Contextual and stress process factors associated with head and neck cancer caregivers' physical and psychological well-being.

Head and neck cancer (HNC) caregivers are especially vulnerable to poor outcomes because the HNC patients are at high risk for physical and functional impairments. This study examines contextual and stress process variables potentially associated with HNC caregivers' physical and psychological well-being. Patient-caregiver variables included socio-demographics, primary stressors (caregiving, patient clinical characteristics, HNC-related symptoms/dysfunction), secondary stressors (caregiver employment, childcare responsibilities and sleep duration <7 hr), appraisal, and response (physical activity). General linear models modeled caregiver well-being, along with depression and anxiety. A total of 33 patient-caregiver dyads were included. Most caregivers were female (81.8%) and patient spouses/partners (72.7%). Factors significantly associated with better caregiver physical well-being included caregiver older age, <2 comorbidities, ≥7 hr of sleep, ≥3 days/week physical activity, and patient swallowing and speech dysfunction. Factors significantly associated with better caregiver mental health functioning were less patient social dysfunction and less perceived caregiving burden. Short nighttime sleep, higher caregiver burden, and <3 days/week physical activity were also significantly related to caregivers' depression and anxiety. Results suggested caregiver behaviors and perceived burden, along with patient HNC concerns are linked with caregiver well-being. These behavioral, cognitive, and patient factors should be incorporated into caregiver screening tools or targeted with behavioral interventions to improve caregiver well-being.

Data processing techniques impact quantification of cortico-cortical evoked potentials.

BACKGROUND: Cortico-cortical evoked potentials (CCEPs) are a common tool for probing effective connectivity in intracranial human electrophysiology. As with all human electrophysiology data, CCEP data are highly susceptible to noise. To address noise, filters and re-referencing are often applied to CCEP data, but different processing strategies are used from study to study. NEW METHOD: We systematically compare how common average re-referencing and filtering CCEP data impacts quantification. RESULTS: We show that common average re-referencing and filters, particularly filters that cut out more frequencies, can significantly impact the quantification of CCEP magnitude and morphology. We identify that high cutoff high pass filters (> 0.5 Hz), low cutoff low pass filters (< 200 Hz), and common average re-referencing impact quantification across subjects. However, we also demonstrate that the presence of noise may impact CCEP quantification, and preprocessing is necessary to mitigate this. We show that filtering is more effective than re-referencing or averaging across trials for reducing most common types of noise. COMPARISON WITH EXISTING METHODS: These results suggest that existing CCEP processing methods must be applied with care to maximize noise reduction and minimize changes to the data. We do not test every available processing strategy; rather we demonstrate that processing can influence the results of CCEP studies. We emphasize the importance of reporting all processing methods, particularly re-referencing methods. CONCLUSIONS: We propose a general framework for choosing an appropriate processing pipeline for CCEP data, taking into consideration the noise levels of a specific dataset. We suggest that minimal gentle filtering is preferable.

Changes in Physical Activity, Functional Capacity, and Cardiac Function during Breast Cancer Therapy.

PURPOSE: Functional capacity and cardiac function can decline during breast cancer (BC) therapy. In non-cancer populations, higher physical activity (PA) is associated with better physical function and cardiac health. This study compared baseline PA, functional capacity, and cardiac function between women with and without BC and tested if greater PA participation was related to higher functional capacity and/or better heart function after three months of BC therapy. METHODS: Data was collected in 104 women without BC (82% Caucasian, baseline only) and 110 women with stage I-III BC (82% Caucasian) before therapy and after three months of treatment. Participants self-reported PA and underwent six-minute walk distance (6MWD) testing to measure functional capacity and cardiovascular magnetic resonance to assess left ventricular ejection fraction (LVEF). Analyses were adjusted for age, race, body mass index (BMI), and medication use. RESULTS: The BC group was older (56.2 ± 10.7 vs 52.1 ± 14.7 yrs, P=0.02) with a higher average BMI than the non-cancer group (30.3 ± 6.8 vs 27.7 ± 6.2 kg/m2, P<0.01). Pre-treatment, BC participants reported lower PA scores (27.9 ± 2.8 vs 34.9 ± 2.8, P=0.04) with similar 6MWD and LVEF relative to those without cancer (485 ± 11 vs 496 ± 11 m, P=0.4 and 59.7 ± 0.7 vs 58.9 ± 0.8%, P=0.37, respectively). After three months of BC therapy, declines were observed for PA scores (27.9 ± 2.8 vs 18.3 ± 2.5, P=0.02), 6MWD (485 ± 11 vs 428 ± 10 m, P<0.001), and LVEF (59.7 ± 0.7 vs 56.1 ± 0.7%, P<0.001). Compared to BC participants who reported no PA at three months (n=24, 22%), BC women who reported any PA (n=78, 86%) had higher 6MWD (442 ± 11 vs 389 ± 17 m, P=0.006) but similar LVEF (56.5 ± 0.9 vs 55.3 ± 1.5%, p=0.5). Women who reported any PA were less likely to exhibit an LVEF below normal (<50%) or decline in LVEF of 'â•10 points compared to inactive women (BMI-adjusted, OR [95% CI]: 0.27 [0.09, 0.85]). CONCLUSIONS: These preliminary results indicate that self-reported PA, LVEF and 6MWD decline in the first three months of BC treatment, but PA participation during BC treatment may mitigate declines in functional capacity and cardiac function. Further research is needed to identify barriers and facilitators of PA participation during BC therapy. FUNDING: Data collection was funded by the Wake Forest NCORP Research Base grant 2UG1CA189824 with support of the NCI Community Oncology Research Program (NCORP). Additional funding for this study was provided by grants from the National Institutes of Health, National Cancer Institute (1R01CA199167 and 5T32CA093423). CLINICAL TRIAL ID: NCT02791581 for WF97415 UPBEAT.

