Scott & White Memorial Hospital

BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

BACKGROUND: The last decade has evidenced a dramatic increase in the development and utilization of pediatric health-related quality of life (HRQOL) measures in an effort to improve pediatric patient health and well-being and determine the value of healthcare services. The emerging paradigm shift toward patient-reported outcomes (PROs) in clinical trials has provided the opportunity to further emphasize the value and essential need for pediatric patient self-reported outcomes measurement. Data from the PedsQL DatabaseSM were utilized to test the hypothesis that children as young as 5 years of age can reliably and validly report their HRQOL. METHODS: The sample analyzed represented child self-report age data on 8,591 children ages 5 to 16 years from the PedsQL 4.0 Generic Core Scales DatabaseSM. Participants were recruited from general pediatric clinics, subspecialty clinics, and hospitals in which children were being seen for well-child checks, mild acute illness, or chronic illness care (n = 2,603, 30.3%), and from a State Children's Health Insurance Program (SCHIP) in California (n = 5,988, 69.7%). RESULTS: Items on the PedsQL 4.0 Generic Core Scales had minimal missing responses for children as young as 5 years old, supporting feasibility. The majority of the child self-report scales across the age subgroups, including for children as young as 5 years, exceeded the minimum internal consistency reliability standard of 0.70 required for group comparisons, while the Total Scale Scores across the age subgroups approached or exceeded the reliability criterion of 0.90 recommended for analyzing individual patient scale scores. Construct validity was demonstrated utilizing the known groups approach. For each PedsQL scale and summary score, across age subgroups, including children as young as 5 years, healthy children demonstrated a statistically significant difference in HRQOL (better HRQOL) than children with a known chronic health condition, with most effect sizes in the medium to large effect size range. CONCLUSION: The results demonstrate that children as young as the 5 year old age subgroup can reliably and validly self-report their HRQOL when given the opportunity to do so with an age-appropriate instrument. These analyses are consistent with recent FDA guidelines which require instrument development and validation testing for children and adolescents within fairly narrow age groupings and which determine the lower age limit at which children can provide reliable and valid responses across age categories.

OBJECTIVES: This guideline provides evidence-based recommendations on managing benign paroxysmal positional vertigo (BPPV), which is the most common vestibular disorder in adults, with a lifetime prevalence of 2.4 percent. The guideline targets patients aged 18 years or older with a potential diagnosis of BPPV, evaluated in any setting in which an adult with BPPV would be identified, monitored, or managed. This guideline is intended for all clinicians who are likely to diagnose and manage adults with BPPV. PURPOSE: The primary purposes of this guideline are to improve quality of care and outcomes for BPPV by improving the accurate and efficient diagnosis of BPPV, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary tests such as radiographic imaging and vestibular testing, and to promote the use of effective repositioning maneuvers for treatment. In creating this guideline, the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of audiology, chiropractic medicine, emergency medicine, family medicine, geriatric medicine, internal medicine, neurology, nursing, otolaryngology-head and neck surgery, physical therapy, and physical medicine and rehabilitation. RESULTS: The panel made strong recommendations that 1) clinicians should diagnose posterior semicircular canal BPPV when vertigo associated with nystagmus is provoked by the Dix-Hallpike maneuver. The panel made recommendations against 1) radiographic imaging, vestibular testing, or both in patients diagnosed with BPPV, unless the diagnosis is uncertain or there are additional symptoms or signs unrelated to BPPV that warrant testing; and 2) routinely treating BPPV with vestibular suppressant medications such as antihistamines or benzodiazepines. The panel made recommendations that 1) if the patient has a history compatible with BPPV and the Dix-Hallpike test is negative, clinicians should perform a supine roll test to assess for lateral semicircular canal BPPV; 2) clinicians should differentiate BPPV from other causes of imbalance, dizziness, and vertigo; 3) clinicians should question patients with BPPV for factors that modify management including impaired mobility or balance, CNS disorders, lack of home support, and increased risk for falling; 4) clinicians should treat patients with posterior canal BPPV with a particle repositioning maneuver (PRM); 5) clinicians should reassess patients within 1 month after an initial period of observation or treatment to confirm symptom resolution; 6) clinicians should evaluate patients with BPPV who are initial treatment failures for persistent BPPV or underlying peripheral vestibular or CNS disorders; and 7) clinicians should counsel patients regarding the impact of BPPV on their safety, the potential for disease recurrence, and the importance of follow-up. The panel offered as options that 1) clinicians may offer vestibular rehabilitation, either self-administered or with a clinician, for the initial treatment of BPPV and 2) clinicians may offer observation as initial management for patients with BPPV and with assurance of follow-up. The panel made no recommendation concerning audiometric testing in patients diagnosed with BPPV. DISCLAIMER: This clinical practice guideline is not intended as a sole source of guidance in managing benign paroxysmal positional vertigo. Rather, it is designed to assist clinicians by providing an evidence-based framework for decision-making strategies. The guideline is not intended to replace clinical judgement or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

