Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PPi), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PPi, resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in Alpl−/− mice, a model for infantile HPP. In Alpl−/− mice, dentin mineralization is specifically delayed in the root, however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the present study, we aimed to define the molecular basis for changes in dentinogenesis observed in Alpl−/− mice. TNAP was found to be highly expressed by mature odontoblasts, and Alpl−/− molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in Alpl−/− dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in Alpl−/− mice, was present in the generally unmineralized Alpl−/− mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in Alpl−/− mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to Alpl−/− mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PPi during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients.
Tissue-nonspecific alkaline phosphatase; TNAP; dentin; pyrophosphate; osteopontin; matrix vesicles
Parathyroid hormone (PTH) anabolic osteoporosis therapy is intrinsically limited by unknown mechanisms. We previously showed that disabling the transcription factor Nmp4/CIZ in mice expanded this anabolic window while modestly elevating bone resorption. This enhanced bone formation requires a lag period to materialize. Wild-type (WT) and Nmp4-knockout (KO) mice exhibited equivalent PTH-induced increases in bone at 2 weeks of treatment, but by 7 weeks, the null mice showed more new bone. At 3-week treatment, serum osteocalcin, a bone formation marker, peaked in WT mice, but continued to increase in null mice. To determine if 3 weeks is the time when the addition of new bone diverges and to investigate its cellular basis, we treated 10-week-old null and WT animals with human PTH (1–34) (30 μg/kg/day) or vehicle before analyzing femoral trabecular architecture and bone marrow (BM) and peripheral blood phenotypic cell profiles. PTH-treated Nmp4-KO mice gained over 2-fold more femoral trabecular bone than WT by 3 weeks. There was no difference between genotypes in BM cellularity or profiles of several blood elements. However, the KO mice exhibited a significant elevation in CFU-F cells, CFU-FAlkPhos+ cells (osteoprogenitors), and a higher percentage of CFU-FAlkPhos+ cells/CFU-F cells consistent with an increase in CD45−/CD146+/CD105+/nestin+ mesenchymal stem cell frequency. Null BM exhibited a 2-fold enhancement in CD8+ T cells known to support osteoprogenitor differentiation and a 1.6-fold increase in CFU-GM colonies (osteoclast progenitors). We propose that Nmp4/CIZ limits the PTH anabolic window by restricting the number of BM stem, progenitor, and blood cells that support anabolic bone remodeling.
We re-examined the observation that γδ T cells, when transferred from mice tolerized to an inhaled conventional antigen (Ag), suppress the allergic IgE response to this Ag specifically. Using ovalbumin and hen egg lysozyme in crisscross fashion, we confirmed the Ag-specific IgE regulatory effect of the γδ T cells. Although only Vγ4+ γδ T cells are regulators, the Ag specificity does not stem from specificity of their γδ TCRs. Instead, the Vγ4+ γδ T cells failed to respond to either Ag, but rapidly acquired Ag-specific regulatory function in vivo following i.v. injection of non-T cells derived from the spleen of Ag-tolerized mice. This correlated with their in vivo Ag acquisition from i.v. injected Ag-loaded splenic non-T cells, and in vivo transfer of membrane label provided evidence for direct contact between the injected splenic non-T cells and the Vγ4+ γδ T cells. Together, our data suggest that Ag itself, when acquired by γδ T cells, directs the specificity of their IgE suppression.
Non-cardiac chest pain (NCCP) is a common and distressing condition. Prior studies suggest that psychotropic medication or pain coping skills training (CST) may benefit NCCP patients. To our knowledge, no clinical trials have examined the separate and combined effects of CST and psychotropic medication in the management of NCCP. This randomized clinical trial examined the separate and combined effects of CST and antidepressant medication (sertraline) in participants with non-cardiac chest pain. A sample of individuals diagnosed with NCCP was randomly assigned to one of four treatments: (1) CST plus sertraline (CST + sertraline), (2) CST plus placebo (CST + placebo), (3) sertraline alone, or (4) placebo alone. Assessments of pain intensity, pain unpleasantness, anxiety, pain catastrophizing, depression, and physical disability were collected prior to treatment, and at 10- and 34-weeks following randomization. Data analyses revealed that CST and sertraline either alone or in combination significantly reduced pain intensity and pain unpleasantness. The combination of CST plus sertraline may have the greatest promise in that, when compared to placebo alone, it not only significantly reduced pain but also pain catastrophizing and anxiety. Overall, these findings support the importance of further research on the effects of CST and sertraline for non-cardiac chest pain.
