Chronic form of Pisa syndrome after prolonged exposure to low-dose amisulpride treatment

Pisa syndrome is a movement problem defined by tonic, sustained lateral flexion with a slight posterior rotation of the trunk. It seems to be a side effect of antipsychotic medicine in most cases. The clinical duration of Pisa syndrome can be acute, chronic, or recurrent. As far as we know, no reports are available in the literature on the chronic form of Pisa syndrome caused by low-dose amisulpride. A case of refractory tardive dystonia form of Pisa syndrome during treatment with stable low-dose amisulpride is presented in this report. Long-term, low-dosage amisulpride therapy may induce tardive dystonia even in patients with no other risk factors for dystonia.

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P6157Indexed coronary volume - A potential novel low-dose CCTA derived predictor for cardiovascular events

European Heart Journal ◽

10.1093/eurheartj/ehz746.0763 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

G Benetos ◽

M Goncalves ◽

E Von Felten ◽

G Rampidis ◽

O Clerc ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Events ◽

Low Dose ◽

Cox Regression ◽

Calcium Score ◽

Kaplan Meier ◽

Lv Mass ◽

Traditional Risk Factors ◽

Artery Disease

Abstract Background Coronary computed tomography angiography (CCTA) provides incremental prognostic information over traditional risk factors in patients with suspected coronary artery disease. However, little is known about the long-term predictive performance of CCTA-derived coronary volumes and mid-diastolic left ventricular (LV) mass. Purpose To assess long-term prognostic value of coronary volumes and mid-diastolic LV mass as novel potential imaging predictors derived from low-dose prospectively ECG-triggered CCTA. Methods Consecutive patients with suspected or known coronary artery disease, referred for low-dose CCTA, were included. Patients with previous revascularization were excluded. The following parameters were evaluated: calcium score, segment involvement score (SIS: 1 point for each coronary segment with presence of plaque), coronary volume, mid-diastolic LV mass and coronary volume indexed to LV mass. Major adverse cardiovascular events (MACE) were defined as all-cause death, non-fatal myocardial infarction and revascularization (PCI or CABG). The association between CCTA measures and the occurrence of events was quantified using cox regression hazard and Kaplan Meier analysis. Results A total of 147 consecutive patients were included in the study. Of them, 93 (63.3%) were male and 79 (53.7%) hat one or more traditional cardiovascular risk factors. There was a weak but statistical significant inverse correlation between indexed coronary volume and both calcium score (R=-0.3, p=0.01) and SIS (R=-0.24, p=0.005). After a median follow-up of 5.8 years 30 MACE occurred in 25 patients, including 3 deaths, 26 revascularizations and 1 non-fatal myocardial infarction. In univariate cox regression hazard analysis calcium score (HR=12.69, 95% CI 2.99–53.83, p<0.001), SIS (HR=1.66, 95% CI 1.43–1.94, p<0.001), LV mass (HR=1.02, 95% CI 1.01–1.03, p=0.007) and indexed coronary volume (HR=0.89, 95% 0.82–0.96, p=0.004) were associated with outcome. In multivariate analysis, indexed coronary volume, remained an independent predictor for MACE when adjusted for traditional risk factors and SIS (HR=0.93, 95% CI 0.87–1.00, p=0.05), while LV mass did not reach statistical significance (p=0.46). By ROC curve analysis, a value of 21.85 mm3/gr was defined as optimal cutoff for indexed coronary volume. In Kaplan Meier plots, patients with low indexed coronary volume (<21.85 mm3/gr) showed higher event rates (log rank p<0.001) compared to high indexed coronary volume (≥21.85 mm3/gr). Conclusions Indexed coronary volume, derived from low-dose CCTA, independently predicts cardiovascular events. Larger studies are mandated to confirm the predictive value of this potential new biomarker.