Signal recovery from stimulation artifacts in intracranial recordings with dictionary learning.

OBJECTIVE: Electrical stimulation of the human brain is commonly used for eliciting and inhibiting neural activity for clinical diagnostics, modifying abnormal neural circuit function for therapeutics, and interrogating cortical connectivity. However, recording electrical signals with concurrent stimulation results in dominant electrical artifacts that mask the neural signals of interest. Here we develop a method to reproducibly and robustly recover neural activity during concurrent stimulation. We concentrate on signal recovery across an array of electrodes without channel-wise fine-tuning of the algorithm. Our goal includes signal recovery with trains of stimulation pulses, since repeated, high-frequency pulses are often required to induce desired effects in both therapeutic and research domains. We have made all of our code and data publicly available. APPROACH: We developed an algorithm that automatically detects templates of artifacts across many channels of recording, creating a dictionary of learned templates using unsupervised clustering. The artifact template that best matches each individual artifact pulse is subtracted to recover the underlying activity. To assess the success of our method, we focus on whether it extracts physiologically interpretable signals from real recordings. MAIN RESULTS: We demonstrate our signal recovery approach on invasive electrophysiologic recordings from human subjects during stimulation. We show the recovery of meaningful neural signatures in both electrocorticographic (ECoG) arrays and deep brain stimulation (DBS) recordings. In addition, we compared cortical responses induced by the stimulation of primary somatosensory (S1) by natural peripheral touch, as well as motor cortex activity with and without concurrent S1 stimulation. SIGNIFICANCE: Our work will enable future advances in neural engineering with simultaneous stimulation and recording.

Total body irradiation and bone marrow transplantation for immunodeficiency disorders in young children.

Congenital immunodeficiency disorders such as severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome, and Chediak-Hegashi syndrome are almost uniformly fatal with most children dying before age one. Allogeneic bone marrow transplant (BMT) is the treatment of choice. Few of these children have matched donors. We use bone marrow processing techniques that allow us to utilize marrow from the parents. Children who lack HLA-identical donors are offered haploidentical, T-cell depleted parental BMTs. Some of these children do not have an immune deficiency severe enough to allow durable engraftment of processed mismatched bone marrow. Successful engraftment may necessitate the use of immunosuppression. Total body irradiation (TBI) is part of our intensive conditioning regimen for children with Wiskott-Aldrich and Chediak-Hegashi syndrome and most children with SCID who have undergone an unsuccessful prior mismatched, T-cell depleted BMT, or who have a high likelihood of donor marrow rejection based on pre-transplant immune function testing. TBI is considered extremely toxic therapy in infancy, with little information available on the acute and chronic effects. The 10 children presented in this report are among the youngest to have received TBI. Five patients were 2 to 6 months of age when they received TBI. The conditioning regimen for all patients was; antithymocyte globulin (25 mg/kg/day, x 3 days), cyclophosphamide (60 mg/kg/day, x 2 days), and TBI. 7.0 Gy TBI was given as a single dose AP-PA at approximately 15 cGy/min. Half value blocks shielded the brain, eyes and lungs. Six of 10 children were alive from 7 to 72 months post transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative image aspects of radiography and computed tomography.

