Atypical radiographic features of skull base cholesterol granuloma.

Cholesterol granulomas (CGs) are the most common benign lesions of the petrous apex (PA) and have distinct computed tomography (CT) and magnetic resonance imaging (MRI) characteristics. On CT, CGs of the PA (PACG) present as expansile lesions with erosion of bony trabeculae. MRI shows a hyperintense lesion on T1-and T2-weighted images and do not enhance with gadolinium. The objective is to describe the radiographic features of CGs of the skull base that do not arise from the PA. This study is a retrospective review. Three patients were operated on for suspected recurrent endolymphatic sac tumor, intracranial cholesteatoma, and recurrent sphenoid wing meningioma based on CT and MRI findings. Pathology results were consistent with CG in all three cases. All patients had bone erosion on CT. These skull base CGs did not demonstrate similar MRI features. These lesions were hyperintense, iso-to-hyperintense, and hypointense on T1-weighted MRI, respectively. These CGs were hyperintense in two cases and iso-to-hyperintense in one case on T2-weighted MRI. These lesions either demonstrated central or rim enhancement after gadolinium administration. Skull base CGs that do not arise from the PA demonstrate a broad spectrum of radiographic characteristics on MRI that are not typical of PACG.

Gene dose influences cellular and calcium channel dysregulation in heterozygous and homozygous T4826I-RYR1 malignant hyperthermia-susceptible muscle.

Malignant hyperthermia susceptibility (MHS) is primarily conferred by mutations within ryanodine receptor type 1 (RYR1). Here we address how the MHS mutation T4826I within the S4-S5 linker influences excitation-contraction coupling and resting myoplasmic Ca(2+) concentration ([Ca(2+)](rest)) in flexor digitorum brevis (FDB) and vastus lateralis prepared from heterozygous (Het) and homozygous (Hom) T4826I-RYR1 knock-in mice (Yuen, B. T., Boncompagni, S., Feng, W., Yang, T., Lopez, J. R., Matthaei, K. I., Goth, S. R., Protasi, F., Franzini-Armstrong, C., Allen, P. D., and Pessah, I. N. (2011) FASEB J. doi:22131268). FDB responses to electrical stimuli and acute halothane (0.1%, v/v) exposure showed a rank order of Hom ≫ Het ≫ WT. Release of Ca(2+) from the sarcoplasmic reticulum and Ca(2+) entry contributed to halothane-triggered increases in [Ca(2+)](rest) in Hom FDBs and elicited pronounced Ca(2+) oscillations in ∼30% of FDBs tested. Genotype contributed significantly elevated [Ca(2+)](rest) (Hom > Het > WT) measured in vivo using ion-selective microelectrodes. Het and Hom oxygen consumption rates measured in intact myotubes using the Seahorse Bioscience (Billerica, MA) flux analyzer and mitochondrial content measured with MitoTracker were lower than WT, whereas total cellular calpain activity was higher than WT. Muscle membranes did not differ in RYR1 expression nor in Ser(2844) phosphorylation among the genotypes. Single channel analysis showed highly divergent gating behavior with Hom and WT favoring open and closed states, respectively, whereas Het exhibited heterogeneous gating behaviors. [(3)H]Ryanodine binding analysis revealed a gene dose influence on binding density and regulation by Ca(2+), Mg(2+), and temperature. Pronounced abnormalities inherent in T4826I-RYR1 channels confer MHS and promote basal disturbances of excitation-contraction coupling, [Ca(2+)](rest), and oxygen consumption rates. Considering that both Het and Hom T4826I-RYR1 mice are viable, the remarkable isolated single channel dysfunction mediated through this mutation in S4-S5 cytoplasmic linker must be highly regulated in vivo.

2,2',3,5',6-Pentachlorobiphenyl (PCB 95) and its hydroxylated metabolites are enantiomerically enriched in female mice.

Epidemiological and laboratory studies link polychlorinated biphenyls and their metabolites to adverse neurodevelopmental outcomes. Several neurotoxic PCB congeners are chiral and undergo enantiomeric enrichment in mammalian species, which may modulate PCB developmental neurotoxicity. This study measures levels and enantiomeric enrichment of PCB 95 and its hydroxylated metabolites (OH-PCBs) in adult female C57Bl/6 mice following subchronic exposure to racemic PCB 95. Tissue levels of PCB 95 and OH-PCBs increased with increasing dose. Dose-dependent enantiomeric enrichment of PCB 95 was observed in brain and other tissues. OH-PCBs also displayed enantiomeric enrichment in blood and liver, but were not detected in adipose and brain. In light of data suggesting enantioselective effects of chiral PCBs on molecular targets linked to PCB developmental neurotoxicity, our observations highlight the importance of accounting for PCB and OH-PCB enantiomeric enrichment in the assessment of PCB developmental neurotoxicity.

