Background: Conjugative plasmid transfer is the prevalent means for spreading antibiotic resistance genes among bacteria.
Results: Surface exposure of transfer protein TraM from the Gram-positive (G+) plasmid pIP501 was confirmed, and its crystal structure was solved.
Conclusion: Structural relations to type IV secretion (T4S) proteins provide a novel classification scheme.
Significance: The novel classification will help elucidate structure-function relationships in G+ T4S systems.
Conjugative plasmid transfer is the most important means of spreading antibiotic resistance and virulence genes among bacteria and therefore presents a serious threat to human health. The process requires direct cell-cell contact made possible by a multiprotein complex that spans cellular membranes and serves as a channel for macromolecular secretion. Thus far, well studied conjugative type IV secretion systems (T4SS) are of Gram-negative (G−) origin. Although many medically relevant pathogens (e.g., enterococci, staphylococci, and streptococci) are Gram-positive (G+), their conjugation systems have received little attention. This study provides structural information for the transfer protein TraM of the G+ broad host range Enterococcus conjugative plasmid pIP501. Immunolocalization demonstrated that the protein localizes to the cell wall. We then used opsonophagocytosis as a novel tool to verify that TraM was exposed on the cell surface. In these assays, antibodies generated to TraM recruited macrophages and enabled killing of pIP501 harboring Enteroccocus faecalis cells. The crystal structure of the C-terminal, surface-exposed domain of TraM was determined to 2.5 Å resolution. The structure, molecular dynamics, and cross-linking studies indicated that a TraM trimer acts as the biological unit. Despite the absence of sequence-based similarity, TraM unexpectedly displayed a fold similar to the T4SS VirB8 proteins from Agrobacterium tumefaciens and Brucella suis (G−) and to the transfer protein TcpC from Clostridium perfringens plasmid pCW3 (G+). Based on the alignments of secondary structure elements of VirB8-like proteins from mobile genetic elements and chromosomally encoded T4SS from G+ and G− bacteria, we propose a new classification scheme of VirB8-like proteins.
Antibiotic Resistance; Bacterial Conjugation; Bacterial Pathogenesis; Crystal Structure; X-ray Crystallography; Conjugative Plasmid; Enteroccucus; Gram-positive; Type IV Secretion System; pIP501
Intramedullary nailing of pertrochanteric femoral fractures has grown in popularity over the past 2 decades likely because this procedure is associated with a low risk for postoperative morbidity and a fast recovery of function. The evaluation of outcomes associated with pertrochanteric nailing has mainly been based on objective measures. The purpose of the present study is to correlate patients’ health-related quality of life results after intramedullary nailing of pertrochanteric fractures with objective outcome measures.
We conducted a single-center study including 62 patients (mean age 80 ± 10 years) with pertrochanteric fractures treated with a Gamma 3 Nail. Health related quality of life was measured using the Short Form-36. These results were compared to both US and Austrian age and sex-adjusted population norms. The objective outcome measures studied at one year postoperatively included Harris Hip Score, range of motion, leg length, body mass index, neck-shaft angle and grade of osteoarthritis.
According to the Harris Hip Score 43 patients (67%) had excellent or good results. There was no significant difference in the average neck-shaft angle comparing affected hip to non-affected hip at 12 months postoperatively. The average osteoarthritis score, for both the injured and uninjured hip, did not differ significantly. We found significant differences between the bodily pain, social functioning and mental health subscales and two summary scores of the Short-Form 36 in comparison to Austrian population norms. Complication rate was 8%.
The results of this study confirm that intramedullary nailing with the use of a Gamma Nail is a safe treatment option for stable and unstable pertrochanteric fractures. Despite good functional and radiographic results we noticed a substantial fall off in patients’ quality of life up to 12 months after operation.
