Arginase II inhibition prevents nitrate tolerance

BACKGROUND AND PURPOSE

Nitrate tolerance, the loss of vascular responsiveness with continued use of nitrates, remains incompletely understood and is a limitation of these therapeutic agents. Vascular superoxide, generated by uncoupled endothelial NOS (eNOS), may play a role. As arginase competes with eNOS for L-arginine and may exacerbate the production of reactive oxygen species (ROS), we hypothesized that arginase inhibition might reduce nitrate tolerance.

EXPERIMENTAL APPROACH

Vasodilator responses were measured in aorta from C57Bl/6 and arginase II knockout (argII –/–) mice using myography. Uncoupling of eNOS, determined as eNOS monomer : dimer ratio, was assessed using low-temperature SDS-PAGE and ROS levels were measured using L-012 and lucigenin-enhanced chemiluminescence.

KEY RESULTS

Repeated application of glyceryl trinitrate (GTN) on aorta isolated from C57Bl/6 mice produced a 32-fold rightward shift of the concentration–response curve. However this rightward shift (or resultant tolerance) was not observed in the presence of the arginase inhibitor (s)-(2-boronethyl)-L-cysteine HCl (BEC; 100 µM) nor in aorta isolated from argII –/– mice. Similar findings were obtained after inducing nitrate tolerance in vivo. Repeated administration of GTN in human umbilical vein endothelial cells induced uncoupling of eNOS from its dimeric state and increased ROS levels, which were reduced with arginase inhibition and exogenous L-arginine. Aortae from GTN tolerant C57Bl/6 mice exhibited increased arginase activity and ROS production, whereas vessels from argII –/– mice did not.

CONCLUSION AND IMPLICATIONS

Arginase II removal prevents nitrate tolerance. This may be due to decreased uncoupling of eNOS and consequent ROS production.     

Primary malignant lymphoma of the cervix uteri: a case report

Primary reticuloendothelial disease of the genital tract is an extremely rare condition. We encountered one such patient with diffuse large cell malignant lymphoma of the cervix uteri who presented with irregular vaginal bleeding. After complete haematological and radiological investigations, satisfactory treatment of the Stage I disease was achieved with total hysterectomy, bilateral salpingo-oophorectomy and post-operative pelvic irradiation.     

Diffusion tensor imaging of normal white matter maturation from late childhood to young adulthood: voxel-wise evaluation of mean diffusivity, fractional anisotropy, radial and axial diffusivities, and correlation with reading development

Using diffusion tensor MR imaging (DTI) and advanced voxel-wise analysis tools, we study diffusivity and anisotropy changes of white matter from late childhood to young adulthood, and correlate quantitative diffusion indices with Chinese and English reading performance scores. Seventy-five normal healthy school going ethnic Chinese students and young adults of three age groups were recruited (group 1, n=24, mean+/-SD=7.4+/-0.3 years; group 2, n=27, mean+/-SD=10.3+/-0.5 years; group 3, n=24, mean+/-SD=22.8+/-2.3 years). DTI was performed with 3 mm isotropic resolution to cover the entire brain. Voxel-wise analysis was performed using Tract-Based Spatial Statistics (TBSS) to localize regions of white matter showing significant changes of fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities between groups. We found increased FA and decreased MD with increasing age in regions of cerebellar white matter, right temporal white matter, and a large portion of the superior frontal and parietal white matter driven by both the reduction of radial diffusivity and axial diffusivity with the former to a greater extent. Changes were continual from late childhood to young adulthood. Findings were confirmed by region-of-interest analysis in specific white matter tracts. After controlling for the effect of age, significant correlation was found between diffusion indices of the anterior limb of the left internal capsule and Chinese reading score (p=0.05), and of the corona radiata and English reading score (p=0.026 and p=0.029 for left and right, respectively).These DTI indices likely reflect the multiple biological processes that occur during brain development which provide the neural substrate for ongoing functional connectivity including for reading development.     

Late-onset pediatric glaucoma associated with cutis marmorata telangiectatica congenita managed with Molteno implant surgery: case report and review of the literature.

