Minnesota Veterans Medical Research and Education Foundation

Early detection of ovarian cancer is difficult owing to the lack of specific and sensitive tests available. Previously, we found expression of nectin 4 to be increased in ovarian cancer compared with normal ovaries. Reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitative RT-PCR validated the overexpression of nectin 4 messenger RNA in ovarian cancer compared with normal ovarian cell lines and tissues. Protein levels of nectin 4 were elevated in ovarian cancer cell lines and tissue compared with normal ovarian cell lines as demonstrated by Western immunoblotting, flow cytometry, and immunohistochemical staining of tissue microarray slides. Cleaved nectin 4 was detectable in a number of patient serum samples by enzyme-linked immunosorbent assay. In patients with benign gynecologic diseases with high serum CA125 levels, nectin 4 was not detected in the majority of cases, suggesting that nectin 4 may serve as a potential biomarker that helps discriminate benign gynecologic diseases from ovarian cancer in a panel with CA125.

Building Spiritual Strength (BSS) is an 8-session, spiritually integrated group intervention designed to address religious strain and enhance religious meaning making for military trauma survivors. It is based upon empirical research on the relationship between spirituality and adjustment to trauma. To assess the intervention's effectiveness, veterans with histories of trauma who volunteered for the study were randomly assigned to a BSS group (n = 26) or a wait-list control group (n = 28). BSS participants showed statistically significant reductions in PTSD symptoms based on self-report measures as compared with those in a wait-list control condition. Further research on spiritually integrated interventions for trauma survivors is warranted.

While some trauma survivors find their faith helpful in recovery, others find it a source of distress, and still others abandon their faith. More complex conceptualizations of religious functioning are needed to explore its relationship with trauma. This study explores such relationships using measures of religious action and behaviors in a community sample of 327 church-going, self-identified trauma survivors. A principal components analysis of positive and negative religious coping, religious comforts and strains, and prayer functions identified two dimensions: Seeking Spiritual Support, which was positively related to posttraumatic growth, and Religious Strain, which was positively related to posttraumatic symptoms.

BACKGROUND AND OBJECTIVES: Patients receiving dialysis undergo parathyroidectomy to improve laboratory parameters in resistant hyperparathyroidism with the assumption that clinical outcomes will also improve. However, no randomized clinical trial data demonstrate the benefits of parathyroidectomy. This study aimed to evaluate clinical outcomes up to 1 year after parathyroidectomy in a nationwide sample of patients receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the US Renal Data System, this study identified prevalent hemodialysis patients aged ≥18 years with Medicare as primary payers who underwent parathyroidectomy from 2007 to 2009. Baseline characteristics and comorbid conditions were assessed in the year preceding parathyroidectomy; clinical events were identified in the year preceding and the year after parathyroidectomy. After parathyroidectomy, patients were censored at death, loss of Medicare coverage, kidney transplant, change in dialysis modality, or 365 days. This study estimated cause-specific event rates for both periods and rate ratios comparing event rates in the postparathyroidectomy versus preparathyroidectomy periods. RESULTS: Of 4435 patients who underwent parathyroidectomy, 2.0% died during the parathyroidectomy hospitalization and the 30 days after discharge. During the 30 days after discharge, 23.8% of patients were rehospitalized; 29.3% of these patients required intensive care. In the year after parathyroidectomy, hospitalizations were higher by 39%, hospital days by 58%, intensive care unit admissions by 69%, and emergency room/observation visits requiring hypocalcemia treatment by 20-fold compared with the preceding year. Cause-specific hospitalizations were higher for acute myocardial infarction (rate ratio, 1.98; 95% confidence interval, 1.60 to 2.46) and dysrhythmia (rate ratio 1.4; 95% confidence interval1.16 to 1.78); fracture rates did not differ (rate ratio 0.82; 95% confidence interval 0.6 to 1.1). CONCLUSIONS: Parathyroidectomy is associated with significant morbidity in the 30 days after hospital discharge and in the year after the procedure. Awareness of clinical events will assist in developing evidence-based risk/benefit determinations for the indication for parathyroidectomy.

