BCL2L12 is a recently identified gene belonging to the BCL2 family, members of which are implicated in hematologic malignancies, including chronic lymphocytic leukemia (CLL). The aim of this study was to analyze the mRNA expression of the novel apoptosis-related gene BCL2L12 in patients with CLL and to examine its prognostic and predictive value and potential clinical application as a novel molecular biomarker for CLL. BCL2L12 expression predicts the presence of CLL, and high BCL2L12 mRNA levels are associated with advanced clinical stage and predict shorter overall survival in CLL patients.
BCL2L12 is a recently identified gene belonging to the BCL2 family, members of which are implicated in hematologic malignancies, including chronic lymphocytic leukemia (CLL). The aim of this study was to analyze the mRNA expression of the novel apoptosis-related gene BCL2L12 in patients with CLL and to examine its prognostic and predictive value and potential clinical application as a novel molecular biomarker for CLL. For this purpose, total RNA was isolated from peripheral blood of 65 CLL patients and 23 healthy donors. An ultrasensitive quantitative real-time polymerase chain reaction methodology for BCL2L12 and BCL2 mRNA quantification was developed using SYBR Green chemistry. After preparing cDNA by reverse transcription, relative quantification analysis was performed using the comparative CT (2−ΔΔCT) method. Furthermore, analysis of IGHV mutational status, CD38 expression, and detection of early apoptosis by double staining with Annexin V-FITC and propidium iodide were performed. According to our findings, BCL2L12 mRNA expression is significantly higher in CLL patients than in healthy donors. Receiver operating characteristic analysis demonstrated that BCL2L12 expression had significant discriminatory value, distinguishing very efficiently CLL patients from the non-leukemic population. Moreover, BCL2L12 expression predicts the presence of CLL, as demonstrated by both univariate and multivariate logistic regression analyses. Finally, high BCL2L12 mRNA levels are associated with advanced clinical stage and predict shorter overall survival in CLL patients.
Chronic lymphocytic leukemia; CLL; BCL2L12; BCL2 family; Real-time PCR; Tumor biomarkers
Dengue fever is endemic in Malaysia, with frequent major outbreaks in urban areas. The major control strategy relies on health promotional campaigns aimed at encouraging people to reduce mosquito breeding sites close to people's homes. However, such campaigns have not always been 100% effective. The concept of self-efficacy is an area of increasing research interest in understanding how health promotion can be most effective. This paper reports on a study of the impact of self-efficacy on dengue knowledge and dengue preventive behaviour.
Methods and Findings
We recruited 280 adults from 27 post-outbreak villages in the state of Terengganu, east coast of Malaysia. Measures of health promotion and educational intervention activities and types of communication during outbreak, level of dengue knowledge, level and strength of self-efficacy and dengue preventive behaviour were obtained via face-to-face interviews and questionnaires. A structural equation model was tested and fitted the data well (χ2 = 71.659, df = 40, p = 0.002, RMSEA = 0.053, CFI = 0.973, TLI = 0.963). Mass media, local contact and direct information-giving sessions significantly predicted level of knowledge of dengue. Level and strength of self-efficacy fully mediated the relationship between knowledge of dengue and dengue preventive behaviours. Strength of self-efficacy acted as partial mediator in the relationship between knowledge of dengue and dengue preventive behaviours.
To control and prevent dengue outbreaks by behavioural measures, health promotion and educational interventions during outbreaks should now focus on those approaches that are most likely to increase the level and strength of self-efficacy.
Dengue fever is one of the most rapidly increasing vector-borne diseases of humans in the tropics. There is currently no treatment and no vaccine, so control of the disease depends on controlling the mosquito vector. Unfortunately health promotional campaigns aimed at encouraging people to reduce mosquito breeding sites have not always been 100% effective. Self-efficacy is an area of increasing research interest and can be thought of as people's confidence in their ability to engage in health behaviours. We report a study of the impact of self-efficacy on dengue preventive behaviour. We conducted face to face interviews in villages in the state of Terengganu, Malaysia that had been affected by dengue outbreaks. A structural equation model was tested and fitted the data well. Mass media, local contact and direct information-giving sessions significantly predicted level of knowledge of dengue. However, self-efficacy fully mediated the relationship between knowledge of dengue and engagement in dengue preventive behaviours. We conclude that educational components of community dengue control programmes should focus on interventions.