Cutis marmorata telangiectatica congenita (CMTC) is characterized by the appearance of telangiectasia, phlebectasia, and a persistent reticular pattern of subcutaneous vasculature at or soon after birth. Up to 90% of cases are associated with systemic abnormalities, which include body asymmetry, cutaneous atrophy, neurological abnormalities, and vascular anomalies (nevus flammeus, Sturge-Weber syndrome, Klippel-Trenaunay syndrome, and capillary and cavernous hemangiomas). Glaucoma is the most commonly reported ocular association of CMTC, usually presenting in infancy. We report a case of CMTC associated with the previously unreported onset of glaucoma in mid-childhood that was managed by glaucoma drainage implant surgery and review the literature on glaucoma associated with this condition.     

“A Conscious Control Over Life and My Emotions:” Mindfulness Practice and Healthy Young People. A Qualitative Study

PurposeAlthough quantitative benefits of mindfulness training have been demonstrated in youth, little is known about the processes involved. The aim of this study was to gain a detailed understanding of how young people engage with the ideas and practices known as mindfulness using qualitative enquiry.MethodsFollowing completion of a six-week mindfulness training program with a nonclinical group of 11 young people (age 16–24), a focus group (N = 7) and open-ended interviews (n = 5) were held and audio-recorded. Qualitative data, collected at eight time points over three months from the commencement of training, were coded with the aid of computer software. Grounded theory methodology informed the data collection process and generation of themes and an explanatory model that captured participants' experiences.ResultsParticipants described their daily lives as beset by frequent experiences of distress sometimes worsened by their unhelpful or destructive reactions. With mindfulness practice, they initially reported greater calm, balance, and control. Subsequently they commented on a clearer understanding of themselves and others. Mindfulness was then described as a “mindset” associated with greater confidence and competence and a lessened risk of future distress.ConclusionsParticipants demonstrated a sophisticated understanding of and engagement with mindfulness principles and practice. Their reported experience aligned well with qualitative research findings in adults and theoretical literature on mindfulness. An encouraging finding was that, with ongoing mindfulness practice and within a relatively short time, participants were able to move beyond improved emotion regulation and gain greater confidence in their ability to manage life challenges.     

Solid-cystic papillary tumor of the pancreas in children

Solid-cystic papillary tumor (SCPT) of the pancreas is a rare neoplasm in children. The current study attempted to estimate the incidence and possible pathological origin of the tumor. Clinicopathologic features of the children under the age of 16 years with pancreatic tumors managed in a single institution between January 1993 and November 1999 were reviewed. Representative blocks of SCPT specimens were immunostained for neuron-specific enolase (NSE) chromogrannin, synaptophysin, insulin, glucagon, somatostatin, and gastrin. There were three SCPTs, two pancreatic endocrine tumors, and one acinar cell carcinoma during the study period. The estimated yearly incidence in the referral area of 2 million population is about 0.01 pediatric SCPT per year per 100,000 population. The children underwent surgical removal of the tumors. Postoperatively, they were followed up for 6 months to 4 years and were well. Immunostaining for NSE, chromogranin, synaptophysin, insulin, somatostatin, and gastrin was negative in all cases. SCPT may thus be the most common pancreatic tumor in the Asian pediatric population. The pathological origin of the tumor remains unclear and requires further investigations. Accepted: 30 October 2000     

Childhood acute disseminated encephalomyelitis: the role of brain and spinal cord MRI

BACKGROUND: It is recognised that the clinical and radiological spectrum of childhood acute disseminated encephalomyelitis (ADEM) is wide. OBJECTIVE: To determine whether initial MRI features are predictive of clinical outcome and to determine the role of MRI in the management of ADEM. MATERIALS AND METHODS: The MRI scans of ten consecutive children (eight boys, two girls), clinically and radiologically diagnosed to have ADEM, were retrospectively reviewed. Follow-up MRI was available for eight patients. RESULTS: Lesions ranged from small and punctate (<1 cm) to moderate sized and confluent (4-5 cm) to diffuse and extensive. Spinal cord lesions, seen in five of seven children, were contiguous or segmental. Seven children (70%) made good clinical recovery while three children (30%) remained severely handicapped. There was no correlation between the site, extent and pattern of involvement and clinical outcome. However, the evolution of MRI findings on follow-up correlated well with the subsequent clinical course and outcome. CONCLUSIONS: Although the extent and site of lesions on initial MRI scans are not predictive of clinical outcome, early MRI of the brain and spine is useful in aiding clinical diagnosis, and subsequent follow-up MRI is helpful in monitoring disease progression.