To assess progesterone treatment of intractable seizures in women with partial epilepsy.
This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles.
There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3.
There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures.
Classification of evidence:
This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.
Objective: To assess the clinical outcomes of triamcinolone acetonide spray for steroid-responsive dermatoses using investigator and patient global assessment scores and evaluate patient satisfaction. Design: This open-label, single-center, noncomparator study enrolled 42 patients (aged 18 years or older) with dermatoses. Patients were instructed to use triamcinolone acetonide spray 1 to 4 times daily, depending on investigator instructions, for up to 28 days. Measurements: Investigators and patients scored the overall severity of dermatoses based on a global assessment scale. Investigators also rated signs and symptoms of dermatoses and evaluated clinical outcomes based on an improvement assessment scale. Patient satisfaction with treatment was assessed at the end of treatment or at Day 28 using a questionnaire. Patients were evaluated on Days 7, 14, 21, and 28. Complete clearing of dermatoses warranted early discontinuation from the study. Results: Triamcinolone acetonide spray effectively improved dermatoses scores, clinical outcomes, and signs and symptoms of dermatoses. More than 80 percent of patients entered the study with moderate or severe dermatoses. Within 14 days, none had severe dermatoses, and by 28 days, 64 percent of patients were completely clear or almost clear. From the patient perspective, 51.3 percent experienced improvement in only three days, and 84.6 percent experienced improvement in seven days. An overwhelming number of patients (95%) preferred triamcinolone acetonide spray over creams and ointments, and more than half experienced a cooling effect upon contact with the spray. Conclusion: Triamcinolone acetonide spray is an effective topical corticosteroid that should be considered for patients with steroid-responsive dermatoses of all ranges of severity.
An intravesical instillation of 100 ml 1 or 2 mmol/l capsaicin has been used to treat detrusor hyperreflexia giving rise to intractable urinary incontinence in 12 patients with spinal cord disease and two other patients with detrusor overactivity of non-spinal origin. Nine patients, all of whom had spinal cord disease, showed some improvement in bladder function. The benefit was only shortlived and partial in four, but the remaining five achieved complete continence while performing intermittent self catheterisation. Urodynamic studies in these nine patients showed an increase in mean (SD) bladder capacity from 106 (57) to 302 (212) ml and a fall in the maximum detrusor pressure from 54 (20) to 36 (10) cm of water. There were no short term ill effects from the instillation and the improvement in bladder function lasted for between three weeks to six months, when in some patients it was repeated. The improvement in bladder behaviour shown in this study can be interpreted as showing that capsaicin sensitive afferents play an important part in the pathogenesis of detrusor hyperreflexia in spinal humans. Intravesical capsaicin seems a promising means of treating intractable detrusor hyperreflexia and studies with this substance may shed new light on other disorders of detrusor activity that cause incontinence.
Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an 18F-radiotracer designed to image FAAH using positron emission tomography (PET) is described.
Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [18F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17–22% (from [18F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82 nM after a preincubation of 60 min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [18F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [18F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts.
We infer from these results that [18F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.
PET; FAAH; radiosynthesis; fluorine-18; rat; endocannabinoid; anandamide
The objective of this study was to evaluate peri-operative and survival outcomes of ovarian cancer patients undergoing percutaneous upper gastrointestinal decompression for malignant bowel obstruction (MBO).
Retrospective chart review was used to identify patients with ovarian, peritoneal, or fallopian tube cancer who underwent palliative decompressive treatment for MBO from 1/2002–12/2010. Kaplan-Meier methods were used to estimate the median survival (MS) and multivariate analysis used to determine if any variables were associated with the hazard of death.
Fifty-three patients met inclusion criteria. Median length of diagnosis prior to intervention was 21 months. Fifteen (28.3%) patients experienced complications and 9 required revision. Forty-nine (92.5%) experienced relief of symptoms after placement, and 91% tolerated some form of oral intake. Following placement, 19 (36%) patients received additional chemotherapy and 21(41%) patients received total parental nutrition (TPN). Thirty-five patients were discharged home/outpatient facility, 16 to hospice care, and 2 died prior to discharge. MS for all patients was 46 days. Patients who received chemotherapy had a MS of 169 days compared to 33 days (p<0.001). We failed to find an association between survival and TPN or performance status.