OBJECTIVES: To compare the safety and cost of clean versus sterile intermittent bladder catheterization in male nursing home residents. To provide evidence to support the hypothesis that intermittent catheterization is a valid, alternative method of bladder management in male residents of long-term care in whom urinary retention is a documented problem. DESIGN: Randomized clinical trial. SETTING: Three long-term care sites having predominantly male populations. PARTICIPANTS: Eighty male veterans, residents of three long-term care facilities, ranging in age from 36 to 96 years with a mean age of 72. INTERVENTIONS: Standardized procedures for clean and sterile intermittent catheterization (IC) were implemented by staff nurses at each site. Patients were randomized into clean and sterile IC groups. Nursing time and catheterization equipment usage were recorded using bar code readers. Clinical data were collected from the medical chart. Treatment of urinary tract infection was prescribed by the medical personnel responsible for each individual resident. MEASUREMENTS: We compared the number of treatment episodes for symptomatic bacteriuria between groups randomized to receive either clean or sterile intermittent catheterization. Laboratory analysis of blood and urine was done on predetermined days. Control variables were research site and patient history of urinary tract infection within the last 6 months. A cost comparison of nursing time and equipment usage for the two catheterization techniques was also performed. RESULTS: No significant differences were found between clean and sterile groups with regard to number of treatment episodes, time to first infection, type of organism cultured, or cost of antibiotic treatment. The cost of sterile technique was considerably higher both in terms of nursing time and supplies. CONCLUSIONS: Findings from this study demonstrate that clean technique intermittent catheterization is a safe and cost-effective bladder management technique with male, nursing home residents, despite the frailty of this high risk population. An annual savings of approximately $1460 per patient in nursing time and catheterization supplies could be anticipated if a patient were catheterized an average of four times per day substituting clean IC technique for sterile IC technique.

Our aims were to further characterize the stimulatory effect of glucagon on brown fat and to test the hypothesis that physiological levels of hyperglucagonemia would stimulate brown fat thermogenesis. In the first set of experiments, glucagon (1 mg/kg sc twice daily) or vehicle control was administered three times in 26 h. This large dose of glucagon produced increases in GDP binding to brown fat mitochondria. In addition, Scatchard analysis indicated a glucagon-induced increase in number of GDP binding sites without evidence for alteration in binding site affinity. No consistent increase in brown fat mitochondrial GDP binding was produced 2 h after a single injection of glucagon (1 mg/kg). In the second set of experiments, glucagon was administered intraperitoneally by constant osmotic minipump infusion. Glucagon in a dose of 150 micrograms.kg-1.day-1 for 5 days produced significant increases in GDP binding to brown fat mitochondria, whereas glucagon serum levels were increased but stayed within the usual physiological range. A larger dose of glucagon administered by constant infusion virtually eliminated body weight gain over 7 days while significantly increasing nucleotide binding (GDP) to brown fat mitochondria. An important role for glucagon in thermogenic regulation is suggested.

Objective: Few studies have examined relations between one important aspect of spiritual/religious functioning-spiritual distress-and pain-related outcomes, and none has examined how spiritual distress and depression conjointly relate to chronic pain. The goal of the present study, then, was to examine veterans' spiritual distress as a predictor of two aspects of chronic pain, catastrophizing and interference, testing a mediational model of depression. Design: Four hundred thirty-six patients seeking treatment in a chronic pain management clinic responded to a mailed survey assessing demographics, spiritual distress, depression, pain catastrophizing, and pain interference. Setting: Participants were drawn from a list of patients enrolled in a chronic pain rehabilitation program at a large Midwestern Veterans Affairs health care system. Subjects: Participants were 436 veterans seeking chronic pain rehabilitation. The sample was predominantly Caucasian and male. Methods: Survey data were subjected to mediational analysis, assessing both direct effects of spiritual distress on pain outcomes and indirect effects of spiritual distress through depression. Results: Results showed that spiritual distress was moderately strongly related to both pain outcomes. Further, depression mediated links between spiritual distress and pain catastrophizing (partially) and interference (fully). Conclusions: These results have implications for further research in spiritually integrated care as a component of holistic, integrative approaches to the management of chronic pain.

