Pharmacokinetics of rituximab in a pediatric patient with therapy-resistant nephrotic syndrome

Background

Rituximab (RTX) has recently been introduced as a second-line therapy for nephrotic syndrome in children. Studies show that RTX given during the nephrotic state may be less effective than treatment during a non-nephrotic state, possibly due to loss of RTX in the urine.

Case-Diagnosis/Treatment

We describe a 10-year-old boy with steroid-resistant nephrotic syndrome (SRNS) treated with RTX during a phase of active non-selective proteinuria. The serum half-life of RTX in this patient was less than 1 day compared to 20 days in patients without protein losses. Urinary clearance was at least 25 %, compared to approximately 0 % in control patients. However, RTX loss in the urine, as well as in pleural effusion and ascites, only partly explains the rapid drop in the serum RTX concentration of this patient.

Conclusions

Serum half-life of RTX can be extremely short, partly due to excessive urinary losses in therapy-resistant nephrotic syndrome with non-selective proteinuria, as seen in our patient. These findings may help to explain the poor results of RTX treatment in patients with active proteinuria.

     

The effect of light-emitting diode and laser on mandibular growth in rats

Objective:To evaluate the effect of a light-emitting diode (LED) and/or low-level laser (LLL) with or without the use of anterior bite jumping appliances (also known as functional appliances [FAs]) on mandibular growth in rats.Materials and Methods:Thirty-six 8-week-old male Sprague-Dawley rats weighing 200 g were obtained from Charles River Canada (St. Constant, QC, Canada) and were divided into six groups of six animals each. Groups were as follows: group 1: LLL; group 2: LLL + FA; group 3: LED; group 4: LED + FA; group 5: FA; and group 6: control (no treatment). Mandibular growth was evaluated by histomorphometric and micro computed tomographic (microCT) analyses.Results:The LED and LED + FA groups showed an increase in all condylar tissue parameters compared with other groups.Conclusion:The LED-treated groups showed more mandibular growth stimulation compared with the laser groups.     

Longitudinal control of blood pressure among a cohort of Ghanaians with hypertension: A multicenter,hospital‐based study

There are limited data on factors associated with longitudinal control of blood pressure (BP) among Ghanaians on antihypertensive treatment. We sought to evaluate associations between prospective BP control and 24 putative factors within socio‐demographic, biological, and organizational domains. This is a cohort study involving 1867 (65%) adults with hypertension and 1006 (35%) with both hypertension and diabetes mellitus at five public hospitals. Clinic BP was measured every 2 months for 18 months of follow‐up. A multivariate logistic regression analysis was fitted via generalized linear mixed models to identify factors associated with clinic BP ≥ 140/90 mm Hg at each clinic visit during follow‐up. Mean age of study participants was 58.9 ± 16.6 years and 76.8% were females. Proportions with controlled BP increased from 46.3% at baseline to 59.8% at month 18, P < .0001. Eight factors with adjusted OR (95% CI) associated prospectively with uncontrolled BP were male gender: 1.37 (1.09‐1.72), secondary education: 1.32 (1.00‐1.74), non‐adherence to antihypertensive treatment: 1.03 (1.00‐1.06), fruit intake: 0.94 (0.89‐1.00), duration of hypertension diagnosis: 1.01 (1.00‐1.02), hypertension with diabetes mellitus: 2.05 (1.72‐2.46), number of antihypertensive medications: 1.63 (1.49‐1.79), and estimated glomerular filtration rate (mL/min rise): 0.82 (0.76‐0.89). Interventions aimed at addressing modifiable factors associated with poorly controlled BP would be critical in prevention of cardiovascular diseases among Ghanaians.     

Two surfaces on the histone chaperone Rtt106 mediate histone binding, replication, and silencing

The histone chaperone Rtt106 binds histone H3 acetylated at lysine 56 (H3K56ac) and facilitates nucleosome assembly during several molecular processes. Both the structural basis of this modification-specific recognition and how this recognition informs Rtt106 function are presently unclear. Guided by our crystal structure of Rtt106, we identified two regions on its double-pleckstrin homology domain architecture that mediated histone binding. When histone binding was compromised, Rtt106 localized properly to chromatin but failed to deliver H3K56ac, leading to replication and silencing defects. By mutating analogous regions in the structurally homologous chromatin-reorganizer Pob3, we revealed a conserved histone-binding function for a basic patch found on both proteins. In contrast, a loop connecting two β-strands was required for histone binding by Rtt106 but was dispensable for Pob3 function. Unlike Rtt106, Pob3 histone binding was modification-independent, implicating the loop of Rtt106 in H3K56ac-specific recognition in vivo. Our studies described the structural origins of Rtt106 function, identified a conserved histone-binding surface, and defined a critical role for Rtt106:H3K56ac-binding specificity in silencing and replication-coupled nucleosome turnover.     

Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation

Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer's diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that tdo-2 functions as a general regulator of protein homeostasis. Analysis of metabolite levels in C. elegans strains with mutations in enzymes that act downstream of tdo-2 indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of tdo-2 increases tryptophan levels, and feeding worms with extra l-tryptophan also suppresses toxicity, suggesting that tdo-2 regulates proteotoxicity through tryptophan. Depletion of tdo-2 extends lifespan in these worms. Together, these results implicate tdo-2 as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.     

Increased afterload induces pathological cardiac hypertrophy: a new in vitro model

Increased afterload results in ‘pathological’ cardiac hypertrophy, the most important risk factor for the development of heart failure. Current in vitro models fall short in deciphering the mechanisms of hypertrophy induced by afterload enhancement. The aim of this study was to develop an experimental model that allows investigating the impact of afterload enhancement (AE) on work-performing heart muscles in vitro. Fibrin-based engineered heart tissue (EHT) was cast between two hollow elastic silicone posts in a 24-well cell culture format. After 2?weeks, the posts were reinforced with metal braces, which markedly increased afterload of the spontaneously beating EHTs. Serum-free, triiodothyronine-, and hydrocortisone-supplemented medium conditions were established to prevent undefined serum effects. Control EHTs were handled identically without reinforcement. Endothelin-1 (ET-1)- or phenylephrine (PE)-stimulated EHTs served as positive control for hypertrophy. Cardiomyocytes in EHTs enlarged by 28.4?% under AE and to a similar extent by ET-1- or PE-stimulation (40.6 or 23.6?%), as determined by dystrophin staining. Cardiomyocyte hypertrophy was accompanied by activation of the fetal gene program, increased glucose consumption, and increased mRNA levels and extracellular deposition of collagen-1. Importantly, afterload-enhanced EHTs exhibited reduced contractile force and impaired diastolic relaxation directly after release of the metal braces. These deleterious effects of afterload enhancement were preventable by endothelin-A, but not endothelin-B receptor blockade. Sustained afterload enhancement of EHTs alone is sufficient to induce pathological cardiac remodeling with reduced contractile function and increased glucose consumption. The model will be useful to investigate novel therapeutic approaches in a simple and fast manner.     

No Effect of Hole Geometry in Microfracture for Talar Osteochondral Defects

Background

Débridement and bone marrow stimulation is an effective treatment option for patients with talar osteochondral defects. However, whether surgical factors affect the success of microfracture treatment of talar osteochondral defects is not well characterized.

Questions/purposes

We hypothesized (1) holes that reach deeper into the bone marrow-filled trabecular bone allow for more hyaline-like repair; and (2) a larger number of holes with a smaller diameter result in more solid integration of the repair tissue, less need for new bone formation, and higher fill of the defect.

Methods

Talar osteochondral defects that were 6 mm in diameter were drilled bilaterally in 16 goats (32 samples). In eight goats, one defect was treated by drilling six 0.45-mm diameter holes in the defect 2 mm deep; in the remaining eight goats, six 0.45-mm diameter holes were punctured to a depth of 4 mm. All contralateral defects were treated with three 1.1-mm diameter holes 3 mm deep, mimicking the clinical situation, as internal controls. After 24 weeks, histologic analyses were performed using Masson-Goldner/Safranin-O sections scored using a modified O’Driscoll histologic score (scale, 0–22) and analyzed for osteoid deposition. Before histology, repair tissue quality and defect fill were assessed by calculating the mean attenuation repair/healthy cartilage ratio on Equilibrium Partitioning of an Ionic Contrast agent (EPIC) micro-CT (μCT) scans. Differences were analyzed by paired comparison and Mann-Whitney U tests.

Results

Significant differences were not present between the 2-mm and 4-mm deep hole groups for the median O’Driscoll score (p = 0.31) and the median of the μCT attenuation repair/healthy cartilage ratios (p = 0.61), nor between the 0.45-mm diameter and the 1.1-mm diameter holes in defect fill (p = 0.33), osteoid (p = 0.89), or structural integrity (p = 0.80).

Conclusions

The results indicate that the geometry of microfracture holes does not influence cartilage healing in the caprine talus.

Clinical Relevance

Bone marrow stimulation technique does not appear to be improved by changing the depth or diameter of the holes.