Malignant bowel obstruction is a common complication of ovarian cancer. Management is palliative; risks and benefits of any therapy must be considered. Percutaneous decompressive therapy provides relief from associated symptoms, and allows patients to be discharged home. Median survival in this group is limited, and decisions regarding aggressive therapy should be individualized.
To analyze quality of life (QOL) in a randomized, placebo-controlled phase III trial concluding that the addition of concurrent and maintenance bevacizumab (Arm 3) to carboplatin and paclitaxel prolongs progression-free survival in front-line treatment of advanced ovarian cancer compared to chemotherapy alone (Arm 1) or chemotherapy with bevacizumab in cycles 2–6 only (Arm 2).
Patients and Methods
The Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary (FACT-O TOI) was used to assess QOL before cycles 1, 4, 7, 13, and 21; and 6 months after completing study therapy. Differences in QOL scores were assessed using a linear mixed model, adjusting for baseline score, and age. The significance level was set at 0.0167 to account for multiple comparisons.
1693 patients were queried. Arm 2 (p<0.001) and Arm 3 (p<0.001) reported lower QOL scores than those in Arm 1. The treatment differences were observed mainly at cycle 4, when the patients receiving bevacizumab (Arm 2 and Arm 3) reported 2.72 points (98.3% CI: 0.88 ~ 4.57; effect size=0.18) and 2.96 points (98.3% CI: 1.13~4.78; effect size=0.20) lower QOL respectively, than those in Arm 1. The difference in QOL scores between Arm 1 and Arm 3 remained statistically significant up to cycle 7. The percentage of patients who reported abdominal discomfort dropped over time, without significant differences among study arms.
The small QOL difference observed during chemotherapy did not persist during maintenance bevacizumab.
X-ray crystallography has provided tremendous insight into the different structural states of membrane proteins and, in particular, of ion channels. However, the molecular forces that determine the thermodynamic stability of a particular state are poorly understood. Here we analyze the different X-ray structures of an inwardly rectifying potassium channel (Kir1.1) in relation to functional data we obtained for over 190 mutants in Kir1.1. This mutagenic perturbation analysis uncovered an extensive, state-dependent network of physically interacting residues that stabilizes the pre-open and open states of the channel, but fragments upon channel closure. We demonstrate that this gating network is an important structural determinant of the thermodynamic stability of these different gating states and determines the impact of individual mutations on channel function. These results have important implications for our understanding of not only K+ channel gating but also the more general nature of conformational transitions that occur in other allosteric proteins.
•Functional validation of different crystallographic states of Kir channels•Presence of a state-dependent gating network revealed by large-scale mutagenesis•Biased effect of mutations on Kir channel gating due to open-state destabilization•Long-range allosteric coupling mediated by a physically connected residue network
The molecular forces that determine the thermodynamic stability of ion channel gating states are poorly understood. Here, Bollepalli et al. show that an extensive state-dependent network of physically interacting residues determines the thermodynamic stability of the different gating states in Kir channels.
Dopamine mediates the rewarding effects of food that can lead to overeating and obesity, which then trigger metabolic neuroadaptations that further perpetuate excessive food consumption. We tested the hypothesis that the dopamine response to calorie intake (independent of palatability) in striatal brain regions is attenuated with increases in weight.
We used positron emission tomography with [11C]raclopride to measure dopamine changes triggered by calorie intake by contrasting the effects of an artificial sweetener (sucralose) devoid of calories to that of glucose to assess their association with body mass index (BMI) in nineteen healthy participants (BMI range 21–35).