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Activity of OTX015 (MK-8628), a BET-Bromodomain Inhibitor, in Acute Myeloid Leukemia (AML) Progenitor Cells

Blood ◽

10.1182/blood.v126.23.2588.2588 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2588-2588 ◽

Cited By ~ 1

Author(s):

Louise Roulin ◽

Ashfaq Ali ◽

Aline Masse ◽

Marie-Magdelaine Coudé ◽

Dominique Bluteau ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Progenitor Cells ◽

Cell Lines ◽

Research Funding ◽

Low Dose ◽

Prolonged Exposure ◽

Target Concentration ◽

Long Term Culture

Abstract CONTEXT: Eradication of leukemic progenitor cells, defined by functional assays such as long-term culture (leukemic long-term culture initiating cells [L-LTC-IC]) is the goal of therapy in AML. Bromodomain and ExtraTerminal (BET) proteins are epigenetic readers that regulate the expression of genes with super-enhancers, including CMYC. BET inhibitors (BETi) such as JQ1 induce proliferation arrest and apoptosis in murine models of AML, in human AML cell lines and primary blasts. Their activity in human leukemic progenitors has not yet been reported. OTX015 (MK-8626) is an orally available BETi that can be safely administered to patients with a continuous low-dose regimen (Dombret et al. Blood. 2014). Single-dose exposure to OTX015 induces gene expression modulation characteristic of bromodomain inhibition, including downregulation of CMYC and upregulation of HEXIM1, inhibiting the viability of AML cell lines, and inducing apoptosis in primary AML blasts (Coudé et al. Oncotarget. 2015). To address the activity of OTX015 on leukemic progenitors, we analyzed (A) the clonogenicity of AML cell lines and (B) the frequency of primary L-LTC-IC after repeated low-dose exposure to OTX015. METHODS: (A) Five AML cell lines (OTX015 IC50 60 - 10,000 nM) were studied: OCI-AML3, NOMO-1, HL-60, KG1a and K562. After 24h starvation, OTX015 or vehicle (DMSO) was added daily to the culture medium for 3 days at various concentrations. After 96h, cells were assessed for gene expression by RT-qPCR and seeded in methycellulose. Colonies were scored after 14 days. (B) Bone-marrow mononuclear cells (BMNC) from AML patients obtained at diagnosis after informed consent were cultured for three weeks in a niche-like hypoxic milieu shown to maintain leukemic stem cells (Griessinger et al. Stem Cells Transl Med. 2014). OTX015 200 nM or DMSO was added weekly. This concentration is in the range of trough concentrations achievable at the MTD of OTX015 in phase I trials. Residual leukemic cells were sorted and plated on methylcellulose. Colonies were scored after 14 days. The resulting L-LTC-IC frequency was reported relative to the number of BMNC initially seeded. RESULTS: (A) To dissect the effect of OTX015 on AML progenitors from that on the leukemic bulk, we determined for each cell line a maximal OTX015 concentration that could be administered repeatedly for 3 days without significantly impairing proliferation or viability (MTT) at day 4 of culture (referred as low-dose concentration). As expected, this target concentration, ranging from 50 to 500 nM, was lower in cell lines with low OTX015 IC50. This prolonged low-dose exposure to OTX015 recapitulated BETi-associated gene expression changes including CMYC downregulation and HEXIM1 upregulation in all cell lines, and significantly reduced clonogenicity compared to DMSO in 4/5 cell lines, but not in NPM1-mutated OCI-AML3 cells (IC50: 60 nM, target concentration 50 nM), despite modulation of CMYC and HEXIM1 expression. Overall, there was no correlation between the level of CMYC repression and clonogenicity. Transcriptome analyses are ongoing to identify gene expression changes specifically associated with inhibition of clonogenicity. (B) L-LTC-IC frequency after prolonged exposure to 200 nM OTX015 was determined in specimens from 11 AML patients with variable oncogenetics. L-LTC-IC frequency was reduced in 5/11 patients, reaching statistical significance in 3 cases; OTX015 reduced L-L-LTC-IC in 3 of 4 NPM1-mutated samples, but not in any of the 3 patients with high-risk cytogenetics. No clear correlation was found between induction of apoptosis on primary blasts after short-term, and L-LTC-IC reduction after long-term 200nM OTX015 exposure respectively. Patients' samples number is being extended to identify oncogenetic predictors of L-LTC-IC reduction. CONCLUSION: Our results suggest that in AML cell lines or primary samples, prolonged exposure to low concentrations of the clinically-available BET inhibitor OTX015 results in activity against leukemic progenitors independent of induction of proliferation arrest or apoptosis in blasts. Molecular mechanisms and oncogenic markers of this activity are being investigated. These results warrant clinical investigation of the anti-leukemic properties of prolonged low-dose OTX015 administration. Disclosures Riveiro: Oncoethix: Research Funding; OTD: Employment. Herait:Oncoethix: Other: shareholder; Oncoethix: Other: Chief medical officer; Oncoethix: Other: shareholder. Dombret:Oncoethix: Research Funding. Itzykson:Oncoethix: Research Funding.

