Rectal Motion in Patients Receiving Preoperative Radiotherapy for Carcinoma of the Rectum


Purpose:

To assess the movement of rectum, mesorectum, and rectal primary during a course of preoperative chemoradiotherapy.
Methods and Materials

Seventeen patients with Stage II or III rectal cancer had a planning CT scan with rectal contrast before commencement of preoperative chemoradiation. The scan was repeated during Weeks 1, 3, and 5 of chemoradiation. The rectal primary (gross tumor volume), rectum, mesorectum, and bladder were contoured on all four scans. An in-house biomechanical model-based deformable image registration technique, Morfeus, was used to measure the three-dimensional spatial change in these structures after bony alignment. The required planning target volume margin for this spatial change, after bone alignment, was also calculated.
Results

Rectal contrast was found to introduce a systematic error in the position of all organs compared with the noncontrast state. The largest change in structures during radiotherapy was in the anterior and posterior directions for the mesorectum and rectum and in the superior and inferior directions for the gross tumor volume. The planning target volume margins required for internal movement for the mesorectum based on the three scans acquired during treatment are 4 mm right, 5 mm left, 7 mm anterior, and 6 mm posterior. For the rectum, values were 8 mm right, 8 mm left, 8 mm anterior, and 9 mm posterior. The greatest movement of the rectum occurred in the upper third.
Conclusions

Contrast is no longer used in CT simulation. Assuming bony alignment, a nonuniform margin of 8 mm anteriorly, 9 mm posteriorly, and 8 mm left and right is recommended.

source: IJROBP(red journal)

Sex After a Field Trip Yields Scientific First


A U.S. vector biologist appears to have accidentally written virological history simply by having sex with his wife after returning from a field trip to Senegal. A study just released in Emerging Infectious Diseases suggests that the researcher, Brian Foy of Colorado State University in Fort Collins, passed to his wife the Zika virus, an obscure pathogen that causes joint pains and extreme fatigue. If so, it would be the first documented case of sexual transmission of an insect-borne disease.

Foy is the first author of the paper, which describes three anonymous patients. But in an interview with Science, he confirmed that he is the anonymous “patient 1”; his Ph.D. student Kevin Kobylinski, who accompanied him on the trip to Senegal and also got sick, is “patient 2.” Foy’s wife, Joy Chilson Foy, a nurse at the Poudre Valley Hospital in Fort Collins, is “patient 3”; she is also a co-author of the paper.

Exactly what happened when Foy and Kobylinski returned from Senegal on 24 August 2008 has remained a mystery for years. As part of their research on malaria, the scientists had been collecting mosquitoes in a southeastern village called Bandafassi, where they were often bitten. About 5 days after their return, both researchers got sick. Both had a rash on their torso, extreme fatigue, headaches, and swollen and painful wrists, knees, and ankles. Foy also had symptoms of prostatitis, including painful urination, and he and his wife noticed what looked like blood in his semen, according to the paper.

On 3 September, Foy’s wife’s fell ill as well, with malaise, chills, extreme headache, hypersensitivity to light, and muscle pains. The couple’s four children remained healthy. The symptoms started receding within about a week in all three patients, although the joint pains lingered.

The scientists suspected they were infected through one of their many mosquito bites but were stumped as to the pathogen. So were several laboratories, including the U.S. Centers for Disease Control and Prevention (CDC), whose lab for insect-borne diseases is in Fort Collins. Antibody tests on serum samples from the two scientists tested positive for dengue, a viral disease that might have explained the symptoms, but samples from Chilson Foy came back negative. “Eventually, the CDC said, ‘We think you had dengue, but we don’t know what your wife had,’ ” says Foy, who decided to keep samples from all three in the freezer.

The mystery might never have been solved if Kobylinski hadn’t gone out for a few beers with Andrew Haddow, a medical entomologist at the University of Texas Medical Branch (UTMB) at Galveston, during another trip to Senegal more than a year later. Haddow, who studies how pathogens survive in the jungle and emerge when humans encroach, had a great personal interest in Zika: His grandfather, Alexander Haddow, was one of three scientists who had isolated the virus from a rhesus monkey in the Zika Forest near Entebbe, Uganda, in 1947 and described it in a paper in 1952. “I read all of my grandfather’s papers, so that stuff really interests me,” Haddow says.

