Low-Serum Media and Dynamic Deformational Loading in Tissue Engineering of Articular Cartilage

High-serum media have been shown to produce significant improvement in the properties of tissue-engineered articular cartilage when applied in combination with dynamic deformational loading. To mitigate concerns regarding the culture variability introduced by serum, we examined the interplay between low-serum/ITS-supplemented media and dynamic deformational loading. Our results show that low serum/ITS supplementation does not support the same level of tissue formation as compared to high serum controls. In free-swelling culture, using a combination of ITS with concentrations of FBS above 2% negated the beneficial effects of ITS. Although there were beneficial effects with loading and 0.2%FBS + ITS, these constructs significantly underperformed relative to 20%FBS constructs. At 2%FBS + ITS, the free-swelling construct stiffness and composition approached or exceeded that of 20%FBS constructs. With dynamic loading, the properties of 2%FBS + ITS constructs were significantly lower than free-swelling controls and 20%FBS constructs by day 42. By priming the chondrocytes in 20%FBS prior to exposure to low-serum/ITS media, we observed that low-serum/ITS media produced significant enhancement in tissue properties compared to constructs grown continuously in 20%FBS.     

Arrhythmogenic difference between the left and right atria in a canine ventricular pacing-induced heart failure model of atrial fibrillation

Background: The detail of biatrial activation during sustained atrial fibrillation (AF) has not been investigated until now. Methods: Five dogs with right ventricular pacing‐induced congestive heart failure (CHF) and five normal dogs were included. Biatrial endocardiac mapping was performed using noncontact mapping system. Results: Noncontact mapping of the right atrium (RA) showed CHF dogs had a higher frequency of focal discharge from Bachmann's bundle, sinoatrial region, and crista terminalis. CHF dogs also had a higher frequency of wave break, wave fusion, and reentry. CHF dogs had greater effective refractory period (ERP) dispersion. Noncontact mapping of the left atrium (LA) showed CHF dogs had more frequent focal discharge from left superior pulmonary vein (PV), right superior PV, and left atrial appendage. CHF dogs had a higher frequency of wave break, wave fusion, and reentry. CHF dogs had greater ERP dispersion. Comparison between RA and LA showed LA had a higher frequency of focal discharge, wave break, wave fusion, and leading circle reentry than the RA. LA also had greater ERP dispersion than RA. Conclusion: CHF dogs had a higher frequency of focal discharge and reentry, suggesting that CHF provided an arrhythmogenic substrate. LA had a higher frequency of focal discharge and reentry, suggesting that LA is more important to maintain AF. (PACE 2012; 35:188–195)     

Early retinal arteriolar changes and peripheral neuropathy in diabetes

OBJECTIVE

To examine the association between early retinal arteriolar abnormalities and diabetic peripheral neuropathy (DPN).

RESEARCH DESIGN AND METHODS

Data from 608 people (aged 40–80 years) with diabetes from the population-based Singapore Malay Eye Study were analyzed. Participants underwent binocular two-field digital retinal photography and quantitative sensory testing. DPN was defined as an abnormal response to a monofilament or neurothesiometer test. Quantitative changes of retinal vascular caliber and arteriolar bifurcation geometry were measured using a computer-based program. Qualitative retinal signs of retinopathy and retinal arteriolar wall signs were graded by standardized methods.

RESULTS

DPN was present in 155 people (25.5%). After adjusting for age, sex, diabetes duration, HbA_1c, cardiovascular risk factors, antihypertensive medication use, and peripheral arterial disease, people with suboptimal arteriolar caliber (odds ratio 1.94 [95% CI 1.22–3.10]), larger arteriolar branching coefficient (1.58 [1.03–2.42]), diabetic retinopathy (1.82 [1.20–2.75]), and focal arteriolar narrowing (2.92 [1.48–5.76]) were more likely to have DPN. Participants with a greater number of retinal microvascular signs were more likely to have DPN than those without retinal changes (6.11 [2.11–17.71] for two or more signs and 3.47 [1.18–10.21] for one sign compared with none).