IMPLICATIONS: We present evidence-based guidelines developed by an international panel of experts for the management of postoperative nausea and vomiting.

BACKGROUND: Advances in biomedical science and technology have resulted in dramatic improvements in the healthcare of pediatric chronic conditions. With enhanced survival, health-related quality of life (HRQOL) issues have become more salient. The objectives of this study were to compare generic HRQOL across ten chronic disease clusters and 33 disease categories/severities from the perspectives of patients and parents. Comparisons were also benchmarked with healthy children data. METHODS: The analyses were based on over 2,500 pediatric patients from 10 physician-diagnosed disease clusters and 33 disease categories/severities and over 9,500 healthy children utilizing the PedsQL 4.0 Generic Core Scales. Patients were recruited from general pediatric clinics, subspecialty clinics, and hospitals. RESULTS: Pediatric patients with diabetes, gastrointestinal conditions, cardiac conditions, asthma, obesity, end stage renal disease, psychiatric disorders, cancer, rheumatologic conditions, and cerebral palsy self-reported progressively more impaired overall HRQOL than healthy children, respectively, with medium to large effect sizes. Patients with cerebral palsy self-reported the most impaired HRQOL, while patients with diabetes self-reported the best HRQOL. Parent proxy-reports generally paralleled patient self-report, with several notable differences. CONCLUSION: The results demonstrate differential effects of pediatric chronic conditions on patient HRQOL across diseases clusters, categories, and severities utilizing the PedsQL 4.0 Generic Core Scales from the perspectives of pediatric patients and parents. The data contained within this study represents a larger and more diverse population of pediatric patients with chronic conditions than previously reported in the extant literature. The findings contribute important information on the differential effects of pediatric chronic conditions on generic HRQOL from the perspectives of children and parents utilizing the PedsQL 4.0 Generic Core Scales. These findings with the PedsQL have clinical implications for the healthcare services provided for children with chronic health conditions. Given the degree of reported impairment based on PedsQL scores across different pediatric chronic conditions, the need for more efficacious targeted treatments for those pediatric patients with more severely impaired HRQOL is clearly and urgently indicated.

Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E(2) (PGE(2)). The PGE(2) converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1.

IMPORTANCE: Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE: To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS: Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES: The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS: Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE: Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00334828.

OBJECTIVE: To prospectively determine risk factors for foot infection in a cohort of people with diabetes. RESEARCH DESIGN AND METHODS: We evaluated then followed 1,666 consecutive diabetic patients enrolled in a managed care-based outpatient clinic in a 2-year longitudinal outcomes study. At enrollment, patients underwent a standardized general medical examination and detailed foot assessment and were educated about proper foot care. They were then rescreened at scheduled intervals and also seen promptly if they developed any foot problem. RESULTS: During the evaluation period, 151 (9.1%) patients developed 199 foot infections, all but one involving a wound or penetrating injury. Most patients had infections involving only the soft tissue, but 19.9% had bone culture-proven osteomyelitis. For those who developed a foot infection, compared with those who did not, the risk of hospitalization was 55.7 times greater (95% CI 30.3-102.2; P < 0.001) and the risk of amputation was 154.5 times greater (58.5-468.5; P < 0.001). Foot wounds preceded all but one infection. Significant (P < 0.05) independent risk factors for foot infection from a multivariate analysis included wounds that penetrated to bone (odds ratio 6.7), wounds with a duration >30 days (4.7), recurrent wounds (2.4), wounds with a traumatic etiology (2.4), and presence of peripheral vascular disease (1.9). CONCLUSIONS: Foot infections occur relatively frequently in individuals with diabetes, almost always follow trauma, and dramatically increase the risk of hospitalization and amputation. Efforts to prevent infections should be targeted at people with traumatic foot wounds, especially those that are chronic, deep, recurrent, or associated with peripheral vascular disease.