Fundamental image descriptors, including contrast, noise, and resolution, were appropriate for computed tomography. These variables were then used to predict limiting system performance as applied to a model for detection of simple tumor-like signals in a homogeneous surround. The results predict that any intrinsic physical advantages of computed tomography may be restricted to a fairly narrow range of tumor diameters, from a few millimeters to a few centimeters, depending on the relative dose levels and scatter levels present in each imaging system. The results indicate high probable yield for radiographic image manipulation involving independent or, preferably, mutual manipulation of scatter levels, contrast enhancement, kVp techniques, and subtraction techniques, where applied to reduce the highly structured backgrounds that can increase the complexity of diagnosis.

Auditory brainstem responses of CBA/J mice with neonatal conductive hearing losses and treatment with GM1 ganglioside.

Exogenous administration of GM1 ganglioside to CBA/J mice with a neonatal conductive hearing loss ameliorates the atrophy of spiral ganglion neurons, ventral cochlear nucleus neurons, and ventral cochlear nucleus volume. The present investigation demonstrates the extent of a conductive loss caused by atresia and tests the hypothesis that GM1 ganglioside treatment will ameliorate the conductive hearing loss. Auditory brainstem responses were recorded from four groups of seven mice each: two groups received daily subcutaneous injections of saline (one group had normal hearing; the other had a conductive hearing loss); the other two groups received daily subcutaneous injections of GM1 ganglioside (one group had normal hearing; the other had a conductive hearing loss). In mice with a conductive loss, decreases in hearing sensitivity were greatest at high frequencies. The decreases were determined by comparing mean ABR thresholds of the conductive loss mice with those of normal hearing mice. The conductive hearing loss induced in the mice in this study was similar to that seen in humans with congenital aural atresias. GM1 ganglioside treatment had no significant effect on ABR wave I thresholds or latencies in either group.

Steatorrhea: a common manifestation in patients with HIV/AIDS.

Multiple infectious causes of diarrhea are known in patients with HIV/AIDS. Maldigestion and malabsorption have been reported in patients with HIV/AIDS and may be independent of infectious etiologies. Among ambulatory patients with HIV/AIDS, we examined the prevalence of fat malabsorption (steatorrhea). Sixty-one patients with unexplained diarrhea (defined as > 2 stools/d) and/or weight loss despite adequate caloric intake (and without clinical evidence of chronic pancreatitis) were evaluated in our outpatient Gastroenterology-Nutrition Clinic between March 1, 1993, and July 1994. Patients were instructed by a dietitian to follow a > or = 100 g/d fat diet for 24 h before submitting a stool sample for qualitative (or quantitative) fecal fat determination. Forty-five patients, 32 with ongoing diarrhea and 13 without diarrhea, submitted stool samples. Twenty-two of 45 patients (49%) had qualitative or quantitative steatorrhea, 16/32 with diarrhea (50%) and 6/13 patients without diarrhea (46%). Thirty of 32 patients with diarrhea had had extensive microbiologic and/or endoscopic evaluations. Only 9 patients had a detectable intestinal pathogen, 5 patients had cytomegalovirus (4 treated), 4 patients had cryptosporidia (3 treated), and 1 patient had microsporidia. Steatorrhea, as determined by abnormal qualitative fecal fat, is detectable in nearly 50% of patients with HIV/AIDS. Fat malabsorption appears to be a primary defect in these patients independent of detectable pathogens. Assessment of fat malabsorption should be considered in patients with unexplained weight loss or diarrhea before extensive evaluation for opportunistic infections.

Serum zinc and protein levels: lack of a correlation in hospitalized patients with AIDS.

Abnormally low serum zinc levels are associated with advanced states of malnutrition. Zinc levels are thought to parallel serum albumin, and repletion of zinc has reportedly led to increased albumin. We examined the correlation between zinc deficiency and serum proteins in hospitalized patients with AIDS. Over 500 inpatient consultations were performed by our Gastroenterology-Nutrition Consult Service from May 1992 to June 1994. We reviewed the medical records from all 228 AIDS patients in whom a serum zinc level was measured (by atomic absorption spectrophotometry). The correlation between serum zinc, albumin, prealbumin, and transferrin drawn on the same hospital day was analyzed by linear regression. The patients were stratified by the level of albumin, group A albumin < 2.0 g/dL, group B albumin 2.0-2.9 g/dL, and group C albumin > 3.0 g/dL, to allow comparison of the incidence of diarrhea and mean zinc level by chi square. Thirty-four patients had more than one serum zinc and albumin determination; the change over time was compared by linear regression. Serum zinc and albumin, prealbumin, and transferrin levels did not correlate strongly (r2 < or = 0.01). Furthermore, changes in zinc over time did not correlate with parallel changes in serum albumin (r2 < or = 0.01). In patients grouped by albumin, the proportion of patients with diarrhea did not differ significantly. The mean zinc levels were also not statistically significantly different. Serum zinc levels do not strongly correlate with serum proteins in hospitalized patients with AIDS. Serial measures of zinc over time also do not correlate strongly with changes in albumin. The incidence of diarrhea was not significantly different in patients with hypoalbuminemia or hypozincemia when compared with patients with near normal albumin or zinc. The relationship between zinc and serum proteins in AIDS patients is not linear. Zinc deficiency should be assessed in patients independent of the serum albumin.

