Blood transcriptomic signature in type-2 biomarker-low severe asthma and asthma control.

BACKGROUND: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids. OBJECTIVES: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores. METHODS: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated. RESULTS: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level. CONCLUSIONS: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.

Treatment of Hepatocellular Carcinoma by Multimodal In Situ Vaccination Using Cryoablation and a Plant Virus Immunostimulant.

PURPOSE: To test the hypothesis that cryoablation combined with intratumoral immunomodulating nanoparticles from cowpea mosaic virus (CPMV) as an in situ vaccination approach induces systemic antitumoral immunity in a murine model of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Mice with bilateral, subcutaneous RIL-175 cell-derived HCCs were randomized to 4 groups: (a) phosphate-buffered saline (control), (b) cryoablation only (Cryo), (c) CPMV-treated only (CPMV), and (d) cryoablation plus CPMV-treated (Cryo + CPMV) (N = 11-14 per group). Intratumoral CPMV was administered every 3 days for 4 doses, with cryoablation performed on the third day. Contralateral tumors were monitored. Tumor growth and systemic chemokine/cytokine levels were measured. A subset of tumors and spleens were harvested for immunohistochemistry (IHC) and flow cytometry. One- or 2-way analysis of variance was performed for statistical comparisons. A P value of <.05 was used as the threshold for statistical significance. RESULTS: At 2 weeks after treatment, the Cryo and CPMV groups, alone or combined, outperformed the control group in the treated tumor; however, the Cryo + CPMV group showed the strongest reduction and lowest variance (1.6-fold ± 0.9 vs 6.3-fold ± 0.5, P < .0001). For the untreated tumor, only Cryo + CPMV significantly reduced tumor growth compared with control (9.2-fold ± 0.9 vs 17.8-fold ± 2.1, P = .01). The Cryo + CPMV group exhibited a transient increase in interleukin-10 and persistently decreased CXCL1. Flow cytometry revealed natural killer cell enrichment in the untreated tumor and increased PD-1 expression in the spleen. Tumor-infiltrating lymphocytes increased in Cryo + CPMV-treated tumors by IHC. CONCLUSIONS: Cryoablation and intratumoral CPMV, alone or combined, demonstrated potent efficacy against treated HCC tumors; however, only cryoablation combined with CPMV slowed the growth of untreated tumors, consistent with an abscopal effect.

A global survey on the attitudes of neurologists and psychiatrists about functional/psychogenic/dissociative/nonepileptic-seizures/attacks, in the search of its name.

PURPOSE: We conducted an observational study to investigate the opinions of neurologists and psychiatrists all around the world who are taking care of patients with seizures [epilepsy and functional seizures (FS)]. METHODS: Practicing neurologists and psychiatrists from around the world were invited to participate in an online survey. On 29th September 2022, an e-mail including a questionnaire was sent to the members of the International Research in Epilepsy (IR-Epil) Consortium. The study was closed on 1st March 2023. The survey, conducted in English, included questions about physicians' opinions about FS and anonymously collected data. RESULTS: In total, 1003 physicians from different regions of the world participated in the study. Both neurologists and psychiatrists identified "seizures" as their preferred term. Overall, the most preferred modifiers for "seizures" were "psychogenic" followed by "functional" by both groups. Most participants (57.9%) considered FS more difficult to treat compared to epilepsy. Both psychological and biological problems were considered as the underlying cause of FS by 61% of the respondents. Psychotherapy was considered the first treatment option for patients with FS (79.9%). CONCLUSION: Our study represents the first large-scale attempt of investigating physicians attitudes and opinions about a condition that is both frequent and clinically important. It shows that there is a broad spectrum of terms used by physicians to refer to FS. It also suggests that the biopsychosocial model has gained its status as a widely used framework to interpret and inform clinical practice on the management of patients.

Low Magnesium Concentration Enforces Bone Calcium Deposition Irrespective of 1,25-Dihydroxyvitamin D3 Concentration.

