Cardiomyocyte proliferation contributes to heart growth in young humans

The human heart is believed to grow by enlargement but not proliferation of cardiomyocytes (heart muscle cells) during postnatal development. However, recent studies have shown that cardiomyocyte proliferation is a mechanism of cardiac growth and regeneration in animals. Combined with evidence for cardiomyocyte turnover in adult humans, this suggests that cardiomyocyte proliferation may play an unrecognized role during the period of developmental heart growth between birth and adolescence. We tested this hypothesis by examining the cellular growth mechanisms of the left ventricle on a set of healthy hearts from humans aged 0–59 y (n = 36). The percentages of cardiomyocytes in mitosis and cytokinesis were highest in infants, decreasing to low levels by 20 y. Although cardiomyocyte mitosis was detectable throughout life, cardiomyocyte cytokinesis was not evident after 20 y. Between the first year and 20 y of life, the number of cardiomyocytes in the left ventricle increased 3.4-fold, which was consistent with our predictions based on measured cardiomyocyte cell cycle activity. Our findings show that cardiomyocyte proliferation contributes to developmental heart growth in young humans. This suggests that children and adolescents may be able to regenerate myocardium, that abnormal cardiomyocyte proliferation may be involved in myocardial diseases that affect this population, and that these diseases might be treatable through stimulation of cardiomyocyte proliferation.     

Promoter polymorphism G-50T of a human CYP2J2 epoxygenase gene is associated with common susceptibility to asthma

BACKGROUND: Cytochrome P-450 2J2 (CYP2J2) has recently been shown to be an important enzyme in the metabolism of epoxygenase-derived eicosanoids that play important functional roles in pulmonary physiology and may contribute to the pathogenesis of asthma. STUDY OBJECTIVE: The focus of our pilot study was to evaluate whether common polymorphism G-50T within the proximal promoter of human CYP2J2 gene is associated with the susceptibility to bronchial asthma. Design and participants: A total of 429 unrelated Russian subjects were recruited in this case-control study, including 215 sex-matched and age-matched patients with asthma and 214 healthy control subjects. The blood samples were analyzed for genetic polymorphism G-50T in the CYP2J2 gene by polymerase chain reaction followed by restriction fragment length polymorphism analysis. RESULTS: The frequency of variant allele -50T of the CYP2J2 gene was significantly higher in asthmatic patients than in healthy subjects (odds ratio [OR], 5.04; 95% confidence interval [CI], 1.99 to 12.77; p = 0.0003). In addition, the heterozygous genotype -50GT of the CYP2J2 gene was found to be significantly associated with susceptibility to allergic asthma (OR, 5.40; 95% CI, 2.05 to 14.26; p = 0.0003) as well as nonallergic asthma (OR, 5.77; 95% CI, 1.84 to 18.10; p = 0.004). The associations of the CYP2J2 gene G-50T polymorphism with asthma remained significant after adjustment for age and gender using multiple logistic regression analysis. CONCLUSIONS: Our data demonstrate for the first time that the CYP2J2 gene might be considered as a novel candidate gene for common susceptibility to asthma and highlight the importance of the P-450 epoxygenase pathway of metabolism of arachidonic acid in the pathogenesis of the disease.     

Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines

In HLA-incompatible hematopoietic stem cell transplantation, alloreactive donor T cells recognizing recipient mismatch HLA cause severe graft-versus-host disease (GVHD). Strategies allowing the selective depletion of alloreactive T cells as well as the enhancement of graft-versus-malignancy immunity would be beneficial. We generated donor CD8 T-cell lines in vitro using allogeneic recipient cells mismatched at a single HLA class I allele or haplotype as stimulators. Recipient cells were obtained from acute myeloid leukemias, renal-cell carcinomas, and CD40L-induced B lymphoblasts. Resulting alloreactive T cells were activated by incubating day 21 T-cell cultures with HLA-mismatch transfected K562 cells or recipient-derived fibroblasts. Selective allodepletion (SAD) was subsequently performed by a newly developed immunomagnetic depletion approach targeting the tumor necrosis factor receptor molecule CD137 (4-1BB). Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation. In 15 different SAD experiments, the frequency of alloreactive CD8 T cells was reduced to a median of 9.5% compared with undepleted control populations. The allodepleted T-cell subsets maintained significant antitumor and antiviral CD8 responses. In vitro expansion of tumor-reactive T cells followed by CD137-mediated SAD might enhance the antitumor efficacy of T-cell allografts with lower risk of inducing GVHD.     