OBJECTIVE: Smoking impairs wound healing, yet the underlying pathophysiological mechanisms are unclear. We evaluated tobacco-altered healing in head and neck surgery by studying the association between biomarkers and tobacco exposure, as well as cutaneous perfusion by smoking status. STUDY DESIGN: Prospective cohort study, tertiary/academic care center, 2011 to present. METHODS: Patients who required head and neck surgery were enrolled prospectively. Postsurgical drain fluid was collected 24 hours postoperatively. Biomarkers associated with postulated mechanisms of smoking-impaired healing were assayed. These included interleukin-1, -6, and -8; tumor necrosis factor- alpha; transforming growth factor-beta; epidermal growth factor (EGF); basic fibroblastic growth factor (bFGF); C-reactive protein; vascular endothelial growth factor; soluble FMS-like tyrosine kinase-1 (sFLT-1); and placental growth factor. Tobacco exposure and clinical outcomes were recorded. Two sample two-sided t tests evaluated the differences in cytokine levels by tobacco exposure. In a second cohort, cutaneous vascular assessment via indocyanine green angiography was compared by smoking status. RESULTS: Twenty-eight patients were enrolled with drain fluid collection. Twenty-one subjects were current/former smokers, whereas seven were never smokers. EGF was higher in never smokers than smokers in a statistically significant manner (P = 0.030). Likewise, sFLT-1 was significantly higher in never smokers (P = 0.011). Cutaneous angiography revealed nonsmokers to have significantly higher cutaneous perfusion than smokers. CONCLUSION: In this head and neck surgical cohort, significantly higher EGF and sFLT-1 levels in wound fluid were associated with never smoking, suggesting that smoking has adverse effects on the inflammatory phase of wound healing. Cutaneous angiography supports the detrimental effect of smoking on skin perfusion. These findings suggest the need for further study as well as therapeutic targets for smokers undergoing surgery. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:618-625, 2018.

We examined the relative contribution of renin-angiotensin system blockade and bradykinin potentiation to the renal hemodynamic effect of the angiotensin converting enzyme inhibitor enalaprilat in sodium-deprived dogs. Six conscious dogs instrumented for monitoring of blood pressure (BP) and renal blood flow (RBF) were employed in five groups of experiments. In group 1, enalaprilat alone was administered, and it decreased BP by -24 +/- 3 mm Hg and increased RBF by 135 +/- 15 ml/min. During a constant intravenous infusion of saralasin (group 2), enalaprilat decreased BP by -7 +/- 3 mm Hg and increased RBF by 84 +/- 7 ml/min (delta BP and delta RBF, p less than 0.01 vs. group 1 by analysis of variance). During a constant intrarenal arterial infusion of saralasin (group 3), the respective changes in BP and RBF after enalaprilat were -10 +/- 3 mm Hg and 69 +/- 12 ml/min, and these results did not differ from those of group 2. The infusion of saralasin intravenously or intrarenal arterially decreased BP slightly and increased RBF. In the presence of an intravenous infusion of a specific bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg.TFA (B5630) (group 4), enalaprilat decreased BP by -28 +/- 4 mm Hg and increased RBF by 82 +/- 24 ml/min (delta RBF, p less than 0.01 vs. group 1).(ABSTRACT TRUNCATED AT 250 WORDS)

HYPOTHESIS: Religious strain would mediate the relationship between stress symptoms at baseline and stress symptoms 1 year later. METHOD: Seventy-nine people with a history of stressful life events (55 women, 23 men, one unknown gender, average age 58 years) from community churches reported stressful life events, spiritual adjustment, and posttraumatic stress symptoms at initial assessment and 1-year follow-up. RESULTS: Religious strain mediated the relationship between baseline and follow-up posttraumatic stress symptoms. CONCLUSIONS: Because religious distress contributed to prediction of stress symptoms over time, it appears that religious distress is related to adjustment to stressful life events.