Zika, he speculated, might account for the trio’s symptoms—even though “it was just a hunch.” After Kobylinski returned home in December 2009 and told Foy about the encounter, they decided to send the samples to Haddow, who asked his UTMB colleague Robert Tesh, a veteran virologist, to run a battery of tests, including one for the Zika virus. Sure enough, all three samples had antibodies to the virus. “Then it all fell into place,” Foy says. The dengue antibodies were a red herring, he says: both researchers had been vaccinated for the yellow fever virus, which is closely related to dengue; antibodies against these viruses often cross-react.

There is no direct evidence that Foy’s wife was infected through sexual contact, but the circumstantial evidence is strong. It’s very unlikely that she was infected by a bite by a mosquito that first bit her husband; the three tropical Aedes mosquito species known to transmit Zika don’t live in northern Colorado, and moreover, the virus has to complete a 2-week life cycle within the insect before it can infect the next human; Foy’s wife fell ill just 9 days after his return. And yes, as the paper puts it, “patients 1 and 3 reported having vaginal sexual intercourse in the days after patient 1 returned home but before the onset of his clinical illness.” (“My wife wasn’t happy with what happened afterwards,” Foy adds.)

Not much is known about the Zika virus, which is found in many parts of Africa and Southeast Asia. Researchers from the Pasteur Institute in Dakar reported in 1993 that it occurs in southeastern Senegal, where Foy and Kobylinski work, but it’s unknown how often it causes disease. Most cases are never reported or are mistaken for dengue, a much more widespread disease, Haddow says. In fact, only 14 Zika cases had ever been described in the medical literature until an explosive outbreak occurred in 2007 on Yap, an island in the Federated States of Micronesia, where it had never been seen before. An extensive investigation of that epidemic by CDC concluded that 73% of the population was infected, an impressive number that suddenly made Zika an emerging pathogen to watch.

Foy and his co-authors believe sexual transmission of a mosquito-borne virus has never been reported before, although there were hints from the literature that it might be possible. Boars experimentally infected with the Japanese encephalitis virus, for instance, shed the virus in their semen, and female pigs artificially inseminated with it become infected.

Scientists already knew that many insect-borne pathogens can be transmitted orally as well, says medical entomologist Paul Reiter of the Pasteur Institute in Paris. So even if it hasn’t been documented before, it’s not a big surprise that infected semen deposited inside the vagina could cause an infection, he says.

What’s still unclear is how important sexual transmission is in Zika’s epidemiology. Haddow believes it plays a very minor role at best and that the vast majority of cases occur through mosquito bites. Yet a few data points from the Yap outbreak hint that sexual transmission may have played a role, Foy says. The population aged between 30 and 59 was hardest hit, and among women, the so-called attack rate—the percentage of people who get sick—was almost 50% higher than among men. (With most sexually transmitted infections, vaginal intercourse poses a higher risk of infection for women.) But there could be other explanations for that as well; Foy says he’s interested in studying the issue.

Haddow is doing more research on Zika as well. Although he never really knew his grandfather, he says that stories about his career inspired him to become a virus hunter, and helping solve the Fort Collins riddle, he adds, was “a very good feeling. … I think my grandfather would have been happy too.”

source: science now

Does Your Brain Bleed Red, White, and Blue?


Politics can be a touchy topic, especially when it comes to neuroscience. Researchers who’ve dared to tackle questions about how people’s political leanings might be reflected in the brain have often earned scoffs and scoldings from their colleagues. A provocative new study is likely to be no exception. It claims to find features of brain anatomy that differ between people who identify themselves as politically conservative or politically liberal.

Cognitive neuroscientist Ryota Kanai and colleagues at University College London recruited 90 student volunteers and had them rate their political philosophy on a five-point scale ranging from very liberal to very conservative. Then the researchers used magnetic resonance imaging to get a look inside their brains. In a paper published online today in Current Biology, the team reports two main findings: political conservatives tend to have a larger right amygdala, a region involved in detecting threats and responding to fearful stimuli, whereas liberals tend to have a larger anterior cingulate cortex, an area that becomes active in situations involving conflict or uncertainty.

There was considerable overlap though. When the researchers looked only at the brain scans, Kanai says they could predict who was liberal and who was conservative with about 75% accuracy—much better than a coin toss but probably not good enough for any high-tech campaign tactics.