Efficient coordination between Mg2+ and vitamin D maintains adequate Ca2+ levels during lactation. This study explored the possible interaction between Mg2+ (0.3, 0.8, and 3 mM) and 1,25-dihydroxyvitamin D3 (1,25D; 0.05 and 5 nM) during osteogenesis using bovine mesenchymal stem cells. After 21 days, differentiated osteocytes were subjected to OsteoImage analysis, alkaline phosphatase (ALP) activity measurements, and immunocytochemistry of NT5E, ENG (endoglin), SP7 (osterix), SPP1 (osteopontin), and the BGLAP gene product osteocalcin. The mRNA expression of NT5E, THY1, ENG, SP7, BGLAP, CYP24A1, VDR, SLC41A1, SLC41A2, SLC41A3, TRPM6, TRPM7, and NIPA1 was also assessed. Reducing the Mg2+ concentration in the medium increased the accumulation of mineral hydroxyapatite and ALP activity. There was no change in the immunocytochemical localization of stem cell markers. Expression of CYP24A1 was higher in all groups receiving 5 nM 1,25D. There were tendencies for higher mRNA abundance of THY1, BGLAP, and NIPA1 in cells receiving 0.3 mM Mg2+ and 5 nM 1,25D. In conclusion, low levels of Mg2+ greatly enhanced the deposition of bone hydroxyapatite matrix. The effect of Mg2+ was not modulated by 1,25D, although the expression of certain genes (including BGLAP) tended to be increased by the combination of low Mg2+ and high 1,25D concentrations.

Depression, Anxiety, and Suicide After Stroke: A Narrative Review of the Best Available Evidence.

Depression and anxiety each affect around 1 in 3 people during the first year after a stroke. Suicide causes the death of about 3 to 4/1000 stroke survivors during the first 5 years. This narrative review describes the best available evidence for the epidemiology of depression, anxiety, and suicide; their prevention; and the treatment of anxiety and depression. We conclude with directions for future research.

Counseling about sudden unexpected death in epilepsy (SUDEP): A global survey of neurologists' opinions.

OBJECTIVE: To investigate the opinions and attitudes of neurologists on the counseling about sudden unexpected death in epilepsy (SUDEP) worldwide. METHODS: Practicing neurologists from around the world were invited to participate in an online survey. On February 18th, 2021, we emailed an invitation including a questionnaire (using Google-forms) to the lead neurologists from 50 countries. The survey anonymously collected the demographic data of the participants and answers to the questions about their opinions and attitudes toward counseling about SUDEP. RESULTS: In total, 1123 neurologists from 27 countries participated; 41.5% of the respondents reported they discuss the risk of SUDEP with patients and their care-givers only rarely. Specific subgroups of patients who should especially be told about this condition were considered to be those with poor antiseizure medication (ASM) adherence, frequent tonic-clonic seizures, or with drug-resistant epilepsy. The propensity to tell all patients with epilepsy (PWE) about SUDEP was higher among those with epilepsy fellowship. Having an epilepsy fellowship and working in an academic setting were factors associated with a comfortable discussion about SUDEP. There were significant differences between the world regions. CONCLUSION: Neurologists often do not discuss SUDEP with patients and their care-givers. While the results of this study may not be representative of practitioners in each country, it seems that there is a severe dissociation between the clinical significance of SUDEP and the amount of attention that is devoted to this matter in daily practice by many neurologists around the world.

Imaging Biomarkers and Liquid Biopsy in Assessment of Cervical Cancer.

ABSTRACT: The role of imaging has been increasing in pretherapy planning and response assessment in cervical cancer, particularly in high-resource settings that provide access to computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). In 2018, imaging was incorporated into the International Federation of Gynecology and Obstetrics staging system for cervical cancer. Magnetic resonance imaging is advantageous over CT for evaluation of the primary cervical cancer size and extent, because of superior contrast resolution. Furthermore, quantitative methods, including diffusion-weighted and dynamic contrast-enhanced MRI, show promise in improving treatment response and prognosis evaluation. Molecular imaging with fluorodeoxyglucose-PET/CT and PET/MRI can be particularly helpful in the detection of nodal disease and distant metastases. Semiautomated delineation of 3-dimensional tumor regions of interest has facilitated the development of novel PET-derived biomarkers that include metabolic volume and radiomics textural analysis features for prediction of outcomes. However, posttreatment inflammatory changes can be a confounder and lymph node evaluation is challenging, even with the use of PET/CT. Liquid biopsy has emerged as a promising tool that may be able to overcome some of the drawbacks inherent with imaging, such as limited ability to detect microscopic metastases or to distinguish between postchemoradiotherapy changes and residual tumor. Preliminary evidence suggests that liquid biopsy may be able to identify cervical cancer treatment response and resistance earlier than traditional methods. Future work should prioritize how to best synergize imaging and liquid biopsy as an integrated approach for optimal cervical cancer management.