Hendra virus (HeV) is a recently emerged severe human pathogen that belongs to the Henipavirus genus within the Paramyxoviridae family. The HeV genome is encapsidated by the nucleoprotein (N) within a helical nucleocapsid. Recruitment of the viral polymerase onto the nucleocapsid template relies on the interaction between the C-terminal domain, NTAIL, of N and the C-terminal X domain, XD, of the polymerase co-factor phosphoprotein (P). Here, we provide an atomic resolution description of the intrinsically disordered NTAIL domain in its isolated state and in intact nucleocapsids using nuclear magnetic resonance (NMR) spectroscopy. Using electron microscopy, we show that HeV nucleocapsids form herringbone-like structures typical of paramyxoviruses. We also report the crystal structure of XD of P that consists of a three-helix bundle. We study the interaction between NTAIL and XD using NMR titration experiments and provide a detailed mapping of the reciprocal binding sites. We show that the interaction is accompanied by α-helical folding of the molecular recognition element of NTAIL upon binding to a hydrophobic patch on the surface of XD. Finally, using solution NMR, we investigate the interaction between intact nucleocapsids and XD. Our results indicate that monomeric XD binds to NTAIL without triggering an additional unwinding of the nucleocapsid template. The present results provide a structural description at the atomic level of the protein-protein interactions required for transcription and replication of HeV, and the first direct observation of the interaction between the X domain of P and intact nucleocapsids in Paramyxoviridae.
The polymerase of negative strand RNA viruses reads the viral RNA that is associated with the nucleoprotein N forming a helical nucleocapsid. The interaction between N and the cofactor of the polymerase, the phosphoprotein P, is essential for transcription and replication of the viral genome. The mechanism by which the polymerase dislodges the RNA from the nucleoprotein for its polymerising activity remains unknown, although it has been proposed that binding to P causes a conformational change in the nucleocapsid. Here, we use nuclear magnetic resonance (NMR) spectroscopy to develop an atomic resolution description of the intrinsically disordered C-terminal domain, NTAIL, of N of Hendra virus, an emerging paramyxovirus, and X-ray crystallography to determine the structure of the X domain (XD) of P. Characterization of the interaction between XD and NTAIL provides evidence for folding of NTAIL upon binding to P. Crucially, we were also able to study, for the first time, the interaction between XD and recombinant paramyxoviral nucleocapsids. NMR spectra of NTAIL in its isolated form and in the context of nucleocapsids demonstrate that binding of XD does not change the dynamics of NTAIL and that the nucleocapsid does not undergo any major rearrangements or unwinding upon interaction with P.
Problems in the perception of emotional material, in particular deficits in the recognition of negative stimuli, have been demonstrated in schizophrenia including in first-episode samples. However, it is largely unknown if emotion recognition impairment is present in people with subthreshold psychotic symptoms. Here, we examined the capacity to recognize facially expressed emotion and affective prosody in 79 individuals at ultra high-risk for psychosis, 30 clinically stable individuals with first-episode schizophrenia assessed as outpatients during the early recovery phase of illness, and 30 unaffected healthy control subjects. We compared (1) scores for a combined fear-sadness aggregate index across face and voice modalities, (2) summary scores of specific emotions across modalities, and (3) scores for specific emotions for each sensory modality. Findings supported deficits in recognition of fear and sadness across both modalities for the clinical groups (the ultra high-risk and first-episode group) as compared with the healthy controls. Furthermore, planned contrasts indicated that compared with the healthy control subjects, both clinical groups had a significant deficit for fear and sadness recognition in faces and for anger recognition in voices. Specific impairments in emotion recognition may be apparent in people at clinical high-risk for schizophrenia before the full expression of psychotic illness. The results suggest a trait deficit and an involvement of the amygdala in the pathology of ultra high-risk states.
facial emotion labeling; affective prosody; ultra high-risk; schizophrenia; adolescents
Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus - serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse.
Valuations of depression are useful to evaluate depression interventions offered to patients with chronic somatic conditions. The only classification system to describe depression developed specifically for valuation purposes is the McSad, but it has not been used among somatic patients. The aim of this study was to test the construct validity of the McSad among diabetes and cancer patients and then to compare the McSad to the commonly used EuroQol – 5 Dimensions (EQ-5DTM) classification system. The comparison was expected to shed light on their capacity to reflect the range of depression states experienced by somatic patients.