Monoacylglycerol lipases (MGLs) catalyse the hydrolysis of monoacylglycerol into free fatty acid and glycerol. MGLs have been identified throughout all genera of life and have adopted different substrate specificities depending on their physiological role. In humans, MGL plays an integral part in lipid metabolism affecting energy homeostasis, signalling processes and cancer cell progression. In bacteria, MGLs degrade short-chain monoacylglycerols which are otherwise toxic to the organism. We report the crystal structures of MGL from the bacterium Bacillus sp. H257 (bMGL) in its free form at 1.2 Å and in complex with phenylmethylsulfonyl fluoride at 1.8 Å resolution. In both structures, bMGL adopts an α/β hydrolase fold with a cap in an open conformation. Access to the active site residues, which were unambiguously identified from the protein structure, is facilitated by two different channels. The larger channel constitutes the highly hydrophobic substrate binding pocket with enough room to accommodate monoacylglycerol. The other channel is rather small and resembles the proposed glycerol exit hole in human MGL. Molecular dynamics simulation of bMGL yielded open and closed states of the entrance channel and the glycerol exit hole. Despite differences in the number of residues, secondary structure elements, and low sequence identity in the cap region, this first structure of a bacterial MGL reveals striking structural conservation of the overall cap architecture in comparison with human MGL. Thus it provides insight into the structural conservation of the cap amongst MGLs throughout evolution and provides a framework for rationalising substrate specificities in each organism.
► First crystal structure of monoacylglycerol lipase from bacterial species. ► Small angle X-ray scattering shows that the protein is a monomer in solution. ► A large hydrophobic channel enables access of the substrate to the active site. ► Molecular dynamic simulations reveal open and closed states of the cap region. ► The cap architecture is conserved on a structural but not on a sequence level.
MGL, monoacylglycerol lipase; bMGL, monoacylglycerol lipase from Bacillus sp. H257; hMGL, human monoacylglycerol lipase; PMSF, phenylmethylsulfonyl fluoride; SAXS, small angle X-ray scattering; RMSD, root mean square deviation; SDS-PAGE, sodium dodecyl sulphate polyacrylamide gel electrophoresis; Monoacylglycerol lipase; Open conformation; Evolutionary conservation; X-ray crystallography; Molecular dynamics simulation; Small-angle X-ray scattering
Working memory deficits are found in different psychiatric populations and are most pronounced in schizophrenia. There is preliminary evidence from pharmacological studies that the verbal and visuospatial subcomponents of working memory are subject to differential neurotransmitter modulation. Here, we investigated the impact of well-known polymorphisms of the dopamine transporter gene (SLC6A3, DAT) and the catechol-O-methyl-transferase gene (COMT) as well as the serotonin transporter gene (SLC6A4, 5-HTT) on these specific working memory subcomponents in a mixed sample of patients and healthy individuals. Twenty healthy subjects and 80 patients diagnosed with schizophrenia, bipolar I disorder, or obsessive-compulsive disorder underwent genotyping for the DAT variable number of tandem repeats (VNTR), the COMT val/met-, and the 5-HTT promoter length polymorphism (5-HTTLPR) and neuropsychological testing using a battery of well-characterized, brain circuit–specific working memory tasks. DAT genotype revealed a significant and selective effect on visuospatial working memory, while there was no effect on verbal working memory functioning. 5-HTT genotype, by contrast, exerted a significant and selective effect on verbal working memory task performance. COMT genotype did not show any influence on either working memory domain. The results of the present study provide evidence for a differential impact of genetic polymorphisms of the dopaminergic and serotonergic systems on verbal and visuospatial working memory functioning. Together with prior evidence suggesting the existence of subgroups of schizophrenia patients exhibiting isolated deficits in only one working memory domain, this finding further supports the idea of endophenotypically and pathophysiologically distinct subgroups of schizophrenia with implications for personalized therapeutic approaches.
Genetics; Schizophrenia; Bipolar disorder; Working memory; Endophenotype; Neuroimaging
Verbal and visuospatial working memory (WM) impairment is a well-documented finding in psychiatric patients suffering from major psychoses such as schizophrenia or bipolar affective disorder. However, in major depression (MDD) the literature on the presence and the extent of WM deficits is inconsistent. The use of a multitude of different WM tasks most of which lack process-specificity may have contributed to these inconsistencies. Eighteen MDD patients and 18 healthy controls matched with regard to age, gender and education were tested using process- and circuit-specific WM tasks for which clear brain-behaviour relationships had been established in prior functional neuroimaging studies. Patients suffering from acute MDD showed a selective impairment in articulatory rehearsal of verbal information in working memory. By contrast, visuospatial WM was unimpaired in this sample. There were no significant correlations between symptom severity and WM performance. These data indicate a dysfunction of a specific verbal WM system in acutely ill patients with MDD. As the observed functional deficit did not correlate with different symptom scores, further, longitudinal studies are required to clarify whether and how this deficit is related to illness acuity and clinical state of MDD patients.
