Journal of negative results in biomedicine最新文献

Background: NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity in Japanese. A previous study has shown that ND2-237 Leu/Met polymorphism modulates the effects of green tea consumption on risk of hypertension. For men with ND2-237Leu, habitual green tea consumption may reduce the risk of hypertension. Moreover, there is a combined effect of ND2-237 Leu/Met polymorphism and alcohol consumption on risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2). Several beneficial effects of green tea on the kidney have been reported. The objective of this study was to investigate whether ND2-237 Leu/Met polymorphism modifies the effects of green tea consumption on risk of mildly decreased eGFR in male Japanese health check-up examinees.

Results: For ND2-237Leu genotypic men, after adjustment for confounding factors, green tea consumption may increase the risk of mildly decreased eGFR (P for trend = 0.016). The adjusted odds ratio (OR) for mildly decreased eGFR was significantly higher in subjects with ND2-237Leu who consume ≥6 cups of green tea per day than those who consume ≤1 cup of green tea per day (adjusted OR = 5.647, 95% confidence interval: 1.528-20.88, P = 0.009). On the other hand, for ND2-237Met genotypic men, green tea consumption does not appear to determine the risk of mildly decreased eGFR.

Conclusion: The present results suggest that ND2-237 Leu/Met polymorphism unexpectedly modifies the effects of green tea consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects.

Background: A Drug Influence Evaluation (DIE) is a formal assessment of an impaired driving suspect, performed by a trained law enforcement officer who uses circumstantial facts, questioning, searching, and a physical exam to form an unstandardized opinion as to whether a suspect's driving was impaired by drugs. This paper first identifies the scientific studies commonly cited in American criminal trials as evidence of DIE accuracy, and second, uses the QUADAS tool to investigate whether the methodologies used by these studies allow them to correctly quantify the diagnostic accuracy of the DIEs currently administered by US law enforcement.

Results: Three studies were selected for analysis. For each study, the QUADAS tool identified biases that distorted reported accuracies. The studies were subject to spectrum bias, selection bias, misclassification bias, verification bias, differential verification bias, incorporation bias, and review bias. The studies quantified DIE performance with prevalence-dependent accuracy statistics that are internally but not externally valid.

Conclusion: The accuracies reported by these studies do not quantify the accuracy of the DIE process now used by US law enforcement. These studies do not validate current DIE practice.

Background: Research on the impact of depression treatment on expenditures is nascent and shows results that vary from negative associations with healthcare expenditures to increased expenditures. However many of these studies did not include psychotherapy as part of the depression treatment. None of these studies included "no treatment" as a comparison group. In addition, no study has included a broad group of chronic physical conditions in studying depression treatment expenditures.

Objective: We determined the association between depression treatment and short-term healthcare expenditures using a nationally representative sample of Medicare beneficiaries with chronic physical conditions and depression.

Method: In this retrospective cohort study, we examined the association between depression treatment in the baseline year and healthcare expenditures in the following year using data from 2000 through 2005 of the Medicare Current Beneficiary Survey (MCBS), a nationally representative survey of Medicare beneficiaries. Using the rotating panel design of MCBS, we derived five two-year cohorts: 2000-2001, 2001-2002, 2002-2003, 2003-2004, and 2004-2005. The study sample included 1,055 elderly Medicare beneficiaries aged 65 or over. We compared healthcare expenditures of no depression treatment group with depression treatment groups using t-tests. Linear regressions of log-transformed dollars were used to assess the relationship between depression treatment and healthcare expenditures after controlling for demographic, socio-economic, health status, lifestyle risk factors, year of observation and baseline expenditures.

Results: Compared to no depression treatment ($16,795), the average total expenditures were higher for those who used antidepressants only ($17,425) and those who used psychotherapy with or without antidepressants ($19,733). After controlling for the independent variables, antidepressant use and psychotherapy with or without antidepressants were associated with 20.2% (95% CI: 14.1-26.7%) and 29.4% (95% CI: 18.8-41.0%) increase in total expenditures, respectively. We observed that depression treatment was positively associated with inpatient, medical provider and prescription drug expenditures.