Safety of Laparoscopic Adrenalectomy in Patients with Large Pheochromocytomas: A Single Institution Review

Background Laparoscopic adrenalectomy is the procedure of choice for small adrenal tumors, but some concerns have been voiced when this approach is adopted for larger tumors and pheochromocytomas. The aim of this study was to examine the results of the laparoscopic resection of large pheochromocytomas. Methods A retrospective review of adrenalectomies performed for adrenal pheochromocytomas >6 cm in diameter. We compiled and analyzed the early operative complications, histologic findings, and cure rates with a minimum of 1 year of follow-up after surgery. Results From 1996 to 2005, a total of 445 laparoscopic adrenalectomies were performed in our institution using the anterolateral transperitoneal approach. From this series we identified 18 procedures for pheochromocytomas with an average diameter on imaging of 78.2 mm (range 60–130 mm). All patients were rendered safe with a standard departmental protocol involving calcium-channel blockade initiated at least 2 weeks prior to surgery. The average peak intraoperative blood pressure was 187 mmHg. Capsular disruption occurred in two cases. One patient required an intraoperative blood transfusion due to intraoperative blood loss. No immediate conversions to an open procedure were required, but one patient underwent a delayed laparotomy for hematoma formation. Histologically, four of the adrenal tumors displayed evidence of vascular invasion. Biochemical cure was achieved in all patients after a median follow-up of 58 months (16–122 months). Conclusions Laparoscopic adrenalectomy appears to be a safe and effective approach for large pheochromocytomas when no preoperative or intraoperative evidence of local invasion is present. Paper Presented at the ISW Congress.     

Toxicity from a clonidine suspension

Background

Clonidine is frequently prescribed to children. Clonidine overdose in children has resulted in major clinical effects and deaths.

Case Report

A 3.5-year-old male with a history of a seizure disorder and night terrors presented following difficulty walking, excessive sleeping, agitation when awake, and possible seizure activity. Chronic medications were valproic acid (VPA) and clonidine. On presentation, he alternated between poor responsiveness and agitation, with initial vitals: blood pressure, BP 144/76 mmHg; heart rate, 65 bpm; respiratory rate, 18 bpm; temperature 99.5°F; and pulse oximetry 96% on room air. VPA level was 35 μg/mL. A toxicology consult the next day noted a dry mouth, 2-mm pupils, intermittent gasping, and central nervous system (CNS) depression, with a diagnostic impression of clonidine overdose. The caregiver had been giving 1 mL (0.1 mg) qd of a pharmacy-compounded clonidine suspension by a provided syringe. The pharmacy procedure record agreed with the physicians order. The amount dispensed was a 30-day supply but the bottle was empty on day 19, leading us to suspect a possible accelerated dosing error. The concentration in the bottle thus could not be confirmed. The child slowly returned to his baseline state over 48 hours. A serum clonidine level drawn approximately 18 hours after his last dose later returned at 300 ng/mL (reference range = 0.5–4.5 ng/mL).

Case Discussion

Compounding and liquid dosing errors are common in children and may result in massive overdoses. There was an accelerated dosing error, but whether a compounding or suspension error or even an acute overdose occurred as well is unknown.

Conclusion

Particular care should be taken with medications that have low therapeutic indices, that are extemporaneously compounded, and are prepared as liquids, where medication errors are more likely.     

Managing difficult catheterisation in nurse‐led catheterisation services: Does guidewire‐assisted urethral catheterisation make a difference?

