Consensus statement on tumour bed localization for radiation after oncoplastic breast surgery.

Background: Oncoplastic surgery (ops) is becoming the new standard of care for breast-conserving surgery, leading to some challenges with adjuvant radiation, particularly when accurate tumour bed (tbd) delineation is needed for focused radiation (that is, accelerated partial breast irradiation or boost radiation). Currently, no guidelines have been published concerning tbd localization for adjuvant targeted radiation after ops. Methods: A modified Delphi method was used to establish consensus by a panel of 20 experts in surgical and radiation oncology at the Canadian Locally Advanced Breast Cancer National Consensus Group and in a subsequent online member survey. Results: These are the main recommendations:■ Surgical clips are necessary and should, at a minimum, be placed along the 4 side walls of the cavity, plus 1-4 clips at the posterior margin if necessary.■ Operative reports should include pertinent information to help guide the radiation oncologists.■ Breast surgeons and radiation oncologists should have a basic understanding of ops techniques and work on "speaking a common language."■ Careful consideration is needed when determining the value of targeted radiation, such as boost, in higher-level ops procedures with extensive tissue rearrangement. Conclusions: The panel developed a total of 6 recommendations on tbd delineation for more focused radiation therapy after ops, with more than 80% agreement on each statement. All are summarized, together with the corresponding evidence or expert opinion.

Brain death in children: a retrospective review of patients at a paediatric intensive care unit.

PURPOSE: Among patients in paediatric intensive care units (PICUs), death is sometimes inevitable despite advances in treatment. Some PICU patients may have irreversible cessation of all brain function, which is considered as brain death (BD). This study investigated demographic and clinical differences between PICU patients with BD and those with cardiopulmonary death. METHODS: All children who died in the PICU at a university-affiliated trauma centre between October 2002 and October 2018 were included in this retrospective study. Demographics and clinical characteristics were compared between patients with BD and patients with cardiopulmonary death. RESULTS: Of the 2784 patients admitted to the PICU during the study period, 127 died (4.6%). Of these 127 deaths, 22 (17.3%) were BD and 105 were cardiopulmonary death. Length of PICU stay was shorter for patients with cardiopulmonary death than for patients with BD (2 vs 8.5 days, P=0.0042). The most common mechanisms of injury in patients with BD were hypoxic-ischaemic injury (40.9%), central nervous system infection (18.2%), and traumatic brain injury (13.6%). The combined proportion of accident and trauma-related injury was greater in patients with BD than in patients with cardiopulmonary death (27.3% vs 3.8%, P<0.001). Organ donation was approved by the families of four of the 22 patients with BD (18.2%) and was performed successfully in three of these four patients. CONCLUSIONS: These findings emphasise the importance of injury prevention in childhood, as well as the need for education of the public regarding acceptance of BD and support for organ donation.

Reconstructing long-term trends in municipal sewage discharge into a small lake in northern Manitoba, Canada.

Ross Lake lies within the City of Flin Flon (Manitoba, Canada), a mining community originally formed by the Hudson Bay Mining and Smelting Company (now Hudbay Minerals Inc.) in 1927. At the time of this investigation, a continuous effluent stream from Hudbay Minerals (approximately 80 years) and a discontinuous and unknown amount of raw and minimally treated municipal sewage (>20 years, likely ending in 1951) was discharged into the north basin of the lake. Maximum concentrations of fecal sterols, such as coprostanol and terrestrial phytosterols, such as: ß-sitosterol, campesterol, stigmastanol were measured in vertical sections of sediment cores, collected from Ross Lake, in the 15-16-cm section, which likely corresponds to the 1930s. Concentrations of coprostanol increased from <1 µg g(-1) in older sediments, to 252.3 µg g(-1) organic carbon at the peak. Observed changes in concentrations of sterols, in combination with radiometric dating and changes to sediment physicochemical characteristics, support the conclusion that sediments of a depth of less than 17.5-cm depth were deposited during the post-industrial era from approximately 1930 onwards. Ratios of coprostanol to cholesterol>1, peaking at 3.6 are consistent with anecdotal information that municipal sewage was discharged into Ross Lake during the early years of urbanization, prior to changes in treatment of sewage and discharge practices that began in 1951. Finally, historical concentrations of terrestrial phytosterols followed trends similar to those of coprostanol and cholesterol and may possibly be the result of an increase in the flux of terrestrial organic matter into Ross Lake as the result of regional deforestation due to logging and fire.