Cross-sectional data were collected online from 114 diabetes and 195 cancer patients; additionally, 241 cancer patients completed part of the survey on paper. Correlational analyses were performed to test the construct validity. Specifically, we hypothesized high correlations of the McSad domains with depression (Center for Epidemiological Studies Depression Scale (CES-D) and the Patient Health Questionnaire (PHQ-9)). We also expected low/moderate correlations with self-esteem (Rosenberg Self-Esteem scale - RSE) and extraversion (Eysenck Personality Questionnaire Extraversion scale - EPQ-e). Multiple linear regression analyses were run so that the proportion of variance in depression scores (CES-D, PHQ-9) explained by the McSad could be compared to the proportion explained by the EQ-5D classification system.
As expected, among all patients groups, we found moderate to high correlations for the McSad domains with the CES-D (.41 to .70) and the PHQ-9 (.52 to .76); we also found low to moderate correlations with the RSE (-.21 to .-48) and the EPQ-e (.18 to .31). Linear regression analyses showed that the McSad explained a greater proportion of variance in depression (CES-D, PHQ-9) (Diabetes: 73%, 82%; Cancer: 72%, 72%) than the EQ-5D classification system (Diabetes: 47%, 59%; Cancer: 51%, 47%).
Findings support the construct validity of the McSad among patients with somatic conditions and demonstrate that it performs better than the EQ-5D classification system to reflect the range of depression states. For future valuation purposes, the McSad classification system could therefore be recommended to describe depression as experienced by patients with a chronic medical condition.
Non-invasive prenatal diagnosis (NIPD) has substantial medical importance as it targets the development of safer and more effective methods to avoid the risk of fetal loss associated with currently used invasive methods. Several approaches have been demonstrated as being proof-of concept for NIPD of chromosomal aneuploidies. These approaches include cell-based and cell-free detection methods, involving the investigation of fetal cells in the maternal circulation, formaldehyde treatment of maternal plasma, DNA methylation studies using sodium bisulfite or restriction enzymes, protein-based studies, identification of fetal-specific mRNAs and digital polymerase chain reaction (PCR) approaches, and recently next-generation sequencing and methylated DNA immunoprecipitation real-time quantitative PCR-based approaches. Although all these NIPD methods have both advantages and limitations, some are moving closer to clinical implementation. Biotechnology companies dedicated to the development of NIPD tests such as the sequencing- or methylation-based approaches are finalizing large clinical trials. It is expected that these new technologies will facilitate safer, more sensitive and accurate prenatal diagnostic tests in the near future. In this review, we highlight the most recent advances in methods for NIPD of aneuploidies, and we discuss their future implications in clinical practice.
fetal DNA; fetal-specific methylation; next generation sequencing; NIPD clinical implementation; non-invasive prenatal diagnosis
One of the big challenges of the 21st century is the utilization of nanotechnology for energy technology. Nanoscale structures may provide novel functionality, which has been demonstrated most convincingly by successful applications such as dye-sensitized solar cells introduced by M. Grätzel. Applications in energy technology are based on the transfer and conversion of energy. Following the example of photosynthesis, this requires a combination of light harvesting, transfer of energy to a reaction center, and conversion to other forms of energy by charge separation and transfer. This may be achieved by utilizing hybrid nanostructures, which combine metallic and nonmetallic components. Metallic nanostructures can interact strongly with light. Plasmonic excitations of such structures can cause local enhancement of the electrical field, which has been utilized in spectroscopy for many years. On the other hand, the excited states in metallic structures decay over very short lifetimes. Longer lifetimes of excited states occur in nonmetallic nanostructures, which makes them attractive for further energy transfer before recombination or relaxation sets in. Therefore, the combination of metallic nanostructures with nonmetallic materials is of great interest. We report investigations of hybrid nanostructured model systems that consist of a combination of metallic nanoantennas (fabricated by nanosphere lithography, NSL) and oxide nanoparticles. The oxide particles were doped with rare-earth (RE) ions, which show a large shift between absorption and emission wavelengths, allowing us to investigate the energy-transfer processes in detail. The main focus is on TiO2 nanoparticles doped with Eu3+, since the material is interesting for applications such as the generation of hydrogen by photocatalytic splitting of water molecules. We use high-resolution techniques such as confocal fluorescence microscopy for the investigation of energy-transfer processes. The experiments are supported by simulations of the electromagnetic field enhancement in the vicinity of well-defined nanoantennas. The results show that the presence of the nanoparticle layer can modify the field enhancement significantly. In addition, we find that the fluorescent intensities observed in the experiments are affected by agglomeration of the nanoparticles. In order to further elucidate the possible influence of agglomeration and quenching effects in the vicinity of the nanoantennas, we have used a commercial organic pigment containing Eu, which exhibits an extremely narrow particle size distribution and no significant agglomeration. We demonstrate that quenching of the Eu fluorescence can be suppressed by covering the nanoantennas with a 10 nm thick SiOx layer.