Research on prayer and posttraumatic growth (PTG) indicates that those who pray report more PTG. Research is beginning to identify which types of prayer may be operating in this relationship. We sought to identify specific prayer functions related to PTG while considering differences due to the types of trauma experienced. Participants were trauma survivors from diverse, Midwestern Christian churches (N = 327). Participants completed questionnaires assessing trauma history, prayer coping functions, and PTG. Multiple linear regression analyses found that praying for calm and focus was independently related to higher levels of PTG. When considering all variables in the model, the relationship between prayer for calm and focus and PTG was not significant for those whose most significant trauma was interpersonal in nature, but significant for those with noninterpersonal trauma.

Abstract A teaching intervention for face-recognition deficits in alcohol dementia (AlcDem) was tested. Participants viewed a sample face, and after a delay, chose which of two faces matched the sample. Under the Specific Outcomes teaching method, the reward for a correct identification was specific to the sample face (e.g., nickel for Face A, point for Face B). Under the comparison teaching method, Nonspecific Outcomes, the outcome was not unique to the sample. The AlcDem group performed with high accuracy similar to that of the Control group only with intervention. The data confirm that face-recognition deficits in alcohol dementia may be improved with simple behavioral interventions.

INTRODUCTION: Approximately, 275,000 American service members deployed to Iraq or Afghanistan have sustained a mild traumatic brain injury (mTBI), with 75% of these incidents involving an explosive blast. Visual processing problems and cognitive dysfunction are common complaints following blast-related mTBI. METHODS: In 127 veterans, we examined resting fMRI functional connectivity (FC) of four key nodes within the visual system: lateral geniculate nucleus (LGN), primary visual cortex (V1), lateral occipital gyrus (LO), and fusiform gyrus (FG). Regression analyses were performed (i) to obtain correlations between time-series from each seed and all voxels in the brain, and (ii) to identify brain regions in which FC variability was related to blast mTBI severity. Blast-related mTBI severity was quantified as the sum of the severity scores assigned to each of the three most significant blast-related injuries self-reported by subjects. Correlations between FC and performance on executive functioning tasks were performed across participants with available behavioral data (n = 94). RESULTS: Greater blast mTBI severity scores were associated with lower FC between: (A) LGN seed and (i) medial frontal gyrus, (ii) lingual gyrus, and (iii) right ventral anterior nucleus of thalamus; (B) V1 seed and precuneus; (C) LO seed and middle and superior frontal gyri; (D) FG seed and (i) superior and medial frontal gyrus, and (ii) left middle frontal gyrus. Finally, lower FC between visual network regions and frontal cortical regions predicted worse performance on the WAIS digit-symbol coding task. CONCLUSION: These are the first published results that directly illustrate the relationship between blast-related mTBI severity, visual pathway neural networks, and executive dysfunction - results that highlight the detrimental relationship between blast-related brain injury and the integration of visual sensory input and executive processes.