Identifying enhancement-based staging markers on baseline MRI in patients with colorectal cancer liver metastases undergoing intra-arterial tumor therapy.

OBJECTIVES: To determine if three-dimensional whole liver and baseline tumor enhancement features on MRI can serve as staging biomarkers and help predict survival of patients with colorectal cancer liver metastases (CRCLM) more accurately than one-dimensional and non-enhancement-based features. METHODS: This retrospective study included 88 patients with CRCLM, treated with transarterial chemoembolization or Y90 transarterial radioembolization between 2001 and 2014. Semi-automated segmentations of up to three dominant lesions were performed on pre-treatment MRI to calculate total tumor volume (TTV) and total liver volumes (TLV). Quantitative 3D analysis was performed to calculate enhancing tumor volume (ETV), enhancing tumor burden (ETB, calculated as ETV/TLV), enhancing liver volume (ELV), and enhancing liver burden (ELB, calculated as ELV/TLV). Overall and enhancing tumor diameters were also measured. A modified Kaplan-Meier method was used to determine appropriate cutoff values for each metric. The predictive value of each parameter was assessed by Kaplan-Meier survival curves and univariable and multivariable cox proportional hazard models. RESULTS: All methods except whole liver (ELB, ELV) and one-dimensional/non-enhancement-based methods were independent predictors of survival. Multivariable analysis showed a HR of 2.1 (95% CI 1.3-3.4, p = 0.004) for enhancing tumor diameter, HR 1.7 (95% CI 1.1-2.8, p = 0.04) for TTV, HR 2.3 (95% CI 1.4-3.9, p < 0.001) for ETV, and HR 2.4 (95% CI 1.4-4.0, p = 0.001) for ETB. CONCLUSIONS: Tumor enhancement of CRCLM on baseline MRI is strongly associated with patient survival after intra-arterial therapy, suggesting that enhancing tumor volume and enhancing tumor burden are better prognostic indicators than non-enhancement-based and one-dimensional-based markers. KEY POINTS: • Tumor enhancement of colorectal cancer liver metastases on MRI prior to treatment with intra-arterial therapies is strongly associated with patient survival. • Three-dimensional, enhancement-based imaging biomarkers such as enhancing tumor volume and enhancing tumor burden may serve as the basis of a novel prognostic staging system for patients with liver-dominant colorectal cancer metastases.

Working restrictions and disability benefits eligibility in patients with functional (psychogenic) seizures: An international survey of physicians' opinions.

OBJECTIVES: In this international study, we aimed to investigate the opinions of physicians dealing with patients with functional seizures (FS) worldwide on working restrictions and disability benefits eligibility. METHODS: International online survey of neurologists/mental health professionals from Argentina, Venezuela, Colombia, Italy, France, Iran, Iraq, United Arab Emirates (UAE), Qatar, Saudi Arabia, Georgia, and Russia. RESULTS: Six hundred and twenty-seven physicians from 12 countries participated in the study. Working as a neurologist was a predictor to think that patients with FS should not be counseled to avoid performing all jobs or professions as long as they have active disease (OR: 0.46; 95% CI: 0.30 to 0.68; p < 0.001). Having managed more than 200 patients was associated with the opinion that patients should not be counseled to avoid performing any type of work (OR: 2.17; 95% CI: 1.02 to 4.59; p = 0.043). Working as a psychiatrist/psychologist was associated with the idea that patients with FS should be qualified for disability benefits (OR: 1.97; 95% CI: 1.21-3.21; p = 0.006), and receive these benefits lifelong (OR: 0.43; 95% CI: 0.22-0.84; p = 0.014). CONCLUSION: Neurologists and mental health professionals have different attitudes and opinions toward working restrictions and disability benefits for patients with FS. Further studies should investigate the reasons for these differences, and propose solutions to avoid discrimination and unequal access to employment and disability benefits.

Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) might theoretically reduce post-stroke disability by direct effects on the brain. This Cochrane Review was first published in 2012 and last updated in 2019. OBJECTIVES: To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post-stroke, and to determine whether treatment with SSRIs is associated with adverse effects. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 7 January 2021), Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, 7 January 2021), MEDLINE (1946 to 7 January 2021), Embase (1974 to 7 January 2021), CINAHL (1982 to 7 January 2021), PsycINFO (1985 to 7 January 2021), and AMED (1985 to 7 January 2021). PsycBITE had previously been searched (16 July 2018). We searched clinical trials registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) recruiting stroke survivors within the first year. The intervention was any SSRI, at any dose, for any period, and for any indication. The comparator was usual care or placebo. Studies reporting at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, cognition, healthcare cost, death, adverse events and leaving the study early) were included in the meta-analysis. The primary analysis included studies at low risk of bias. DATA COLLECTION AND ANALYSIS: We extracted data on demographics, stroke type and, our pre-specified outcomes, and bias sources. Two review authors independently extracted data. We used mean difference (MD) or standardised mean differences (SMDs) for continuous variables, and risk ratios (RRs) for dichotomous variables, with 95% confidence intervals (CIs). We assessed bias risks and applied GRADE criteria. MAIN RESULTS: We identified 76 eligible studies (13,029 participants); 75 provided data at end of treatment, and of these two provided data at follow-up. Thirty-eight required participants to have depression to enter. The duration, drug, and dose varied. Six studies were at low risk of bias across all domains; all six studies did not need participants to have depression to enter, and all used fluoxetine. Of these six studies, there was little to no difference in disability between groups SMD -0.0; 95% CI -0.05 to 0.05; 5 studies, 5436 participants, high-quality evidence) or in independence (RR 0.98; 95% CI 0.93 to 1.03; 5 studies, 5926 participants; high-quality evidence) at the end of treatment. In the studies at low risk of bias across all domains, SSRIs slightly reduced the average depression score (SMD 0.14 lower, 95% CI 0.19 lower to 0.08 lower; 4 studies; 5356 participants, high-quality evidence) and there was a slight reduction in the proportion with depression (RR 0.75, 95% CI 0.65 to 0.86; 3 studies, 5907 participants, high-quality evidence). Cognition was slightly better in the control group (MD -1.22, 95% CI -2.37 to -0.07; 4 studies, 5373 participants, moderate-quality evidence). Only one study (n = 30) reported neurological deficit score (SMD -0.39, 95% CI -1.12 to 0.33; low-quality evidence). SSRIs resulted in little to no difference in motor deficit (SMD 0.03, -0.02 to 0.08; 6 studies, 5518 participants, moderate-quality evidence). SSRIs slightly increased the proportion leaving the study early (RR 1.57, 95% CI 1.03 to 2.40; 6 studies, 6090 participants, high-quality evidence). SSRIs slightly increased the outcome of a seizure (RR 1.40, 95% CI 1.00 to 1.98; 6 studies, 6080 participants, moderate-quality evidence) and a bone fracture (RR 2.35, 95% CI 1.62 to 3.41; 6 studies, 6080 participants, high-quality evidence). One study at low risk of bias across all domains reported gastrointestinal side effects (RR 1.71, 95% CI 0.33, to 8.83; 1 study, 30 participants). There was no difference in the total number of deaths between SSRI and placebo (RR 1.01, 95% CI 0.82 to 1.24; 6 studies, 6090 participants, moderate quality evidence). SSRIs probably result in little to no difference in fatigue (MD -0.06; 95% CI -1.24 to 1.11; 4 studies, 5524 participants, moderate-quality of evidence), nor in quality of life (MD 0.00; 95% CI -0.02 to 0.02, 3 studies, 5482 participants, high-quality evidence). When all studies, irrespective of risk of bias, were included, SSRIs reduced disability scores but not the proportion independent. There was insufficient data to perform a meta-analysis of outcomes at end of follow-up. Several small ongoing studies are unlikely to alter conclusions. AUTHORS' CONCLUSIONS: There is high-quality evidence that SSRIs do not make a difference to disability or independence after stroke compared to placebo or usual care, reduced the risk of future depression, increased bone fractures and probably increased seizure risk.

The Combined Influence of Magnesium and Insulin on Central Metabolic Functions and Expression of Genes Involved in Magnesium Homeostasis of Cultured Bovine Adipocytes.

At the onset of lactation, dairy cows suffer from insulin resistance, insulin deficiency or both, similar to human diabetes, resulting in lipolysis, ketosis and fatty liver. This work explored the combined effects of different levels of magnesium (0.1, 0.3, 1 and 3 mM) and insulin (25, 250 and 25,000 pM) on metabolic pathways and the expression of magnesium-responsive genes in a bovine adipocyte model. Magnesium starvation (0.1 mM) and low insulin (25 pM) independently decreased or tended to decrease the accumulation of non-polar lipids and uptake of the glucose analog 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-6-deoxyglucose (6-NBDG). Activity of glycerol 3-phosphate dehydrogenase (GPDH) was highest at 25 pM insulin and 3 mM magnesium. Expression of SLC41A1 and SLC41A3 was reduced at 0.1 mM magnesium either across insulin concentrations (SLC41A1) or at 250 pM insulin (SLC41A3). MAGT1 expression was reduced at 3 mM magnesium. NIPA1 expression was reduced at 3 mM and 0.1 mM magnesium at 25 and 250 pM insulin, respectively. Expression of SLC41A2, CNNM2, TRPM6 and TRPM7 was not affected. We conclude that magnesium promotes lipogenesis in adipocytes and inversely regulates the transcription of genes that increase vs. decrease cytosolic magnesium concentration. The induction of GAPDH activity by surplus magnesium at low insulin concentration can counteract excessive lipomobilization.