Major depression; Neurocognition; Cognitive endophenotype; Psychosis; Brain imaging
Congenital heart disease (CHD) is the most common birth abnormality and the etiology is unknown in the overwhelming majority of cases. ISLET1 (ISL1) is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages. The fundamental role of ISL1 in cardiac morphogenesis makes this an exceptional candidate gene to consider as a cause of complex congenital heart disease. We evaluated whether genetic variation in ISL1 fits the common variant–common disease hypothesis. A 2-stage case-control study examined 27 polymorphisms mapping to the ISL1 locus in 300 patients with complex congenital heart disease and 2,201 healthy pediatric controls. Eight genic and flanking ISL1 SNPs were significantly associated with complex congenital heart disease. A replication study analyzed these candidate SNPs in 1,044 new cases and 3,934 independent controls and confirmed that genetic variation in ISL1 is associated with risk of non-syndromic congenital heart disease. Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations.
Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer-based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia.
Neurocognitive functioning; Working memory; Schizophrenia
Purpose:The objective was to explore whether body mass and day 3 follicle-stimulating hormone have predictive value on odds of pregnancy after in vitro fertilisation. Few studies show that obesity produces a variety of alterations in the reproductive system, and that women with an elevation of day 3 FSH have declining ovarian function.
Methods: The data of one-hundred-seventy-one women who underwent a standard regime of controlled ovarian hyperstimulation was analyzed with particular reference to variations in body mass and hormone levels.
Results: By raising BMI and FSH (mIU/mL) by one unit, the odds for pregnancy were decreased by the respective factors 0.84 (95% confidence interval 0.73–0.97) and 0.77 (95% confidence interval 0.59–1.00).
Conclusions: The results demonstrate that for the purpose of raising the odds of pregnancy BMI should be reduced. A low FSH value may cause the same effect. Nontheless, obesity and hormonal function may be independent risk factors for failure in assisted reproduction.
BMI; body weight; FSH; IVF; pregnancy outcome
Postactivation potentiation (PAP) has been defined as the increase in twitch torque after a conditioning contraction. The present study aimed to investigate the effectiveness of hops as conditioning contractions to induce PAP and increase performance in subsequent maximal drop jumps. In addition, we wanted to test if and how PAP can contribute to increases in drop jump rebound height. Twelve participants performed 10 maximal two-legged hops as conditioning contractions. Twitch peak torques of triceps surae muscles were recorded before and after the conditioning hops. Then, subjects performed drop jumps with and without 10 conditioning hops before each drop jump. Recordings included ground reaction forces, ankle and knee angles and electromyographic activity in five leg muscles. In addition, efferent motoneuronal output during ground contact was estimated with V-wave stimulation. The analyses showed that after the conditioning hops, twitch peak torques of triceps surae muscles were 32% higher compared to baseline values (P < 0.01). Drop jumps performed after conditioning hops were significantly higher (12%, P < 0.05), but V-waves and EMG activity remained unchanged. The amount of PAP and the change in drop jump rebound height were positively correlated (r2 = 0.26, P < 0.05). These results provide evidence for PAP in triceps surae muscles induced by a bout of hops and indicate that PAP can contribute to the observed performance enhancements in subsequent drop jumps. The lack of change in EMG activity and V-wave amplitude suggests that the underlying mechanisms are more likely intramuscular than neural in origin.
Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. In this study, an in silico modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. Consequently, slower mitochondrial fusion-fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited.