Importance: Mild traumatic brain injury (TBI) may predispose individuals to progressive neurodegeneration. Objective: To identify evidence of neurodegeneration through longitudinal evaluation of changes in retinal layer thickness using optical coherence tomography in veterans with a history of mild TBI. Design, Setting, and Participants: This longitudinal cohort study evaluated veterans who were receiving services at the Minneapolis Veterans Affairs Health Care System. Symptomatic or mild TBI was diagnosed according to the Mayo TBI Severity Classification System. Participants in the age-matched control group had no history of TBI. Participants with any history or evidence of retinal or optic nerve disease that could affect retinal thickness were excluded. Data analysis was performed from July 2019 to February 2020. Exposures: The presence and severity of mild TBI were determined through consensus review of self-report responses during the Minnesota Blast Exposure Screening Tool semistructured interview. Main Outcomes and Measures: Change over time of retinal nerve fiber layer (RNFL) thickness. Results: A total of 139 veterans (117 men [84%]; mean [SD] age, 49.9 [11.1] years) were included in the study, 69 in the TBI group and 70 in the control group. Veterans with mild TBI showed significantly greater RNFL thinning compared with controls (mean [SE] RNFL slope, -1.47 [0.24] μm/y vs -0.31 [0.32] μm/y; F1,122 = 8.42; P = .004; Cohen d = 0.52). Functionally, veterans with mild TBI showed greater declines in visual field mean deviation (mean [SE] slope, -0.09 [0.14] dB/y vs 0.46 [0.23] dB/y; F1,122 = 4.08; P = .046; Cohen d = 0.36) and pattern standard deviation (mean [SE] slope, 0.09 [0.06] dB/y vs -0.10 [0.07] dB/y; F1,122 = 4.78; P = .03; Cohen d = 0.39) and high spatial frequency (12 cycles/degree) contrast sensitivity compared with controls. Cognitively, there was a significantly greater decrease in the number of errors over time during the Groton Maze Learning Test (GMLT) in controls compared with veterans with mild TBI (mean [SE] slope, -9.30 [1.48] errors/y vs -5.23 [1.24] errors/y; F1,127 = 4.43; P = .04; Cohen d = 0.37). RNFL tissue loss was significantly correlated with both worsening performance on the GMLT over time (Spearman ρ = -0.20; P = .03) and mild TBI severity (Spearman ρ = -0.25; P = .006). The more severe the mild TBI (larger Minnesota Blast Exposure Screening Tool severity score), the faster the reduction in RNFL thickness (ie, the more negative the slope) across time. Conclusions and Relevance: This cohort study found longitudinal evidence for significant, progressive neural degeneration over time in veterans with mild TBI, as indicated by greater RNFL tissue loss in patients with mild TBI vs controls, as well as measures of function. These results suggest that these longitudinal measures may be useful biomarkers of neurodegeneration. Changes in this biomarker may provide early detection of subsequent cognitive and functional deficits that may impact veterans' independence and need for care.

BACKGROUND AND OBJECTIVES: There is a trend in the United States to maintenance dialysis initiation at higher levels of estimated GFR. This study aimed to determine whether provider characteristics and pre-ESRD nephrology care and vascular access are independently associated with higher estimated GFR at initiation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study used US Renal Data System data for patients who initiated dialysis in 2006 (n=83,621) and American Medical Association Physician Master File data for provider characteristics. Patient characteristics and estimated GFR were defined, and providers at dialysis initiation were identified. Earlier dialysis initiation was defined as initiation at estimated GFR>10 ml/min per 1.73 m(2). Nephrologist density per 100 ESRD patients was calculated by Health Service Area in 2006. Associations between provider characteristics and estimated GFR were determined using logistic regression and linear regression models, accounting for provider clustering. RESULTS: Of the cohort, 47.8% of patients initiated dialysis at estimated GFR>10 ml/min per 1.73 m(2), and 16.2% of patients initiated dialysis at estimated GFR≥15 ml/min per 1.73 m(2). Predialysis nephrologist care for 0-12 months was associated with greater odds of earlier initiation compared with no care. Patients initiating with an arteriovenous fistula or graft were more likely to initiate earlier than patients initiating with a catheter. Provider sex was not associated with timing of dialysis initiation as measured by estimated GFR. Care by providers who graduated from nondomestic medical schools was associated with greater odds of earlier initiation. Greater provider experience was associated with lower likelihood of earlier initiation. CONCLUSION: This study supports the hypothesis that provider factors are associated with timing of dialysis initiation in the United States.

A patient with Hodgkin's disease is described who developed chronic myelogenous leukemia 8 1/2 years after the start of radiation therapy. This therapy was fractional and was administered to most of the patient's skeleton. The radiation was an important factor in the development of leukemia. The presence of positive reactions to the antileukemic fluorescent antibodies may be consistent with the hypothesis that viruses are concerned with human leukemia.