Neither the measured blood glucose concentrations prior to the sucralose and the glucose challenge days, nor the glucose concentrations following the glucose challenge vary as a function of BMI. In contrast the dopamine changes in ventral striatum (assessed as changes in non-displaceable binding potential of [11C]raclopride) triggered by calorie intake (contrast glucose – sucralose) were significantly correlated with BMI (r = 0.68) indicating opposite responses in lean than in obese individuals. Specifically whereas in normal weight individuals (BMI <25) consumption of calories was associated with increases in dopamine in the ventral striatum in obese individuals it was associated with decreases in dopamine.
These findings show reduced dopamine release in ventral striatum with calorie consumption in obese subjects, which might contribute to their excessive food intake to compensate for the deficit between the expected and the actual response to food consumption.
Existing descriptions of bi-directional ammonia (NH3) land–atmosphere exchange incorporate temperature and moisture controls, and are beginning to be used in regional chemical transport models. However, such models have typically applied simpler emission factors to upscale the main NH3 emission terms. While this approach has successfully simulated the main spatial patterns on local to global scales, it fails to address the environment- and climate-dependence of emissions. To handle these issues, we outline the basis for a new modelling paradigm where both NH3 emissions and deposition are calculated online according to diurnal, seasonal and spatial differences in meteorology. We show how measurements reveal a strong, but complex pattern of climatic dependence, which is increasingly being characterized using ground-based NH3 monitoring and satellite observations, while advances in process-based modelling are illustrated for agricultural and natural sources, including a global application for seabird colonies. A future architecture for NH3 emission–deposition modelling is proposed that integrates the spatio-temporal interactions, and provides the necessary foundation to assess the consequences of climate change. Based on available measurements, a first empirical estimate suggests that 5°C warming would increase emissions by 42 per cent (28–67%). Together with increased anthropogenic activity, global NH3 emissions may increase from 65 (45–85) Tg N in 2008 to reach 132 (89–179) Tg by 2100.
ammonia; emission; deposition; atmospheric modelling
Global nitrogen fixation contributes 413 Tg of reactive nitrogen (Nr) to terrestrial and marine ecosystems annually of which anthropogenic activities are responsible for half, 210 Tg N. The majority of the transformations of anthropogenic Nr are on land (240 Tg N yr−1) within soils and vegetation where reduced Nr contributes most of the input through the use of fertilizer nitrogen in agriculture. Leakages from the use of fertilizer Nr contribute to nitrate (NO3−) in drainage waters from agricultural land and emissions of trace Nr compounds to the atmosphere. Emissions, mainly of ammonia (NH3) from land together with combustion related emissions of nitrogen oxides (NOx), contribute 100 Tg N yr−1 to the atmosphere, which are transported between countries and processed within the atmosphere, generating secondary pollutants, including ozone and other photochemical oxidants and aerosols, especially ammonium nitrate (NH4NO3) and ammonium sulfate (NH4)2SO4. Leaching and riverine transport of NO3 contribute 40–70 Tg N yr−1 to coastal waters and the open ocean, which together with the 30 Tg input to oceans from atmospheric deposition combine with marine biological nitrogen fixation (140 Tg N yr−1) to double the ocean processing of Nr. Some of the marine Nr is buried in sediments, the remainder being denitrified back to the atmosphere as N2 or N2O. The marine processing is of a similar magnitude to that in terrestrial soils and vegetation, but has a larger fraction of natural origin. The lifetime of Nr in the atmosphere, with the exception of N2O, is only a few weeks, while in terrestrial ecosystems, with the exception of peatlands (where it can be 102–103 years), the lifetime is a few decades. In the ocean, the lifetime of Nr is less well known but seems to be longer than in terrestrial ecosystems and may represent an important long-term source of N2O that will respond very slowly to control measures on the sources of Nr from which it is produced.
