BACKGROUND

National guidelines recommend that physicians discuss end-of-life (EOL) care planning with patients with cancer whose life expectancy is less than 1 year.

OBJECTIVE

To evaluate the incidence of EOL care discussions for patients with stage IV lung or colorectal cancer and where, when, and with whom these discussions take place.

METHODS

Prospective cohort study of patients diagnosed with lung or colorectal cancer from 2003 to 2005.

METHODS

Participants lived in Northern California, Los Angeles County, North Carolina, Iowa, or Alabama or received care in 1 of 5 large HMOs or 1 of 15 Veterans Health Administration sites.

METHODS

2155 patients with stage IV lung or colorectal cancer.

METHODS

End-of-life care discussions reported in patient and surrogate interviews or documented in medical records through 15 months after diagnosis.

RESULTS

73% of patients had EOL care discussions identified by at least 1 source. Among the 1470 patients who died during follow-up, 87% had EOL care discussions, compared with 41% of the 685 patients who were alive at the end of follow-up. Of the 1081 first EOL care discussions documented in records, 55% occurred in the hospital. Oncologists documented EOL care discussions with only 27% of their patients. Among 959 patients with documented EOL care discussions who died during follow-up, discussions took place a median of 33 days before death.

CONCLUSIONS

The depth and quality of EOL care discussions was not evaluated. Much of the information about discussions came from surrogates of patients who died before baseline interviews could be obtained.

CONCLUSIONS

Although most patients with stage IV lung or colorectal cancer discuss EOL care planning with physicians before death, many discussions occur during acute hospital care, with providers other than oncologists, and late in the course of illness.

BACKGROUND

National Cancer Institute and Department of Veterans Affairs.

Lipopolysaccharide (LPS) from gram-negative bacteria causes polyclonal activation of B cells and stimulation of macrophages and other APC. We show here that, under in vivo conditions, LPS also induces strong stimulation of T cells. As manifested by CD69 upregulation, LPS injection stimulates both CD4 and CD8(+) T cells, and, at high doses, stimulates naive (CD44(lo)) cells as well as memory (CD44(hi)) cells. However, in terms of cell division, the response of T cells after LPS injection is limited to the CD44(hi) subset of CD8(+) cells. In contrast with B cells, proliferative responses of CD44(hi) CD8(+) cells require only very low doses of LPS (10 ng). Based on studies with LPS-nonresponder and gene-knockout mice, LPS-induced proliferation of CD44(hi) CD8(+) cells appears to operate via an indirect pathway involving LPS stimulation of APC and release of type I (alpha, beta) interferon (IFN-I). Similar selective stimulation of CD44(hi) CD8(+) cells occurs in viral infections and after injection of IFN-I, implying a common mechanism. Hence, intermittent exposure to pathogens (gram-negative bacteria and viruses) could contribute to the high background proliferation of memory-phenotype CD8(+) cells found in normal animals.

OBJECTIVE

Esomeprazole, the S isomer of omeprazole, has been shown to have higher healing rates of erosive esophagitis than omeprazole. This study compared esomeprazole with lansoprazole for the healing of erosive esophagitis and resolution of heartburn.

METHODS

This United States multicenter, randomized, double blind, parallel group trial was performed in 5241 adult patients (intent-to-treat population) with endoscopically documented erosive esophagitis, which was graded by severity at baseline (Los Angeles classification). Patients received 40 mg of esomeprazole (n = 2624) or 30 mg of lansoprazole (n = 2617) once daily before breakfast for up to 8 wk. The primary efficacy endpoint was healing of erosive esophagitis at week 8. Secondary assessments included proportion of patients healed at week 4, resolution of investigator-recorded heartburn, time to first and time to sustained resolution of patient diary-recorded heartburn, and proportion of heartburn-free days and nights.

RESULTS

Esomeprazole (40 mg) demonstrated significantly higher healing rates (92.6%, 95% CI = 91.5-93.6%) than lansoprazole (30 mg) (88.8%, 95% CI = 87.5-90.0%) at week 8 (p = 0.0001, life-table estimates, intent-to-treat analysis). A significant difference in healing rates favoring esomeprazole was also observed at week 4. The difference in healing rates between esomeprazole and lansoprazole increased as baseline severity of erosive esophagitis increased. Sustained resolution of heartburn occurred faster and in more patients treated with esomeprazole. Sustained resolution of nocturnal heartburn also occurred faster with esomeprazole. Both treatments were well tolerated.

