CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients.

Neurobiol Aging. 2017 Jul 11;59:1-9

Authors: Skillbäck T, Delsing L, Synnergren J, Mattsson N, Janelidze S, Nägga K, Kilander L, Hicks R, Wimo A, Winblad B, Hansson O, Blennow K, Eriksdotter M, Zetterberg H

Abstract
A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology.

PMID: 28779628 [PubMed - as supplied by publisher]

The metabolomics window into diabetic complications.

J Diabetes Investig. 2017 Aug 05;:

Authors: Wu T, Qiao S, Shi C, Wang S, Ji G

Abstract
Diabetes has become a major global health problem. The elucidation of characteristic metabolic alterations during the diabetic progression is critical for better understanding its pathogenesis and identifying potential biomarkers and drug targets. Metabolomics is a promising tool to reveal the metabolic changes and the underlying mechanism involved in the pathogenesis of diabetic complications. The present review provides an update on the application of metabolomics in diabetic complications, including diabetic coronary artery disease, diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy, and this review provides notes on the prevention and prediction of diabetic complications. This article is protected by copyright. All rights reserved.

PMID: 28779528 [PubMed - as supplied by publisher]

Cellular redox dysfunction in the development of cardiovascular diseases.

Biochim Biophys Acta. 2017 Aug 01;:

Authors: Kanaan GN, Harper ME

Abstract
To meet its exceptionally high energy demands, the heart relies largely on fatty acid oxidation, which then drives the oxidative phosphorylation system in mitochondria. Each day, this system produces about 6kg of ATP to sustain heart function. Fatty acid oxidation is sometimes associated with high rates of mitochondrial reactive oxygen species (ROS) production. By definition, ROS are singlet electron intermediates formed during the partial reduction of oxygen to water and they include radical and non-radical intermediates like superoxide, hydrogen peroxide and hydroxyl radical. Superoxide can also interact with nitric oxide to produce peroxynitrite that in turn can give rise to other radical or non-radical reactive nitrogen species (RNS) like nitrogen dioxide, dinitrogen trioxide and others. While mitochondrial and cellular functions can be impaired by ROS if they accumulate, under normal physiological conditions ROS are important signaling molecules in the cardiovascular system. A fine balance between ROS production and antioxidant systems, including glutathione redox, is essential in the heart; otherwise the ensuing damage can contribute to pathogenic processes, which can culminate in endothelial dysfunction, atherosclerosis, hypertension, cardiac hypertrophy, arrhythmias, myocardial ischemia/reperfusion damage, and heart failure. Here we provide a succinct review of recent findings.

PMID: 28778485 [PubMed - as supplied by publisher]

The first succinylome profile of Trichophyton rubrum reveals lysine succinylation on proteins involved in various key cellular processes.

BMC Genomics. 2017 Aug 04;18(1):577

Authors: Xu X, Liu T, Yang J, Chen L, Liu B, Wei C, Wang L, Jin Q

Abstract
BACKGROUND: Dermatophytes, the most common cause of fungal infections, affect millions of individuals worldwide. They pose a major threat to public health because of the severity and longevity of infections caused by dermatophytes and their refractivity to therapy. Trichophyton rubrum (T. rubrum), the most common dermatophyte species, is a promising model organism for dermatophyte research. Post-translational modifications (PTMs) have been shown to be essential for many biological processes, particularly in the regulation of key cellular processes that contribute to pathogenicity. Although PTMs have important roles, little is known about their roles in T. rubrum and other dermatophytes. Succinylation is a new PTM that has recently been identified. In this study, we assessed the proteome-wide succinylation profile of T. rubrum. This study sought to systematically identify the succinylated sites and proteins in T. rubrum and to reveal the roles of succinylated proteins in various cellular processes as well as the differences in the succinylation profiles in different growth stages of the T. rubrum life cycle.
RESULTS: A total of 569 succinylated lysine sites were identified in 284 proteins. These succinylated proteins are involved in various cellular processes, such as metabolism, translation and epigenetic regulation. Additionally, 24 proteins related to pathogenicity were found to be succinylated. Comparison of the succinylome at the conidia and mycelia stages revealed that most of the succinylated proteins and sites were growth-stage specific. In addition, the succinylation modifications on histone and ribosomal proteins were significantly different between these two growth stages. Moreover, the sequence features surrounding the succinylated sites were different in the two stages, thus indicating the specific recognition of succinyltransferases in each growth phase.
CONCLUSIONS: In this study, we explored the first T. rubrum succinylome, which is also the first PTM analysis of dermatophytes reported to date. These results revealed the major roles of the succinylated proteins involved in T. rubrum and the differences in the succinylomes between the two major growth stages. These findings should improve understanding of the physiological and pathogenic properties of dermatophytes and facilitate future development of novel drugs and therapeutics for treating superficial fungal infections.