CONCLUSIONS

Individuals with diabetes with early retinal arteriolar abnormalities are more likely to have DPN, independent of hyperglycemia and major vascular risk factors. These data support the hypothesis that early microvascular dysfunction, evident in the retina, is an independent risk factor for DPN.Diabetic peripheral neuropathy (DPN) is one of the most common long-term complications of diabetes and is the major predisposing factor for foot ulceration, lower extremity amputation, and death (1). Despite extensive research, the exact pathophysiologic mechanisms of DPN remain unclear. DPN has been widely classified as a “microvascular complication” of diabetes (2), and microvascular damage, followed by impaired blood supply to the peripheral nerves, may contribute to demyelination and axonal degeneration and eventually lead to signs and symptoms (3). However, few studies have specifically documented a link between microvascular dysfunction and DPN (4).The retinal microvasculature provides a direct means of visualizing the systemic microcirculation, and retinal vascular changes reflect the deleterious effects of hyperglycemia on the systemic microcirculation (5,6). Previous studies have reported an association between overt diabetic retinopathy (DR) signs (e.g., microaneurysms and hemorrhages) and an increased risk of DPN or lower extremity amputation (6). However, DR signs represent a relatively late manifestation of microvascular disease in the eye.New quantitative measurements of retinal microvascular structure and geometry, such as retinal vascular caliber and arteriolar bifurcation geometry, have been shown to inform early and preclinical processes in the pathophysiology of diabetes (7,8). As yet, there are scarce data on the association between these quantitatively measured retinal vascular parameters and DPN. In the Wisconsin Epidemiology Study of Diabetes Retinopathy (WESDR), retinal arteriolar caliber narrowing was associated with lower extremity amputation, but neither arteriolar nor venular caliber was associated with self-reported DPN (9). In contrast, retinal arteriolar caliber dilatation was associated with objectively measured DPN in a multiethnic Asian population with diabetes (10).In view of these inconsistencies, we examined the relationship between a spectrum of retinal arteriolar abnormalities, measured qualitatively and quantitatively, reflecting early microcirculatory dysfunction, and DPN using data from a population-based study.     

Gene therapy for aromatic L-amino acid decarboxylase deficiency

Aromatic L-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector-mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[(18)F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.     

Copy number alterations in prostate tumors and disease aggressiveness

Detecting genomic alterations that result in more aggressive prostate cancer may improve clinical treatment and our understanding of the biology underlying this common but complex disease. To this end, we undertook a genome-wide copy number alterations (CNAs) study of clinicopathological characteristics of 62 prostate tumors using the Illumina 1M single nucleotide polymorphism array. The highest overall frequencies of CNAs were on chromosomes 8q (gains), 8p (loss and copy-neutral), and 6q (copy-loss). Combined loss and copy-neutral events were associated with increasing disease grade (P = 0.03), stage (P = 0.01), and diagnostic prostate specific antigen (PSA) (P = 0.01). Further evaluation of CNAs using gene ontology identified pathways involved with disease aggressiveness. The "regulation of apoptosis" pathway was associated with stage of disease (P = 0.004), while the "reproductive cellular process" pathway was associated with diagnostic PSA (P = 0.00038). Specific genes within these pathways exhibited strong associations with clinical characteristics; for example, in the apoptosis pathway BNIP3L was associated with increasing prostate tumor stage (P = 0.007). These findings confirm known regions of CNAs in prostate cancer and localize additional regions and possible genes (e.g., BNIP3L, WWOX, and GATM) that may help to clarify the genetic basis of prostate cancer aggressiveness.     

Nanomaterial-Based Biosensor as an Emerging Tool for Biomedical Applications

The combination of nanomaterials and biological sensing elements to selectively recognize chemical or biological molecules has resulted in the development of novel nanobiosensors. Nanobiosensors offer several important advantages over conventional biological procedures, and could have a significant impact on humankind. Hence, the momentum toward building miniaturized, reliable, sensitive, and selective sensing instruments has focused on combining nanomaterials with biomolecules for detection of a wide range of analytes. In this article, we present an overview of the various nanomaterial-based biosensors that utilize different biological recognition elements for biomedical applications. In this review, several types of nanomaterial-based biosensors along with their applications are discussed, including the latest developments in the field of nanobiosensors for biomedical applications.     

Early life infections and onset of puberty: evidence from Hong Kong's children of 1997 birth cohort

As economic development increases, puberty occurs at younger ages, and this could contribute to an increase in the incidence of cardiovascular diseases and hormone-related cancers. The factors that determine pubertal timing are poorly understood. The growth axis that is active during puberty is active in the first 6 months of life and interacts with the immune system. The authors examined whether prior infections, proxied by number of hospital admissions for infections at different ages, were associated with age at pubertal onset (Tanner stage II) using interval-censored regression in the Children of 1997 cohort, which is a population-representative Chinese birth cohort (n = 7,527). Mediation by growth was also examined. Girls, but not boys, who were hospitalized for infections at least twice in the first 6 months of life experienced pubertal onset about 8 months later (mean = 10.3 years, time ratio = 1.08, 95% confidence interval: 1.04, 1.12) than did those without such hospitalizations (mean = 9.6 years) after adjustment for infant characteristics and socioeconomic position (sex interaction: P = 0.02). There were no such associations for infections at 6 months to ≤8 years of age. Growth did not mediate the association. Early infectious morbidity in girls may be associated with later puberty, perhaps via suppression of the gonadotropic axis. The lowering of the number of infections in early life that accompanies economic development could be an additional factor that contributes to earlier puberty.