Functional and biochemical properties of ryanodine receptor type 1 channels from heterozygous R163C malignant hyperthermia-susceptible mice.

Mutations in ryanodine receptor type 1 (RyR1) confer malignant hyperthermia susceptibility. How inherent impairments in Ca(2+) channel regulation affect skeletal muscle function in myotubes and adult fibers under basal (nontriggering) conditions are not understood. Myotubes, adult flexor digitorum brevis (FDB) fibers, and sarcoplasmic reticulum skeletal membranes were isolated from heterozygous knockin R163C and wild-type (WT) mice. Compared with WT myotubules, R163C myotubes have reduced Ca(2+) transient amplitudes in response to electrical field pulses; however, R163C FDB fibers do not differ in their responses to electrical stimuli, despite heightened cellular cytoplasmic resting Ca(2+) ([Ca(2+)](rest)) and sensitivity to halothane. Immunoblotting of membranes from each genotype shows similar expression of RyR1, FK506 binding protein 12 kDa, and Ca(2+)-ATPase, but RyR1 (2844)Ser phosphorylation in R163C muscle is 31% higher than that of WT muscle (p < 0.001). RyR1 channels reconstituted in planar lipid bilayers reveal ∼65% of R163C channels exhibit ≥2-fold greater open probability (P(o)) than WT, with prolonged mean open dwell times and shortened closed dwell times. [(3)H]Ryanodine (Ry) binding and single-channel analyses show that R163C-RyR1 has altered regulation compared with WT: 1) 3-fold higher sensitivity to Ca(2+) activation; 2) 2-fold greater [(3)H]Ry receptor occupancy; 3) comparatively higher channel activity, even in reducing glutathione buffer; 4) enhanced RyR1 activity both at 25 and 37°C; and 5) elevated cytoplasmic [Ca(2+)](rest). R163C channels are inherently more active than WT channels, a functional impairment that cannot be reversed by dephosphorylation with protein phosphatase. Dysregulated R163C channels produce a more overt phenotype in myotubes than in adult fibers in the absence of triggering agents, suggesting tighter negative regulation of R163C-RyR1 within the Ca(2+) release unit of adult fibers.

Physiotherapy and related management for childhood obesity: A systematic scoping review.

INTRODUCTION: Despite targeted efforts globally to address childhood overweight/obesity, it remains poorly understood and challenging to manage. Physiotherapists have the potential to manage children with obesity as they are experts in movement and physical activity. However, their role remains unclear due to a lack of physiotherapy-specific guidelines. This scoping review aims to explore existing literature, critically appraising and synthesising findings to guide physiotherapists in the evidence-based management of childhood overweight/obesity. METHOD: A scoping review was conducted, including literature up to May 2020. A review protocol exists on Open Science Framework at https://osf.io/fap8g/. Four databases were accessed including PubMed, Embase, CINAHL, Medline via OVID, with grey literature searched through google via "file:pdf". A descriptive synthesis was undertaken to explore the impact of existing interventions and their efficacy. RESULTS: From the initial capture of 1871 articles, 263 intervention-based articles were included. Interventions included qualitative focused physical activity, quantitative focused physical activity and multicomponent interventions. Various outcome measures were utilised including health-, performance- and behaviour-related outcomes. The general trend for physiotherapy involvement with children who are obese appears to favour: 1) multicomponent interventions, implementing more than one component with environmental modification and parental involvement and 2) quantitative physical activity interventions, focusing on the quantity of bodily movement. These approaches most consistently demonstrated desirable changes across behavioural and health-related outcome measures for multicomponent and quantitative physical activity interventions respectively. CONCLUSION: When managing children with obesity, physiotherapists should consider multicomponent approaches and increasing the quantity of physical activity, given consistent improvements in various obesity-related outcomes. Such approaches are well suited to the scope of physiotherapists and their expertise in physical activity prescription for the management of childhood obesity. Future research should examine the effect of motor skill interventions and consider the role of environmental modification/parental involvement as factors contributing to intervention success.