In current clinical practice, genetic testing to detect Lynch syndrome mutations ideally begins with diagnostic testing of an individual affected with cancer before offering predictive testing to at-risk relatives. An alternative strategy that warrants exploration involves screening unaffected individuals via demographic and family histories, and offering genetic testing to those individuals whose risks for carrying a mutation exceed a selected threshold. Whether this approach would improve health outcomes in a manner that is cost-effective relative to current standards of care has yet to be demonstrated. To do so, we developed a simulation framework that integrated models of colorectal and endometrial cancers with a 5-generation family history model to predict health and economic outcomes of 20 primary screening strategies (at a wide range of compliance levels) aimed at detecting individuals with mismatch repair gene mutations and their at-risk relatives. These strategies were characterized by (i) different screening ages for starting risk assessment and (ii) different risk thresholds above which to implement genetic testing. For each strategy, 100,000 simulated individuals, representative of the U.S. population, were followed from the age of 20, and the outcomes were compared with current practice. Findings indicated that risk assessment starting at ages 25, 30, or 35, followed by genetic testing of those with mutation risks exceeding 5%, reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%, respectively. For a population of 100,000 individuals containing 392 mutation carriers, this strategy increased quality-adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY. The cost-effectiveness of screening for mismatch repair gene mutations is comparable to that of accepted cancer screening activities in the general population such as colorectal cancer screening, cervical cancer screening, and breast cancer screening. These results suggest that primary screening of individuals for mismatch repair gene mutations, starting with risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost-effective manner relative to current practice.
To explore the usefulness of protein profiling for characterization of ichthyoses, we here determined the profile of human epidermal stratum corneum by shotgun proteomics. Samples were analyzed after collection on tape circles from six anatomic sites (forearm, palm, lower leg, forehead, abdomen, upper back), demonstrating site-specific differences in profiles. Additional samples were collected from the forearms of subjects with ichthyosis vulgaris (filaggrin (FLG) deficiency), recessive X-linked ichthyosis (steroid sulfatase (STS) deficiency) and autosomal recessive congenital ichthyosis type lamellar ichthyosis (transglutaminase 1 (TGM1) deficiency). The ichthyosis protein expression patterns were readily distinguishable from each other and from phenotypically normal epidermis. In general, the degree of departure from normal was lower from ichthyosis vulgaris than from lamellar ichthyosis, parallel to the severity of the phenotype. Analysis of samples from families with ichthyosis vulgaris and concomitant modifying gene mutations (STS deficiency, GJB2 deficiency) permitted correlation of alterations in protein profile with more complex genetic constellations.
A novel influenza A virus (IAV) of the H7N9 subtype has been isolated from severely diseased patients with pneumonia and acute respiratory distress syndrome and, apparently, from healthy poultry in March 2013 in Eastern China. We evaluated replication, tropism, and cytokine induction of the A/Anhui/1/2013 (H7N9) virus isolated from a fatal human infection and two low-pathogenic avian H7 subtype viruses in a human lung organ culture system mimicking infection of the lower respiratory tract. The A(H7N9) patient isolate replicated similarly well as a seasonal IAV in explanted human lung tissue, whereas avian H7 subtype viruses propagated poorly. Interestingly, the avian H7 strains provoked a strong antiviral type I interferon (IFN-I) response, whereas the A(H7N9) virus induced only low IFN levels. Nevertheless, all viruses analyzed were detected predominantly in type II pneumocytes, indicating that the A(H7N9) virus does not differ in its cellular tropism from other avian or human influenza viruses. Tissue culture-based studies suggested that the low induction of the IFN-β promoter correlated with an efficient suppression by the viral NS1 protein. These findings demonstrate that the zoonotic A(H7N9) virus is unusually well adapted to efficient propagation in human alveolar tissue, which most likely contributes to the severity of lower respiratory tract disease seen in many patients.
Humans are usually not infected by avian influenza A viruses (IAV), but this large group of viruses contributes to the emergence of human pandemic strains. Transmission of virulent avian IAV to humans is therefore an alarming event that requires assessment of the biology as well as pathogenic and pandemic potentials of the viruses in clinically relevant models. Here, we demonstrate that an early virus isolate from the recent A(H7N9) outbreak in Eastern China replicated as efficiently as human-adapted IAV in explanted human lung tissue, whereas avian H7 subtype viruses were unable to propagate. Robust replication of the H7N9 strain correlated with a low induction of antiviral beta interferon (IFN-β), and cell-based studies indicated that this is due to efficient suppression of the IFN response by the viral NS1 protein. Thus, explanted human lung tissue appears to be a useful experimental model to explore the determinants facilitating cross-species transmission of the H7N9 virus to humans.