Zinc levels and infections in hospitalized patients with AIDS.

Impaired cellular and humoral immunity and phagocytic function have been attributed to zinc deficiency. This study examined the association between low serum zinc concentration and opportunistic infections in hospitalized patients with the acquired immune deficiency syndrome (AIDS). We examined the records from all 505 inpatient consultations performed by our Nutrition Service from May 1992 through June 1994. The medical records from all 228 patients with AIDS with known serum zinc levels (determined by atomic absorption spectrophotometry) were reviewed. The length of HIV seropositivity, most recent CD4 count, presence of diarrhea, and degree of malnutrition were noted. The principal diagnosis accounting for the admission was grouped according to the type of infection: Pneumocystis carinii pneumonia (PCP), viral, fungal, bacterial, and other. Sixty-seven patients (29%) had abnormally low serum zinc levels (LSZ < 55 micrograms/dL), 49 patients (21%) had borderline low serum zinc (BSZ > or = 55 and < or = 65 microgram/dL), and 112 (49%) patients had normal serum zinc levels (NSZ > 65 micrograms/dL). There was no significant difference among the groups in CD4 count, length of HIV seropositivity, presence of diarrhea, or severity of malnutrition. Patients with zinc deficiency (LSZ) had a significantly higher incidence of bacterial infection than did patients with normal zinc. Patients with borderline zinc levels had an intermediate incidence of bacterial infection. There were no significant differences among the three groups in the incidence of PCP, viral, or fungal infections. Severe zinc deficiency was noted in 29% and borderline levels in an additional 21% of hospitalized AIDS patients. A low zinc level was not associated with the length of HIV seropositivity, CD4 count, or degree of malnutrition. Hypozincemia was associated with an increased incidence of concomitant systemic bacterial infections.

Evaluation of abdominal pain.

This article discusses the approach to evaluation of abdominal pain in the Emergency Department setting. The physiologic differences among visceral, somatic, and referred pain are reviewed, as is the clinical significance of anorexia, nausea, and vomiting. The correlation of historical facts, interrelationships of symptoms, and pain patterns with specific intra-abdominal processes is reviewed. Recommendations for high-yield expedient laboratory studies to facilitate diagnosis are provided. Proficiency in the recognition and interpretation of these clinical symptoms, physical signs, laboratory data, ECGs, and radiographic findings is important when evaluating acutely ill, uncooperative, or unresponsive patients.

Phantoms for specifications and quality assurance of MR imaging scanners.

The accompanying paper examines the subject of NMR phantoms. The paper reports on initial experience with existing phantoms and reviews proposals from various standards groups and professional organizations. Many image tests are illustrated by existing vendor phantoms. The paper concludes that many phantoms already meet or exceed most of the suggestions for tests of classical imaging parameters, which can be pursued by first order adaptations of CT phantoms. The paper does, however, point out the limitations of existing phantoms and raise the possibility of developing phantoms that more accurately reflect human shapes and cavities, and which present more realistic resistive losses, and T1 and T2 values.

Neurochemical changes within human early blind occipital cortex.

Early blindness results in occipital cortex neurons responding to a wide range of auditory and tactile stimuli. These changes in tuning properties are accompanied by an extensive reorganization of the occipital cortex that includes alterations in anatomical structure, neurochemical and metabolic pathways. Although it has been established in animal models that neurochemical pathways are heavily affected by early visual deprivation, the effects of blindness on these pathways in humans is still not well characterized. Here, using (1)H magnetic resonance spectroscopy in nine early blind and normally sighted subjects, we find that early blindness is associated with higher levels of creatine, choline and myo-Inositol and indications of lower levels of GABA within the occipital cortex. These results suggest that the cross-modal responses associated with early blindness may, at least in part, be driven by changes within occipital biochemical pathways.

Local functional connectivity as a pre-surgical tool for seizure focus identification in non-lesion, focal epilepsy.