BACKGROUND: Caring for a family member with dementia is extremely stressful, contributes to psychiatric and physical illness among caregivers, and increases the risk for caregiver death. Finding better ways to support family caregivers is a major public health challenge. OBJECTIVE: To test the effects of a structured multicomponent intervention on quality of life and clinical depression in caregivers and on rates of institutional placement of care recipients in 3 diverse racial or ethnic groups. DESIGN: Randomized, controlled trial. SETTING: In-home caregivers in 5 U.S. cities. PARTICIPANTS: 212 Hispanic or Latino, 219 white or Caucasian, and 211 black or African-American caregivers and their care recipients with Alzheimer disease or related disorders. INTERVENTION: Caregivers within each racial or ethnic group were randomly assigned to an intervention or to a control group. The intervention addressed caregiver depression, burden, self-care, and social support and care recipient problem behaviors through 12 in-home and telephone sessions over 6 months. Caregivers in the control group received 2 brief "check-in" telephone calls during the 6-month intervention. MEASUREMENTS: The primary outcome was a quality-of-life indicator comprising measures of 6-month caregiver depression, burden, self-care, and social support and care recipient problem behaviors. Secondary outcomes were caregiver clinical depression and institutional placement of the care recipient at 6 months. RESULTS: Hispanic or Latino and white or Caucasian caregivers in the intervention group experienced significantly greater improvement in quality of life than those in the control group (P < 0.001 and P = 0.037, respectively). Black or African-American spouse caregivers also improved significantly more (P = 0.003). Prevalence of clinical depression was lower among caregivers in the intervention group (12.6% vs. 22.7%; P = 0.001). There were no statistically significant differences in institutionalization at 6 months. LIMITATIONS: The study used only a single 6-month follow-up assessment, combined heterogeneous cultures and ethnicities into a single group, and excluded some ethnic groups. CONCLUSIONS: A structured multicomponent intervention adapted to individual risk profiles can increase the quality of life of ethnically diverse dementia caregivers. ClinicalTrials.gov identifier: NCT00177489.

OBJECTIVE: Disagreement exists concerning the appropriate delivery room management of the airway of vigorous meconium-stained infants. Some suggest a universal approach to intubation and suctioning of the airway in all such neonates, whereas others advocate a selective approach. We performed this investigation: 1) to assess whether intubation and suctioning of apparently vigorous, meconium-stained neonates would reduce the incidence of meconium aspiration syndrome (MAS); and 2) to determine the frequency of complications from delivery room intubation and suctioning of such infants. METHODS: Inclusion criteria included: 1) gestational age >/=37 weeks; 2) birth through meconium-stained amniotic fluid of any consistency; and 3) apparent vigor immediately after birth. Subjects were randomized to be intubated and suctioned (INT) or to expectant management (EXP). Primary outcome measures included: 1) the incidence of respiratory distress, including MAS, and 2) the incidence of complications from intubation. RESULTS: A total of 2094 neonates were enrolled from 12 participating centers (1051 INT and 1043 EXP). Meconium-stained amniotic fluid consistency was similar in both groups. Of the 149 (7.1%) infants that subsequently demonstrated respiratory distress, 62 (3.0%) had MAS and 87 (4.2%) had findings attributed to other disorders. There were no significant differences between groups in the occurrence of MAS (INT = 3.2%; EXP = 2.7%) or in the development of other respiratory disorders (INT = 3.8%; EXP = 4.5%). Of 1098 successfully intubated infants, 42 (3.8%) had a total of 51 complications of the procedure. In all cases, the complications were mild and transient in nature. CONCLUSIONS: Compared with expectant management, intubation and suctioning of the apparently vigorous meconium-stained infant does not result in a decreased incidence of MAS or other respiratory disorders. Complications of intubation are infrequent and short-lived.