CCL3 induced migration occurs independently of intracellular calcium release.

The molecular signalling pathway of cell migration and whether it can occur independently of the release of intracellular calcium is still not completely understood. Therefore we investigated here the molecular mechanisms of CCL3 induced cell migration and the importance of intracellular calcium for chemotaxis in more detail. We show that CCL3 induced cell migration is dependent on activation of PLC. Several PKC inhibitors block the release of intracellular calcium independently of CCL3 activation and do not affect cell migration. This confirms that the release of intracellular calcium is not necessary for chemotaxis towards CCL3 and that PKC inhibitors should be used with caution in calcium release assays.

Primary percutaneous coronary intervention for ST elevation myocardial infarction: performance with focus on timeliness of treatment.

OBJECTIVE: To review primary percutaneous coronary interventions performed for patients with ST elevation myocardial infarction with a focus on door-to-treatment time, especially after introduction of a new management programme in November 2003. DESIGN: Retrospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: All patients with ST elevation myocardial infarction who underwent primary percutaneous coronary intervention in our hospital from January 2002 to December 2007. RESULTS: In all, 209 patients with ST elevation myocardial infarction had primary percutaneous coronary interventions between January 2002 and December 2007; 140 of them were admitted within office hours, 125 of whom came directly from Accident and Emergency Department. The mean door-to-balloon time of these patients was 115 minutes, and in 41% the time was less than 90 minutes (as recommended by the American College of Cardiology/American Heart Association guidelines). Since introduction of the new programme, the mean door-to-balloon time has diminished significantly, from 146 to 116 minutes (P=0.047). Delay in diagnosis (28%) and Cardiac Catheterization Laboratory being occupied (20%) were the two most common reasons for prolonged door-to-balloon times. CONCLUSION: We achieved satisfactory performance in our primary percutaneous coronary intervention programme, providing timely reperfusion therapy for patients with ST elevation myocardial infarction. A well-organised and systematic clinical pathway is a prerequisite for a centre that provides a timely and effective primary percutaneous coronary intervention service for patients with ST elevation myocardial infarction. Better public education and greater awareness on the part of medical service providers are needed, so as to facilitate urgent revascularisation and improve outcomes in patients with ST elevation myocardial infarction.

Enhanced synaptic responses in the piriform cortex associated with sexual stimulation in the male rat.

Male rats that copulate to ejaculation with female rats bearing an odor show a learned preference to ejaculate selectively with females that bear the odor. This conditioned ejaculatory preference reflects an association between the odor and the reward state induced by ejaculation. Although little is known about the neuronal mechanisms that mediate this form of learning, convergence of genitosensory and olfactory inputs occurs in both hypothalamic and cortical regions, notably within primary olfactory (piriform) cortex, which may be involved in the encoding or storage of the association. The present study contrasted the ability of genital investigations, mounts, intromissions, ejaculations, and a sexually conditioned olfactory stimulus, to enhance evoked synaptic field potentials in the piriform cortex. Rats in the Paired group underwent conditioning trials in which they copulated with sexually receptive females bearing an almond odor. Rats in the Unpaired control group copulated with receptive females bearing no odor. Responses in the piriform cortex evoked by electrical stimulation of the olfactory bulb were recorded in male rats as they engaged in different aspects of sexual behavior, and were also recorded after conditioning, during exposure to cotton swabs bearing the almond odor. The monosynaptic component of responses was increased during intromission and ejaculation, and the late component of responses was increased during anogenital sniffing and mounting (with or without intromission). However, no differences in the amplitudes of evoked responses were found between the Paired and Unpaired groups, and no differences in synaptic responses were found during presentation of the odor after conditioning. These data indicate that short-term alterations in synaptic responsiveness occur in piriform cortex as a function of sexual stimulation in the male rat, but that responses are not significantly altered by a conditioned odor.

Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome.

In the current study our objective was to develop a murine model of human hyper-IgD syndrome (HIDS) and severe mevalonic aciduria (MA), autoinflammatory disorders associated with mevalonate kinase deficiency (MKD). Deletion of one Mvk allele (Mvk (+/-)) yielded viable mice with significantly reduced liver Mvk enzyme activity; multiple matings failed to produce Mvk (-/-) mice. Cholesterol levels in tissues and blood, and isoprene end-products (ubiquinone, dolichol) in tissues were normal in Mvk (+/-) mice; conversely, mevalonate concentrations were increased in spleen, heart, and kidney yet normal in brain and liver. While the trend was for higher IgA levels in Mvk (+/-) sera, IgD levels were significantly increased (9-12-fold) in comparison to Mvk (+/+) littermates, in both young (<15 weeks) and older (>15 weeks) mice. Mvk (+/-) animals manifested increased serum TNF-alpha as compared to wild-type littermates, but due to wide variation in levels between individual Mvk (+/-) mice the difference in means was not statistically significant. Mvk (+/-) mice represent the first animal model of HIDS, and should prove useful for examining pathophysiology associated with this disorder.

Mathematical modeling of guided neurite extension in an engineered conduit with multiple concentration gradients of nerve growth factor (NGF).

Neurotrophic factors such as nerve growth factor (NGF) provide essential cues to navigate growing axon toward their targets. Concentration and concentration gradient of NGF are key parameters affecting the growth rate and direction of neurites and axons. However, the maximum distance for guided nerve growth under stimulation of a single concentration gradient is limited and is thus unfavorable in nerve regeneration. Since the sensitivity of PC12 cells to NGF signals is restorable even after brief removal of the factors, exposure to multiple concentration gradients of the factor can achieve longer distances and greater rates of guided growth. In this study, a mathematical model simulating nerve growth in a virtually constructed nerve conduit incorporating multiple NGF concentration gradients is established. Using a genetic algorithm, optimized initial profiles of NGF able to achieve 4.5 cm of guided growth with a significantly improved growth rate has been obtained. The model also predicts an inverse relationship between the diffusion coefficient of the factor and the neurite growth rate. This model provides a useful tool for evaluating various conduit designs before fabrication and evaluation.

Feasibility of transradial coronary angiography and angioplasty in Chinese patients.

OBJECTIVE: To assess the clinical applicability, efficacy, and safety of coronary angiography and angioplasty via a transradial approach in local Chinese patients. DESIGN: Prospective case series. SETTING: Regional hospital, Hong Kong. PATIENTS: All patients undergoing coronary angiography and coronary angioplasty between 1 January and 30 June 2004. INTERVENTIONS: Transradial coronary angiography and coronary angioplasty. MAIN OUTCOME MEASURES: Feasibility, success rate, and complications. RESULTS: A total of 268 coronary angiographies (62% of all coronary angiographies) and 118 coronary angioplasties (48% of all coronary angioplasties) were performed via a transradial approach. The procedural success rate for coronary angiography was 93.7% with a mean duration of 21.8 (standard deviation, 13.5) minutes compared with 17.9 (10.0) minutes for angiography via a femoral approach. Most (99%) patients were free from any complications. Of those patients who underwent elective transradial coronary angiography in the morning, 64% were discharged on the same day. Comparison of data in the first half of the study period with those in the second half revealed a significant increase in the percentage of coronary angiographies performed via a transradial approach (from 52% to 73%, P<0.0001), and an improved procedural success rate (from 91.5% to 95.3%, P=0.1). For transradial coronary angioplasty, the procedural success rate was 98%. A total of 246 lesions (2.08 lesions per patient) were treated with no procedure-related complications. CONCLUSIONS: Transradial coronary angiography and angioplasty are feasible in a significant proportion of local Chinese patients and achieve a high success rate and low complication rate. It tends to prolong procedural duration, but improves patients' comfort and permits earlier ambulation and discharge. The procedural success rate improves with accumulating experience.