nitrogen fixation; denitrification; emissions; deposition; global budgets
We hypothesized that rapamycin, through induction of autophagy and promotion of an antiapoptotic phenotype, would permit lentiviral (LV)-based transgene delivery to human T-Rapa cells, which are being tested in phase II clinical trials in the setting of allogeneic hematopoietic cell transplantation. Manufactured T-Rapa cells were exposed to supernatant enriched for a LV vector encoding a fusion protein consisting of truncated CD19 (for cell surface marking) and DTYMK/TMPKΔ, which provides “cell-fate control” due to its ability to phosphorylate (activate) AZT prodrug. LV-transduction in rapamycin-treated T-Rapa cells: (1) resulted in mitochondrial autophagy and a resultant antiapoptotic phenotype, which was reversed by the autophagy inhibitor 3-MA; (2) yielded changes in MAP1LC3B and SQSTM1 expression, which were reversed by 3-MA; and (3) increased T-Rapa cell expression of the CD19-DTYMKΔ fusion protein, despite their reduced proliferative status. Importantly, although the transgene-expressing T-Rapa cells expressed an antiapoptotic phenotype, they were highly susceptible to cell death via AZT exposure both in vitro and in vivo (in a human-into-mouse xenogeneic transplantation model). Therefore, rapamycin induction of T cell autophagy can be used for gene therapy applications, including the CD19-DTYMKΔ cell-fate control axis to improve the safety of T cell immuno-gene therapy.
autophagy; DTYMK/TMPK; rapamycin; cell-fate control; suicide gene
The femoral canal is frequently measured preoperatively in cases where an intramedullary device is planned for operative fixation of a fracture. To our knowledge, a formal assessment of validity and reliability of preoperative canal measurements has not been previously performed.
This study aims to determine the validity and reliability of preoperative canal measurements of the femur made on plain radiographs using comparison with curved planar reformation software as the gold standard.
Fifty-six patients were identified based on availability of anterior–posterior (AP) and lateral radiographs of the femur and computed tomography (CT) of the lower extremity. Four “raters” measured the canal diameter at its narrowest point and the distance from the lesser trochanter to the isthmus on the AP, lateral radiograph, and CT. The width of the femoral nail on AP radiographs was also measured to determine magnification error. Curved planar reformation (CPR) was used to provide the most accurate calculation of the canal diameter.
Compared to the isthmus position determined by CPR, the measurement was most accurate on an AP and the diameter of the canal was most accurate using coronal CT, followed by AP radiographs. The measured canal diameter of the fractured femur on APs was compared to that of the used implant and varied by 1 mm.
The AP plain radiographic measurement was found to be more accurate for determination of the canal diameter compared to the lateral radiograph. These findings confirm the utility of preoperative canal measurements in predicting the feasibility of placing a specific size intramedullary implant.
Electronic supplementary material
The online version of this article (doi:10.1007/s11420-013-9334-z) contains supplementary material, which is available to authorized users.
femur; canal; measurements; radiographic; preoperative
Cryopreservation is often used to store cellular therapies, but little is known about how well CD3+ or CD34+ cells tolerate this process.
Viable CD34+ cell recoveries were analyzed from related and unrelated donor G-CSF-mobilized peripheral blood stem cell (PBSC) products and viable CD3+ cell recoveries from G-CSF-mobilized and non-mobilized apheresis products from related and unrelated donors. All products were cryopreserved with 5% dimethyl sulfoxide and 6% pentastarch using a controlled-rate freezer and were stored in liquid nitrogen. Related donor products were cryopreserved immediately after collection and unrelated donor products greater than 12 hours post-collection.
The post-thaw recovery of CD34+ cells from related donor PBSCs was high (n=86; 97.5±23.1%) and there was no difference in post-thaw CD34+ cell recovery from unrelated donor PBSCs (n=14; 98.8±37.2%; p=0.863). In related donor lymphocyte products the post-thaw CD3+ cell recovery (n=48, 90.7±21.4%) was greater than that of unrelated donor products (n=14, 66.6±35.8%, p=0.00251). All unrelated donor lymphocyte products were from G-CSF mobilized products, while most related donor lymphocyte products were from non-mobilized products. A comparison of the CD3+ cell recovery from related donor G-CSF-mobilized products (n=19, 85.0±29.2%) with that of unrelated donor products found no significant difference (p=0.137).