Diversity among executives is widely assumed to influence a firm's strategic decision processes, but empirical research on this linkage has been virtually nonexistent. To partially fill the void, we drew upon three separate studies to examine the impact of executive diversity on comprehensiveness of strategic decision-making and extensiveness of strategic planning. Contrary to common assumptions of researchers and executives, our results suggest that executive diversity inhibits rather than promotes comprehensive examinations of current opportunities and threats, and inhibits rather than promotes extensive long-range planning. In light of the cumulative research showing that firm performance is related to both comprehensiveness and extensiveness, our results provide evidence for an indirect connection between executive diversity and firm performance. © 1998 John Wiley & Sons, Ltd.

BACKGROUND: Health-related quality of life (HRQOL) measurement has emerged as an important health outcome in clinical trials, clinical practice improvement strategies, and healthcare services research and evaluation. While pediatric patient self-report should be considered the standard for measuring perceived HRQOL, there are circumstances when children are too young, too cognitively impaired, too ill or fatigued to complete a HRQOL instrument, and reliable and valid parent proxy-report instruments are needed in such cases. Further, it is typically parents' perceptions of their children's HRQOL that influences healthcare utilization. Data from the PedsQL DatabaseSM were utilized to test the reliability and validity of parent proxy-report at the individual age subgroup level for ages 2-16 years as recommended by recent FDA guidelines. METHODS: The sample analyzed represents parent proxy-report age data on 13,878 children ages 2 to 16 years from the PedsQL 4.0 Generic Core Scales DatabaseSM. Parents were recruited from general pediatric clinics, subspecialty clinics, and hospitals in which their children were being seen for well-child checks, mild acute illness, or chronic illness care (n = 3,718, 26.8%), and from a State Children's Health Insurance Program (SCHIP) in California (n = 10,160, 73.2%). RESULTS: The percentage of missing item responses for the parent proxy-report sample as a whole was 2.1%, supporting feasibility. The majority of the parent proxy-report scales across the age subgroups exceeded the minimum internal consistency reliability standard of 0.70 required for group comparisons, while the Total Scale Scores across the age subgroups approached or exceeded the reliability criterion of 0.90 recommended for analyzing individual patient scale scores. Construct validity was demonstrated utilizing the known groups approach. For each PedsQL scale and summary score, across age subgroups, healthy children demonstrated a statistically significant difference in HRQOL (better HRQOL) than children with a known chronic health condition, with most effect sizes in the medium to large effect size range. CONCLUSION: The results demonstrate the feasibility, reliability, and validity of parent proxy-report at the individual age subgroup for ages 2-16 years. These analyses are consistent with recent FDA guidelines which require instrument development and validation testing for children and adolescents within fairly narrow age groupings and which determine the lower age limit at which reliable and valid responses across age categories are achievable. Even as pediatric patient self-report is advocated, there remains a fundamental role for parent proxy-report in pediatric clinical trials and health services research.

BACKGROUND: Hemodialysis patients are at high risk for cognitive impairment due to their older age and high prevalence of stroke and cardiovascular risk factors. METHODS: Using a cross-sectional design, the authors measured cognitive function in 374 hemodialysis patients aged 55 years and older and an age-matched comparison group in Minneapolis and St. Paul, MN. Cognitive performance was measured in three domains: memory, executive function, and language. Subjects were classified as having no, mild, moderate, or severe cognitive impairment. RESULTS: Of 338 subjects who completed testing in at least two of the three cognitive domains, 13.9% (95% CI 10.4, 18.1) were classified with mild impairment, 36.1% (31.0, 41.5) with moderate impairment, 37.3% (32.1, 42.7) with severe impairment, and 12.7% (9.4, 16.8) with normal cognition. Only 2.9% had a documented history of cognitive impairment. Factors associated with severe cognitive impairment on adjusted logistic regression were stroke (adjusted OR [AOR] 1.95; 95% CI 1.08, 3.49; p < 0.03), equilibrated Kt/V > 1.2 (1.67; 1.01, 2.75; p < 0.05), and education >12 years (0.32; 0.14, 0.72; p < 0.01). The AOR for severe cognitive impairment in a random sample of 101 hemodialysis patients vs an age-matched comparison group was 3.54 (1.28, 9.78; p < 0.02). CONCLUSIONS: Moderate to severe cognitive impairment is common and undiagnosed in hemodialysis patients. Further studies are needed to determine whether dialysis exacerbates the cognitive impairment attributable to underlying disease. Cognitive testing in hemodialysis patients before dialysis initiation and periodically may be warranted.