BACKGROUND: Intestinal gas is thought to be the cause abdominal discomfort in infants. Little is known about the type and amount of gas produced by the infant's colonic microflora and whether diet influences gas formation. METHODS: Fresh stool specimens were collected from 10 breast-fed infants, 5 infants fed a soy-based formula, and 3 infants fed a milk-based formula at approximately 1, 2, and 3 months of age. Feces were incubated anaerobically for 4 hours at 37 degrees C followed by quantitation of hydrogen (H2), methane (CH4), carbon dioxide (CO2), hydrogen sulfide (H2S), methanethiol (CH3SH), and dimethyl sulfide (CH3SCH3) in the head-space. RESULTS: H2 was produced in greater amounts by breast-fed infants than by infants in either formula group, presumably the consequence of incomplete absorption of breast milk oligosaccharides. CH4 was produced in greater amounts by infants fed soy formula than by infants on other diets. CO2 was produced in similar amounts by infants in all feeding groups. Production of CH3SH was conspicuously low by feces of breast-fed infants and production of H2S was high by soy-formula-fed infants. CH3SCH3 was not detected. Only modest changes with age were observed and there was no relation between gas production and stool consistency, although stools were more likely to be malodorous when concentrations of H2S and/or CH3SH were high. CONCLUSIONS: Gas release by infant feces is strongly influenced by an infant's diet. Of particular interest are differences in production of the highly toxic sulfur gases, H2S and CH3SH, because of the role that these gases may play in certain intestinal disorders of infants.

Sonic hedgehog (Shh) is essential for limb development, and the mechanisms that govern the propagation and maintenance of its expression has been well studied; however, the mechanisms that govern the initiation of Shh expression are incomplete. Here we report that ETV2 initiates Shh expression by changing the chromatin status of the developmental limb enhancer, ZRS. Etv2 expression precedes Shh in limb buds, and Etv2 inactivation prevents the opening of limb chromatin, including the ZRS, resulting in an absence of Shh expression. Etv2 overexpression in limb buds causes nucleosomal displacement at the ZRS, ectopic Shh expression, and polydactyly. Areas of nucleosome displacement coincide with ETS binding site clusters. ETV2 also functions as a transcriptional activator of ZRS and is antagonized by ETV4/5 repressors. Known human polydactyl mutations introduce novel ETV2 binding sites in the ZRS, suggesting that ETV2 dosage regulates ZRS activation. These studies identify ETV2 as a pioneer transcription factor (TF) regulating the onset of Shh expression, having both a chromatin regulatory role and a transcriptional activation role.

abstract — The purpose of this investigation was to study colonization and sequencing of oral microorganisms in human tooth fissures. Five human subjects carried a total of 45 crowns of extracted, fully‐impacted third molars which were held in place by means of an intraoral appliance. Each specimen was exposed to the oral environment for 1, 2, 3, 5, 7, 9, 12, 15 or 21 d, and prepared under anaerobic conditions for microbiologic analysis of the fissure content. At day 1 and throughout the time sequence studied, cocci (40–70%), Gram‐positive rods (20–40%) and Gram‐negative rods (5–9%) constituted the predominant flora. Filaments were scarce and were recovered only from plaque more than 15 d old. Approximately 74% of the recovered organisms were acidogenic. S. mutans was found in the fissures of all subjects, but not in all specimens carried by the subjects. The percentage of S. mutans varied largely within the fissures (0–88.9%). S. sanguis was found in amounts equal to S. mutans in all subjects. Lactobacilli were recovered only in a few fissures and then in small numbers. While veillonella was present in all the fissures examined, neisseria was detected in only two subjects.

Ischemic heart disease affects millions of people around the world. Current treatment options, including coronary artery bypass grafting, do not result in full functional recovery, highlighting the need for novel adjunctive therapeutic approaches. Hibernation describes the myocardial response to prolonged ischemia and involves a set of complex cytoprotective metabolic and functional adaptations. PGC1-alpha, a key regulator of mitochondrial energy metabolism and inhibitor of oxidant-stress-inflammatory signaling, is known to be downregulated in hibernating myocardium. PGC1-alpha is a critical component of cellular stress responses and links cellular metabolism with inflammation in the ischemic heart. While beneficial in the acute setting, a chronic state of hibernation can be associated with self-perpetuating oxidant stress-inflammatory signaling which leads to tissue injury. It is likely that incomplete functional recovery following revascularization of chronically ischemic myocardium is due to persistence of metabolic changes as well as prooxidant and proinflammatory signaling. Enhancement of PGC1-alpha signaling has been proposed as a possible way to improve functional recovery in patients with ischemic heart disease. Adjunctive mesenchymal stem cell therapy has been shown to induce PGC1-alpha signaling in hibernating myocardium and could help improve clinical outcomes for patients undergoing bypass surgery.