Conclusion: Among the elderly Medicare beneficiaries with chronic physical conditions, depression treatment was associated with greater short-term healthcare expenditures. Future research needs to replicate these findings and also examine whether depression treatment reduces expenditures over a longer period of time.

Background: From a mechanistic or physical perspective there is no basis to suspect that electric charges on clusters of air molecules (air ions) would have beneficial or deleterious effects on respiratory function. Yet, there is a large lay and scientific literature spanning 80 years that asserts exposure to air ions affects the respiratory system and has other biological effects.

Aims: This review evaluates the scientific evidence in published human experimental studies regarding the effects of exposure to air ions on respiratory performance and symptoms.

Methods: We identified 23 studies (published 1933-1993) that met our inclusion criteria. Relevant data pertaining to study population characteristics, study design, experimental methods, statistical techniques, and study results were assessed. Where relevant, random effects meta-analysis models were utilized to quantify similar exposure and outcome groupings.

Results: The included studies examined the therapeutic benefits of exposure to negative air ions on respiratory outcomes, such as ventilatory function and asthmatic symptoms. Study specific sample sizes ranged between 7 and 23, and studies varied considerably by subject characteristics (e.g., infants with asthma, adults with emphysema), experimental method, outcomes measured (e.g., subjective symptoms, sensitivity, clinical pulmonary function), analytical design, and statistical reporting.

Conclusions: Despite numerous experimental and analytical differences across studies, the literature does not clearly support a beneficial role in exposure to negative air ions and respiratory function or asthmatic symptom alleviation. Further, collectively, the human experimental studies do not indicate a significant detrimental effect of exposure to positive air ions on respiratory measures. Exposure to negative or positive air ions does not appear to play an appreciable role in respiratory function.

Background: Rapamycin-induced translocation systems can be used to manipulate biological processes with precise temporal control. These systems are based on rapamycin-induced dimerization of FK506 Binding Protein 12 (FKBP12) with the FKBP Rapamycin Binding (FRB) domain of mammalian target of rapamycin (mTOR). Here, we sought to adapt a rapamycin-inducible phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phosphatase (Inp54p) system to deplete PIP2 in nociceptive dorsal root ganglia (DRG) neurons.

Results: We genetically targeted membrane-tethered CFP-FRBPLF (a destabilized FRB mutant) to the ubiquitously expressed Rosa26 locus, generating a Rosa26-FRBPLF knockin mouse. In a second knockin mouse line, we targeted Venus-FKBP12-Inp54p to the Calcitonin gene-related peptide-alpha (CGRPα) locus. We hypothesized that after intercrossing these mice, rapamycin treatment would induce translocation of Venus-FKBP12-Inp54p to the plasma membrane in CGRP+ DRG neurons. In control experiments with cell lines, rapamycin induced translocation of Venus-FKBP12-Inp54p to the plasma membrane, and subsequent depletion of PIP2, as measured with a PIP2 biosensor. However, rapamycin did not induce translocation of Venus-FKBP12-Inp54p to the plasma membrane in FRBPLF-expressing DRG neurons (in vitro or in vivo). Moreover, rapamycin treatment did not alter PIP2-dependent thermosensation in vivo. Instead, rapamycin treatment stabilized FRBPLF in cultured DRG neurons, suggesting that rapamycin promoted dimerization of FRBPLF with endogenous FKBP12.

Conclusions: Taken together, our data indicate that these knockin mice cannot be used to inducibly deplete PIP2 in DRG neurons. Moreover, our data suggest that high levels of endogenous FKBP12 could compete for binding to FRBPLF, hence limiting the use of rapamycin-inducible systems to cells with low levels of endogenous FKBP12.