The use of guidewires is well established in medical practice, but relatively new in nurse‐led catheterisation services (NCS). We investigate the incidence of difficult urethral catheterisation and whether guidewire‐assisted catheterisation reduces disrupted patient care. A retrospective Audit (September 2016‐August 2017) recorded incidence and management of difficult catheterisation in two NCS. In NCS‐A, nurses were familiar with improvised guidewire‐assisted catheterisation, whereas in NCS‐B nurses were not enabled and had to refer patients to urologists when they encountered problems. From September 2017 to August 2018, a National Institute for Health and Care Excellence (NICE)‐approved urethral catheterisation device with integrated guidewire (Urethrotech UCD) was used in NCS‐B for difficult urethral catheterisation. User and patient satisfaction was evaluated prospectively. Of 540 men attending NCS‐A for trial without catheter (TWOC), 31% (169/540) were recatheterized, of whom 4%(6/169) required a guidewire‐catheterisation technique to manage difficult catheterisation without problems. This was also done in 45 of 146 men attending for long‐term catheter change with known history of difficult catheter change. Of 1002 men attending NCS‐B for TWOC, 23% (226/1002) were recatheterized. This was difficult in 25% (57/226), of which 40% (23/57) suffered complications with bleeding from repeated catheterisation attempts and 10 men had to be admitted for specialist interventions to manage retention and catheterisation‐associated urethral injury. During the prospective audit, 945 men attended the TWOC‐clinic of NCS‐B. In 11% (13/120), the UCD was used for failed Foley‐catheterisation without complications. Patients and users were very satisfied because the difficult recatheterisation episode was managed successfully without patient harm and care delay. Difficult urethral catheterisation is a frequent occurrence in NCS with significant risk of urethral trauma. Catheterisation‐associated urethral injury can be prevented with guidewire‐assisted urethral catheterisation techniques. The NICE‐approved UCD with integrated guidewire was easy to use with high user and patient satisfaction avoiding patient care delay and is supporting nurses to manage difficult urethral catheterisation safely making efficient use of specialist resources.     

Prostaglandin E2 secretion from gingival fibroblasts treated with interleukin-1β: effects of lipid extracts from Porphyromonas gingivalis or calculus

Complex lipids of Porphyromonas gingivalis have been identified in lipid extracts from calculus-contaminated root surfaces and in diseased gingival tissues. However, little is known about the biological effects of these complex lipids on host cells. The purpose of this study was to evaluate the effects of P. gingivalis or calculus lipids on prostaglandin secretion from gingival fibroblasts. Lipids were extracted from paired subgingival plaque and teeth samples, and calculus-contaminated root surfaces before and after scaling and root planing, in order to determine the relevant levels of lipid extracts for the treatment of gingival fibroblasts in culture. Primary cultures of gingival fibroblasts were exposed to lipid extracts from either P. gingivalis or calculus/teeth for a period of 7 days. Control and lipid-treated cultures were exposed to human recombinant interleukin-1β for 48 h and prostaglandin secretion from interleukin-1β-treated fibroblasts was compared with control and lipid-treated fibroblasts without interleukin-1β treatment. These experiments demonstrated that P. gingivalis lipids or calculus-tooth lipids potentiate interleukin-1β-mediated prostaglandin secretory responses from gingival fibroblasts. Additionally, P. gingivalis or calculus-tooth lipid extracts were readily taken up by gingival fibroblasts as measured by bacterial fatty acid recovery in lipid extracts of cultured fibroblasts. These results indicate that bacterial lipid penetration into gingival tissues in combination with a chronic inflammatory response may substantially potentiate prostaglandin secretion from gingival fibroblasts, thereby promoting tissue destructive processes associated with adult periodontitis.     

Psoriasis: Targeting Therapy Towards the Inflammatory Cascade

Alopecia areata is an unpredictable hair-loss condition. As there is no cure for alopecia areata and no effective conventional therapy, a substantial number of alopecia areata patients resort to complementary and alternative medical remedies and therapies (CAM). This review on the application of CAM in alopecia areata addresses two pertinent aspects. First, it provides a current overview of the published medical literature on CAM used in alopecia areata, and alopecia areata-related studies. Second, it presents a thorough assessment of the considerations and limitations of the use of CAM for the treatment of alopecia areata. A systematic MEDLINE search yielded 13 studies of the clinical use of CAM in the management of alopecia areata, all belonging to one of the five main categories of CAM. Methodological quality was analyzed using objective assessment scores (Wilson and Lawrence scores). Unfortunately, no study was of sufficient internal validity to provide robust evidence of the benefit of CAM. This might be attributable to several specific disease characteristics of alopecia areata, which require an especially solid trial design to properly assess the therapeutic effects of CAM. The review concludes with some recommendations for improving the quality of trials incorporating CAM in the treatment of alopecia areata