Human mesenchymal stem/progenitor cells (hMSCs) repair tissues and modulate immune systems but the mechanisms are not fully understood. We demonstrated that hMSCs are activated by inflammatory signals to secrete the anti-inflammatory protein, TNF-α-stimulated gene 6 protein (TSG-6) and thereby create a negative feedback loop that reduces inflammation in zymosan-induced peritonitis. The results demonstrate for the first time that TSG-6 interacts through the CD44 receptor on resident macrophages to decrease zymosan/TLR2-mediated nuclear translocation of the NF-κB. The negative feedback loop created by MSCs through TSG-6 attenuates the inflammatory cascade that is initiated by resident macrophages and then amplified by mesothelial cells and probably other cells of the peritoneum. Because inflammation underlies many pathologic processes, including immune responses, the results may explain the beneficial effects of MSCs and TSG-6 in several disease models.

Research on stem cells has progressed at a rapid pace and, as might be anticipated, the results have generated several controversies, a few myths and a change in a major paradigm. Some of these issues will be reviewed in this study with special emphasis on how they can be applied to the adult stem/progenitor cells from bone marrow, referred to as MSCs.

This article reports the first randomized prospective multicenter evaluation of a bioabsorbable conduit for nerve repair. The study enrolled 98 subjects with 136 nerve transections in the hand and prospectively randomized the repair to two groups: standard repair, either end-to-end or with a nerve graft, or repair using a polyglycolic acid conduit. Two-point discrimination was measured by a blinded observer at 3, 6, 9, and 12 months after repair. There were 56 nerves repaired in the control group and 46 nerves repaired with a conduit available for follow-up. Three patients had a partial conduit extrusion as a result of loss of the initially crushed skin flap. The overall results showed no significant difference between the two groups as a whole. In the control group, excellent results were obtained in 43 percent of repairs, good results in 43 percent, and poor results in 14 percent. In those nerves repaired with a conduit, excellent results were obtained in 44 percent, good results in 30 percent, and poor results in 26 percent (p = 0.46). When the sensory recovery was examined with regard to length of nerve gap, however, nerves with gaps of 4 mm or less had better sensation when repaired with a conduit; the mean moving two-point discrimination was 3.7 +/- 1.4 mm for polyglycolic acid tube repair and 6.1 +/- 3.3 mm for end-to-end repairs (p = 0.03). All injured nerves with deficits of 8 mm or greater were reconstructed with either a nerve graft or a conduit. This subgroup also demonstrated a significant difference in favor of the polyglycolic acid tube. The mean moving two-point discrimination for the conduit was 6.8 +/- 3.8 mm, with excellent results obtained in 7 of 17 nerves, whereas the mean moving two-point discrimination for the graft repair was 12.9 +/- 2.4 mm, with excellent results obtained in none of the eight nerves (p < 0.001 and p = 0.06, respectively). This investigation demonstrates improved sensation when a conduit repair is used for nerve gaps of 4 mm or less, compared with end-to-end repair of digital nerves. Polyglycolic acid conduit repair also produces results superior to those of a nerve graft for larger nerve gaps and eliminates the donor-site morbidity associated with nerve-graft harvesting.