As recent studies highlight the importance of alternative mechanisms in the control of bone turnover, new therapeutic approaches can be envisaged for bone diseases and periodontitis-induced bone loss. Recently, it has been shown that Fluoxetine and Venlafaxine, serotonin re-uptake inhibitors commonly used as antidepressants, can positively or negatively affect bone loss in rat models of induced periodontitis. Serotonin is a neurotransmitter that can be found within specific nuclei of the central nervous system, but can also be produced in the gut and be sequestered inside platelet granules. Although it is known to be mainly involved in the control of mood, sleep, and intestinal physiology, recent evidence has pointed at far reaching effects on bone metabolism, as a mediator of the effects of Lrp5, a membrane receptor commonly associated with Wnt canonical signaling and osteoblast differentiation. Deletion of Lrp5 in mice lead to increased expression of Tryptophan Hydroxylase 1, the gut isoform of the enzyme required for serotonin synthesis, thus increasing serum levels of serotonin. Serotonin, in turn, could bind to HTR1B receptors on osteoblasts and stop their proliferation by activating PKA and CREB.Although different groups have reported controversial results on the existence of an Lrp5-serotonin axis and the action of serotonin in bone remodeling, there is convincing evidence that serotonin modulators such as SSRIs can affect bone turnover. Consequently, the effects of this drug family on periodontal physiology should be thoroughly explored.

Background: The aim of the present study was to explore serological biomarkers which predict the outcome of tonsillectomy for chronic tonsillitis.

Methods: A case study in a University ENT department of 24 adult patients with chronic tonsillitis (CHT) in comparison to 24 patients with acute peritonsillar abscess (PTA) was performed. Blood samples for clinical routine hematological and serological parameters were assessed prior to surgery (T-1) and five days (T5) after tonsillectomy. Outcome 6 months later (T180) was documented using the Glasgow Benefit Inventory (GBI) and the Specific Benefits from Tonsillectomy Inventory (SBTI). Correlation analyses between CHT and PTA group as well as between the different time points within each group concerning the serological parameters and the outcome parameters were performed.

Results: At T-1, patients in the CHT group presented with significantly higher lymphocytes counts (relative and absolute), basophils (relative and absolute) and eosinophils but less white-cells, monocytes, neutrophils (absolute and relative), alpha-1, alpha-2, beta globulins, immunoglobulin and lower C-reactive protein and procalcitonin values than patients in the PTA group (all p < 0.05, respectively). Within each group, different significant changes of the serum parameters (often in opposite direction) were observed between T-1 and T5. SBTI scores at T-1 were significantly lower in the CHT group. In contrast, most GBI scores at T180 were significantly higher in the CHT group. Between T-1 and T180 the SBTI scores improved in three quarters of the CHT patients but only in three fifths of the PTA patients. Higher eosinophil counts and immunoglobulin E levels at T-1 predicted higher GBI scores at T180 in the CHT group.

Conclusions: This pilot study showed a specific serological pattern for patients with chronic tonsillitis with a specific pattern of changes after tonsillectomy. But there is no established role for biomarkers currently used in clinical practice to predict the outcome of tonsillectomy for chronic tonsillitis.

Background: Design and execution of immunotherapy trials for seasonal allergies may be complicated by numerous factors including variable allergy testing methods, pollen levels, and timing and intensity of other seasonal allergens. We evaluated grass allergy immunotherapy tablet (AIT) treatment in North American adults with grass pollen-induced allergic rhinitis with or without conjunctivitis (AR/C), with/without asthma.

Methods: Subjects age 18-65 with clinical history of grass pollen-induced AR/C, with/without asthma were randomized 1:1 to once-daily 2800 BAU Timothy grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, containing approximately 15 μg of Phl p 5) or placebo. The AR/C symptom and medication scores were recorded daily. The primary end point was the average AR/C daily symptom score (DSS) during the entire grass pollen season (GPS). Ranked key secondary end points were Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, daily medication score (DMS), and percentage of well days, all over entire GPS. Safety was monitored through adverse event reporting.