PMID: 28778155 [PubMed - in process]

Effect of renal function on antihypertensive drug safety and efficacy in children.

Pediatr Nephrol. 2017 Aug 04;:

Authors: Watt KM, Avant D, Sherwin J, Benjamin DK, Hornik C, Benjamin DK, Li JS, Smith PB

Abstract
BACKGROUND: Hypertension and chronic kidney disease (CKD) are common comorbidities. Guidelines recommend treating hypertension in children with CKD because it is a modifiable risk factor for subsequent cardiovascular disease. Children with CKD are frequently excluded from antihypertensive drug trials. Consequently, safety and efficacy data for antihypertensive drugs are lacking in children with CKD.
METHODS: We determined the incidence of adverse events in 10 pediatric antihypertensive trials to determine the effect of renal function on antihypertensive safety and efficacy in children. These trials were submitted to the US Food and Drug Administration from 1998 to 2005. We determined the number and type of adverse events reported during the trials and compared these numbers in participants with normal renal function and those with decreased function (defined as an estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m(2) calculated using the original Schwartz equation).
RESULTS: Among the 1,703 children in the 10 studies, 315 had decreased renal function. We observed no difference between the two cohorts in the incidence of adverse events or adverse drug reactions related to study drug. Only 5 participants, all with decreased renal function, experienced a serious adverse event; none was recorded by investigators to be study drug-related. Among treated participants, children with decreased renal function who received a high dose of study drug had a significantly larger drop in diastolic blood pressure compared with children with normal renal function.
CONCLUSIONS: These data show that antihypertensive treatment in children with renal dysfunction can be safe and efficacious, and consideration should be given to their inclusion in selected drug development programs.

PMID: 28779238 [PubMed - as supplied by publisher]

Drug-Induced Hypersomnolence.

Sleep Med Clin. 2017 Sep;12(3):383-393

Authors: Pagel JF

Abstract
Daytime somnolence is among the most commonly reported drug side effects. The United States has the highest rate of motor vehicular accident (MVA) deaths with sedating drug use a factor in more than 30%. Sedating drug use extends beyond drugs of abuse to sedating medications. This paper presents pharmacodynamics, performance and driving tests, and MVAs for somnolence inducing agents classified as hypnotics, sedatives, and/or sedation as a side effect. This classification, based on the drug tendency to induce next-day sedation after nighttime use, can be cogently used by prescribers, pharmacists, regulatory agencies, and in direct to consumer marketing.

PMID: 28778236 [PubMed - in process]

STK11 rs2075604 Polymorphism Is Associated with Metformin Efficacy in Chinese Type 2 Diabetes Mellitus.