The post-thaw recovery of CD34+ cells was high in both related and unrelated donor products, but the recovery of CD3+ cells in unrelated donor G-CSF-mobilized products was lower. G-CSF-mobilized unrelated donor products may contain less CD3+ cells than non-G-CSF exposed products upon thaw and, when indicated, cell doses should be monitored.
T cells; cryopreservation; donor lymphocyte infusions; hematopoietic stem cell transplantation
Sterilization of pathogens with γ-radiation is an attractive approach for development of inactivated whole-organism vaccines. However, the radiation doses required to ensure sterility also destroy immunogenic epitopes needed to mount a protective immune response. We report that genome damage and killing can be uncoupled from epitope damage using a reconstituted manganous peptide complex of Deinococcus radiodurans, a radiation-resistant bacterium. The Mn2+ complex preserved antigenic structures in aqueous preparations of bacteriophage lambda, Venezuelan equine encephalitis virus (VEEV), and Staphylococcus aureus during supralethal irradiation (25-40 kGy). An irradiated vaccine elicited both antibody and CD4 T cell IL-17 (Th17) responses, and induced B cell- and T cell-dependent protection against methicillin-resistant S. aureus (MRSA) in mice. We demonstrate that structural integrity of viruses and bacteria can be preserved at radiation doses far above those which abolish infectivity. This approach could expedite vaccine production for emerging and established pathogens for which no protective vaccines exist.
Hybrid sterility is one of the earliest postzygotic isolating mechanisms to evolve between two recently diverged species. Here we identify causes underlying hybrid infertility of two recently diverged fission yeast species Schizosaccharomyces pombe and S. kambucha, which mate to form viable hybrid diploids that efficiently complete meiosis, but generate few viable gametes. We find that chromosomal rearrangements and related recombination defects are major but not sole causes of hybrid infertility. At least three distinct meiotic drive alleles, one on each S. kambucha chromosome, independently contribute to hybrid infertility by causing nonrandom spore death. Two of these driving loci are linked by a chromosomal translocation and thus constitute a novel type of paired meiotic drive complex. Our study reveals how quickly multiple barriers to fertility can arise. In addition, it provides further support for models in which genetic conflicts, such as those caused by meiotic drive alleles, can drive speciation.
It is widely thought that all of the billions of species on Earth are descended from a common ancestor. New species are created via a process called speciation, and nature employs various ‘barriers’ to keep closely related species distinct from one another. One of these barriers is called hybrid sterility. Horses and donkeys, for example, can mate to produce hybrids called mules, but mules cannot produce offspring of their own because they are infertile.
Hybrid sterility can occur for a number of reasons. Mules are infertile because they inherit 32 chromosomes from their horse parent, but only 31 chromosomes from their donkey parent—and so have an odd chromosome that they cannot pair-off when they make sperm or egg cells. However, even if a hybrid inherits the same number of chromosomes from each parent, if the chromosomes from the two parents have different structures, the hybrid may still be infertile.
Zanders et al. have now looked at two species of fission yeast—S. pombe and S. kambucha—that share 99.5% of their DNA sequence. Although hybrids of these two species inherit three chromosomes from each parent, the majority of spores (the yeast equivalent of sperm) that these hybrids produce fail to develop into new yeast cells. Zanders et al. identified two causes of this infertility: one of these was chromosomal rearrangement; the other was due to three different sites in the DNA of S. kambucha that interfere with the development of the spores that inherit S. pombe chromosomes.
Since these two yeast species are so closely related, the findings of Zanders et al. reveal how quickly multiple barriers to fertility can arise. In addition, these findings provide further support for models in which conflicts between different genes in genomes can drive the process of speciation.
speciation; meiotic drive; chromosomal rearrangements; recombination; S. pombe
Overweight or obesity is prevalent among college students and many gain weight during this time. Traditional face-to-face weight loss interventions have not worked well in this population. Facebook is an attractive tool for delivering weight loss interventions for college students because of its popularity, potential to deliver strategies found in successful weight loss interventions, and ability to support ongoing adaptation of intervention content.