CONCLUSIONS

Esomeprazole (40 mg) is more effective than lansoprazole (30 mg) in healing erosive esophagitis and resolving heartburn. Healing rates are consistently high with esomeprazole, irrespective of baseline disease severity.

Complement forms an important arm of innate immunity against invasive meningococcal infections. Binding of the alternative complement pathway inhibitor factor H (fH) to fH-binding protein (fHbp) is one mechanism meningococci employ to limit complement activation on the bacterial surface. fHbp is a leading vaccine candidate against group B Neisseria meningitidis. Novel mechanisms that meningococci employ to bind fH could undermine the efficacy of fHbp-based vaccines. We observed that fHbp deletion mutants of some meningococcal strains showed residual fH binding suggesting the presence of a second receptor for fH. Ligand overlay immunoblotting using membrane fractions from one such strain showed that fH bound to a approximately 17 kD protein, identified by MALDI-TOF analysis as Neisserial surface protein A (NspA), a meningococcal vaccine candidate whose function has not been defined. Deleting nspA, in the background of fHbp deletion mutants, abrogated fH binding and mAbs against NspA blocked fH binding, confirming NspA as a fH binding molecule on intact bacteria. NspA expression levels vary among strains and expression correlated with the level of fH binding; over-expressing NspA enhanced fH binding to bacteria. Progressive truncation of the heptose (Hep) I chain of lipooligosaccharide (LOS), or sialylation of lacto-N-neotetraose LOS both increased fH binding to NspA-expressing meningococci, while expression of capsule reduced fH binding to the strains tested. Similar to fHbp, binding of NspA to fH was human-specific and occurred through fH domains 6-7. Consistent with its ability to bind fH, deleting NspA increased C3 deposition and resulted in increased complement-dependent killing. Collectively, these data identify a key complement evasion mechanism with important implications for ongoing efforts to develop meningococcal vaccines that employ fHbp as one of its components.

The lamina propria (LP) of the small intestine contains many dendritic cells (DC), which are likely to be in close contact with luminal antigens, but their role in intestinal immune responses has been overlooked. Here we show that after feeding mice ovalbumin (OVA), the majority of antigen uptake is associated with DC in the small intestinal LP, and we describe the isolation, purification and initial characterization of theses DC. We obtained >90% CD11c(+) DC using magnetic cell sorting, of which the majority were CD11b(+)CD8alpha(-), with smaller numbers of CD11b(-)CD8alpha(+) and CD11b(-)CD8alpha(-) DC as well as a distinct population of CD11c(int)class II MHC(lo) B220(+) DC. Freshly isolated LP DC expressed variable but generally low levels of CD40, CD80 and CD86, which were up-regulated by activation with LPS. LP DC were endocytic in vivo and in vitro and could present antigen to OVA-specific CD4(+) T cells in vitro. Antigen-loaded LP DC from OVA-fed mice also primed specific CD4(+) T cells in vivo and in vitro, but adoptive transfer of these DC into naive recipients induced hyporesponsiveness to subsequent challenge. LP DC also expressed significant levels of mRNA for IL-10 and type I IFN, but not IL-12, suggesting they may play a central and unique role in immune homeostasis in the gut.

West Nile virus (WNV) was first isolated in California during July 2003 from a pool of Culex tarsalis collected near El Centro, Imperial County. WNV transmission then increased and spread in Imperial and Coachella Valleys, where it was tracked by isolation from pools of Cx. tarsalis, seroconversions in sentinel chickens, and seroprevalence in free-ranging birds. WNV then dispersed to the city of Riverside, Riverside County, and to the Whittier Dam area of Los Angeles County, where it was detected in dead birds and pools of Cx. pipiens quinquefasciatus. By October, WNV was detected in dead birds collected from riparian corridors in Los Angeles, west to Long Beach, and through inland valleys south from Riverside to San Diego County. WNV was reported concurrently from Arizona in mid-August and from Baja, Mexico, in mid-November. Possible mechanisms for virus introduction, amplification, and dispersal are discussed.

OBJECTIVE

Inflammation is increasingly viewed as a new therapeutic target in subacute stages of brain infarction. However, apart from causing secondary damage, inflammation could equally promote beneficial lesion remodeling and repair. Distinct subpopulations of monocytes/macrophages (MOs/MPs) may critically determine the outcome of lesion-associated inflammation.