Int J Endocrinol. 2017;2017:3402808

Authors: Li Q, Li C, Li H, Zeng L, Kang Z, Mao Y, Tang X, Zheng P, He L, Luo F, Li Z

Abstract
Metformin is a classical oral antidiabetic drug, often recommended to be the first-choice treatment of type 2 diabetes mellitus (T2DM). Based on the previous research on STK11 and diabetes, we aimed to investigate the distributive characteristic of STK11 rs2075604 polymorphism and the potential influence of STK11 rs2075604 polymorphism on metformin efficacy among Chinese T2DM patients. There was no significant difference between T2DM patients (G = 64.8%, T = 35.2%) and healthy subjects (G = 62.7%, T = 37.2%) in STK11 rs2075604 genotype and allele frequencies. After 12 weeks of treatment, 62 patients were defined as the responders and 32 patients as nonresponders according to the decrease of HbA1c level. And the GT + TT genotype in STK11 rs2075604 can decrease HbA1c level more significantly than the GG genotype. Furthermore, the allele frequency of T in the STK11 rs2075604 was higher in the responders than the nonresponders (43.55% versus 26.56%). The T allele in the STK11 rs2075604 had a 2.133 times great chance of responding to metformin treatment. In conclusion, this study suggested that the STK11 rs2075604 genetic polymorphism was significantly associated with metformin efficacy in Chinese T2DM patients and the carriers of the T allele may gain a better therapeutic metformin efficacy compared with the G allele. This trial is registered with clinical study registration number NCT03155087.

PMID: 28775741 [PubMed]

A computational study of VEGF production by patterned retinal epithelial cell colonies as a model for neovascular macular degeneration.

J Biol Eng. 2017;11:26

Authors: Baker QB, Podgorski GJ, Vargis E, Flann NS

Abstract
BACKGROUND: The configuration of necrotic areas within the retinal pigmented epithelium is an important element in the progression of age-related macular degeneration (AMD). In the exudative (wet) and non-exudative (dry) forms of the disease, retinal pigment epithelial (RPE) cells respond to adjacent atrophied regions by secreting vascular endothelial growth factor (VEGF) that in turn recruits new blood vessels which lead to a further reduction in retinal function and vision. In vitro models exist for studying VEGF expression in wet AMD (Vargis et al., Biomaterials 35(13):3999-4004, 2014), but are limited in the patterns of necrotic and intact RPE epithelium they can produce and in their ability to finely resolve VEGF expression dynamics.
RESULTS: In this work, an in silico hybrid agent-based model was developed and validated using the results of this cell culture model of VEGF expression in AMD. The computational model was used to extend the cell culture investigation to explore the dynamics of VEGF expression in different sized patches of RPE cells and the role of negative feedback in VEGF expression. Results of the simulation and the cell culture studies were in excellent qualitative agreement, and close quantitative agreement.
CONCLUSIONS: The model indicated that the configuration of necrotic and RPE cell-containing regions have a major impact on VEGF expression dynamics and made precise predictions of VEGF expression dynamics by groups of RPE cells of various sizes and configurations. Coupled with biological studies, this model may give insights into key molecular mechanisms of AMD progression and open routes to more effective treatments.

PMID: 28775765 [PubMed]

Complete genome sequence of the sand-sediment actinobacterium Nocardioides dokdonensis FR1436(T).

Stand Genomic Sci. 2017;12:44

Authors: Kwak MJ, Kwon SK, Kim JF

Abstract
Nocardioides dokdonensis, belonging to the class Actinobacteria, was first isolated from sand sediment of a beach in Dokdo, Korea, in 2005. In this study, we determined the genome sequence of FR1436, the type strain of N. dokdonensis, and analyzed its gene contents. The genome sequence is the second complete one in the genus Nocardioides after that of Nocardioides sp. JS614. It is composed of a 4,376,707-bp chromosome with a G + C content of 72.26%. From the genome sequence, 4,104 CDSs, three rRNA operons, 51 tRNAs, and one tmRNA were predicted, and 71.38% of the genes were assigned putative functions. Through the sequence analysis, dozens of genes involved in steroid metabolism, especially its degradation, were detected. Most of the identified genes were located in large gene clusters, which showed high similarities with the gene clusters in Pimelobacter simplex VKM Ac-2033D. Genomic features of N. dokdonensis associated with steroid catabolism indicate that it could be used for research and application of steroids in science and industry.