Understanding how multiple environmental stressors interact to affect seagrass health (measured as morphological and physiological responses) is important for responding to global declines in seagrass populations. We investigated the interactive effects of temperature stress (24, 27, 30 and 32°C) and shading stress (75, 50, 25 and 0% shade treatments) on the seagrass Zostera muelleri over a 3-month period in laboratory mesocosms. Z. muelleri is widely distributed throughout the temperate and tropical waters of south and east coasts of Australia, and is regarded as a regionally significant species. Optimal growth was observed at 27°C, whereas rapid loss of living shoots and leaf mass occurred at 32°C. We found no difference in the concentration of photosynthetic pigments among temperature treatments by the end of the experiment; however, up-regulation of photoprotective pigments was observed at 30°C. Greater levels of shade resulting in high photochemical efficiencies, while elevated irradiance suppressed effective quantum yield (ΔF/FM’). Chlorophyll fluorescence fast induction curves (FIC) revealed that the J step amplitude was significantly higher in the 0% shade treatment after 8 weeks, indicating a closure of PSII reaction centres, which likely contributed to the decline in ΔF/FM’ and photoinhibition under higher irradiance. Effective quantum yield of PSII (ΔF/FM’) declined steadily in 32°C treatments, indicating thermal damage. Higher temperatures (30°C) resulted in reduced above-ground biomass ratio and smaller leaves, while reduced light led to a reduction in leaf and shoot density, above-ground biomass ratio, shoot biomass and an increase in leaf senescence. Surprisingly, light and temperature had few interactive effects on seagrass health, even though these two stressors had strong effects on seagrass health when tested in isolation. In summary, these results demonstrate that populations of Z. muelleri in south-eastern Australia are sensitive to small chronic temperature increases and light decreases that are predicted under future climate change scenarios.
Performing total knee replacement, accurate alignment and neutral rotation of the femoral component are widely believed to be crucial for the ultimate success. Contrary to absolute bone referenced alignment, using a ligament balancing technique does not automatically rotate the femoral component parallel to the transepicondylar axis. In this context we established the hypothesis that rotational alignment of the femoral component parallel to the transepicondylar axis (0° ± 3°) results in better outcome than alignment outside of this range.
We analysed 204 primary cemented mobile bearing total knee replacements five years postoperatively. Femoral component rotation was measured on axial radiographs using the condylar twist angle (CTA). Knee society score, range of motion as well as subjective rating documented outcome.
In 96 knees the femoral component rotation was within the range 0 ± 3° (neutral rotation group), and in 108 knees the five-year postoperative rotational alignment of the femoral component was outside of this range (outlier group). Postoperative CTA showed a mean of 2.8° (±3.4°) internal rotation (IR) with a range between 6° external rotation (ER) and 15° IR (CI 95). No difference with regard to subjective and objective outcome could be detected.
The present work shows that there is a large given natural variability in optimal rotational orientation, in this study between 6° ER and 15° IR, with numerous co-factors determining correct positioning of the femoral component. Further studies substantiating pre- and postoperative determinants are required to complete the understanding of resulting biomechanics in primary TKA.
Allergy is the result of a disbalanced immune response to environmental innocuous antigens. Despite of accumulating data to define the pathomechanisms that take place in case of allergic diseases a detailed understanding of sequence of events that lead to the "normal" scenario of tolerance development are still under debate. Allergen-specific immunotherapy is the only causal treatment of allergic diseases. It modifies the immune response to a particular antigen to achieve tolerance against the symptom-causing allergen. This process is considered to mirror physiological peripheral tolerance induction. A number of immunological changes have been described to occur under allergen immunotherapy, including the generation of allergen-specific regulatory T cells, the induction of allergen-specific IgG4, an increase in the Th1/Th2 cytokine ratio and decreased activation and function of effector cells such as mast cells, basophils and eosinophils.