METHODS

We addressed the role of bone marrow-derived MOs/MPs in 2 different mouse models of ischemic stroke using a combined cell-specific depletion, chemokine receptor knockout, bone marrow chimeric, and pharmacological approach.

RESULTS

Starting within 24 hours of stroke onset, immature Ly6c(hi) monocytes infiltrated into the infarct border zone and differentiated into mature Ly6c(lo) phagocytes within the lesion compartment. MO/MP infiltration was CCR2-dependent, whereas we did not obtain evidence for additional recruitment via CX3CR1. Depletion of circulating MOs/MPs or selective targeting of CCR2 in bone marrow-derived cells caused delayed clinical deterioration and hemorrhagic conversion of the infarctions. Bleeding frequently occurred around thin-walled, dilated neovessels in the infarct border zone and was accompanied by decreased expression of transforming growth factor (TGF)-β1 and collagen-4, along with diminished activation of Smad2. Injection of TGF-β1 into the lesion border zone greatly reduced infarct bleeding in MO/MP-depleted mice.

CONCLUSIONS

Bone marrow-derived MOs/MPs recruited via CCR2 and acting via TGF-β1 are essential for maintaining integrity of the neurovascular unit following brain ischemia. Future therapies should be aimed at enhancing physiological repair functions of CCR2(+) MOs/MPs rather than blocking their hematogenous recruitment.

12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide.

This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129.

Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019).

Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile.

National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech.

BACKGROUND

Traumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescence-activated cell sorting for a CD133(+) and CD24(-/lo) population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.

RESULTS

hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.

CONCLUSIONS

The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the "window of opportunity" for intervention.

BACKGROUND

The primary treatments for clinically localized prostate cancer confer equivalent cancer control for most patients but disparate side effects. In the current study, the authors sought to compare health-related quality of life (HRQOL) outcomes after the most commonly used treatments.

METHODS

A total of 580 men completed the Medical Outcomes Study Short Form-36, the University of California-Los Angeles (UCLA) Prostate Cancer Index, and the American Urological Association Symptom Index before and through 24 months after treatment with radical prostatectomy (RP), external beam radiation therapy (EBRT), or brachytherapy (BT).

RESULTS

General HRQOL did not appear to be affected by treatment. Obstructive and irritative urinary symptoms were more common after BT (P<.001). Urinary control and sexual function were better after EBRT than BT (P<.001 and P=.02, respectively) and better after BT than RP (P<.001 and P=.01, respectively). Among potent men, recovery of sexual function was best after EBRT and was equivalent after bilateral nerve-sparing surgery or BT. Sexual bother was more common than urinary or bowel bother after all 3 treatments. Bowel dysfunction was more common after EBRT or BT than RP (P<.001).

CONCLUSIONS

In the current study, treatment for localized prostate cancer was found to differentially affect HRQOL outcomes. Urinary control and sexual function were better after EBRT, although bilateral nerve-sparing surgery diminished these differences among potent men undergoing RP. BT caused more obstructive and irritative symptoms, while both forms of radiation caused more bowel dysfunction. These results may inform medical decision-making in men with localized prostate cancer.

Estrogen is a negative regulator of lymphopoiesis and provides an experimental tool for probing relationships between lymphocyte precursors and stem cells. We found that expression of lymphocyte-associated genes and immunoglobulin (Ig) gene rearrangement occurred before CD45R acquisition. Lymphoid-restricted progenitors that were Lin(-)IL-7R alpha(+)c-kit(lo)TdT(+) (lineage marker(-), interleukin receptor 7 alpha(+), c-kit(lo) and terminal deoxynucleotidyl transferase(+)) were selectively depleted in estrogen-treated mice; within a less differentiated Lin-c-kit(hi) fraction, functional precursors of B and T, but not myeloid, cells were also selectively depleted. TdT and an Ig heavy chain transgene were detected within a hormone-regulated Lin(-)c-kit(hi)Sca-1(+)CD27(+)Flk-2(+)IL-7R alpha(-) subset of this multipotential progenitor population. Identification of these extremely early lymphoid precursors should facilitate investigation of the molecular mechanisms that control lineage-fate decisions in hematopoiesis.

OBJECTIVE

The authors' goal was to evaluate the association between impairment in daily function and subsyndromal depressive symptoms as well as major depression to determine the economic and societal significance of these conditions.