PMID: 28770029 [PubMed]

A Proteomic View on the Role of Legume Symbiotic Interactions.

Front Plant Sci. 2017;8:1267

Authors: Larrainzar E, Wienkoop S

Abstract
Legume plants are key elements in sustainable agriculture and represent a significant source of plant-based protein for humans and animal feed worldwide. One specific feature of the family is the ability to establish nitrogen-fixing symbiosis with Rhizobium bacteria. Additionally, like most vascular flowering plants, legumes are able to form a mutualistic endosymbiosis with arbuscular mycorrhizal (AM) fungi. These beneficial associations can enhance the plant resistance to biotic and abiotic stresses. Understanding how symbiotic interactions influence and increase plant stress tolerance are relevant questions toward maintaining crop yield and food safety in the scope of climate change. Proteomics offers numerous tools for the identification of proteins involved in such responses, allowing the study of sub-cellular localization and turnover regulation, as well as the discovery of post-translational modifications (PTMs). The current work reviews the progress made during the last decades in the field of proteomics applied to the study of the legume-Rhizobium and -AM symbioses, and highlights their influence on the plant responses to pathogens and abiotic stresses. We further discuss future perspectives and new experimental approaches that are likely to have a significant impact on the field including peptidomics, mass spectrometric imaging, and quantitative proteomics.

PMID: 28769967 [PubMed]

NF-Y Binding Site Architecture Defines a C-Fos Targeted Promoter Class.

PLoS One. 2016;11(8):e0160803

Authors: Haubrock M, Hartmann F, Wingender E

Abstract
ChIP-seq experiments detect the chromatin occupancy of known transcription factors in a genome-wide fashion. The comparisons of several species-specific ChIP-seq libraries done for different transcription factors have revealed a complex combinatorial and context-specific co-localization behavior for the identified binding regions. In this study we have investigated human derived ChIP-seq data to identify common cis-regulatory principles for the human transcription factor c-Fos. We found that in four different cell lines, c-Fos targeted proximal and distal genomic intervals show prevalences for either AP-1 motifs or CCAAT boxes as known binding motifs for the transcription factor NF-Y, and thereby act in a mutually exclusive manner. For proximal regions of co-localized c-Fos and NF-YB binding, we gathered evidence that a characteristic configuration of repeating CCAAT motifs may be responsible for attracting c-Fos, probably provided by a nearby AP-1 bound enhancer. Our results suggest a novel regulatory function of NF-Y in gene-proximal regions. Specific CCAAT dimer repeats bound by the transcription factor NF-Y define this novel cis-regulatory module. Based on this behavior we propose a new enhancer promoter interaction model based on AP-1 motif defined enhancers which interact with CCAAT-box characterized promoter regions.

PMID: 27517874 [PubMed - indexed for MEDLINE]

In silico model of the human ClC-Kb chloride channel: pore mapping, biostructural pathology and drug screening.

Sci Rep. 2017 Aug 03;7(1):7249

Authors: Louet M, Bitam S, Bakouh N, Bignon Y, Planelles G, Lagorce D, Miteva MA, Eladari D, Teulon J, Villoutreix BO

Abstract
The human ClC-Kb channel plays a key role in exporting chloride ions from the cytosol and is known to be involved in Bartter syndrome type 3 when its permeation capacity is decreased. The ClC-Kb channel has been recently proposed as a potential therapeutic target to treat hypertension. In order to gain new insights into the sequence-structure-function relationships of this channel, to investigate possible impacts of amino-acid substitutions, and to design novel inhibitors, we first built a structural model of the human ClC-Kb channel using comparative modeling strategies. We combined in silico and in vitro techniques to analyze amino acids involved in the chloride ion pathway as well as to rationalize the possible role of several clinically observed mutations leading to the Bartter syndrome type 3. Virtual screening and drug repositioning computations were then carried out. We identified six novel molecules, including 2 approved drugs, diflusinal and loperamide, with Kd values in the low micromolar range, that block the human ClC-Kb channel and that could be used as starting point to design novel chemical probes for this potential therapeutic target.