confocal microscopy; energy transfer; field enhancement; light harvesting; luminescence; nano-antennas; nanosphere lithography; nanostructures; plasmonics; simulation; TiO2 nanoparticles
CD40–CD40 ligand (CD40L) interactions appear to play pathogenic roles in autoimmune disease. Here we quantify CD40 expression on fibrocytes, circulating, and bone marrow–derived progenitor cells. The functional consequences of CD40 ligation are determined since these may promote tissue remodeling linked with thyroid-associated ophthalmopathy (TAO).
CD40 levels on cultivated fibrocytes and orbital fibroblasts (GOFB) from patients with Graves' disease (GD), as well as fibrocyte abundance, were determined by flow cytometry. CD40 mRNA expression was evaluated by real-time PCR, whereas response to CD40 ligation was measured by Luminex and RT-PCR. Protein kinase B (Akt) and nuclear factor (NF)–kappa B (NF-κB) signaling were determined by Western blot and immunofluorescence.
Basal CD40 expression on fibrocytes is greater than that on GOFB. IFN-γ upregulates CD40 in both cell types and its actions are mediated at the pretranslational level. Fibrocytes produce high levels of cytokines, including interleukin-6 (IL-6), TNF-α, IL-8, MCP-1, and RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) in response to CD40L. IL-6 induction results from an increase in steady state IL-6 mRNA, and is mediated through Akt and NF-κB activation. Circulating CD40+CD45+Col1+ fibrocytes are far more frequent in vivo in donors with TAO compared with healthy subjects.
Particularly high levels of functional CD40 are displayed by fibrocytes. CD40L-provoked signaling results in the production of several cytokines. Among these, IL-6 expression is mediated through Akt and NF-κB pathways. The frequency of circulating CD40+ fibrocytes is markedly increased in patients with TAO, suggesting that this receptor might represent a therapeutic target for TAO.
Engagement of CD40 by CD40 ligand (CD154) provokes IL-6 production in fibrocytes, events that are mediated by Akt and NF-κB pathways. The functional consequences of CD40 ligation may promote tissue activation and remodeling in thyroid-associated ophthalmopathy.
Myocarditis, often triggered by viral infection, may lead to heart auto-immunity and dilated cardiomyopathy. What determines the switch between disease resolution and progression is however incompletely understood. We show that pharmacological inhibition of STAT3, the main mediator of IL-6 signalling and of Th17-cell differentiation, protects mice from the development of Experimental Auto-immune Myocarditis reducing liver production of the complement component C3, and can act therapeutically when administered at disease peak. Further, we demonstrate that STAT3 is sufficient when constitutively active for triggering the onset of immune-mediated myocarditis, involving enhanced complement C3 production and IL-6 signalling amplification in the liver. Disease development can be prevented by C3 depletion and IL-6 receptor neutralization. This appears to be relevant to disease pathogenesis in humans, since acute myocarditis patients display significantly elevated circulating IL-6 and C3 levels and activated heart STAT3. Thus, aberrant IL-6/STAT3-mediated induction of liver acute phase response genes including C3, which occurs as a consequence of pre-existing inflammatory conditions, might represent an important factor determining the degree of myocarditis and its clinical outcome.
complement C3; experimental autoimmune myocarditis; interleukin-6; immune-mediated myocarditis; STAT3
The expression, purification and crystallization of the SARS coronavirus nsp16 RNA-cap AdoMet-dependent (nucleoside-2′O)-methyltransferase in complex with its activating factor nsp10 are reported.