METHODS

Using 12-month prevalence data gathered by the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Program (ECA), based on responses to the NIMH Diagnostic Interview Schedule, the authors divided the 2,393 subjects from the Los Angeles ECA site into three groups: subjects with subsyndromal depressive symptoms (N = 270), major depression (N = 102), and no depressive disorder or symptoms (N = 2,021). The groups were compared on 10 domains of functional outcome and well-being.

RESULTS

Significantly more subjects with depressive symptoms than subjects who had no disorder reported high levels of household strain, social irritability, and financial strain as well as limitations in physical or job functioning, restricted activity days, bed days, and poor health status. Significantly more subjects with major depression than subjects with no disorder reported major financial losses, bed days, high levels of financial strain, limitations in physical or job functioning, and poor health status. Except for lower self-ratings of health status, no significant differences were found between subjects with subsyndromal symptoms and those with major depression.

CONCLUSIONS

Significantly more people with subsyndromal depressive symptoms or major depression reported impairment in eight of 10 functional domains than did subjects with no disorder. The high 1-year prevalence of subsyndromal depressive symptoms, combined with the associated functional impairment, emphasizes the clinical and public health importance and need for additional investigations into these symptoms.

BACKGROUND

Little is known about cancer-screening practices of various Asian subgroups, and even less is known about factors that may predict screening in these populations.

METHODS

Two independent surveys were conducted with 218 Filipino and 229 Korean female immigrants, aged 50 years and older, residing in Los Angeles.

RESULTS

In these convenience samples, 48% of Filipino and 41% of Korean women reported receipt of a Pap smear within the past 2 years; 41% of Filipino and 25% of Korean women reported receipt of a mammogram and a clinical breast exam within the past 2 years; and 25% of Filipino and 38% of Korean women reported colorectal cancer screening (blood stool test within the past 12 months or sigmoidoscopy/colonoscopy within the past 5 years). Only 14% of Filipino and 10% of Korean women were adherent to cancer-screening guidelines for all three sites. These differences in screening rates were statistically significant in multivariate analyses of the combined sample, controlling for all demographic characteristics, including age, percent of lifetime in the United States, education, marital status, health insurance, employment, and ethnicity. The two variables that were most consistently independently associated with adherence to cancer screening in both samples were higher percentage of lifetime spent in the United States and ever having had a checkup when no symptoms were present.

CONCLUSIONS

These two variables-percent of lifetime in the United States and ever having had a checkup when no symptoms were present-can alert a physician that cancer-screening tests may be overdue among Korean and Filipino immigrants in the United States. Future research should identify predictors of cancer screening among other Asian immigrant groups and U.S.-born Asian women to assist in targeting intervention efforts.

We screened for surface proteins expressed only by the early progenitor cells present in low-passage, low-density cultures of the adult stem/progenitor cells from bone marrow referred to as mesenchymal stem cells or multipotent stromal cells (MSCs). Six proteins were identified that were selectively expressed in the early progenitors: podocalyxin-like protein (PODXL), alpha6-integrin (CD49f), alpha4-integrin (CD49d), c-Met, CXCR4, and CX3CR1. All were previously shown to be involved in cell trafficking or tumor progression. Antibodies to CD49f and PODXL, a sialomucin in the CD34 family, were the most robust for FACScan assays. PODXL(hi)/CD49f(hi) MSCs were more clonogenic and differentiated more efficiently than PODXL(lo)/CD49f(lo) cells. Inhibition of expression of PODXL with RNA interference caused aggregation of the cells. Furthermore, PODXL(hi)/CD49f(hi) MSCs were less prone to produce lethal pulmonary emboli, and larger numbers were recovered in heart and kidney after intravenous infusion into mice with myocardial infarcts.

In this paper, we describe the ability of nontypeable Haemophilus influenzae (NTHi) to coexist with the human host and the devastating results associated with disruption of the delicate state of balanced pathogenesis, resulting in both acute and chronic respiratory tract infections. It has been seen that the strains of NTHi causing disease show a marked genetic and phenotypic diversity but that changes in the lipooligosaccharide (LOS) and protein size and antigenicity in chronically infected individuals indicate that individual strains of NTHi can remain and adapt themselves to avoid expulsion from their infective niche. The lack of reliance of NTHi on a single mechanism of attachment and its ability to interact with the host with rapid responses to its environment confirmed the success of this organism as both a colonizer and a pathogen. In vitro experiments on cell and organ cultures, combined with otitis media and pulmonary models in chinchillas, rats, and mice, have allowed investigations into individual interactions between NTHi and the mammalian host. The host-organism interaction appears to be a two-way process, with NTHi using cell surface structures to directly interact with the mammalian host and using secreted proteins and LOS to change the mammalian host in order to pave the way for colonization and invasion. Many experiments have also noted that immune system evasion through antigenic variation, secretion of enzymes and epithelial cell invasion allowed NTHi to survive for longer periods despite a specific immune response being mounted to infection. Several outer membrane proteins and LOS derivatives are discussed in relation to their efficacy in preventing pulmonary infections and otitis media in animals. General host responses with respect to age, genetic makeup, and vaccine delivery routes are considered, and a mucosal vaccine strategy is suggested.