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Long-term strategies in patients with unprovoked venous thromboembolism

Phlebologie ◽

10.12687/phleb2372-5-2017 ◽

2017 ◽

Vol 46 (05) ◽

pp. 288-291

Author(s):

P. Prandoni

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Low Dose ◽

Risk Profile ◽

Substantial Proportion ◽

First Episode ◽

Vein Thrombosis ◽

Recurrent Venous Thromboembolism ◽

D Dimer

SummaryOnce anticoagulation is stopped, the risk of recurrent venous thromboembolism (VTE) over years approaches 40 % of all patients with a first episode of VTE. The risk is twice as high in patients with unprovoked VTE than in those with minor (either transient or persistent) risk factors of thrombosis. Although the latest international guidelines suggest indefinite anticoagulation for most patients with a first episode of unprovoked VTE, strategies that incorporate the assessment of residual vein thrombosis and D-dimer have the potential to identify a substantial proportion of subjects in whom anticoagulation can be safely discontinued. For those patients in whom anticoagulation cannot be discontinued, new opportunities are offered by the availability of low-dose anti-Xa compounds, which have been found to possess an extremely favorable benefit/risk profile.

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Cumulative metabolic effects of low-dose benzo(a)pyrene exposure on human cells

Toxicology Research ◽

10.1039/c5tx00378d ◽

2016 ◽

Vol 5 (1) ◽

pp. 107-115 ◽

Cited By ~ 5

Author(s):

Qian Ba ◽

Chao Huang ◽

Yijing Fu ◽

Junyang Li ◽

Jingquan Li ◽

...

Keyword(s):

Low Dose ◽

Human Cells ◽

Metabolic Effects ◽

Group I ◽

Low Dosage

Benzo(a)pyrene (B[a]P) is a common environmental and foodborne pollutant which has been identified as a Group I carcinogen. And the global metabolic effects of long-term B[a]P exposure at low dosage were investigated.

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Effects of low-dose contraceptive pills on the risk factors of cardiovascular diseases among 15-35-year-old women: A retrospective cohort

International Journal of Reproductive BioMedicine ◽

10.18502/ijrm.v17i10.5496 ◽

2019 ◽

Author(s):