Kanai is at pains to make clear that the findings don’t mean political views are “hard-wired” into the brain. He acknowledges that the data don’t prove that these neuroanatomical differences actually cause political differences, but he suspects that they might play a role. He says psychological studies suggest that conservatives are more sensitive to negative emotions like fear and disgust, whereas liberals are more tolerant of situations involving conflict and uncertainty. (To armchair psychologists, this might explain some stereotypical behavior, such as the spike in blood pressure a hard-core conservative might experience when Fox News plays a new recording from Osama bin Laden, or the half-hour it might take an Earth-loving liberal to decide whether to buy the organic apple flown in from Chile or the local apple treated with pesticides.) Kanai speculates that subtle size differences in the amygdala and anterior cingulate might predispose people to particular “cognitive styles or personality traits” that in turn make them gravitate toward a particular worldview.

“It’s provocative,” says social cognitive neuroscientist David Amodio of New York University. Amodio is no stranger to political neurocontroversy. A paper he published in Nature Neuroscience in 2007 resulted in some hyperbolic headlines and punditry in the mainstream media and a critical backlash from skeptical neuroscience bloggers. In that study, when Amodio and colleagues used electroencephalography to investigate brain activity, they found a correlation between greater activity in the anterior cingulate and political liberalism. The picture that emerges from that work, Kanai’s study, and other research is that “even complex political views are probably rooted in more basic psychological and brain processes,” Amodio says.

It’s an appealing story and a topic worth investigating, says cognitive neuroscientist Martha Farah of the University of Pennsylvania. But there’s plenty of reason to be cautious, she says. For one, it’s not clear what a bigger amygdala—or a bigger anything in the brain—actually means in terms of brain function and behavior. The research, she says, is unclear and often contradictory on this point.

Another problem is that most brain regions have multiple functions, Farah says: “Who says fear is the only function of the amygdala?” She notes that this brain region also responds to sexually arousing images and pictures of happy faces, and one recent study found a correlation between amygdala volume and the size of people’s social networks. Likewise, the anterior cingulate cortex has been implicated in a long list of cognitive functions. By picking and choosing from the previous studies, “they’re indulging in a bit of just-so storytelling,” Farah says.

source: science now

A Quantitative Description of the Percentage of Breast Density Measurement Using Full-field Digital Mammography


Breast density is a significant breast cancer risk factor that is measured from mammograms. However, uncertainty remains in both understanding its underlying physical properties as it relates to the breast and determining the optimal method for its measurement. A quantitative description of the information captured by the standard operator-assisted percentage of breast density (PD) measure was developed using full-field digital mammography (FFDM) images that were calibrated to adjust for interimage acquisition technique differences.

Materials and Methods

The information captured by the standard PD measure was quantified by developing a similar measure of breast density (PDc) from calibrated mammograms automatically by applying a static threshold to each image. The specific threshold was estimated by first sampling the probability distributions for breast tissue in calibrated mammograms. A percent glandular (PG) measure of breast density was also derived from calibrated mammograms. The PD, PDc, and PG breast density measures were compared using both linear correlation (R) and quartile odds ratio measures derived from a matched case-control study.

Results

The standard PD measure is an estimate of the number of pixel values above a fixed idealized x-ray attenuation fraction. There was significant correlation (P < .0001) between the PDc-PD (r = 0.78), PDc-PG (r = 0.87), and PD-PG (r = 0.71) measures of breast density. Risk estimates associated with the lowest to highest quartiles for the PDc measure (odds ratio [OR]: 1.0 ref., 3.4, 3.6, and 5.6), and the standard PD measure (OR 1.0 ref., 2.9, 4.8, and 5.1) were similar and greater than that of the calibrated PG measure (OR 1.0 ref., 2.0, 2.4, and 2.4).

