or GFOGER-GPP peptide). GPVI was found to be crucial for aggregate formation, Ca(2+) signaling, and phosphatidylserine (PS) exposure, but not for primary adhesion, even with more than 97% receptor blockade. Inhibiting alpha(2)beta(1) revealed its involvement in regulating Ca(2+) signaling, PS exposure, and aggregate size. Both GPIb alpha and alpha(2)beta(1) contributed to primary adhesion, showing overlapping function. The coinhibition of receptors revealed synergism in thrombus formation: the coinhibition of adenosine diphosphate (ADP) receptors with collagen receptors further decreased adhesion and aggregation, and, crucially, the complete eradication of thrombus formation required the coinhibition of GPVI with either GPIb alpha or alpha(2)beta(1). In summary, human platelet deposition on collagen depends on the concerted interplay of several receptors: GPIb in synergy with alpha(2)beta(1) mediating primary adhesion, reinforced by activation through GPVI, which further regulates the thrombus formation.     

Short Bouts of Intensive Exercise During the Workday Have a Positive Effect on Neuro‐cognitive Performance

Beside its positive impact on physical health, exercise is indicated to positively affect cognitive performance based on a relocation of cortical activity. This study examined the influence of different types of breaks on cognitive performance and related cortical activity in office‐based employees. Breaks were filled with exercise, resting or a usual break and a control condition where employees continued working without any break. Cognitive performance was assessed using the d2‐R test and two commercially available cognitive tasks. Brain cortical activity was recorded using electroencephalography before and after breaks. Individual's mood was analysed using a profile of mood state. Results indicate a positive effect of a 3‐min boxing intervention on cognitive performance, mirrored by a decrease in prefrontal cortex activity. Although perceived psychological state was increased after the usual break, this is reflected in neither cortical activity nor cognitive performance. With respect to the fact that also bike activity resulted an increase in prefrontal alpha‐2 activity, a positive effect of exercise on neuro‐cognitive performance can be stated. Health and economic benefits may result from brief physical activity breaks and help to maintain workplace performance and job satisfaction. Copyright © 2015 John Wiley & Sons, Ltd.     

Alterations in midline cortical thickness and gyrification patterns mapped in children with 22q11.2 deletions

The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome)is a neurogenetic condition associated with visuospatial deficits,as well as elevated rates of attentional disturbance, mood disorder,and psychosis. Previously, we detected pronounced cortical thinningin superior parietal and right parieto-occipital cortices inpatients with this syndrome, regions critical for visuospatialprocessing. Here we applied cortical pattern-matching algorithmsto structural magnetic resonance images obtained from 21 childrenwith confirmed 22q11.2 deletions (ages 8–17) and 13 demographicallymatched comparison subjects, in order to map cortical thicknessacross the medial hemispheric surfaces. In addition, corticalmodels were remeshed in frequency space to compute their surfacecomplexity. Cortical maps revealed a pattern of localized thinningin the ventromedial occipital–temporal cortex, criticalfor visuospatial representation, and the anterior cingulate,a key area for attentional control. However, children with 22q11.2DSshowed significantly increased gyral complexity bilaterallyin occipital cortex. Regional gray matter volumes, particularlyin medial frontal cortex, were strongly correlated with bothverbal and nonverbal cognitive functions. These findings suggestthat aberrant parieto-occipital brain development, as evidencedby both increased complexity and cortical thinning in theseregions, may be a neural substrate for the deficits in visuospatialand numerical understanding characteristic of this syndrome.     

Impact of thyroid function and polymorphisms in the type 2 deiodinase on blood pressure: the Rotterdam Study and the Rotterdam Scan Study

Introduction  Thyroid function and genetic variation in the hypothalamus–pituitary–thyroid axis have been implicated in blood pressure regulation and susceptibility to hypertension. However studies conducted thus far were small with controversial results.
Objective  To examine whether serum thyroid parameters and polymorphisms in the type 2 deiodinase and the TSH receptor are associated with blood pressure and the presence of hypertension in two large cohorts of elderly subjects.
Design and participants  We studied a random sample of 1444 subjects of the Rotterdam study, and 997 subjects of the Rotterdam Scan study, two population-based cohort studies among elderly individuals aged 55–90 years.
Outcome measurements  Data on blood pressure and hypertension were obtained, and serum thyroid parameters, D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were determined.
Results  In contrast to previous findings, no consistent and/or significant associations were found between serum TSH and FT4 and blood pressure in both cohorts. In addition, the D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were not associated with blood pressure or the risk of hypertension.
Conclusions  In two large populations of elderly subjects, neither serum thyroid parameters nor polymorphisms in the type 2 deiodinase and the TSH receptor, were associated with blood pressure or the presence of hypertension. Our data suggest that thyroid function is not an important determinant of hypertension in elderly Dutch subjects.     

Thiazide diuretics and the risk for hip fracture

Since most hip fractures are related to osteoporosis, treating accelerated bone loss can be an important strategy to prevent hip fractures. Thiazides have been associated with reduced age-related bone loss by decreasing urinary calcium excretion.