BACKGROUND: Intrahepatic cholangiocarcinomas are malignant tumors arising from the intrahepatic biliary tract. The pathogenesis of these tumors remains unknown. Although there is a marked global variation in prevalence, some recent studies have suggested an increase in mortality from intrahepatic cholangiocarcinoma in several regions of low endemicity. As the study of mortality trends may yield clues to possible etiological factors, we analyzed worldwide time trends in mortality from biliary tract malignancies. METHODS: Annual age-standardized rates for individual countries were compiled for deaths from biliary tract malignancies using the WHO database. These data were used to analyze gender and site-specific trends in mortality rates. RESULTS: An increasing trend for mortality from intrahepatic cholangiocarcinoma was noted in most countries. The average estimated annual percentage change (EAPC) in mortality rates for males was 6.9 +/- 1.5, and for females was 5.1 +/- 1.0. Increased mortality rates were observed in all geographic regions. Within Europe, increases were higher in Western Europe than in Central or Northern Europe. In contrast, mortality rates for extrahepatic biliary tract malignancies showed a decreasing trend in most countries, with an overall average EAPC of -0.3 +/- 0.4 for males, but -1.3 +/- 0.4 for females. CONCLUSIONS: There has been a marked global increase in mortality from intrahepatic, but not extra-hepatic, biliary tract malignancies.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of a temperature monitoring instrument to reduce the incidence of foot ulcers in individuals with diabetes who have a high risk for lower extremity complications. RESEARCH DESIGN AND METHODS: In this physician-blinded, randomized, 15-month, multicenter trial, 173 subjects with a previous history of diabetic foot ulceration were assigned to standard therapy, structured foot examination, or enhanced therapy groups. Each group received therapeutic footwear, diabetic foot education, and regular foot care. Subjects in the structured foot examination group performed a structured foot inspection daily and recorded their findings in a logbook. If standard therapy or structured foot examinations identified any foot abnormalities, subjects were instructed to contact the study nurse immediately. Subjects in the enhanced therapy group used an infrared skin thermometer to measure temperatures on six foot sites each day. Temperature differences >4 degrees F (>2.2 degrees C) between left and right corresponding sites triggered patients to contact the study nurse and reduce activity until temperatures normalized. RESULTS: The enhanced therapy group had fewer foot ulcers than the standard therapy and structured foot examination groups (enhanced therapy 8.5 vs. standard therapy 29.3%, P = 0.0046 and enhanced therapy vs. structured foot examination 30.4%, P = 0.0029). Patients in the standard therapy and structured foot examination groups were 4.37 and 4.71 times more likely to develop ulcers than patients in the enhanced therapy group. CONCLUSIONS: Infrared temperature home monitoring, in serving as an "early warning sign," appears to be a simple and useful adjunct in the prevention of diabetic foot ulcerations.

Human mesenchymal stromal cells (hMSCs) were injected into the hippocampus of adult mice 1 day after transient global ischemia. The hMSCs both improved neurologic function and markedly decreased neuronal cell death of the hippocampus. Microarray assays indicated that ischemia up-regulated 586 mouse genes. The hMSCs persisted for <7 days, but they down-regulated >10% of the ischemia-induced genes, most of which were involved in inflammatory and immune responses. The hMSCs also up-regulated three mouse genes, including the neuroprotective gene Ym1 that is expressed by activated microglia/macrophages. In addition, the transcriptomes of the hMSC changed with up-regulation of 170 human genes and down-regulation of 54 human genes. Protein assays of the hippocampus demonstrated increased expression in microglia/macrophages of Ym1, the cell survival factor insulin-like growth factor 1, galectin-3, cytokines reflective of a type 2 T cell immune bias, and the major histocompatibility complex II. The observed beneficial effects of hMSCs were largely explained by their modulation of inflammatory and immune responses, apparently by alternative activation of microglia and/or macrophages.

In this longitudinal study of 1666 persons with diabetes, there was an observed trend toward an increased risk for amputation (chi(2) test for trend, 108.0; P<.001), higher-level amputation (chi(2) test for trend, 113.3; P<.001), and lower extremity-related hospitalization (chi(2) test for trend, 118.6; P<.001) with increasing infection severity. The Infectious Diseases Society of America's foot infection classification system may be a useful tool for grading foot infections.