Non-cardiac chest pain; Pain; Pain catastrophizing; Coping skills training; Sertraline; Anxiety
Although the importance of detecting, treating, and controlling hypertension has been recognized for decades, the majority of patients with hypertension remain uncontrolled. The path from evidence to practice contains many potential barriers, but their role has not been reviewed systematically. This review aimed to synthesize and identify important barriers to hypertension control as reported by patients and healthcare providers.
Electronic databases MEDLINE, EMBASE and Global Health were searched systematically up to February 2013. Two reviewers independently selected eligible studies. Two reviewers categorized barriers based on a theoretical framework of behavior change. The theoretical framework suggests that a change in behavior requires a strong commitment to change [intention], the necessary skills and abilities to adopt the behavior [capability], and an absence of health system and support constraints.
Twenty-five qualitative studies and 44 quantitative studies met the inclusion criteria. In qualitative studies, health system barriers were most commonly discussed in studies of patients and health care providers. Quantitative studies identified disagreement with clinical recommendations as the most common barrier among health care providers. Quantitative studies of patients yielded different results: lack of knowledge was the most common barrier to hypertension awareness. Stress, anxiety and depression were most commonly reported as barriers that hindered or delayed adoption of a healthier lifestyle. In terms of hypertension treatment adherence, patients mostly reported forgetting to take their medication. Finally, priority setting barriers were most commonly reported by patients in terms of following up with their health care providers.
This review identified a wide range of barriers facing patients and health care providers pursuing hypertension control, indicating the need for targeted multi-faceted interventions. More methodologically rigorous studies that encompass the range of barriers and that include low- and middle-income countries are required in order to inform policies to improve hypertension control.
Despite the frequent detection of circulating tumor antigen–specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8+ effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8+ effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8+ effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8+ T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.
Although data clearly link major depression and smoking, little is known about the association between dysthymia and minor depression and smoking behavior. The current study examined changes in smoking over three years for current and former smokers with and without dysthymia and minor depression.
Participants who were current or former daily cigarette smokers at Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions and completed the Wave 2 assessment were included in these analyses (n=11,973; 46% female). Analyses examined the main and gender-specific effects of current dysthymia, lifetime dysthymia, and minor depression (a single diagnostic category that denoted current and or lifetime prevalence) on continued smoking for Wave 1 current daily smokers and continued abstinence for Wave 1 former daily smokers.
Wave 1 current daily smokers with current dysthymia (OR=2.13, 95% CI=1.23, 3.70) or minor depression (OR=1.53, 95% CI=1.07, 2.18) were more likely than smokers without the respective diagnosis to report continued smoking at Wave 2. Wave 1 former daily smokers with current dysthymia (OR=0.44, 95% CI=0.20, 0.96) and lifetime dysthymia (OR=0.37, 95% CI=0.15, 0.91) were less likely than those without the diagnosis to remain abstinent from smoking at Wave 2. The gender-by-diagnosis interactions were not significant, suggesting that the impact of dysthymia and minor depression on smoking behavior is similar among men and women.
Current dysthymia and minor depression are associated with a greater likelihood of continued smoking; current and lifetime dysthymia are associated with a decreased likelihood of continued smoking abstinence.
Smoking; Cessation; Relapse; Dysthymia; Minor Depression; Gender; Epidemiological Data
The perirhinal cortex (Brodmann's area 35) is a multimodal area that is important for normal memory function. Specifically, perirhinal cortex is involved in detection of novel objects and manifests neurofibrillary tangles in Alzheimer's disease very early in disease progression. We scanned ex vivo brain hemispheres at standard resolution (1 mm × 1 mm × 1 mm) to construct pial/white matter surfaces in FreeSurfer and scanned again at high resolution (120 μm × 120 μm × 120 μm) to determine cortical architectural boundaries. After labeling perirhinal area 35 in the high resolution images, we mapped the high resolution labels to the surface models to localize area 35 in fourteen cases. We validated the area boundaries determined using histological Nissl staining. To test the accuracy of the probabilistic mapping, we measured the Hausdorff distance between the predicted and true labels and found that the median Hausdorff distance was 4.0 mm for left hemispheres (n = 7) and 3.2 mm for right hemispheres (n = 7) across subjects. To show the utility of perirhinal localization, we mapped our labels to a subset of the Alzheimer's Disease Neuroimaging Initiative dataset and found decreased cortical thickness measures in mild cognitive impairment and Alzheimer's disease compared to controls in the predicted perirhinal area 35. Our ex vivo probabilistic mapping of perirhinal cortex provides histologically validated, automated and accurate labeling of architectonic regions in the medial temporal lobe, and facilitates the analysis of atrophic changes in a large dataset for earlier detection and diagnosis.