Conclusions

The information captured by the standard PD measure was quantified as it relates to calibrated mammograms and used to develop an automated method for measuring breast density. These findings represent an initial step for developing an automated measure built on an established calibration platform. A fully developed automated measure may be useful for both research- and clinical-based risk applications.

source: academic radiology

Prooxidants Ameliorate Radiation Induced Apoptosis Through Activation of Calcium-ERK1/2-Nrf2 Pathway


There are no reports describing the ability of prooxidants to protect against radiation-induced apoptosis. Activation of redox-sensitive transcription factor Nrf2 by low-levels of ROS is known to protect against oxidative stress-induced cell death. In the present study, hydrogen peroxide, diethylmaleate and 1,4-naphthoquinone (NQ) exhibited complete protection against radiation-induced cell death in lymphocytes as estimated by propidium-iodide staining. Radioprotection by NQ was demonstrated by inhibition of caspase activation, decrease in cell size, DNA-fragmentation, nuclear-blebbing and clonogenic assay. Interestingly, NQ offered protection to lymphocytes even when added to cells post-irradiation. NQ increased intracellular ROS levels and decreased GSH levels. NQ activated Nrf2 and increased the expression of cytoprotective gene hemeoxygenase-1 in lymphocytes. NQ increased ERK phosphorylation which is upstream to Nrf2 and this ERK activation was through increased intracellular calcium levels. Administration of NQ to mice offered protection against whole body irradiation (WBI)-induced apoptosis in splenic lymphocytes and loss of viability of spleen and bonemarrow cells. It restored WBI mediated changes in hematological parameters and functional responses of lymphocytes. Importantly, NQ rescued mice against WBI-induced mortality. These results demonstrated that a prooxidant like NQ can protect against radiation-induced apoptosis by activation of multiple prosurvival mechanisms including activation of calcium-ERK1/2-Nrf2 pathway.

source: free radial biology and medicine

A novel approach for computer assisted EEG monitoring in the adult ICU


The implementation of a computer assisted system for real-time classification of the electroencephalogram (EEG) in critically ill patients.

Methods

Eight quantitative features were extracted from the raw EEG and combined into a single classifier. The system was trained with 41 EEG recordings and subsequently evaluated using an additional 20 recordings. Through visual analysis, each recording was assigned to one of the following categories: normal, iso-electric, low voltage, burst suppression, slowing, and EEGs with generalized periodic discharges or seizure activity.

Results

36 (88%) recordings from the training set and 17 (85%) recordings from the test set were classified correctly. A user interface was developed to present both trend-curves and a diagnostic output in text form. Implementation in a dedicated EEG monitor allowed real-time analysis in the intensive care unit (ICU) during pilot measurements in four patients.

Conclusions

We present the first results from a computer assisted EEG interpretation system, based on a combination of eight quantitative features. Our system provided an initial, reasonably accurate interpretation by non-experts of the most common EEG patterns observed in neurological patients in the adult ICU.

Significance

Computer assisted EEG monitoring may improve early detection of seizure activity and ischemia in critically ill patients.

source: clinical neurophysiology

Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial


Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise.

Methods

We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260.

Findings

67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12 537 (95% CI 6593–23 840) versus 86 (63–118) in recipients of placebo recipients; p<0·0001) and seropositive (118 395; 64 503–217 272) versus 24 682 (17 909–34 017); p<0·0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0·0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0·0480) and number of days of ganciclovir treatment (p=0·0287) were reduced in vaccine recipients.

Interpretation

Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients.

source: lancet

Early Fluid Resuscitation Reduces Morbidity Among Patients with Acute Pancreatitis


Early fluid resuscitation is recommended to reduce morbidity and mortality among patients with acute pancreatitis (AP), although the impact of this intervention has not been quantified. We investigated the association between early fluid resuscitation and outcome of patients admitted to the hospital with AP.

Methods

Non-transfer patients admitted to our center with AP, from 1985 to 2009, were identified retrospectively. Patients were stratified into groups based on early (n=340) or late resuscitation (n=94). Early resuscitation was defined as receiving ≥ 1/3 of the total 72 h fluid volume within 24 hours of presentation, whereas late resuscitation was defined as receiving ≥ 1/3 of the total 72 h fluid volume within 24 hours of presentation. The primary outcomes were frequency of the systemic inflammatory response syndrome (SIRS), organ failure, and death.

Results

Early resuscitation was associated with decreased SIRS, compared with late resuscitation, at 24 h (15% vs. 32% P =0.001), 48 h (14% vs. 33%, P =0.001), and 72 h (10% vs. 23%, P =0.01), as well as reduced organ failure at 72 h (5% vs. 10%, P <0.05), a lower rate of admission to the intensive-care unit (6% vs. 17%, P < 0.001), and a reduced length of hospital stay (8 vs. 11 days, P =0.01). Subgroup analysis demonstrated that these benefits were more pronounced in patients with interstitial, rather than severe, pancreatitis at admission.