T-cells; allergen-specific immunotherapy; allergy; tolerance
Joint travel is a common social activity of many group-living animals, which requires some degree of coordination, sometimes through communication signals. Here, we studied the use of an acoustically distinct vocalisation in chimpanzees, the ‘travel hoo’, a signal given specifically in the travel context. We were interested in how this call type was produced to coordinate travel, whether it was aimed at specific individuals and how recipients responded. We found that ‘travel hoos’ were regularly given prior to impending departures and that silent travel initiations were less successful in recruiting than vocal initiations. Other behaviours associated with departure were unrelated to recruitment, suggesting that ‘travel hoos’ facilitated joint travel. Crucially, ‘travel hoos’ were more often produced in the presence of allies than other individuals, with high rates of recruitment success. We discuss these findings as evidence for how motivation to perform a specific social activity can lead to the production of a vocal signal that qualifies as ‘intentional’ according to most definitions, suggesting that a key psychological component of human language may have already been present in the common ancestor of chimpanzees and humans.
Aureochromes constitute a family of blue light (BL) receptors which are found exclusively in heterokont algae such as diatoms (Bacillariophyceae) and yellow-green algae (Xanthophyceae). Previous studies on the diatom Phaeodactylum tricornutum indicate that the formation of a high light acclimated phenotype is mediated by the absorption of BL and that aureochromes might play an important role in this process. P. tricornutum possesses four genes encoding aureochromes. In this study we confirm the nuclear localisation of the PtAUREO1a, 1b and 2 proteins. Furthermore we studied the physiology of light quality acclimation in genetically transformed P. tricornutum cell lines with reduced expression of the aureochrome 1a gene. The results demonstrate that the AUREO1a protein has a distinct function in light acclimation. However, rather unexpectedly AUREO1a seems to repress high light acclimation which resulted in a state of ‘hyper’ high light acclimation in aureo1a silenced strains. This was indicated by characteristic changes of several photosynthetic parameters, including increased maximum photosynthesis rates, decreased chlorophyll a contents per cell and increased values of non-photochemical quenching in AUREO1a silenced strains compared to wild type cultures. Strikingly, AUREO1a silenced strains exhibited phenotypic differences compared to wild type cells during cultivation under BL as well as under red light (RL) conditions. Therefore, AUREO1a might influence the RL signalling process, suggesting an interaction of AUREO1a with RL perception pathways.
To retrospectively determine whether relative cerebral blood volume (CBV) measurements can be used to predict clinical outcome in patients with high-grade gliomas (HGGs) and low-grade gliomas (LGGs) and specifically whether patients who have gliomas with a high initial relative CBV have more rapid progression than those who have gliomas with a low relative CBV.
Materials and Methods
Approval for this retrospective HIPAA-compliant study was obtained from the Institutional Board of Research Associates, with waiver of informed consent. One hundred eighty-nine patients (122 male and 67 female patients; median age, 43 years; range, 4–80 years) were examined with dynamic susceptibility-weighted contrast material–enhanced perfusion magnetic resonance (MR) imaging and were followed up clinically with MR imaging (median follow-up, 334 days). Log-rank tests were used to evaluate the association between relative CBV and time to progression by using Kaplan-Meier curves. Binary logistic regression was used to determine whether age, sex, and relative CBV were associated with an adverse event (progressive disease or death).
Values for the mean relative CBV for patients according to each clinical response were as follows: 1.41 ± 0.13 (standard deviation) for complete response (n = 4), 2.36 ± 1.78 for stable disease (n = 41), 4.84 ± 3.32 for progressive disease (n = 130), and 3.82 ± 1.93 for death (n = 14). Kaplan-Meier estimates of median time to progression in days indicated that patients with a relative CBV of less than 1.75 had a median time to progression of 3585 days, whereas patients with a relative CBV of more than 1.75 had a time to progression of 265 days. Age and relative CBV were also independent predictors for clinical outcome.
Dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can be used to predict median time to progression in patients with gliomas, independent of pathologic findings. Patients who have HGGs and LGGs with a high relative CBV (>1.75) have a significantly more rapid time to progression than do patients who have gliomas with a low relative CBV.
Similar patient populations and favorable regulations have led many home health agencies to become Medicare and/or Medicaid certified as hospice agencies (mixed), but home health and hospice programs differ in focus and scope. Little research has been performed examining the differences between mixed hospices and those agencies only certified as hospices (non-mixed).
To describe the differences in agency characteristics between mixed and non-mixed agencies; and to compare frequencies of service provision by mixed and non-mixed agencies.
Cross-sectional study using data from the 2000 National Home and Hospice Care Survey.