morphometry; mesocortex; Alzheimer's disease; localization
Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence
of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a
cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found
evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age
from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans
(86% of whom were also athletes) and one individual who engaged in self-injurious
head banging behaviour. Eighteen age- and gender-matched individuals without a history of
repetitive mild traumatic brain injury served as control subjects. In chronic traumatic
encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from
focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to
severe tauopathy affecting widespread brain regions, including the medial temporal lobe,
thereby allowing a progressive staging of pathology from stages I–IV. Multifocal
axonal varicosities and axonal loss were found in deep cortex and subcortical white matter
at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43
immunoreactive inclusions and neurites were also found in 85% of cases, ranging
from focal pathology in stages I–III to widespread inclusions and neurites in stage
IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of
attention and concentration. Additional symptoms in stage II included depression,
explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive
impairment were found, and in stage IV, dementia, word-finding difficulty and aggression
were characteristic. Data on athletic exposure were available for 34 American football
players; the stage of chronic traumatic encephalopathy correlated with increased duration
of football play, survival after football and age at death. Chronic traumatic
encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed
with motor neuron disease (12%), seven with Alzheimer’s disease (11%),
11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration
(6%). There is an ordered and predictable progression of hyperphosphorylated tau
abnormalities through the nervous system in chronic traumatic encephalopathy that occurs
in conjunction with widespread axonal disruption and loss. The frequent association of
chronic traumatic encephalopathy with other neurodegenerative disorders suggests that
repetitive brain trauma and hyperphosphorylated tau protein deposition promote the
accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43,
amyloid beta protein and alpha-synuclein.
axonal injury; brain trauma; frontotemporal lobar degeneration; neurodegenerative disorders; traumatic brain injury
Reprogramming of somatic cells into iPSCs involves a dramatic reorganization of chromatin. To identify posttranslational histone modifications that change in global abundance during this process, we have applied a quantitative mass-spectrometry-based approach. We found that iPSCs, compared to both the starting fibroblasts and a late reprogramming intermediate (pre-iPSCs), are enriched for histone modifications associated with active chromatin, and depleted for marks of transcriptional elongation and a subset of repressive modifications including H3K9me2/me3. Dissecting the contribution of H3K9methylation to reprogramming, we show that the H3K9methyltransferases Ehmt1, Ehmt2, and Setdb1 regulate global H3K9me2/me3 levels and that their depletion increases iPSC formation from both fibroblasts and pre-iPSCs. Similarly, inhibition of heterochromatin-protein-1γ (Cbx3), a protein known to recognize H3K9methylation, enhances reprogramming. Genome-wide location analysis revealed that Cbx3 predominantly binds active genes in both pre-iPSCs and pluripotent cells but with a strikingly different distribution: in pre-iPSCs, but not in ESCs, Cbx3 associates with active transcriptional start sites, suggesting a developmentally-regulated role for Cbx3 in transcriptional activation. Despite largely non-overlapping functions and the association of Cbx3 with active transcription, the H3K9methyltransferases and Cbx3 both inhibit reprogramming by repressing the pluripotency factor Nanog. Together, our findings demonstrate that Cbx3 and H3K9methylation restrict late reprogramming events, and suggest that a dramatic change in global chromatin character is an epigenetic roadblock for reprogramming.