PMID: 28775266 [PubMed - in process]

Drug combination approach to overcome resistance to EGFR tyrosine kinase inhibitors in lung cancer.

Cancer Lett. 2017 Jul 31;:

Authors: Tong CWS, Wu WKK, Loong HHF, Cho WCS, To KKW

Abstract
The discovery of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) has led to unprecedented clinical response in a subset of lung cancer patients carrying the sensitizing EGFR mutations (L858R or exon 19 deletion). However, disease progression invariably occurs within a year after the initial TKI treatment, predominantly due to the development of acquired resistance caused by the secondary EGFR T790M mutation. Numerous second generation irreversible and third generation EGFR T790M selective EGFR TKIs have been developed to overcome resistance. Besides developing new EGFR TKIs, combination therapy represents another promising strategy to combat resistance. This approach aims at circumventing drug resistance through a so-called bypass signaling mechanism by targeting horizontal pathways or vertical pathways or both. The logical combinations of different molecular targeted drugs inhibiting various oncogenic signaling have been studied. On the other hand, the repurposing of drugs with indications other than oncology has also emerged as a promising approach. In this review, we focus on the effectiveness of combination therapy of EGFR-TKIs with different agents in advanced lung cancer.

PMID: 28774798 [PubMed - as supplied by publisher]

Discovery of novel therapeutic properties of drugs from transcriptional responses based on multi-label classification.

Sci Rep. 2017 Aug 02;7(1):7136

Authors: Xie L, He S, Wen Y, Bo X, Zhang Z

Abstract
Drug repositioning strategies have improved substantially in recent years. At present, two advances are poised to facilitate new strategies. First, the LINCS project can provide rich transcriptome data that reflect the responses of cells upon exposure to various drugs. Second, machine learning algorithms have been applied successfully in biomedical research. In this paper, we developed a systematic method to discover novel indications for existing drugs by approaching drug repositioning as a multi-label classification task and used a Softmax regression model to predict previously unrecognized therapeutic properties of drugs based on LINCS transcriptome data. This approach to complete the said task has not been achieved in previous studies. By performing in silico comparison, we demonstrated that the proposed Softmax method showed markedly superior performance over those of other methods. Once fully trained, the method showed a training accuracy exceeding 80% and a validation accuracy of approximately 70%. We generated a highly credible set of 98 drugs with high potential to be repositioned for novel therapeutic purposes. Our case studies included zonisamide and brinzolamide, which were originally developed to treat indications of the nervous system and sensory organs, respectively. Both drugs were repurposed to the cardiovascular category.

PMID: 28769090 [PubMed - in process]

Improved anticancer drug response prediction in cell lines using matrix factorization with similarity regularization.

BMC Cancer. 2017 Aug 02;17(1):513

Authors: Wang L, Li X, Zhang L, Gao Q

Abstract
BACKGROUND: Human cancer cell lines are used in research to study the biology of cancer and to test cancer treatments. Recently there are already some large panels of several hundred human cancer cell lines which are characterized with genomic and pharmacological data. The ability to predict drug responses using these pharmacogenomics data can facilitate the development of precision cancer medicines. Although several methods have been developed to address the drug response prediction, there are many challenges in obtaining accurate prediction.
METHODS: Based on the fact that similar cell lines and similar drugs exhibit similar drug responses, we adopted a similarity-regularized matrix factorization (SRMF) method to predict anticancer drug responses of cell lines using chemical structures of drugs and baseline gene expression levels in cell lines. Specifically, chemical structural similarity of drugs and gene expression profile similarity of cell lines were considered as regularization terms, which were incorporated to the drug response matrix factorization model.
RESULTS: We first demonstrated the effectiveness of SRMF using a set of simulation data and compared it with two typical similarity-based methods. Furthermore, we applied it to the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets, and performance of SRMF exceeds three state-of-the-art methods. We also applied SRMF to estimate the missing drug response values in the GDSC dataset. Even though SRMF does not specifically model mutation information, it could correctly predict drug-cancer gene associations that are consistent with existing data, and identify novel drug-cancer gene associations that are not found in existing data as well. SRMF can also aid in drug repositioning. The newly predicted drug responses of GDSC dataset suggest that mTOR inhibitor rapamycin was sensitive to non-small cell lung cancer (NSCLC), and expression of AK1RC3 and HINT1 may be adjunct markers of cell line sensitivity to rapamycin.
CONCLUSIONS: Our analysis showed that the proposed data integration method is able to improve the accuracy of prediction of anticancer drug responses in cell lines, and can identify consistent and novel drug-cancer gene associations compared to existing data as well as aid in drug repositioning.