Successful resection of cortical tissue engendering seizure activity is efficacious for the treatment of refractory, focal epilepsy. The pre-operative localization of the seizure focus is therefore critical to yielding positive, post-operative outcomes. In a small proportion of focal epilepsy patients presenting with normal MRI, identification of the seizure focus is significantly more challenging. We examined the capacity of resting state functional MRI (rsfMRI) to identify the seizure focus in a group of four non-lesion, focal (NLF) epilepsy individuals. We predicted that computing patterns of local functional connectivity in and around the epileptogenic zone combined with a specific reference to the corresponding region within the contralateral hemisphere would reliably predict the location of the seizure focus. We first averaged voxel-wise regional homogeneity (ReHo) across regions of interest (ROIs) from a standardized, probabilistic atlas for each NLF subject as well as 16 age- and gender-matched controls. To examine contralateral effects, we computed a ratio of the mean pair-wise correlations of all voxels within a ROI with the corresponding contralateral region (IntraRegional Connectivity - IRC). For each subject, ROIs were ranked (from lowest to highest) on ReHo, IRC, and the mean of the two values. At the group level, we observed a significant decrease in the rank for ROI harboring the seizure focus for the ReHo rankings as well as for the mean rank. At the individual level, the seizure focus ReHo rank was within bottom 10% lowest ranked ROIs for all four NLF epilepsy patients and three out of the four for the IRC rankings. However, when the two ranks were combined (averaging across ReHo and IRC ranks and scalars), the seizure focus ROI was either the lowest or second lowest ranked ROI for three out of the four epilepsy subjects. This suggests that rsfMRI may serve as an adjunct pre-surgical tool, facilitating the identification of the seizure focus in focal epilepsy.

Addiction toxin Fst has unique effects on chromosome segregation and cell division in Enterococcus faecalis and Bacillus subtilis.

The Fst toxin of the Enterococcus faecalis pAD1-encoded par addiction module functions intracellularly to kill plasmid-free segregants. Previous results had shown that Fst induction results in membrane permeabilization and cessation of macromolecular synthesis, but only after 45 min. Electron micrographs of toxin-induced cells showed no obvious membrane abnormalities but did reveal defects in nucleoid segregation and cell division, begging the question of which is the primary effect of Fst. To distinguish the possibilities, division septae and nucleoids were visualized simultaneously with fluorescent vancomycin and a variety of DNA stains. Results showed that division and segregation defects occurred in some cells within 15 min after induction. At these early time points, affected cells remained resistant to membrane-impermeant DNA stains, suggesting that loss of membrane integrity is a secondary effect caused by ongoing division and/or segregation defects. Fst-resistant mutants showed greater variability in cell length and formed multiple septal rings even in the absence of Fst. Fst induction was also toxic to Bacillus subtilis. In this species, Fst induction caused only minor division abnormalities, but all cells showed a condensation of the nucleoid, suggesting that effects on the structure of the chromosomal DNA might be paramount.

Xenoestrogen action in breast cancer: impact on ER-dependent transcription and mitogenesis.

Several estrogen mimics (xenoestrogens) inappropriately activate the estrogen receptor (ER) in the absence of endogenous ligand. Given the importance of the ER in breast cancer growth and regulation, delineating the impact of these agents under conditions related to tumor treatment is of significant importance. We examined the effect of two prevalent xenoestrogens (bisphenol A and coumestrol) on ER activation and ER-dependent mitogenesis in breast cancer cells. We show that the ability of these agents to induce mitogenesis was restricted to conditions of estrogen depletion, and that these agents failed to cooperate with estradiol to induce MCF-7 breast cancer cell growth. These observations are consistent with the impact of each agent specifically on exogenous ER activation as monitored in HeLa cells, wherein the xenoestrogens activated the receptor in the absence of estradiol but failed to cooperate with estrogen. Tamoxifen blocked bisphenol A and coumestrol-mediated ER activation, indicating that exposure to these agents is unlikely to disrupt such therapeutic intervention. The response of tumor-derived ER alleles to these xenoestrogens was also examined. Although the xenoestrogens failed to alter ER-Y537S function, the ER-D351Y mutant demonstrated an enhanced response to bisphenol A. Moreover, tamoxifen enhanced the agonistic effects of xenoestrogens on ER-D351Y. Lastly, we examined the impact of ER co-activator overexpression on xenoestrogen response. Bisphenol A and coumestrol exhibited differential responses to co-activators with regard to ER activation. However, when using mitogenesis as an endpoint, these co-activators were insufficient to provide a significant growth advantage. Combined, these data demonstrate that bisphenol A and coumestrol can impact ER activity and ER-dependent proliferation in breast cancer cells, but the influence of these agents is restricted to conditions of estrogen depletion, selective mutation of the ER, and expression of specific co-activators.