Conclusions

In patients with AP, early fluid resuscitation was associated with reduced incidence of SIRS and organ failure at 72 hours. These effects were most pronounced in patients admitted with interstitial, rather than severe, disease.

source: clinical gastroenterology and hepatology

Usefulness of extracorporeal membrane oxygenation for early cardiac allograft dysfunction


Owing to persisting donor shortages, the use of “marginal hearts” has increased. Because patients who receive a marginal heart may require hemodynamic support in the early post-operative period, extracorporeal membrane oxygenation (ECMO) may be used until recovery of acute graft dysfunction.

Methods

A retrospective file review of 124 primary adult heart transplant patients from 2003 to 2008 was conducted. We compared 17 patients who received post-transplant ECMO support with 107 transplant recipients without ECMO. Donor and recipient pre-transplant, intra-operative, and post-transplant clinical variables to 6 months after transplant were compared.

Results

Pre-operative demographics of the 2 groups were similar. Eight (47%) of the patients in the ECMO group received marginal donor hearts, compared with 1 (1%) in the non-ECMO group (p < 0.05). There were 3 early deaths in the ECMO group (2 of whom had received optimal donor hearts), resulting in lower Day 30 ECMO survival of 82.4% vs 100% for non-ECMO, respectively (p < 0.001), and 6-month survival of 82.4% vs 95.6%, respectively (p < 0.02). Most of the difference in survival was in patients who required salvage ECMO despite normal pre-transplant donor LV function. The rate of early dialysis was higher in the ECMO group, at 18% vs 6% at Day 3, but there was no difference between the 2 groups by Day 7. Pre-discharge ventricular function was normal in all discharged ECMO patients and all but 1 non-ECMO patient. ECMO patients had a longer intensive care unit stay (8.9 ± 3.4 vs 4.8 ± 5.4 days, p < 0.005), but there was a slightly shorter ward stay, resulting in a similar overall hospitalization length of stay (22.9 ± 8.3 vs 25.1 ± 25.2 days).

Conclusions

ECMO allows for salvage of acute graft dysfunction and may allow use of marginal donor hearts. Survival rates are lower in patients who require ECMO compared with optimal donors, but early cardiac dysfunction normalizes in most without long-term cardiac or renal sequelae. Despite longer ventilation times, overall hospitalization is not prolonged.

source: the journal of heart and lung transplant

Decreased efferocytosis and mannose binding lectin in the airway in bronchiolitis obliterans syndrome


Mannose binding lectin (MBL) is a key mediator of both innate immunity and efferocytosis (phagocytosis of apoptotic cells) in the airway. Defective efferocytosis results in a net increase in apoptotic material that can undergo secondary necrosis, leading to tissue damage and chronic inflammation. We have shown reduced MBL and efferocytosis in other chronic inflammatory lung diseases; we therefore hypothesized that reduced MBL and efferocytosis in the airways may be a determinant of bronchiolitis obliterans syndrome (BOS) after lung transplantation.

Methods

We investigated MBL (enzyme-linked immunosorbent assay [ELISA]), MBL-mediated complement deposition (UC4, ELISA), and efferocytosis of apoptotic bronchial epithelial cells (flow cytometry) in bronchoalveolar lavage (BAL) and peripheral blood from 75 lung transplant recipients, comprising 16 with stable graft function, 34 stable with proven infection, 25 with BOS, and 14 healthy controls.

Results

In plasma, MBL levels were highly variable (0–17.538 μg/ml), but increased in infected patients vs control (p = 0.09) or stable groups (p = 0.003). There was a similar increase in UC4 in infected patients and a significant correlation between MBL and UC4. There was no correlation between MBL and time after transplant. In BAL, MBL levels were less variable (0–73.3 ng/ml) and significantly reduced in patients with BOS vs controls and stable groups. Efferocytosis was significantly reduced in the BOS group vs control and stable groups (mean [SEM] control, 20% [1.3%]; stable, 20.5% [2.5%]; infected, 17.3% [2.8%]; BOS, 11.3% [1.5%], p = 0.04).

Conclusions

Low levels of MBL in the airway may play a role in reduced efferocytosis, subsequent tissue damage, and BOS after lung transplantation.

source: journal of heart and lung transplant