To date, the SARS coronavirus is the only known highly pathogenic human coronavirus. In 2003, it was responsible for a large outbreak associated with a 10% fatality rate. This positive RNA virus encodes a large replicase polyprotein made up of 16 gene products (nsp1–16), amongst which two methyltransferases, nsp14 and nsp16, are involved in viral mRNA cap formation. The crystal structure of nsp16 is unknown. Nsp16 is an RNA-cap AdoMet-dependent (nucleoside-2′-O-)-methyltransferase that is only active in the presence of nsp10. In this paper, the expression, purification and crystallization of nsp10 in complex with nsp16 are reported. The crystals diffracted to a resolution of 1.9 Å resolution and crystal structure determination is in progress.
SARS coronavirus; nsp10; nsp16
Cell migration is a fundamental biological function, critical during development and regeneration, whereas deregulated migration underlies neurological birth defects and cancer metastasis. MARCKS-like protein 1 (MARCKSL1) is widely expressed in nervous tissue, where, like Jun N-terminal protein kinase (JNK), it is required for neural tube formation, though the mechanism is unknown. Here we show that MARCKSL1 is directly phosphorylated by JNK on C-terminal residues (S120, T148, and T183). This phosphorylation enables MARCKSL1 to bundle and stabilize F-actin, increase filopodium numbers and dynamics, and retard migration in neurons. Conversely, when MARCKSL1 phosphorylation is inhibited, actin mobility increases and filopodium formation is compromised whereas lamellipodium formation is enhanced, as is cell migration. We find that MARCKSL1 mRNA is upregulated in a broad range of cancer types and that MARCKSL1 protein is strongly induced in primary prostate carcinomas. Gene knockdown in prostate cancer cells or in neurons reveals a critical role for MARCKSL1 in migration that is dependent on the phosphorylation state; phosphomimetic MARCKSL1 (MARCKSL1S120D,T148D,T183D) inhibits whereas dephospho-MARCKSL1S120A,T148A,T183A induces migration. In summary, these data show that JNK phosphorylation of MARCKSL1 regulates actin homeostasis, filopodium and lamellipodium formation, and neuronal migration under physiological conditions and that, when ectopically expressed in prostate cancer cells, MARCKSL1 again determines cell movement.
Noninvasive prenatal diagnosis of chromosomal aneuploidies, although challenging, has been achieved through the implementation of novel methodologies such as methylated DNA immunoprecipitation and next generation sequencing technologies. Nevertheless, additional developments are required towards the interpretation of other fetal abnormalities of higher complexity, such as de novo mutations including microdeletion and microduplication syndromes as well as complex diseases. The application of next generation sequencing technologies towards fetal whole genome recovery has demonstrated great potential to achieve the above goal. In a research article published in Genome Medicine, Chen et al. presented a novel approach that allowed more robust and accurate characterization of parental alleles compared with previous studies. This was achieved through a revolutionary strategy based on the use of trios and unrelated individuals that simultaneously targets the interpretation of the fetal haplotype and phenotype in one step. It is hereby shown that the implementation of a more accurate experimental design in combination with proper analytical tools can provide robust noninvasive fetal whole genome recovery with the potential for further developments beyond the DNA level.
Fetal whole genome recovery; next generation sequencing; noninvasive prenatal diagnosis
Unconscious processing of words during general anaesthesia has been suggested. We used the process dissociation procedure (PDP) to test memory performance during sevoflurane and propofol anaesthesia in relation to hypnotic depth.
Material and methods
One hundred participants anaesthetised for elective surgery (50 with propofol and 50 with sevoflurane) and 50 non-anaesthetized listened to a list of words. The bispectral index (BIS) of the anaesthetised patients was recorded. Within 36 h after word presentation, memory was assessed using a word stem completion task, based on Buchner's model applied on the PDP.
There was evidence of memory for words presented during light (BIS 61-80) (p = 0.001) and adequate (BIS 41-60) (p = 0.008) but not deep anaesthesia (BIS 21-40) (p = 0.09). The PDP showed a significant implicit but not explicit memory contribution (mean total explicit memory scores: 0.04 ±0.07 in all BIS categories; mean implicit memory scores: 0.01 ±0.04, 0.1 ±0.08, and 0.05 ±0.09 at BIS = 21-40, 41-60, and 61-80, respectively). There was a statistically significant difference between the mean implicit memory score (I) of the propofol and sevoflurane group in the BIS category 41-60 in general (p = 0.016), and after incision (IA.I.) (p = 0.005) in particular, with propofol depressing I more than sevoflurane in both cases. Memory performance of nonanaesthetized participants was better, with a higher contribution of explicit and a comparable contribution of implicit memory.