PMID: 28768489 [PubMed - in process]

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.

Am J Hum Genet. 2017 Aug 03;101(2):267-273

Authors: Edvardson S, Nicolae CM, Agrawal PB, Mignot C, Payne K, Prasad AN, Prasad C, Sadler L, Nava C, Mullen TE, Begtrup A, Baskin B, Powis Z, Shaag A, Keren B, Moldovan GL, Elpeleg O

Abstract
Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

PMID: 28777933 [PubMed - in process]

High oxygen affinity hemoglobins.

Rev Med Interne. 2017 Feb;38(2):106-112

Authors: Mangin O

Abstract
High oxygen affinity hemoglobins are responsible for rare and heterogeneous autosomic dominant genetic diseases. They cause pure erythrocytosis, sometimes accountable for hyperviscosity and thrombosis, or hemolysis. Differential diagnoses must be first ruled out. The diagnosis is based on the identification of a decreased P50, and their possible characterization by cation exchange-high performance liquid chromatography and capillary electrophoresis. Finally, genetic studies of the responsible globin chain gene will confirm the mutation. The prognosis mainly relies on the P50 decrease rate and on the hemoglobin cooperativity impairment. Disease management should be personalized, and it should primarily depend on smoking cessation and physical activity. Phlebotomy and platelet aggregation inhibitors' prescriptions can be discussed. There is no contraindication to flights, high-altitude conditions, or pregnancy. Nevertheless, blood donation must be prohibited.

PMID: 27637720 [PubMed - indexed for MEDLINE]

Role of B cells in the pathogenesis of systemic sclerosis.

Rev Med Interne. 2017 Feb;38(2):113-124

Authors: Sanges S, Guerrier T, Launay D, Lefèvre G, Labalette M, Forestier A, Sobanski V, Corli J, Hauspie C, Jendoubi M, Yakoub-Agha I, Hatron PY, Hachulla E, Dubucquoi S

Abstract
Systemic sclerosis (SSc) is an orphan disease characterized by progressive fibrosis of the skin and internal organs. Aside from vasculopathy and fibrotic processes, its pathogenesis involves an aberrant activation of immune cells, among which B cells seem to play a significant role. Indeed, B cell homeostasis is disturbed during SSc: the memory subset is activated and displays an increased susceptibility to apoptosis, which is responsible for their decreased number. This chronic loss of B cells enhances bone marrow production of the naïve subset that accounts for their increased number in peripheral blood. This permanent activation state can be explained mainly by two mechanisms: a dysregulation of B cell receptor (BCR) signaling, and an overproduction of B cell survival signals, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). These disturbances of B cell homeostasis induce several functional anomalies that participate in the inflammatory and fibrotic events observed during SSc: autoantibody production (some being directly pathogenic); secretion of pro-inflammatory and pro-fibrotic cytokines (interleukin-6); direct cooperation with other SSc-involved cells [fibroblasts, through transforming growth factor-β (TGF-β) signaling, and T cells]. These data justify the evaluation of anti-B cell strategies as therapeutic options for SSc, such as B cell depletion or blockage of B cell survival signaling.