fMRI studies have revealed three scene-selective regions in human visual cortex [the parahippocampal place area (PPA), transverse occipital sulcus (TOS), and retrosplenial cortex (RSC)], which have been linked to higher-order functions such as navigation, scene perception/recognition, and contextual association. Here, we document corresponding (presumptively homologous) scene-selective regions in the awake macaque monkey, based on direct comparison to human maps, using identical stimuli and largely overlapping fMRI procedures. In humans, our results showed that the three scene-selective regions are centered near-but distinct from-the gyri/sulci for which they were originally named. In addition, all these regions are located within or adjacent to known retinotopic areas. Human RSC and PPA are located adjacent to the peripheral representation of primary and secondary visual cortex, respectively. Human TOS is located immediately anterior/ventral to retinotopic area V3A, within retinotopic regions LO-1, V3B, and/or V7. Mirroring the arrangement of human regions fusiform face area (FFA) and PPA (which are adjacent to each other in cortex), the presumptive monkey homolog of human PPA is located adjacent to the monkey homolog of human FFA, near the posterior superior temporal sulcus. Monkey TOS includes the region predicted from the human maps (macaque V4d), extending into retinotopically defined V3A. A possible monkey homolog of human RSC lies in the medial bank, near peripheral V1. Overall, our findings suggest a homologous neural architecture for scene-selective regions in visual cortex of humans and nonhuman primates, analogous to the face-selective regions demonstrated earlier in these two species.

OBJECTIVE

Obesity has been associated with gastroesophageal reflux disease (GERD) and its complication, but the mechanism is unclear. We evaluated the association between obesity and function of lower esophageal sphincter (LOS) in subjects without GERD.

METHODS

We prospectively recruited consecutive obese (BMI >30) patients referred for weight reduction procedure and age- and sex-matched overweight (BMI 25-30) and normal weight (BMI>> or =20 and <25) subjects. Exclusion criteria included esophagitis, reflux symptoms, use of proton pump inhibitor, hiatus hernia >2 cm, and diabetes mellitus with microvascular complication. All participants underwent combined 2-hour postprandial esophageal manometry and pH monitoring after a standard test meal followed by 24-hour ambulatory pH monitoring.

RESULTS

Eighty-four subjects (obese, 28; overweight, 28; normal weight, 28) were studied. All 3 groups had comparable mean LOS pressure, LOS length, and peristaltic function. During the postprandial period, both obese and overweight groups had substantial increase in 2-hour rate of transient lower esophageal sphincter relaxation (TLOSR) (normal weight: 2.1 +/- 1.2 vs overweight: 3.8 +/- 1.6 vs obese: 7.3 +/- 2.0, P < .001), proportion of TLOSR with acid reflux (normal weight: 17.6% +/- 22.0% vs overweight 51.8% +/- 22.5% vs obese: 63.5% +/- 21.7%, P < .001), and gastroesophageal pressure gradient (GOPG) (normal weight: 4.5 +/- 1.2 mm Hg vs overweight: 7.1 +/- 1.4 mm Hg vs obese: 10.0 +/- 1.5 mm Hg, P < .001). Using multiple regression model, BMI (r(2): 0.70, B: 0.28, 95% CI: 0.24-0.33, P < .001) and waist circumference (r(2): 0.65, unstandardized regression coefficient [B]: 0.10, 95% CI: 0.08-0.11, P < .001) were significantly correlated with TLOSR.

CONCLUSIONS

Obesity is associated with increased TLOSR and acid reflux during the postprandial period in subjects without GERD. Abnormal postprandial LOS function may be an early event in the pathogenesis of obesity-related GERD.