The low body mass index (BMI) phenotype of less than 18.5 has been linked to medical and psychological morbidity as well as increased mortality risk. Although genetic factors have been shown to influence BMI across the entire BMI, the contribution of genetic factors to the low BMI phenotype is unclear. We hypothesized genetic factors would contribute to risk of a low BMI phenotype. To test this hypothesis, we conducted a genealogy data analysis using height and weight measurements from driver's license data from the Utah Population Data Base. The Genealogical Index of Familiality (GIF) test and relative risk in relatives were used to examine evidence for excess relatedness among individuals with the low BMI phenotype. The overall GIF test for excess relatedness in the low BMI phenotype showed a significant excess over expected (GIF 4.47 for all cases versus 4.10 for controls, overall empirical p-value<0.001). The significant excess relatedness was still observed when close relationships were ignored, supporting a specific genetic contribution rather than only a family environmental effect. This study supports a specific genetic contribution in the risk for the low BMI phenotype. Better understanding of the genetic contribution to low BMI holds promise for weight regulation and potentially for novel strategies in the treatment of leanness and obesity.
The objective of this study is to comprehensively define the genetic basis of Early Onset Myasthenia Gravis.
We have carried out a two-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the HLA region.
We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10−92, OR = 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10−113, OR = 6.41). In addition to the expected association with PTPN22 (rs2476601, OR =1.71, p = 8.2 ×10−10), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR = 1.91, p = 3.2 × 10−10).
The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8+ T-cells may play a key role in disease initiation or pathogenesis.
Little is known about overall or gender-specific factors that may influence the relationship between negative affect and smoking behavior such as smoking expectancies. This paper presents a secondary analysis from a laboratory studying gender differences in smoking behavior following a musical mood induction [Weinberger, A.H., & McMcKee, S.A., 2012, Gender differences in smoking following an implicit mood induction. Nicotine & Tobacco Research, 14(5), 621–625]. The current analyses examine the role of expectancies (endorsement and accessibility) in the relationship of gender, affect, and smoking. Ninety adult smokers (50% female) were randomly assigned to a negative mood induction, positive mood induction, or neutral condition while completing a single laboratory session. Expectancy endorsement, expectancy accessibility, affect, and smoking topography were assessed following the mood induction. Female smokers with faster accessibility of negative reinforcement expectancies smoked more cigarettes, had longer puff durations, and had shorter inter-puff intervals. Women with faster expectancy accessibility were also more likely to endorse negative reinforcement smoking expectancies. This study was the first to demonstrate links among gender, mood, and accessibility of smoking-related beliefs. Information about the role of expectancy accessibility in smoking behavior can lead to both a better understanding of gender-specific mechanisms of smoking behavior and new directions for smoking treatment development.
expectancies; accessibility; smoking; negative affect; gender
Podocytes are specialized cells that contribute critically to the normal structure and function of the glomerular filtration barrier. Their depletion plays an important role in the pathogenesis of glomerulosclerosis. Here, we report generation of a genetic model of conditional podocyte ablation and regeneration in zebrafish using a bacterial nitroreductase strategy to convert a prodrug, Metronidazole, into a cytotoxic metabolite. A transgenic zebrafish line was generated that expresses a green fluorescence protein (GFP) and the nitroreductase fusion protein under the control of the podocin promoter Tg(podocin:nitroreductase-GFP). Treatment of these transgenic zebrafish with Metronidazole results in podocyte apoptosis, a loss of nephrin and podocin expression, foot process effacement, and a leaky glomerular filtration barrier. Following Metronidazole washout, proliferating cells were detected in the glomeruli of recovering transgenic fish with a restoration of nitroreductase-GFP fluorescence, nephrin and podocin expression, a reestablishment of normal foot process architecture and glomerular barrier function. Thus, our studies show that zebrafish podocytes are capable of regenerating following depletion and establish the Tg(podocin:NTR-GFP) fish as a new model to study podocyte injury and repair.