Necrotic cardiac haemangioma masquerading as sepsis with disseminated intravascular coagulation.

Cardiac haemangiomas are exceptionally rare benign vascular tumours. We report a case of cardiac haemangioma presenting with pyrexia of unknown origin and clinical features simulating sepsis with disseminated intravascular coagulation. The clinical course was complicated by systemic embolism.

Differential effect of Coriolus versicolor (Yunzhi) extract on cytokine production by murine lymphocytes in vitro.

Being one of the commonly used Chinese medicinal herbs, Coriolus versicolor (CV), also named as Yunzhi, was known to possess both anti-tumor and immunopotentiating activities. The present study aimed to investigate the in vitro immunomodulatory effect of a standardized ethanol-water extract prepared from CV on the proliferation of murine splenic lymphocytes using the MTT assay, and the production of six T helper (Th)-related cytokines using the enzyme-linked immunosorbent assay (ELISA) technique. The results showed that the CV extract significantly augmented the proliferation of murine splenic lymphocytes in a time- and dose-dependent manner, maximally by 2.4-fold. Moreover, the production of two Th1-related cytokines, including interleukin (IL)-2 and IL-12, in culture supernatants from the CV extract-activated lymphocytes was prominently upregulated at 48 and 72 h. Positive correlations were found between the levels of these two cytokines and the MTT-based proliferative response. In contrast, the production of two other Th1-related cytokines, including interferon (IFN)-gamma and IL-18, was significantly augmented only at 24 h, but not at 48 and 72 h. On the other hand, the levels of two Th2-related cytokines such as IL-4 and IL-6 were undetectable in the culture supernatants of lymphocytes treated with the CV extract. The CV extract was suggested to be a lymphocyte mitogen by differentially enhancing the production of Th1-related cytokines.

Primary granulocytic sarcoma of the mediastinum.

Primary granulocytic sarcoma (GS) is rare, and poses a diagnostic pitfall for both pathologists and oncologists. Previous literature showed that almost half of the patients with primary GS were misdiagnosed initially. We presented the clinico-pathological and radiological features of a patient with primary mediastinal GS, and discussed the differential diagnoses and clinical management.

Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis.

Coriolus versicolor (CV), also known as Yunzhi, is one of the commonly used Chinese medicinal herbs. Although recent studies have demonstrated its antitumour activities on cancer cells in vitro and in vivo, the exact mechanism is not fully elucidated. Hence, the objective of this study was to examine the in vitro cytotoxic activities of a standardized aqueous ethanol extract prepared from Coriolus versicolor on a B-cell lymphoma (Raji) and two human promyelocytic leukemia (HL-60, NB-4) cell lines using a MTT cytotoxicity assay, and to test whether the mechanism involves induction of apoptosis. Cell death ELISA was employed to quantify the nucleosome production resulting from nuclear DNA fragmentation during apoptosis. The present results demonstrated that CV extract at 50 to 800 microg/ml dose-dependently suppressed the proliferation of Raji, NB-4, and HL-60 cells by more than 90% (p < 0.01), with ascending order of IC50 values: HL-60 (147.3 +/- 15.2 microg/ml), Raji (253.8 +/- 60.7 microg/ml) and NB-4 (269.3 +/- 12.4 microg/ml). The extract however did not exert any significant cytotoxic effect on normal liver cell line WRL (IC50 > 800 microg/ml) when compared with a chemotherapeutic anticancer drug, mitomycin C (MMC), confirming the tumour-selective cytotoxicity. Nucleosome productions in HL-60, NB-4 and Raji cells were significantly increased by 3.6-, 3.6- and 5.6-fold respectively upon the treatment of CV extract, while no significant nucleosome production was detected in extract-treated WRL cells. The CV extract was found to selectively and dose-dependently inhibit the proliferation of lymphoma and leukemic cells possibly via an apoptosis-dependent pathway.

Use of common Chinese herbs in the treatment of psoriasis.