How vaccines control the development of antigen-specific effector and memory T helper cells is central to protective immunity but remains poorly understood. Here we found that protein vaccination selected high-affinity, CXCR5+ICOS(hi) follicular B-helper T cells (T(FH) cells) that developed in draining lymphoid tissue to regulate B cell responses. In the memory phase, reservoirs of antigen-specific CXCR5+ICOS(lo) T(FH) cells persisted with less effector activity but accelerated antigen-recall ability. This new compartment of memory T(FH) cells was retained in draining lymphoid sites with antigen-specific memory B cells, persistent complexes of peptide and major histocompatibility complex class II and continued expression of CD69. Thus, protein vaccination promotes B cell immunity by selecting high-affinity effector T(FH) cells and creating lymphoid reservoirs of antigen-specific memory T(FH) cells in vivo.

BACKGROUND

The purpose of this trial was to investigate the effectiveness of an exercise rehabilitation program commencing during ICU admission and continuing into the outpatient setting compared with usual care on physical function and health-related quality of life in ICU survivors.

METHODS

We conducted a single-center, assessor-blinded, randomized controlled trial. One hundred and fifty participants were stratified and randomized to receive usual care or intervention if they were in the ICU for 5 days or more and had no permanent neurological insult. The intervention group received intensive exercises in the ICU and the ward and as outpatients. Participants were assessed at recruitment, ICU admission, hospital discharge and at 3-, 6- and 12-month follow-up. Physical function was evaluated using the Six-Minute Walk Test (6MWT) (primary outcome), the Timed Up and Go Test and the Physical Function in ICU Test. Patient-reported outcomes were measured using the Short Form 36 Health Survey, version 2 (SF-36v2) and Assessment of Quality of Life (AQoL) Instrument. Data were analyzed using mixed models.

RESULTS

The a priori enrollment goal was not reached. There were no between-group differences in demographic and hospital data, including acuity and length of acute hospital stay (LOS) (Acute Physiology and Chronic Health Evaluation II score: 21 vs 19; hospital LOS: 20 vs 24 days). No significant differences were found for the primary outcome of 6MWT or any other outcomes at 12 months after ICU discharge. However, exploratory analyses showed the rate of change over time and mean between-group differences in 6MWT from first assessment were greater in the intervention group.

CONCLUSIONS

Further research examining the trajectory of improvement with rehabilitation is warranted in this population.

BACKGROUND

The trial was registered with the Australian New Zealand Clinical Trials Registry ACTRN12605000776606.

OBJECTIVE

To determine whether hospital length of stay(LOS) for acute bronchiolitis is influenced by the infecting pathogen.

METHODS

A prospective observational cohort study was performed during 3 consecutive years.

METHODS

Sixteen US hospitals participated in the study.

METHODS

Children younger than 2 years hospitalized with bronchiolitis were included.

METHODS

The results of nasopharyngeal aspirate polymerase chain reaction pathogen testing served as the main exposure.

METHODS

Hospital LOS was determined.

RESULTS

Of 2207 participants, 72.0% had respiratory syncytial virus (RSV) and 25.6% had human rhinovirus(HRV); the incidence of each of the other viruses and bacteria was 7.8% or less. Multiple pathogen infections were present in 29.8% of the children. There were 1866 children(84.5%) with RSV and/or HRV. Among these 1866 children, the median age was 4 months and 59.5% were male. The median LOS was 2 days (interquartile range,1-4 days). Compared with children who had only RSV,an LOS of 3 or more days was less likely among children with HRV alone (adjusted odds ratio [AOR], 0.36; 95%CI, 0.20-0.63; P.001) and those with HRV plus non-RSV pathogens (AOR, 0.39; 95% CI, 0.23-0.66; P.001)but more likely among children with RSV plus HRV(AOR,1.33; 95% CI, 1.02-1.73; P=.04), controlling for 15 demographic and clinical factors.

CONCLUSIONS

In this multicenter study of children hospitalized with bronchiolitis, RSV was the most common virus detected, but HRV was detected in one-quarter of the children. Since 1 in 3 children had multiple virus infections and HRV was associated with LOS, these data challenge the effectiveness of current RSV-based cohorting practices, the sporadic testing for HRV in bronchiolitis research, and current thinking that the infectious etiology of severe bronchiolitis does not affect short-term outcomes.

BACKGROUND

Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis.

METHODS

Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored.

RESULTS

Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury.

CONCLUSIONS

Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury.

BACKGROUND

ClinicalTrials.gov identifier NCT01434121.