The objective of this study was to describe participant exposure to a Facebook page designed to deliver content to overweight/obese college students in a weight loss randomized controlled trial (N=404) and examine participant engagement with behavior change campaigns for weight loss delivered via Facebook.
The basis of the intervention campaign model were 5 self-regulatory techniques: intention formation, action planning, feedback, goal review, and self-monitoring. Participants were encouraged to engage their existing social network to meet their weight loss goals. A health coach moderated the page and modified content based on usage patterns and user feedback. Quantitative analyses were conducted at the Facebook post- and participant-level of analysis. Participant engagement was quantified by Facebook post type (eg, status update) and interaction (eg, like) and stratified by weight loss campaign (sequenced vs nonsequenced). A subset of participants were interviewed to evaluate the presence of passive online engagement or “lurking.”
The health coach posted 1816 unique messages to the study’s Facebook page over 21 months, averaging 3.45 posts per day (SD 1.96, range 1-13). In all, 72.96% (1325/1816) of the posts were interacted with at least once (eg, liked). Of these, approximately 24.75% (328/1325) had 1-2 interactions, 23.39% (310/1325) had 3-5 interactions, 25.13% (333/1325) had 6-8 interactions, and 41 posts had 20 or more interactions (3.09%, 41/1325). There was significant variability among quantifiable (ie, visible) engagement. Of 199 participants in the final intervention sample, 32 (16.1%) were highly active users and 62 (31.2%) never visibly engaged with the intervention on Facebook. Polls were the most popular type of post followed by photos, with 97.5% (79/81) and 80.3% (386/481) interacted with at least once. Participants visibly engaged less with posts over time (partial r=–.33; P<.001). Approximately 40% of the participants interviewed (12/29, 41%) reported passively engaging with the Facebook posts by reading but not visibly interacting with them.
Facebook can be used to remotely deliver weight loss intervention content to college students with the help of a health coach who can iteratively tailor content and interact with participants. However, visible engagement with the study’s Facebook page was highly variable and declined over time. Whether the level of observed engagement is meaningful in terms of influencing changes in weight behaviors and outcomes will be evaluated at the completion of the overall study.
overweight; obesity; students; social networking; behavior; social behavior
While it is known that positive surgical margins increase the risk of cervical cancer recurrence, little is known about the effect of close surgical margins (CSM). Therefore, we set out to determine the impact of margin status on recurrence and survival in patients with early-stage cervical cancer.
A retrospective review was conducted of patients undergoing radical hysterectomy from 2000 to 2010 with Stage IA2-IIA cervical cancer. CSM were defined as ≤5 mm; association with other clinicopathologic factors as well as recurrence and survival was evaluated.
Of the 119 patients, 75 (63%) with CSM had a recurrence rate of 24% compared to 9% without CSM. Though not independently associated with recurrence, CSM were significantly associated with positive lymph nodes (44% vs. 18%), positive parametria (33.3% vs. 2.3%), larger tumors (3.5 vs. 2.5 cm), greater depth of stromal invasion (DOI) (84% vs. 33%), and lymphovascular space invasion (LVSI) (61.3% vs. 34.1%). We failed to find an association between adjuvant therapy and recurrence in those with CSM. Exploratory analysis revealed that a surgical margin of ≤2 mm was significantly associated with an increased risk of overall recurrence (36% vs. 9%, p=0.009) as well as loco-regional recurrence (22% vs. 4%, p=0.0034).
Surgical margins of ≤5 mm on radical hysterectomy specimens are often associated with other high or intermediate risk factors for recurrence. While not a proven independent risk factor, the distance to surgical margin may warrant further investigation as an intermediate risk factor along with tumor size, DOI and LVSI.