760 Medicare and/or Medicaid certified hospice agencies providing services during the survey, including 393 mixed agencies (52% of sample) and 367 non-mixed hospices.
Survey responses by administrators about services provided by agency
Non-mixed agencies were significantly more likely than mixed agencies to provide many types of services, including: volunteers (96.1% vs. 77.4%, respectively, OR 7.27, 95%CI (5.26-10.05)), social services (96.1% vs. 93.5%, OR 1.70 (1.20-2.40)), spiritual care (95.1% vs. 77.8%, OR 5.53 (4.13-7.41)), bereavement care (93.5% vs. 79.8%, OR 3.63 (2.80-4.72)), counseling (89.5% vs. 70.2%, OR 3.62 (2.92-4.48)), and physician services (87.2% vs. 52.0%, OR 6.30 (5.18-7.66)). In logistic regression models, these differences remained significant after adjustment for census region, operation by a hospital, number of patients and number of hospice patients, and Medicare and Medicaid hospice certification status.
Mixed agencies provide a narrower range of services to hospice patients than non-mixed agencies, including fewer services considered cornerstones of hospice treatment.
hospice & palliative medicine; Medicare; Medicaid; home care; care delivery system
To compare Medicare payments of nursing home residents triaged to nursing home with those of nursing home residents triaged to the hospital for acute infection care.
Observational study with propensity score matching.
Fifty-nine nursing homes in Maryland.
Two thousand two hundred eighty-five individuals admitted to the 59 nursing homes and followed between 1992 and 1997.
Demographic and clinical data were obtained from interviews and medical record review and linked to Medicare payment records. Incident infection was ascertained according to medical record review for new infectious diagnoses or prescription of antibiotics. Hospital triage was defined as hospital transfer within 3 days of infection onset. Hospital triage patients were paired with similar nursing home triage patients using propensity score matching. Medicare expenditures for triage groups were compared in 1997 dollars.
Of 3,618 infection cases, 28% were genitouri-nary infections, 20% skin, 14% upper respiratory, 12% lower respiratory, 4% gastrointestinal, and 2% bloodstream. Two hundred fifty-six pairs of hospital and nursing home triage cases fulfilled matching criteria. Mean Medicare payments ± standard deviation were $5,202 ± 7,310 and $996 ± 2,475 per case in the hospital and nursing home triage groups, respectively, for a mean difference of $4,206 (95% confidence interval = $3,260–5,151). Mean payments per case in the hospital triage group were $3,628 higher in inpatient expenditures, $482 higher in physician visit expenditures, $161 higher in emergency department expenditures, and $147 higher in skilled nursing day expenditures.
Per-case Medicare expenditures are higher with hospital triage than for nursing home triage for nursing home residents with acute infection. This result may be used to estimate cost savings to Medicare of interventions designed to reduce hospital use by nursing home residents.
infection; nursing homes; health expenditures; Medicare
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
mesial temporal lobe epilepsy; mesial temporal sclerosis; SCN1A; association; complex genetics
Marijuana (MJ) remains the most widely abused illicit substance in the United States, and in recent years, a decline in perceived risk of MJ use has been accompanied by a simultaneous increase in rates of use among adolescents. In the current study, we hypothesized that chronic MJ smokers would perform cognitive tasks, specifically those that require executive function more poorly than control subjects, and that individuals who started smoking MJ regularly prior to age 16 (early onset) would have more difficulty than those who started after age 16 (late onset). Thirty-four chronic, heavy MJ smokers separated into early and late onset groups and 28 non-MJ smoking controls completed a battery of neurocognitive measures. As hypothesized, MJ smokers performed more poorly than controls on several measures of executive function. Age of onset analyses revealed that these between-group differences were largely attributed to the early onset group, who were also shown to smoke twice as often and nearly three times as much MJ per week relative to the late onset smokers. Age of onset, frequency and magnitude of MJ use were all shown to impact cognitive performance. Findings suggest that earlier MJ onset is related to poorer cognitive function and increased frequency and magnitude of MJ use relative to later MJ onset. Exposure to MJ during a period of neurodevelopmental vulnerability, such as adolescence, may result in altered brain development and enduring neuropsychological changes.
Cognitive function; marijuana; adolescence; early onset