Results: Efficacy analysis included 289 subjects. Over the entire GPS, mean DSS was 6% lower with AIT versus placebo (5.69 vs. 6.06), but this difference was not statistically significant (p = 0.3475) despite significantly higher immunological response in the grass AIT group. No significant between-group differences were seen for key secondary end points. In general, DSS was high before GPS began and no clear relationship between DSS and grass pollen counts was seen during GPS. In post hoc analysis of subjects with pre-seasonal DSS ≤3, mean DSS and DMS were both significantly lower with grass AIT versus placebo (27%; p = 0.0327 and 68%; p = 0.0060, respectively). In this subgroup a relationship between DSS and grass pollen counts was observed. Grass AIT was generally well tolerated, with no events of anaphylactic shock or respiratory compromise.

Conclusions: In this trial, 2800 BAU grass AIT did not demonstrate significant symptom improvement versus placebo. Lack of relationship between pollen count and symptom score in the study population, and post hoc findings among subjects with low pre-seasonal symptoms, suggest that the symptoms reported in this study were not primarily reflective of the effects of grass pollen exposure.

Trial registration: NCT00421655.

Background: Guaranà (Paulinia cupana) seed extracts are increasingly popular worldwide for their stimulant, cognitive and behavioral effects. To assess the effects on psychological well-being, anxiety and mood of a commercially available guaranà preparation taken regularly over several days according to the labelled dosages and instructions, 27 healthy volunteers were enrolled in a prospective, randomized, single-blind, placebo-controlled, crossover study.

Results: Guaranà 350 mg × 3 daily just after breakfast or placebo were given for 5 consecutive days. Assessment was performed one day after the last intake and included the psychological well-being (PWB) scales, the self-rating anxiety state scale (SAS), and the Bond-Lader mood scales. There were no significant differences between guaranà and placebo in any of the 6 areas of PWB, in SAS, as well as in any of the 16 mood scales.

Conclusions: In healthy subjects a 5-day treatment with a commercial preparation of guaranà used according to labelled instructions provided no evidence for any major effects on psychological well-being, anxiety and mood. Considering the increasing popularity of guaranà-containing products sold as dietary supplements for fitness purposes, controlled studies are strongly warranted to assess their benefits in comparison to the labelled claims.

Background: Proteases are well-known virulence factors that promote survival, pathogenesis and immune evasion of many pathogens. Several lines of evidence suggest that the blood-brain barrier permeability is a prerequisite in microbial invasion of the central nervous system. Because proteases are frequently associated with vascular permeability by targeting junctional proteins, here it is hypothesized that neuropathogenic Escherichia coli K1 exhibit proteolytic activities to exert its pathogenicity.

Methods: Zymographic assays were performed using collagen and gelatin as substrates. The lysates of whole E. coli K1 strain E44, or E. coli K-12 strain HB101 were tested for proteolytic activities. The conditioned media were prepared by incubating bacteria in RPMI-1640 in the presence or absence of serum. The cell-free supernatants were collected and tested for proteases in zymography as mentioned above. Additionally, proteolytic degradation of host immune factors was determined by co-incubating conditioned media with albumin/immunoglobulins using protease assays.

Results: When collagen or gelatin were used as substrates in zymographic assays, neither whole bacteria nor conditioned media exhibited proteolytic activities. The conditioned media of neuropathogenic E. coli K1 strain E44, or E. coli K-12 strain HB101 did not affect degradation of albumin and immunoglobulins using protease assays.

Conclusions: Neither zymographic assays nor protease assays detected proteolytic activities in either the whole bacteria or conditioned media of E. coli K1 strain E44 and E. coli K-12 strain HB101. These findings suggest that host cell monolayer disruptions and immune evasion strategies are likely independent of proteolytic activities of neuropathogenic E. coli K1.