A case of elephantiasis nostras verrucosa treated successfully by a new type of compressive garment.

Elephantiasis nostras verrucosa (ENV) is a clinical manifestation composed of hyperkeratotic, verrucous, and papillomatous lesions and dermal fibrosis, which complicate chronic lymphedema. There is currently no cure for ENV, however, several measures have been used to reduce lymphedema and the resultant pseudoepidermal hyperplasia. Supportive dressings and compression therapy still constitute an important part of the treatment. In this report, we present a 69-year-old male patient with ENV developed due to chronic lymphedema caused by venous insufficiency. After failure of healing with conventional two- and three-layered bandages, and elastic stockings, he was successfully treated by a new type of compression garment. We recommend this user friendly garment for prevention of frictional trauma, contact dermatitis, and secondary infection, which all may complicate compression treatments.

Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.

BACKGROUND: Stroke is a major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression and other mood disorders after stroke. The 2012 Cochrane Review of SSRIs for stroke recovery demonstrated positive effects on recovery, even in people who were not depressed at randomisation. A large trial of fluoxetine for stroke recovery (fluoxetine versus placebo under supervision) has recently been published, and it is now appropriate to update the evidence. OBJECTIVES: To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post-stroke, and to determine whether treatment with SSRIs is associated with adverse effects. SEARCH METHODS: For this update, we searched the Cochrane Stroke Group Trials Register (last searched 16 July 2018), the Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, July 2018), MEDLINE (1946 to July 2018), Embase (1974 to July 2018), CINAHL (1982 July 2018), PsycINFO (1985 to July 2018), AMED (1985 to July 2018), and PsycBITE March 2012 to July 2018). We also searched grey literature and clinical trials registers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that recruited ischaemic or haemorrhagic stroke survivors at any time within the first year. The intervention was any SSRI, given at any dose, for any period, and for any indication. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. To be included, trials had to collect data on at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early). DATA COLLECTION AND ANALYSIS: We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. Two review authors independently extracted data from each trial. We used standardised mean differences (SMDs) to estimate treatment effects for continuous variables, and risk ratios (RRs) for dichotomous effects, with their 95% confidence intervals (CIs). We assessed risks of bias and applied GRADE criteria. MAIN RESULTS: We identified a total of 63 eligible trials recruiting 9168 participants, most of which provided data only at end of treatment and not at follow-up. There was a wide age range. About half the trials required participants to have depression to enter the trial. The duration, drug, and dose varied between trials. Only three of the included trials were at low risk of bias across the key 'Risk of bias' domains. A meta-analysis of these three trials found little or no effect of SSRI on either disability score: SMD -0.01 (95% CI -0.09 to 0.06; P = 0.75; 2 studies, 2829 participants; moderate-quality evidence) or independence: RR 1.00 (95% CI 0.91 to 1.09; P = 0.99; 3 studies, 3249 participants; moderate-quality evidence). We downgraded both these outcomes for imprecision. SSRIs reduced the average depression score (SMD 0.11 lower, 0.19 lower to 0.04 lower; 2 trials, 2861 participants; moderate-quality evidence), but there was a higher observed number of gastrointestinal side effects among participants treated with SSRIs compared to placebo (RR 2.19, 95% CI 1.00 to 4.76; P = 0.05; 2 studies, 148 participants; moderate-quality evidence), with no evidence of heterogeneity (I2 = 0%). For seizures there was no evidence of a substantial difference. When we included all trials in a sensitivity analysis, irrespective of risk of bias, SSRIs appeared to reduce disability scores but not dependence. One large trial (FOCUS) dominated the results. We identified several ongoing trials, including two large trials that together will recruit more than 3000 participants. AUTHORS' CONCLUSIONS: We found no reliable evidence that SSRIs should be used routinely to promote recovery after stroke. Meta-analysis of the trials at low risk of bias indicate that SSRIs do not improve recovery from stroke. We identified potential improvements in disability only in the analyses which included trials at high risk of bias. A further meta-analysis of large ongoing trials will be required to determine the generalisability of these findings.