Ryanodine Receptor Type 2: A Molecular Target for Dichlorodiphenyltrichloroethane- and Dichlorodiphenyldichloroethylene-Mediated Cardiotoxicity.

Dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyl-dichloroethylene (DDE) are ubiquitously found in the environment and linked to cardiovascular diseases-with a majority of the work focused on hypertension. Studies investigating whether DDx can interact with molecular targets on cardiac tissue to directly affect cardiac function are lacking. Therefore, we investigated whether o,p'-DDT, p,p'-DDT, o,p'-DDE, or p,p'-DDE (DDx, collectively) can directly alter the function of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) by assessing their effect(s) on hiPSC-CMs Ca2+ dynamics. DDx (0.1-10 µM) affected hiPSC-CMs synchronous Ca2+ oscillation frequency in a concentration-dependent manner, with p,p'-DDT and p,p'-DDE also decreasing Ca2+ stores. HEK-RyR2 cells cultured under antibiotic selection to induce expression of wild-type mouse ryanodine receptor type 2 (RyR2) are used to further investigate whether DDx alters hiPSC-CMs Ca2+ dynamics through engagement with RyR2, a protein critical for cardiac muscle excitation-contraction coupling (ECC). Acute treatment with 10 µM DDx failed to induce Ca2+ release in HEK293-RyR2, whereas pretreatment with DDx (0.1-10 µM) for 12- or 24-h significantly decreased sarcoplasmic reticulum Ca2+ stores in HEK-RyR2 cells challenged with caffeine (1 mM), an RyR agonist. [3H]ryanodine-binding analysis using murine cardiac RyR2 homogenates further confirmed that all DDx isomers (10 µM) can directly engage with RyR2 to favor an open (leaky) confirmation, whereas only the DDT isomers (10 µM) modestly (≤10%) inhibited SERCA2a activity. The data demonstrate that DDx increases heart rate and depletes Ca2+ stores in human cardiomyocytes through a mechanism that impairs RyR2 function and Ca2+ dynamics. IMPACT STATEMENT: DDT/DDE interactions with RyR2 alter cardiomyocyte Ca2+ dynamics that may contribute to adverse cardiovascular outcomes associated with exposures.

Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes.

Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we use the Dmp1Cre:Socs3f/f mouse, with delayed cortical bone consolidation, to characterise cortical maturation and identify control signals. We show that cortical maturation requires a reduction in cortical porosity, and a transition from low to high density bone, which continues even after cortical shape is established. Both processes were delayed in Dmp1Cre:Socs3f/f mice. SOCS3 (suppressor of cytokine signalling 3) inhibits signalling by leptin, G-CSF, and IL-6 family cytokines (gp130). In Dmp1Cre:Socs3f/f bone, STAT3 phosphorylation was prolonged in response to gp130-signalling cytokines, but not G-CSF or leptin. Deletion of gp130 in Dmp1Cre:Socs3f/f mice suppressed STAT3 phosphorylation in osteocytes and osteoclastic resorption within cortical bone, leading to rescue of the corticalisation defect, and restoration of compromised bone strength. We conclude that cortical bone development includes both pore closure and accumulation of high density bone, and that these processes require suppression of gp130-STAT3 signalling in osteocytes.

Comparison of Chlorantraniliprole and Flubendiamide Activity Toward Wild-Type and Malignant Hyperthermia-Susceptible Ryanodine Receptors and Heat Stress Intolerance.

Chlorantraniliprole (CP) and flubendiamide (FD) are widely used in agriculture globally to control lepidopteran pests. Both insecticides target ryanodine receptors (RyRs) and promote Ca2+ leak from sarcoplasmic reticulum (SR) within insect skeletal muscle yet are purportedly devoid of activity toward mammalian RyR1 and muscle. RyRs are ion channels that regulate intracellular Ca2+ release from SR during physiological excitation-contraction coupling. Mutations in RYR1 genes confer malignant hyperthermia susceptibility (MHS), a potentially lethal pharmacogenetic disorder in humans and animals. Compared with vehicle control, CP (10 µM) triggers a 65-fold higher rate of Ca2+ efflux from Ca2+-loaded mammalian WT-RyR1 SR vesicles, whereas FD (10 µM) produces negligible influence on Ca2+ leak. We, therefore, compared whether CP or FD differentially influence patterns of high-affinity [3H]ryanodine ([3H]Ry) binding to RyR1 isolated from muscle SR membranes prepared from adult C57BL/6J mice expressing WT, homozygous C-terminal MHS mutation T4826I, or heterozygous N-terminal MHS mutation R163C. Basal [3H]Ry binding differed among genotypes with rank order T4826I ≫R163C∼WT, regardless of [Ca2+] in the assay medium. Both CP and FD (0.01-100 µM) elicited concentration-dependent increase in [3H]Ry binding, although CP showed greater efficacy regardless of genotype or [Ca2+]. Exposure to CP (500 mg/kg; p.o) failed to shift intolerance to heat stress (38°C) characteristic of R163C and T4826I MHS mice, nor cause lethality in WT mice. Although nM-µM of either diamide is capable of differentially altering WT and MHS RyR1 conformation in vitro, human RyR1 mutations within putative diamide N- and C-terminal interaction domains do not alter heat stress intolerance (HSI) in vivo.

Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1.

Dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) are ubiquitous in the environment and detected in tissues of living organisms. Although DDT owes its insecticidal activity to impeding closure of voltage-gated sodium channels, it mediates toxicity in mammals by acting as an endocrine disruptor (ED). Numerous studies demonstrate DDT/DDE to be EDs, but studies examining muscle-specific effects mediated by nonhormonal receptors in mammals are lacking. Therefore, we investigated whether o,p'-DDT, p,p'-DDT, o,p'-DDE, and p,p'-DDE (DDx, collectively) alter the function of ryanodine receptor type 1 (RyR1), a protein critical for skeletal muscle excitation-contraction coupling and muscle health. DDx (0.01-10 µM) elicited concentration-dependent increases in [3H]ryanodine ([3H]Ry) binding to RyR1 with o,p'-DDE showing highest potency and efficacy. DDx also showed sex differences in [3H]Ry-binding efficacy toward RyR1, where [3H]Ry-binding in female muscle preparations was greater than male counterparts. Measurements of Ca2+ transport across sarcoplasmic reticulum (SR) membrane vesicles further confirmed DDx can selectively engage with RyR1 to cause Ca2+ efflux from SR stores. DDx also disrupts RyR1-signaling in HEK293T cells stably expressing RyR1 (HEK-RyR1). Pretreatment with DDx (0.1-10 µM) for 100 s, 12 h, or 24 h significantly sensitized Ca2+-efflux triggered by RyR agonist caffeine in a concentration-dependent manner. o,p'-DDE (24 h; 1 µM) significantly increased Ca2+-transient amplitude from electrically stimulated mouse myotubes compared with control and displayed abnormal fatigability. In conclusion, our study demonstrates DDx can directly interact and modulate RyR1 conformation, thereby altering SR Ca2+-dynamics and sensitize RyR1-expressing cells to RyR1 activators, which may ultimately contribute to long-term impairments in muscle health.

A mismatch repair-deficient and HPV-negative anorectal squamous cell carcinoma.

Invasive primary squamous cell carcinomas involving the anorectal region are challenging to manage. Microsatellite instability has been shown to impact clinical courses and outcomes of patients affected by many types of carcinomas. To the best of our knowledge, there are no reports on microsatellite instability in anorectal squamous cell carcinomas. Here, we report a HPV-negative anorectal squamous cell carcinoma which, despite cisplatin-based chemoradiation therapy, showed progression. Interestingly, after identification of its mismatch repair-deficiency (MLH1/PMS2-absent, MSH2/MSH6-intact), pembrolizumab-based immunotherapy was initiated, leading to a marked clinical response. This unique case illustrates that microsatellite instability testing and immunotherapy targeting immune checkpoint blockade should be considered for managing anorectal squamous cell carcinomas that fail conventional chemoradiation therapies or when patients are non-surgical candidates. This report provides the first evidence of microsatellite instability in anorectal squamous cell carcinomas and supports the role for microsatellite instability testing in this cancer type to optimize patient management.

Long-Term Signs of T Cell and Myeloid Cell Activation After Intestinal Transplantation With Cellular Rejections Contributing to Further Increase of CD16+ Cell Subsets.