During general anaesthesia, implicit memory persists even in adequate hypnotic states. Sevoflurane affects the implicit memory of adequately anaesthetised subjects less than propofol.
implicit/explicit memory; process dissociation procedure; bispectral index
We report a case of tumor lysis syndrome (TLS) in a patient with gallbladder carcinoma. TLS has not been reported in association with this type of tumor. TLS typically occurs in cases of highly proliferative hematological malignancies and small cell carcinoma. Two factors that may have contributed to TLS in this case include multifactorial mild acute renal failure shortly before the administration of chemotherapy and the aggressive morphology of the gallbladder carcinoma, which was a poorly differentiated sarcomatoid variant. This case raises concern for the development of TLS in certain types of patients with solid tumors.
tumor lysis syndrome; gallbladder carcinoma; solid tumors; gemcitabine; renal failure
Background. Cognitive deterioration may impair COPD patient's ability to perform tasks like driving vehicles. We investigated: (a) whether subclinical neuropsychological deficits occur in stable COPD patients with mild hypoxemia (PaO2 > 55 mmHg), and (b) whether these deficits affect their driving performance. Methods. We recruited 35 stable COPD patients and 10 normal subjects matched for age, IQ, and level of education. All subjects underwent an attention/alertness battery of tests for assessing driving performance based on the Vienna Test System. Pulmonary function tests, arterial blood gases, and dyspnea severity were also recorded. Results. COPD patients performed significantly worse than normal subjects on tests suitable for evaluating driving ability. Therefore, many (22/35) COPD patients were classified as having inadequate driving ability (failure at least in one of the tests), whereas most (8/10) healthy individuals were classified as safe drivers (P = 0.029). PaO2 and FEV1 were correlated with almost all neuropsychological tests. Conclusions. COPD patients should be warned of the potential danger and risk they face when they drive any kind of vehicle, even when they do not exhibit overt symptoms related to driving inability. This is due to the fact that stable COPD patients may manifest impaired information processing operations.
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with or without radiotherapy was compared with CHOP with or without RT for the treatment of patients with primary mediastinal large B-cell lymphoma. R-CHOP was more effective than CHOP, with results comparable with those of more intensive regimens.
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Describe the effect of the addition of rituximab to standard CHOP chemotherapy on the outcome of patients with primary mediastinal large B-cell lymphoma.Explain potential changes in the use of radiotherapy and aggressive chemotherapy in the rituximab era.
This article is available for continuing medical education credit at CME.TheOncologist.com
More aggressive treatment approaches (methotrexate, cytarabine, cyclophosphamide, vincristine, prednisone, and bleomycin [the MACOP-B regimen] or consolidation with high-dose therapy and autologous stem cell transplantation) have been considered to be superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with primary mediastinal large B-cell lymphoma (PMLBCL). Rituximab-CHOP (R-CHOP) is the standard of care for diffuse large B-cell lymphoma, whereas efficacy in PMLBCL has not been adequately confirmed.
Patient and Methods.
Seventy-six consecutive PMLBCL patients who received R-CHOP with or without radiotherapy (RT) were compared with 45 consecutive historical controls treated with CHOP with or without RT. Baseline characteristics of the two groups were balanced.
The rate of early treatment failure was much lower with R-CHOP with or without RT (9% versus 30%; p = .004). The 5-year freedom from progression rate after R-CHOP with or without RT was 81%, versus 48% for CHOP with or without RT (p < .0001). The 5-year event-free survival rates were 80% and 47% (p < .0001) and the 5-year overall and lymphoma-specific survival rates were 89% and 69% (p = .003) and 91% and 69% (p = .001), respectively, with only seven of 76 lymphoma-related deaths. Among R-CHOP responders, 52 of 68 received RT.
Based on these results, most patients with PMLBCL appear to be cured by R-CHOP in 21-day cycles with or without RT, which could be the current standard of care. Therefore, the need for more aggressive treatment strategies is questionable unless high-risk patients are adequately defined. Further studies are required to establish the precise role of RT.
Rituximab; CHOP; Large B-cell lymphoma; Primary mediastinal; Radiotherapy; Standard of care
Nonadherence is common among patients with schizophrenia, although the rates vary according to means of assessment and patient population. Failure to adhere to medication can have a major impact on the course of illness and treatment outcomes, including increasing the risk of relapse and rehospitalization. Understanding psychiatrists’ perception of the causes and consequences of nonadherence is crucial to addressing adherence problems effectively.