Podocyte; nitroreductase; zebrafish; ablation; kidney regeneration
A screen of a library of synthetic drugs and natural product extracts identified a botanical extract that modulates the processing of amyloid precursor protein (APP) in cultured cells to produce a lowered ratio of amyloid-beta peptide (1–42) (Aβ42) relative to Aβ40. This profile is of interest as a potential treatment for Alzheimer’s disease. The extract, from the black cohosh plant (Actaea racemosa), was subjected to bioassay guided fractionation to isolate active components. Using a combination of normal-phase and reverse-phase chromatography, a novel triterpene monoglycoside, 1, was isolated. This compound was found to have an IC50 of 100 nM for selectively reducing the production of amyloidogenic Aβ42 while having a much smaller effect on the production of Aβ40 (IC50 6.3 μM) in cultured cells overexpressing APP. Using IP-MS methods, this compound was found to modulate the pool of total Aβ produced by reducing the proportion of Aβ42 while increasing the relative amounts of shorter and less amyloidogenic Aβ37 and Aβ39. Concentrations of 1 sufficient to lower levels of Aβ42 substantially (up to 10 μM) did not significantly affect the processing of Notch or other aspects of APP processing. When 1 (10 μg) was administered to CD-1 normal mice intracerebroventricularly, the level of Aβ42 in brain was reduced. Assays for off-target pharmacology and the absence of overt signs of toxicity in mice dosed with compound 1 suggest a comparatively selective pharmacology for this triterpenoid. Compound 1 represents a new lead for the development of potential treatments for Alzheimer’s disease via modulation of gamma-secretase.
Alzheimer’s disease; amyloid-beta peptide; gamma-secretase modulator; botanical extract; Actaea racemosa; triterpene glycoside
Coping and negative cognitive style were studied in relation to depressive symptoms in children at risk for depression. In a sample of 165 children (ages 9–15) of depressed parents, the main and interaction effects of coping and negative cognitive style were examined in association with children’s depressive symptoms measured by parent and child report on questionnaires and diagnostic interviews. Negative cognitive style was related to three types of coping (primary control, secondary control, and disengagement). Furthermore, coping and negative cognitive style made independent contributions to depressive symptoms. Little support emerged for interactive effects on depressive symptoms. Implications for future research with this high-risk population of children are considered.
Coping; Negative Cognitive Style; Children; Depression; Parental depression
In the title compound, C12H8N2O5, the aromatic rings are inclined to one another by 56.14 (7)°. The nitro groups are inclined by to the benzene rings to which they are attached by 3.86 (17) and 9.65 (15)°. In the crystal, molecules are linked by C—H⋯O hydrogen bonds, forming a three-dimensional structure. The title compound is a new monoclinic polymorph, crystallizing in space group P21/c. The first polymorph crystallized in space group C2/c and the molecule possesses twofold rotation symmetry. Two low-temperature structures of this polymorph (150 K and 100 K, respectively) have been reported [Meciarova et al. (2004). Private Communication (refcode IXOGAD). CCDC, Cambridge, England, and Dey & Desiraju (2005). Chem. Commun. pp. 2486–2488].
To facilitate translational work in medications development for smoking cessation, we have developed a human laboratory analogue of smoking lapse behavior. Our paradigm models 2 critical features of smoking lapse: the ability to resist the first cigarette and subsequent ad
libitum smoking. In this paper we present the results of 2 studies designed to develop and validate the effect of nicotine deprivation on smoking lapse behavior.
Study 1 (n = 30) was designed to develop the model parameters by examining varying levels of nicotine deprivation (1, 6, and 18 hr; within-subject) and identifying optimum levels of monetary reinforcement to provide while modeling the ability to resist smoking. Study 2 was designed to validate the model by screening smoking cessation medications with known clinical efficacy. Subjects (n = 62) were randomized to either varenicline 2 mg/day, bupropion 300 mg/day, or placebo, and we then modeled their ability to resist smoking and subsequent ad
In Study 1, increasing levels of nicotine deprivation and decreasing levels of monetary reinforcement decreased the ability to resist smoking. In Study 2, the lapse model was found to be sensitive to medication effects among smokers who demonstrated a pattern of heavy, uninterrupted, and automated smoking (i.e., smoked within 5 min of waking). Ratings of craving, mood, withdrawal, and subjective cigarette effects are presented as secondary outcomes with results mirroring clinical findings.
Our smoking lapse model demonstrates promise as a translational tool to screen novel smoking cessation medications. Next steps in this line of research will focus on evaluating predictive validity.
Cigarette smoking and alcohol consumption are positively correlated, and the concurrent use of tobacco and alcohol exacerbates the health risks associated with the singular use of either product. Indoor smoke-free policies have been effective in reducing smoking, but little is known about any impact of these policies on drinking behavior. The purpose of this study was to evaluate the potential association between the implementation of smoke-free bar policies and smokers’ alcohol consumption.