The intestine mediates a delicate balance between tolerogenic and inflammatory immune responses. The continuous pathogen encounter might also augment immune cell responses contributing to complications observed upon intestinal transplantation (ITx). We thus hypothesized that ITx patients show persistent signs of immune cell activation affecting both the adaptive and innate immune cell compartment. Information on the impact of intestinal grafts on immune cell composition, however, especially in the long-term is sparse. We here assessed activated and differentiated adaptive and innate immune subsets according to time, previous experience of cellular or antibody-mediated rejections or type of transplant after ITx applying multi-parametric flow cytometry, gene expression, serum cytokine and chemokine profiling. ITx patients showed an increase in CD16 expressing monocytes and myeloid dendritic cells (DCs) compared to healthy controls. This was even detectable in patients who were transplanted more than 10 years ago. Also, conventional CD4+ and CD8+ T cells showed persistent signs of activation counterbalanced by increased activated CCR4+ regulatory T cells. Patients with previous cellular rejections had even higher proportions of CD16+ monocytes and DCs, whereas transplanting higher donor mass with multi-visceral grafts was associated with increased T cell activation. The persistent inflammation and innate immune cell activation might contribute to unsatisfactory results after ITx.

Effects of floral resources on the longevity and parasitism of Cotesia vestalis Haliday (Hymenoptera: Braconidae) on Plutella xylostella (L.) (Lepidoptera: Plutellidae) in Vietnam.

Parasitoids are important biological control of crop pests. In Vietnam, Cotesia vestalis is a native wasp species that has demonstrated its applicability as a natural insect pest enemy. Many adult parasitoids require food resources such as nectar and pollen to optimize their life cycles. Potential effects of yellow cosmos (Cosmos sulphureus), shrub verbena flower (Lantana camara), common zinnia (Zinnia elegans), and coriander flower (Coriandrum sativum L.) on the longevity and parasitism of C. vestalis were investigated. Results showed that nutrition resources from yellow cosmos (C. sulphureus) and shrub verbena flower (Lantana camara) significantly increased the longevity of C. vestalis in comparison with water (P < 0.001). Kaplan-Meier estimates of survival functions of female Cotesia vestalis exposed to different food sources indicated a significant difference in the treatments (P < 0.01). Male and female wasps feeding on Cosmos sulphureus, Lantana camara, and Coriandrum sativum survived significantly longer than wasps fed on water or Zinnia elegans. Parasitism efficiency of C. vestalis was tested on diamondback moth Plutella xylostella (L.) larvae for different food resources. Cosmos sulphureus, Lantana camara, Coriandrum sativum treatments gave the different mean number of emergence parasitoids per day compared to water treatment. Results implied that food resources from flowers benefitted the longevity of C. vestalis.

Killer-like receptors and GPR56 progressive expression defines cytokine production of human CD4+ memory T cells.

All memory T cells mount an accelerated response on antigen reencounter, but significant functional heterogeneity is present within the respective memory T-cell subsets as defined by CCR7 and CD45RA expression, thereby warranting further stratification. Here we show that several surface markers, including KLRB1, KLRG1, GPR56, and KLRF1, help define low, high, or exhausted cytokine producers within human peripheral and intrahepatic CD4+ memory T-cell populations. Highest simultaneous production of TNF and IFN-γ is observed in KLRB1+KLRG1+GPR56+ CD4 T cells. By contrast, KLRF1 expression is associated with T-cell exhaustion and reduced TNF/IFN-γ production. Lastly, TCRß repertoire analysis and in vitro differentiation support a regulated, progressive expression for these markers during CD4+ memory T-cell differentiation. Our results thus help refine the classification of human memory T cells to provide insights on inflammatory disease progression and immunotherapy development.

Proteasome activator and antigen-processing aminopeptidases are regulated by virus-induced type I interferon in the hepatitis C virus-infected liver.

Many components of the class I antigen-processing pathway are thought to be regulated solely by interferon-gamma (IFN-gamma). Herein, we report type I IFN-mediated induction of proteasome activator (PA28) subunits alpha and beta, endoplasmic reticulum aminopeptidase 1 (ERAP1), ERAP2, and leucine aminopeptidase (LAP). This mechanism was initiated by either synthetic RNA (poly(I-C)) or by hepatitis C virus (HCV) RNA-mediated induction of type I IFN and abrogated by blocking of type I IFN. In serial liver biopsies of chimpanzees with acute HCV infection, increases in PA28 subunit and aminopeptidase mRNA levels correlated with intrahepatic type I IFN responses and preceded intrahepatic IFN-gamma responses by several weeks. Thus, viral RNA-induced type I IFN regulates the antigen-processing machinery early during viral infection and prior to IFN-gamma response. This mechanism may contribute to the high effectiveness of type I IFN-based therapies if administered early during acute HCV infection.