The Europe, the Middle East, and Africa (EMEA) Spanish Adherencia Terapéutica en la Esquizofrenia (ADHES) survey was conducted by questionnaire during January–March 2010 among psychiatrists treating patients with schizophrenia in 36 countries. The survey comprised 20 questions. In addition to recording the demographic details of the 4722 respondents (~12% response rate), it canvassed their preferred methods of assessing adherence, their perceptions of adherence rates, reasons for nonadherence, and strategies to improve adherence.
Psychiatrists estimated that 53% of their patients with schizophrenia were partially/nonadherent during the previous month. They estimated only one-third of patients who deteriorated after stopping medication were able to attribute this to nonadherence. Psychiatrists assessed adherence most often by patient interview. Lack of insight was viewed as the most important cause of medication discontinuation, followed by patients feeling better and thinking their medication unnecessary, and experiencing undesirable side effects. Considerably fewer psychiatrists viewed insufficient efficacy, cognitive impairment, or drug/alcohol abuse as the most important reasons for their patients stopping medication.
Psychiatrists throughout EMEA recognize the impact of partial/nonadherence to medication, with patient enquiry being the most commonly used means of assessment. There remains a need for more proactive management of patients with schizophrenia, particularly in increasing patient insight of their illness in order to improve adherence and minimize the consequences of relapse. Strategies focused on raising awareness of the importance of adherence are also warranted, with the aim of improving patient outcomes in schizophrenia.
adherence; schizophrenia; psychiatrist; survey; ADHES
Mammalian target of rapamycin (mTOR) is a giant protein kinase that controls cell proliferation, growth, and metabolism. mTOR is regulated by nutrient availability, by mitogens, and by stress, and operates through two independently regulated hetero-oligomeric complexes. We have attempted to identify the cellular components necessary to maintain the activity of mTOR complex 1 (mTORC1), the amino acid-dependent, rapamycin-inhibitable complex, using a whole genome approach involving RNAi-induced depletion of cellular polypeptides. We have used a pancreatic ductal adenocarcinoma (PDAC) cell line, Mia-PaCa for this screen; as with many pancreatic cancers, these cells exhibit constitutive activation of mTORC1. PDAC is the most common form of pancreatic cancer and the 5-year survival rate remains 3–5% despite current nonspecific and targeted therapies. Although rapamycin-related mTOR inhibitors have yet to demonstrate encouraging clinical responses, it is now evident that this class of compounds is capable of only partial mTORC1 inhibition. Identifying previously unappreciated proteins needed for maintenance of mTORC1 activity may provide new targets and lead to the development of beneficial therapies for pancreatic cancer.
rpS6; Phosphorylation; mTOR; Genome wide; RNAi; Screen; Immunofluorescence; Pancreatic cancer
Alzheimer’s dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and non-industrialized nations. To date, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance. Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist. Treatments capable of stopping or at least effectively modifying the course of AD, referred to as ‘disease-modifying’ drugs, are still under extensive research. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation, oxidative damage, iron deregulation and cholesterol metabolism. In this review we discuss current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I–III trials.
Alzheimer’s disease; amyloid; disease-modifying drugs; inflammation; tau protein; therapeutic targets
Hox gene clusters are very frequent in many animal genomes and their role in development is pivotal. Particularly in vertebrates, intensive efforts have established several properties of Hox clusters. The collinearity of Hox gene expressions (spatial, temporal and quantitative) is a common feature of the vertebrates. During the last decade, genetic engineering experiments have revealed some important facets of collinearity during limb and trunk development in mice. Two models have been proposed to explain all these properties. On one hand the ‘two-phases model’ makes use of the molecular regulatory mechanisms acting on the Hox genes. On the other hand, the’biophysical model’ is based on the signals transduced inside the cell nucleus and the generation of forces which apply on the cluster and lead to a coordinated activation of Hox genes. The two models differ fundamentally and a critical and detailed comparison is presented. Furthermore, experiments are proposed for which the two models provide divergent predictions. The outcome of these experiments will help to decide which of the two models is valid (if any).
Chromatin; collinearity; Hox genes; limb; mouse; trunk; vertebrate.