A prospective, multi-country cohort survey design was utilized. Participants were nationally representative samples of smokers from the United Kingdom, Australia, Canada, and the United States, who were interviewed as part of the International Tobacco Control Four Country Survey (ITC-4) in 2005, 2007, or 2008 (N = 11914). Changes in the frequency and amount of alcohol consumption were assessed as functions of change in the presence of smoke-free bar policies over time.
Overall, changes in alcohol consumption were statistically indistinguishable between those whose bars became smoke-free and those whose bars continued to allow smoking. However, implementation of smoke-free policies was associated with small reductions in the amount of alcohol typically consumed by those who were classified as hazardous drinkers, along with small reductions in the frequency of alcohol consumption among heavy smokers.
Smoking bans in public places, which protect millions of non-smokers from the harmful effects of second-hand smoke, do not appear to be associated with sizable reductions in smokers’ alcohol consumption in general, but may be associated with small consumption reductions among subgroups.
Smoke-free policies; alcohol consumption; International Tobacco Control Four Country Survey
Urogenital schistosomiasis caused by Schistosoma haematobium is widely distributed across Africa and is increasingly being targeted for control. Genome sequences and population genetic parameters can give insight into the potential for population- or species-level drug resistance. Microsatellite DNA loci are genetic markers in wide use by Schistosoma researchers, but there are few primers available for S. haematobium.
We sequenced 1,058,114 random DNA fragments from clonal cercariae collected from a snail infected with a single Schistosoma haematobium miracidium. We assembled and aligned the S. haematobium sequences to the genomes of S. mansoni and S. japonicum, identifying microsatellite DNA loci across all three species and designing primers to amplify the loci in S. haematobium. To validate our primers, we screened 32 randomly selected primer pairs with population samples of S. haematobium.
We designed >13,790 primer pairs to amplify unique microsatellite loci in S. haematobium, (available at http://www.cebio.org/projetos/schistosoma-haematobium-genome). The three Schistosoma genomes contained similar overall frequencies of microsatellites, but the frequency and length distributions of specific motifs differed among species. We identified 15 primer pairs that amplified consistently and were easily scored. We genotyped these 15 loci in S. haematobium individuals from six locations: Zanzibar had the highest levels of diversity; Malawi, Mauritius, Nigeria, and Senegal were nearly as diverse; but the sample from South Africa was much less diverse.
About half of the primers in the database of Schistosoma haematobium microsatellite DNA loci should yield amplifiable and easily scored polymorphic markers, thus providing thousands of potential markers. Sequence conservation among S. haematobium, S. japonicum, and S. mansoni is relatively high, thus it should now be possible to identify markers that are universal among Schistosoma species (i.e., using DNA sequences conserved among species), as well as other markers that are specific to species or species-groups (i.e., using DNA sequences that differ among species). Full genome-sequencing of additional species and specimens of S. haematobium, S. japonicum, and S. mansoni is desirable to better characterize differences within and among these species, to develop additional genetic markers, and to examine genes as well as conserved non-coding elements associated with drug resistance.
Africa; Differentiation; FST; Genomic; Microsatellites; Primer database; Schistosoma haematobium; Urogenital schistosomiasis
Advanced Trauma Life Support (ATLS) protocols provide a common approach for trauma resuscitations. This was a quality review assessing compliance with ATLS protocols at a Level I trauma center; specifically whether the presence or absence of a trauma team leader (TTL) influenced adherence.
This retrospective study was conducted on adult major trauma patients with acute injuries over a one-year period in a Level I Canadian trauma center. Data were collected from the Alberta Trauma Registry, and adherence to ATLS protocols was determined by chart review.