Cervical cancer; Surgical margins; Recurrence risk; Radical hysterectomy
The role of vancomycin has been challenged by the availability of alternative antibiotics, increased reports of vancomycin failure, and uncertainties in dosing. This manuscript considers the optimal treatment of methicillin-resistant Staphylococcus aureus infections.
For more than 4 decades, vancomycin has been the antibiotic of choice for methicillin-resistant Staphylococcus aureus (MRSA) infections. Recently, infections due to isolates with high but susceptible vancomycin minimum inhibitory concentrations have been associated with additional treatment failures and patient mortality. These poorer outcomes may in part be explained by the inability of attaining appropriate vancomycin levels in these patients. However, assumptions that these poor outcomes are solely due to failure to achieve optimal serum levels of vancomycin are premature. The availability of effective alternatives further erodes the position of vancomycin as first-line therapy. The emergence of resistance and cost considerations, however, favor a more measured approach when using alternative antimicrobials. Collectively, the current available data suggest that the optimal therapy for MRSA infections remains unclear. In the absence of further data, the Infectious Diseases Society of America guidelines remain relevant and inform clinicians of best practice for treating patients with MRSA infections.
Staphylococcus aureus; MRSA, hVISA, VISA; vancomycin; AUC/MIC targets; minimum inhibitory concentration (MIC)
The microenvironment of human follicular lymphoma (FL), an incurable B-cell non-Hodgkin lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular helper T cells (TFH) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17, but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17 but not CCL22 in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4–producing T cells rather than IFN-γ–producing T cells, and antibodies to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4–producing T cells, which in turn may stimulate more chemokine production in a feed-forward cycle. Thus, TFH appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk between TFH, tumor cells, and Tregs in FL and offer potential targets for development of therapeutic strategies to overcome immune evasion.
A complex interplay between genetic and environmental factors is thought to be involved in the etiology of Parkinson's disease (PD). A recent genome-wide association and interaction study (GWAIS) identified GRIN2A, which encodes an NMDA-glutamate-receptor subunit involved in brain's excitatory neurotransmission, as a PD genetic modifier in inverse association with caffeine intake. Here in, we attempted to replicate the reported association of a single nucleotide polymorphism, GRIN2A_rs4998386, and its interaction with caffeine intake with PD in patient-control study in an ethnically homogenous population in southeastern Sweden, as consistent and independent genetic association studies are the gold standard for the validation of genome-wide association studies. All the subjects (193 sporadic PD patients and 377 controls) were genotyped, and the caffeine intake data was obtained by questionnaire. We observed an association between rs4998386 and PD with odds ratio (OR) of 0.61, 95% confidence intervals (CI) of 0.39–0.96, p = 0.03, under a model excluding rare TT allele. There was also a strong significance in joint effects of gene and caffeine on PD risk (TC heavy caffeine vs. CC light caffeine: OR = 0.38, 95%CI = [0.20–0.70], p = 0.002) and gene-caffeine interaction (OR = 0.998, 95%CI = [0.991–0.999], p<0.001). Overall, our results are in support of the findings of the GWAIS and provided additional evidence indicating PD protective effects of coffee drinking/caffeine intake as well as the interaction with glutamate receptor genotypes.
Dementia affects over 4 million people in the US and is frequently unrecognized and underdiagnosed in primary care. Routine dementia screening in primary care is not recommended by the US Preventive Services Task Force due to lack of empirical data on the benefits and harms of screening. This trial seeks to fill this gap and contribute information about the benefits, harms, and costs of routine screening for dementia in primary care.
Single-blinded, parallel, randomized controlled clinical trial with 1:1 allocation. A total of 4,000 individuals aged ≥65 years without a diagnosis of dementia, cognitive impairment, or serious mental illness receiving care at primary care practices within two cities in Indiana. Subjects will be randomized to either i) screening for dementia using the Memory Impairment Screen Telephone version or ii) no screening for dementia. Subjects who screen positive for dementia will be referred to the local Aging Brain Care program that delivers an evidence-based collaborative care model for dementia and depression. Research assistants will administer the 15-item Health Utility Index, Patient Health Questionnaire, Generalized Anxiety Disorder Scale, and Medical Outcomes Study at baseline, 1, 6, and 12 months. Information about advanced care planning will be collected at baseline and 12 months. All enrollees’ medical records will be reviewed to collect data on health care utilization and costs.