The emergence of severe pulmonary hemorrhagic leptospirosis: questions to consider.

Since the 1980s, the incidence of severe pulmonary hemorrhage caused by Leptospira spp. infection has increased. The mild, non-specific symptoms or the more classical form of severe disease with hepatorenal manifestations, Weil's syndrome, predominate world-wide. However, several regions of the world have seen increases in numbers of patients with pulmonary hemorrhage attributed to leptospirosis. The reasons behind the emergence of this syndrome, which carries a high mortality rate, are not known. Several avenues for future research may shed light on the mechanisms involved in development of pulmonary hemorrhage, and inform targeted therapeutics to improve outcomes. Possibilities to consider include: (1) emergence of new bacterial strains, (2) acquisition of virulence traits by strains in the endemic regions, (3) changes in underlying health of the affected human populations, and (4) increased recognition of the syndrome and better record keeping by the medical and veterinary communities. Determining the causes of emerging clinical manifestations presents challenges and opportunities for potentially life-saving research into the pathogenesis of a number of infectious diseases, including leptospirosis.

Ganglionated plexi modulate extrinsic cardiac autonomic nerve input: effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation.

OBJECTIVES: This study sought to systematically investigate the interactions between the extrinsic and intrinsic cardiac autonomic nervous system (ANS) in modulating electrophysiological properties and atrial fibrillation (AF) initiation. BACKGROUND: Systematic ganglionated plexi (GP) ablation to evaluate the extrinsic and intrinsic cardiac ANS relationship has not been detailed. METHODS: The following GP were exposed in 28 dogs: anterior right GP (ARGP) near the sinoatrial node, inferior right ganglionated plexi (IRGP) at the junction of the inferior vena cava and atria, and superior left ganglionated plexi (SLGP) near the junction of left superior pulmonary vein and left pulmonary artery. With unilateral vagosympathetic trunk stimulation (0.6 to 8.0 V, 20 Hz, 0.1 ms in duration), sinus rate (SR), and ventricular rate (VR) during AF were compared before and after sequential ablation of SLGP, ARGP, and IRGP. RESULTS: The SLGP ablation significantly attenuated the SR and VR slowing responses with right or left vagosympathetic trunk stimulation. Subsequent ARGP ablation produced additional effects on SR slowing but not VR slowing. After SLGP + ARGP ablation, IRGP ablation eliminated VR slowing but did not further attenuate SR slowing with vagosympathetic trunk stimulation. Unilateral right and left vagosympathetic trunk stimulation shortened the effective refractory period and increased AF inducibility of atrium and pulmonary vein near the ARGP and SLGP, respectively. The ARGP ablation eliminated ERP shortening and AF inducibility with right vagosympathetic trunk stimulation, whereas SLGP ablation eliminated ERP shortening but not AF inducibility with left vagosympathetic trunk stimulation. CONCLUSIONS: The GP function as the "integration centers" that modulate the autonomic interactions between the extrinsic and intrinsic cardiac ANS. This interaction is substantially more intricate than previously thought.

Pycnogenol as an adjunct in the management of childhood asthma.

A randomized, placebo-controlled, double-blind study involving 60 subjects, aged 6-18 years old, was conducted over a period of 3 months to determine the effect of Pycnogenol (a proprietary mixture of water-soluble bioflavonoids extracted from French maritime pine) on mild-to-moderate asthma. After baseline evaluation, subjects were randomized into two groups to receive either Pycnogenol or placebo. Subjects were instructed to record their peak expiratory flow with an Assess Peak Flow Meter each evening. At the same time, symptoms, daily use of rescue inhalers (albuterol), and any changes in oral medications were also recorded. Urine samples were obtained from the subjects at the end of the run-in period, and at 1-, 2-, and 3-month visits. Urinary leukotriene C4/D4/E4 was measured by an enzyme immunoassay. Compared with subjects taking placebo, the group who took Pycnogenol had significantly more improvement in pulmonary functions and asthma symptoms. The Pycnogenol group was able to reduce or discontinue their use of rescue inhalers more often than the placebo group. There was also a significant reduction of urinary leukotrienes in the Pycnogenol group. The results of this study demonstrate the efficacy of Pycnogenol as an adjunct in the management of mild-to-moderate childhood asthma.