Zahra Momeni ◽

Ali Dehghani ◽

Hossein Fallahzadeh ◽

Moslem Koohgardi ◽

Maryam Dafei ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Diseases ◽

Systolic Blood Pressure ◽

Retrospective Cohort ◽

Low Dose ◽

Density Lipoprotein ◽

Oral Contraceptive Pills ◽

Contraceptive Pills

Background: Cardiovascular diseases could be preventable; as a result, understanding the risk factors was regarded as the major priority for healthcare providers. Objective: The main objective of this research was to achieve a deeper insight into the effect of long-term use of low-dose oral contraceptive pills (OCP) on the risk factors of cardiovascular diseases. Materials and Methods: This research was a retrospective cohort conducted (historical and prospectively) conducted on 100 women with normal menstrual cycles aged 15 to 35 yr, who were referred to the healthcare centers in Yazd, Iran. The participants were categorized into two groups: The OCP group was consuming the pills for 3, 4-23, and 24-36 months, and the non-OCP group. Participants were followed up for a minimum of 3 months and a maximum of six months. Results: The highest level of low-density lipoprotein (LDL), homocysteine, cholesterol, triglyceride levels, and systolic blood pressure was observed in the OCP group in the duration of 24 to 36 months. The Tukey’s test demonstrated that there were comprehensible differences in the LDL (p = 0.01), cholesterol (p = 0.01), triglyceride (p < 0.001), and homocysteine levels (p < 0.001), also systolic blood pressure (p = 0.04). Conclusion: It was realized that the long-term consumption of low-dose OCP can augment the incidence of some risk factors (systolic blood pressure, homocysteine levels, cholesterol, LDL-c, and triglyceride) and lead to developing cardiovascular diseases amongst the healthy women. Key words: Birth control pills, Homocysteine, Nitric oxide, Dyslipidemias, Coronary artery diseases.

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Ovarian Dysfunction in Fetally Irradiated Beagles

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100080717 ◽

1977 ◽

Vol 35 ◽

pp. 658-659

Author(s):

T. M. Seed ◽

M. H. Sanderson ◽

D. L. Gutzeit ◽

T. E. Fritz ◽

D. V. Tolle ◽

...

Keyword(s):

Gamma Rays ◽

Low Dose ◽

Long Term Effects ◽

Ovarian Dysfunction ◽

Dose Rates ◽

Highly Sensitive ◽

Microscopic Evaluation ◽

Ovarian Pathology ◽

Normal Offspring

The developing mammalian fetus is thought to be highly sensitive to ionizing radiation. However, dose, dose-rate relationships are not well established, especially the long term effects of protracted, low-dose exposure. A previous report (1) has indicated that bred beagle bitches exposed to daily doses of 5 to 35 R 60Co gamma rays throughout gestation can produce viable, seemingly normal offspring. Puppies irradiated in utero are distinguishable from controls only by their smaller size, dental abnormalities, and, in adulthood, by their inability to bear young.We report here our preliminary microscopic evaluation of ovarian pathology in young pups continuously irradiated throughout gestation at daily (22 h/day) dose rates of either 0.4, 1.0, 2.5, or 5.0 R/day of gamma rays from an attenuated 60Co source. Pups from non-irradiated bitches served as controls. Experimental animals were evaluated clinically and hematologically (control + 5.0 R/day pups) at regular intervals.

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The Acute Effect of Alcohol on Various Memory Processes

Journal of Psychophysiology ◽

10.1027/0269-8803/a000038 ◽

2010 ◽

Vol 24 (4) ◽

pp. 249-252 ◽

Cited By ~ 7

Author(s):

Márk Molnár ◽

Roland Boha ◽

Balázs Czigler ◽

Zsófia Anna Gaál

Keyword(s):

Low Dose ◽

Short Term Memory ◽

Acute Effect ◽

Long Term Memory ◽

Term Memory ◽

Memory Processes ◽

Different Types ◽

The Brain ◽

Legal Consequences

This review surveys relevant and recent data of the pertinent literature regarding the acute effect of alcohol on various kinds of memory processes with special emphasis on working memory. The characteristics of different types of long-term memory (LTM) and short-term memory (STM) processes are summarized with an attempt to relate these to various structures in the brain. LTM is typically impaired by chronic alcohol intake but according to some data a single dose of ethanol may have long lasting effects if administered at a critically important age. The most commonly seen deleterious acute effect of alcohol to STM appears following large doses of ethanol in conditions of “binge drinking” causing the “blackout” phenomenon. However, with the application of various techniques and well-structured behavioral paradigms it is possible to detect, albeit occasionally, subtle changes of cognitive processes even as a result of a low dose of alcohol. These data may be important for the consideration of legal consequences of low-dose ethanol intake in conditions such as driving, etc.

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