Chinese herbal medicines have been shown to be effective in the treatment of atopic eczema. However, the Western scientific/medical literature has not fully examined the potential usefulness of herbal treatments in the management of psoriasis. This article aims to provide an Eastern insight into psoriasis, considering the diagnosis of psoriasis using Chinese medical terminology and its treatment using herbal medicine, as well as how these herbs might work.

A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell.

cAMP, the classical second messenger, regulates many diverse cellular functions. The primary effector of cAMP signals, protein kinase A, differentially phosphorylates hundreds of cellular targets. Little is known, however, about the spatial and temporal nature of cAMP signals and their information content. Thus, it is largely unclear how cAMP, in response to different stimuli, orchestrates such a wide variety of cellular responses. Previously, we presented evidence that cAMP is produced in subcellular compartments near the plasma membrane, and that diffusion of cAMP from these compartments to the bulk cytosol is hindered. Here we report that a uniform extracellular stimulus initiates distinct cAMP signals within different cellular compartments. By using cyclic nucleotide-gated ion channels engineered as cAMP biosensors, we found that prostaglandin E(1) stimulation of human embryonic kidney cells caused a transient increase in cAMP concentration near the membrane. Interestingly, in the same time frame, the total cellular cAMP rose to a steady level. The decline in cAMP levels near the membrane was prevented by pretreatment with phosphodiesterase inhibitors. These data demonstrate that spatially and temporally distinct cAMP signals can coexist within simple cells.

In vivo assessment of local phosphodiesterase activity using tailored cyclic nucleotide-gated channels as cAMP sensors.

Phosphodiesterases (PDEs) catalyze the hydrolysis of the second messengers cAMP and cGMP. However, little is known about how PDE activity regulates cyclic nucleotide signals in vivo because, outside of specialized cells, there are few methods with the appropriate spatial and temporal resolution to measure cyclic nucleotide concentrations. We have previously demonstrated that adenovirus-expressed, olfactory cyclic nucleotide-gated channels provide real-time sensors for cAMP produced in subcellular compartments of restricted diffusion near the plasma membrane (Rich, T.C., K.A. Fagan, H. Nakata, J. Schaack, D.M.F. Cooper, and J.W. Karpen. 2000. J. Gen. Physiol. 116:147-161). To increase the utility of this method, we have modified the channel, increasing both its cAMP sensitivity and specificity, as well as removing regulation by Ca(2)+-calmodulin. We verified the increased sensitivity of these constructs in excised membrane patches, and in vivo by monitoring cAMP-induced Ca(2)+ influx through the channels in cell populations. The improved cAMP sensors were used to monitor changes in local cAMP concentration induced by adenylyl cyclase activators in the presence and absence of PDE inhibitors. This approach allowed us to identify localized PDE types in both nonexcitable HEK-293 and excitable GH4C1 cells. We have also developed a quantitative framework for estimating the K(I) of PDE inhibitors in vivo. The results indicate that PDE type IV regulates local cAMP levels in HEK-293 cells. In GH4C1 cells, inhibitors specific to PDE types I and IV increased local cAMP levels. The results suggest that in these cells PDE type IV has a high K(m) for cAMP, whereas PDE type I has a low K(m) for cAMP. Furthermore, in GH4C1 cells, basal adenylyl cyclase activity was readily observable after application of PDE type I inhibitors, indicating that there is a constant synthesis and hydrolysis of cAMP in subcellular compartments near the plasma membrane. Modulation of constitutively active adenylyl cyclase and PDE would allow for rapid control of cAMP-regulated processes such as cellular excitability.

Usability issues in developing a Web-based consumer health site.

ClinicalTrials.gov is a Web-based system intended for a diverse audience, including patients, family members and other members of the public. Throughout the system design and development process, our decisions have been driven by usability concerns. We first describe the overall design of the site, including the home page, which provides a site overview and rapid access to the information contained within it. Next we discuss the data presentation format which has been standardized in spite of data coming to us from many different sources. We provide a detailed description of the search and browse features that are intended to simplify the complexities of medical terminology and support information discovery. We conclude with a review of our evaluation activities and future plans.