The study identified 508 patients with a mean Injury Severity Score of 24.5 (SD 10.7), mean age 39.7 (SD 17.6), 73.8% were male and 91.9% were involved in blunt trauma. The overall compliance rate was 81.8% for primary survey and 75% for secondary survey. The TTL group compared to non-TTL group was more likely to complete the primary survey (90.9% vs. 81.8%, p = 0.003), and the secondary survey (100% vs. 75%, p = 0.004). The TTL group was more likely than the non-TTL group to complete the following tasks: insertion of two large bore IVs (68.2% vs. 57.7%, p = 0.014), digital rectal exam (64.6% vs. 54.7%, p = 0.023), and head to toe exam (77% vs. 67.1%, p = 0.013). Mean times from emergency department arrival to diagnostic imaging were also significantly shorter in the TTL group compared to the non-TTL group, including times to pelvis xray (mean 68min vs. 107min, p = 0.007), CT chest (mean 133min vs. 172min, p = 0.005), and CT abdomen and pelvis (mean 136min vs. 173min, p = 0.013). Readmission rates were not significantly different between the TTL and non-TTL groups (3.5% vs. 4.5%, p = 0.642).
While many studies have demonstrated the effectiveness of trauma systems on outcomes, few have explored the direct influence of the TTL on ATLS compliance. This study demonstrated that TTL involvement during resuscitations was associated with improved adherence to ATLS protocols, and increased efficiency (compared to non TTL involvement) to diagnostic imaging. Findings from this study will guide future quality improvement and education for early trauma management.
Advanced trauma life support; Quality improvement; Trauma team leader; Major trauma; Wounds & injuries
As broadly demonstrated for the formation of a functional skeleton, proper mineralization of periodontal alveolar bone and teeth – where calcium phosphate crystals are deposited and grow within an extracellular matrix – is essential to dental function. Mineralization defects in tooth dentin and cementum of the periodontium invariably lead to a weak (soft or brittle) dentition such that teeth become loose and prone to infection and are lost prematurely. Mineralization of the extremities of periodontal ligament fibres (Sharpey's fibres) where they insert into tooth cementum and alveolar bone is also essential for the function of the tooth suspensory apparatus in occlusion and mastication. Molecular determinants of mineralization in these tissues include mineral ion concentrations (phosphate and calcium), pyrophosphate, small integrin-binding ligand N-linked glycoproteins (SIBLINGs), and matrix vesicles. Amongst the enzymes important in regulating these mineralization determinants, two are discussed at length here with clinical examples given, namely tissue-nonspecific alkaline phosphatase (TNAP) and phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). Inactivating mutations in these enzymes in humans and in mouse models lead to the soft bones and teeth characteristic of hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH), respectively, where levels of local and systemic circulating mineralization determinants are perturbed. In XLH, in addition to renal phosphate wasting causing low circulating phosphate levels, phosphorylated mineralization-regulating SIBLING proteins such as matrix extracellular phosphoglycoprotein (MEPE) and osteopontin (OPN), and the phosphorylated peptides proteolytically released from them such as the acidic serine- and aspartate-rich motif (ASARM) peptide, may accumulate locally to impair mineralization in this disease.
Although depression and smoking are highly correlated, the relationship of Major Depressive Disorder (MDD) to smoking cessation and relapse remains unclear. This study compared changes in smoking for current and former smokers with and without Current and Lifetime MDD over a three year period.
Analysis of two waves of longitudinal data from the National Institute on Alcohol Abuse and Alcoholism’s National Epidemiologic Survey on Alcohol and Related Conditions (Wave 1, 2001–2002; Wave 2, 2004–2005).
Data were collected through face-to-face interviews from non-institutionalized United States civilians, 18 years and older, in 50 states and the District of Columbia.
11,973 adults (46% female) classified as Current or Former Daily Smokers at Wave 1 and completed Wave 2.
Classification as Current or Former Smokers at Wave 1 and Wave 2.
Smoking status remained stable for most participants. Wave 1 Current Daily Smokers with Current MDD (OR=1.38, 95% CI=1.03, 1.85) and Lifetime MDD (OR=1.48, 95% CI=1.18, 1.85) were more likely than those without the respective diagnosis to report continued smoking at Wave 2. Wave 1 Former Daily Smokers with Current MDD (OR=0.44, 95% CI=0.26, 0.76) were less likely to report continued abstinence at Wave 2. None of the gender by MDD diagnosis interactions were significant. Patterns of results remained similar when analyses were limited to smokers with nicotine dependence.
Current and Lifetime Major Depressive Disorder are associated with a lower likelihood of quitting smoking and Current Major Depressive Disorder is associated with greater likelihood of smoking relapse.