PMID: 27020403 [PubMed - indexed for MEDLINE]

Amantadine for Antipsychotic-Related Weight Gain: Meta-Analysis of Randomized Placebo-Controlled Trials.

J Clin Psychopharmacol. 2017 Jun;37(3):341-346

Authors: Zheng W, Wang S, Ungvari GS, Ng CH, Yang XH, Gu YH, Li M, Xiang YQ, Xiang YT

Abstract
PURPOSE: Weight gain associated with antipsychotics in schizophrenia has been an ongoing concern. This meta-analysis examined the efficacy and safety of amantadine as an adjunctive treatment of weight gain in schizophrenia by systematically searching and analyzing randomized controlled trials (RCTs). RCTs comparing adjunctive amantadine with placebo in adult patients with schizophrenia were included in the meta-analysis.
METHODS: Two independent investigators searched the literature and extracted data. Weighted and standardized mean differences (WMDs/SMDs) and risk ratio ± 95% confidence intervals were calculated.
RESULTS: Five RCTs (n = 265) with double-blinded design lasting 8.2 ± 5.9 weeks were included in the analysis. Amantadine outperformed placebo regarding weight reduction with moderate effect size (trials, 3; n = 205; WMD -2.22 kg; P = 0.001, I = 45%). Amantadine also outperformed placebo at endpoint in the negative symptom (the Positive and Negative Syndrome Scale [PANSS] [1 trial] and the Scale for the Assessment of Negative Symptoms [1 trial]) scores (trials, 2; n = 84; SMD, -0.56; P = 0.01, I = 12%), but not in the PANSS total scores (trials, 2) (SMD, -0.31; P = 0.16, I = 0%) and the positive symptom (PANSS [1 trial] and the Scale for the Assessment of Positive Symptoms [1 trial]) scores (SMD, 0.13; P = 0.54, I = 0%). Except for insomnia (P = 0.007; number needed to harm, 6; 95% confidence interval, 4-16), all-cause discontinuation (risk ratio, 1.12; P = 0.54, I = 0%) and other adverse events were similar between the amantadine and placebo groups.
CONCLUSIONS: According to this meta-analysis of 5 RCTs, adjunctive amantadine seems to be an effective option for attenuating antipsychotic-related weight gain in patients with schizophrenia. More RCTs are needed to inform clinical recommendations.

PMID: 28383359 [PubMed - indexed for MEDLINE]

Lithiumeter: Version 2.0.

Bipolar Disord. 2016 Dec;18(8):631-641

Authors: Malhi GS, Gershon S, Outhred T

Abstract
BACKGROUND: The Lithiumeter was developed as a visual and practical guide for determining lithium levels in the management of bipolar disorder (BD). It appears to have been well received, as evidenced by its increasing popularity amongst doctors as a deskside clinical aide, and adoption and reproduction of the schematic in clinical guidelines and texts. However, since its publication 5 years ago, key basic neuroscience and clinical research developments pertaining to lithium have significantly advanced our understanding, necessitating further refinement of guidance concerning the practicalities of lithium therapy.
METHODS: Literature concerning the indications for, and therapeutic levels of, lithium and the associated acute and chronic risks of therapy was scrutinized as part of updating clinical practice guidelines. We have reviewed these updates and identified significant areas of change with respect to the previous Lithiumeter (version 1.0).
RESULTS: Since 2011, updated clinical practice guidelines have narrowed the indicated plasma lithium concentration for maintenance therapy, suggesting that additional guidance is necessary for optimizing treatment. Relevant updated clinical guidance was integrated to constitute the Lithiumeter 2.0, which provides a more comprehensive overview of the practical aspects of lithium therapy while maintaining a focus on optimization of lithium levels, such as differential titration of lithium depending on the current mood state.
CONCLUSIONS: The Lithiumeter 2.0 is an update that clinicians will find useful for their practice. By addressing some of the issues faced in clinical practice, translational clinical research will continue to inform the Lithiumeter in future updates.

PMID: 28063207 [PubMed - indexed for MEDLINE]