We have two primary hypotheses; first, in comparison to non-screened subjects, those who are screened and referred to a dementia collaborative care program will have a higher health-related quality of life as measured by the Health Utility Index at 12 months post-screening. Second, in comparison to non-screened subjects, those who are screened and referred to a dementia collaborative care program will not have higher depression or anxiety at one month post-screening as measured by the Patient Health Questionnaire and Generalized Anxiety Disorder Scale scales. Our secondary hypothesis is that screened subjects will have an Incremental Cost-Effectiveness Ratio below the maximum acceptable threshold of $60,000 per quality adjusted life year saved at 12 months.
Ongoing; registered on September 19, 2012. ClinicalTrials.gov Identifier: 2012 NCT01699503.
Alzheimer’s disease; Dementia screening; Dementia; Primary care
Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus –infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
Staphylococcus aureus causes life-threatening infections in humans. Host genetic determinants influence the outcome of S. aureus infection, yet are poorly understood. Susceptible A/J and resistant C57BL/6J mice provide a unique platform to study the genetic difference responsible for variable host response to S. aureus infection. We showed that chromosome 11 in A/J was responsible for susceptibility to S. aureus. We further identified a QTL locus on Chromosome 11 significantly associated with S. aureus susceptibility. Five genes in the QTL (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) were significantly differently expressed in a) susceptible vs. resistant mice, and b) humans with S. aureus blood stream infection vs. healthy human subjects. Three genes (Dusp3, Psme3, and Dcaf7) were down-regulated in susceptible A/J mice. siRNA-mediated knockdown of Dusp3 and Psme3 in bone marrow derived macrophage (BMDMs) significantly enhanced cytokine responses through NF-κB activity upon S. aureus challenge in a pattern that was also present in S. aureus-challenged BMDMs from susceptible CSS11 (chr. 11 from A/J but otherwise C57BL/6J) mice, but not resistant C57BL/6J mice. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
A novel virtual environment (VE) system was developed and used as an adjunct to cognitive behavior therapy (CBT) with six socially anxious patients recovering from psychosis. The novel aspect of the VE system is that it uses video capture so the patients can see a life-size projection of themselves interacting with a specially scripted and digitally edited filmed environment played in real time on a screen in front of them. Within-session process outcomes (subjective units of distress and belief ratings on individual behavioral experiments), as well as patient feedback, generated the hypothesis that this type of virtual environment can potentially add value to CBT by helping patients understand the role of avoidance and safety behaviors in the maintenance of social anxiety and paranoia and by boosting their confidence to carry out “real-life” behavioral experiments.
The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus faecalis, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.
The purpose of this study was to investigate relationships between environmental factors of odor, noise, light, and color and perceived stress, job satisfaction, and turnover intention.
The physical work environment may positively or negatively influence nurses’ stress, and stress may negatively impact their job satisfaction and intention to change jobs.
The research questions were answered using a descriptive, correlational design. The sample (n = 116) consisted of medical-surgical nurses working in acute-care settings. A 36-item questionnaire addressed odor, noise, light, color, perceived stress, job satisfaction, and turnover intention.
Significant relationships were found between noise and perceived stress, perceived stress and job satisfaction, job satisfaction and turnover intention, and perceived stress and turnover intention.
Nurses tend to overlook their physical environment and “do their job.” Common environmental stressors in the work environment can be stressful to staff and influence job satisfaction and, ultimately, intention to change jobs. Mitigating or eliminating these environmental factors has the potential to improve staff satisfaction and retention. Stress influences nursing job satisfaction and, ultimately, intention to change jobs.