BACKGROUND

Neonatal infection is an important cause of morbidity and mortality. Neonatal infection surveillance networks are necessary for defining the epidemiology of infections and monitoring changes over time.

METHODS

Prospective multicentre surveillance using a web-based database.

METHODS

12 English neonatal units.

METHODS

Newborns admitted in 2006-2008, with positive blood, cerebrospinal fluid or urine culture and treated with antibiotics for at least 5 days.

METHODS

Incidence, age at infection, pathogens and antibiotic resistance profiles.

RESULTS

With the inclusion of coagulase negative Staphylococci (CoNS), the incidence of all neonatal infection was 8/1000 live births and 71/1000 neonatal admissions (2007-2008). The majority of infections occurred in premature (<37 weeks) and low birthweight (<2500 g) infants (82% and 81%, respectively). The incidence of early onset sepsis (EOS; ≤48 h of age) was 0.9/1000 live births and 9/1000 neonatal admissions, and group B Streptococcus (58%) and Escherichia coli (18%) were the most common organisms. The incidence of late onset sepsis (LOS; >48 h of age) was 3/1000 live births and 29/1000 neonatal admissions (7/1000 live births and 61/1000 admissions including CoNS) and the most common organisms were CoNS (54%), Enterobacteriaceae (21%) and Staphylococcus aureus (18%, 11% of which were methicillin resistant S aureus). Fungi accounted for 9% of LOS (72% Candida albicans). The majority of pathogens causing EOS (95%) and LOS (84%) were susceptible to commonly used empiric first line antibiotic combinations of penicillin/gentamicin and flucloxacillin/gentamicin, respectively (excluding CoNS).

CONCLUSIONS

The authors have established NeonIN in England and defined the current epidemiology of neonatal infections. These data can be used for benchmarking among units, international comparisons and as a platform for interventional studies.

The androgen receptor genotype was determined in the white blood cell DNA of 45 African-American, 39 non-Hispanic white, and 39 Asian (Chinese, Japanese) normal subjects and 68 patients with prostate cancer (57 whites), all of whom were residents of Los Angeles County. For each subject, we measured the number of repeats in the polymorphic CAG and GGC microsatellites of exon 1 of the androgen receptor gene. In normal subjects, the distributions of CAG and GGC microsatellites differed significantly among the races (two-sided P = 0.046 and < 0.0005, respectively). The prevalence of short CAG alleles (< 22 repeats) was highest (75%) in African-American males with the highest risk for prostate cancer, intermediate (62%) in intermediate-risk non-Hispanic whites, and lowest (49%) in Asians at very low risk for prostate cancer. High-risk African-Americans also had the lowest frequency (20%) of the GGC allele with 16 repeats; the comparable values for intermediate-risk whites and low-risk Asians were 57% and 70%, respectively. Consistent with the interracial variation in CAG and GGC distributions, there was an excess of white patients with < 22 CAG and not-16 GGC repeats relative to white controls (relative risk, 2.1; one-sided P = 0.08). We observed no association (linkage) between the two microsatellites among normal subjects. On the other hand, there was a statistically significant negative association between the numbers of CAG and GGC repeats among the prostate cancer patients studied (two-sided P = 0.008). Among the 47 subjects with short CAG alleles (< 22 repeats), 43% had long GGC alleles >> 16 repeats) whereas only 15% of the 20 subjects with long CAG alleles >> or = 22 repeats) had long GGC alleles. Overall, our data suggest a possible association between CAG and GGC microsatellites of the androgen receptor gene and prostate cancer development.

Two novel early B lymphocyte precursor populations have been identified by their capacity to differentiate in Whitlock-Witte bone marrow cultures. Cells expressing neither the B lineage antigen B220 nor Thy-1 contain committed B cell precursors which differentiate in short-term culture into pre-B and B cells. The other population expresses low levels of Thy-1, and lacks B220 as well as the T cell markers L3T4 and Lyt-2. The Thy-1+ cells which initiate long-term B cell cultures contain clonogenic B cell precursors at a frequency of 1 in 11, a 100-fold enrichment over unseparated bone marrow. Thy-1+ cells are also highly enriched for myeloid-erythroid precursors (CFU-S). Thy-1+ cells allow long-term survival of lethally irradiated mice and fully reconstitute the hematopoietic system, including T and B lymphocyte compartments. These results indicate that this population (approximately 0.1% of bone marrow) may contain the pluripotent hematopoietic stem cell.