Lobomycosis, also known as Jorge Lobo’s disease, represents a rare chronic subcutaneous mycosis caused by the fungus Lacazia loboi, an organism that is found within lesions but has not been cultured to date. The natural reservoir of L. loboi is unknown but it is believed to be aquatic, or associated with soil and vegetation. More than 550 human cases have been reported, especially in patients with a history of travel or residence in endemic areas (Central and South America, particularly Brazil) or in communities along rivers.
We describe a 64-year-old Greek female farmer living in a coastal region, who presented with an erythematous plaque on her left inner thigh resembling a keloid. The diagnosis was based on the triad: 1) absence of fungal growth in cultures, 2) positive direct microscopic examination of the lesion and 3) histopathology, all consistent with lobomycosis. Particularly, skin biopsy showed deep cutaneous fungal infection with granulomatous reaction. Fungal cells were found inside giant cells. The fungi were thick-walled with some budding, isolated or in short chains. Dermal fibrosis was present. Our patient had a medical history of common variable immunodeficiency but no history of travel to South or Central America. She probably acquired this rare infection by injury during her agricultural works.
Our case represents probably the first documented case of human lobomycosis in Southeastern Europe. This case is unusual due to the rarity of lobomycosis in Mediterranean countries, particularly in Southeastern Europe.
immunodeficiency; infection; lobomycosis; Lacazia loboi; lacaziosis; Lobo’s disease; mycosis
Background. The aim of this study was to investigate the association of oxytocin with trait and state psychological factors in type 2 diabetic patients. Methods. OXT and psychological variables were analyzed from 86 controlled diabetic patients (glycosylated haemoglobin A1c (HbA1c) < 7%) from 45 uncontrolled diabetic patients (HbA1c ≥ 7). Psychological characteristics were assessed with the Eysenck Personality Questionnaire (EPQ), while state psychological characteristics were measured with the Symptom Checklist 90-R (SCL 90-R). Blood samples were taken for measuring oxytocin in both subgroups during the initial phase of the study. One year later, the uncontrolled diabetic patients were reevaluated with the use of the same psychometric instruments. Results. During the first evaluation of the uncontrolled diabetic patients, a statistically significant positive relationship between the levels of OXT and psychoticism in EPQ rating scale (P < 0.013) was observed. For controlled diabetic patients, a statistically significant negative relationship between oxytocin and somatization (P < 0.030), as well as obsessive-compulsive scores (P < 0.047) in SCL-90 rating scale, was observed. During the second assessment, the values of OXT decreased when the patients managed to control their metabolic profile. Conclusions. The OXT is in association with psychoticism, somatization, and obsessionality may be implicated in T2DM.
Meningitis is characterized by an inflammation of the meninges, or the membranes surrounding the brain and spinal cord. Early diagnosis and treatment is crucial for a positive outcome, yet identifying meningitis is a complex process involving an array of signs and symptoms and multiple causal factors which require novel solutions to support clinical decision-making. In this work, we explore the potential of fuzzy cognitive map to assist in the modeling of meningitis, as a support tool for physicians in the accurate diagnosis and treatment of the condition.
Fuzzy cognitive mapping (FCM) is a method for analysing and depicting human perception of a given system. FCM facilitates the development of a conceptual model which is not limited by exact values and measurements and thus is well suited to representing relatively unstructured knowledge and associations expressed in imprecise terms. A team of doctors (physicians), comprising four paediatricians, was formed to define the multifarious signs and symptoms associated with meningitis and to identify risk factors integral to its causality, as indicators used by clinicians to identify the presence or absence of meningitis in patients. The FCM model, consisting of 20 concept nodes, has been designed by the team of paediatricians in collaborative dialogue with the research team.
The paediatricians were supplied with a form containing various input parameters to be completed at the time of diagnosing meningitis among infants and children. The paediatricians provided information on a total of 56 patient cases amongst children whose age ranged from 2 months to 7 years. The physicians’ decision to diagnose meningitis was available for each individual case which was used as the outcome measure for evaluating the model. The FCM was trained using 40 cases with an accuracy of 95%, and later 16 test cases were used to analyze the accuracy and reliability of the model. The system produced the results with sensitivity of 83.3% and specificity of 80%.
This work suggests that the application and development of a knowledge based system, using the formalization of FCMs for understanding the symptoms and causes of meningitis in children and infants, can provide a reliable front-end decision-making tool to better assist physicians.