Irinotecan-Eluting 75-150-µm Embolics Lobar Chemoembolization in Patients with Colorectal Cancer Liver Metastases: A Prospective Single-Center Phase I Study.

PURPOSE: The primary end point of this trial was to determine the feasibility and safety of transarterial chemoembolization with the use of 75-150-µm drug-eluting embolics loaded with irinotecan (DEE-IRI) for the treatment of metastatic colorectal cancer (CRC) refractory to systemic chemotherapy. MATERIALS AND METHODS: Fourteen patients (mean age 57.9 years) with liver-dominant metastatic disease (14.3% unilobar, 85.7% bilobar), who had failed at least 1 line of chemotherapy, were enrolled and received up to 4 (mean 2.3) cycles of DEE-IRI lobar transarterial chemoembolization. Technical complications and adverse events were recorded, and response was assessed by means of imaging-based criteria. Levels of irinotecan and angiogenesis biomarkers in the serum were measured at multiple time points. RESULTS: Thirty-two DEE-IRI transarterial chemoembolizations were successfully performed, and the full dose (100 mg) was delivered in all cases. The only grade 3-4 toxicity was abdominal pain (29%). One patient had objective response according to the Response Evaluation Criteria in Solid Tumors and World Health Organization, and 3 patients had objective response according to the European Association for the Study of the Liver. The median overall survival was 18.14 months, and the 1-year survival was 65%. The average plasma Cmax of the active metabolite was 41.5 ± 26.1 ng/mL, with average Tmax of 1.3 ± 0.5 hours. The treatment significantly reduced levels of vascular endothelial growth factor receptor 1 (VEGFR1) at 24 hours. CONCLUSIONS: Lobar transarterial chemoembolization with the use of DEE-IRI is a technically feasible and well tolerated palliative treatment for patients with refractory liver-predominant CRC metastatic disease and has acceptable pharmacokinetics. VEGFR1 is a potential biomarker for predicting treatment efficacy and risk of adverse events.

Dual diagnosis of epilepsy and psychogenic nonepileptic seizures: Systematic review and meta-analysis of frequency, correlates, and outcomes.

Comorbid epilepsy and psychogenic nonepileptic seizures (PNES) represent a serious challenge for the clinicians. However, the frequency, associations, and outcomes of dual diagnosis of epilepsy and PNES are unclear. The aim of the review was to determine the frequency, correlates, and outcomes of a dual diagnosis. A systematic review of all published observational studies (from inception to Dec. 2016) was conducted to determine the frequency, correlates, and outcomes of dual diagnosis. We included studies of individuals of any age reporting a dual diagnosis of epilepsy and PNES. All observational study designs were included with the exception of case reports and case series with fewer than 10 participants. The mean frequency of epilepsy in patients with PNES across all studies was 22% (95% confidence intervals [CI] 20 to 25%, range: 0% to 90%) while the mean frequency of PNES in patients with epilepsy was 12% (95% CI 10 to 14%, range: 1% to 62%). High heterogeneity means that these pooled estimates should be viewed with caution. A number of correlates of dual diagnosis were reported. Some studies delineated differences in semiology of seizures in patients with dual diagnosis vs. PNES or epilepsy only. However, most of the correlates were inconclusive. Only a few studies examined outcome in patients with dual diagnosis. Dual diagnosis is common in clinical practice, especially among patients referred to specialized services, and requires careful diagnosis and management.

Assessment of an Innovative Voluntary Substance Abuse Treatment Program Designed to Replace Compulsory Drug Detention Centers in Malaysia.

BACKGROUND: As part of an ongoing initiative by the Malaysian government to implement alternative approaches to involuntary detention of people who use drugs, the National Anti-Drug Agency has created new voluntary drug treatment programs known as Cure and Care (C&C) Centers that provide free access to addiction treatment services, including methadone maintenance therapy, integrated with social and health services. OBJECTIVES: We evaluated early treatment outcomes and client satisfaction among patients accessing C&C treatment and ancillary services at Malaysia's second C&C Center located in Kota Bharu, Kelantan. METHODS: In June-July 2012, a cross-sectional convenience survey of 96 C&C inpatients and outpatients who entered treatment >30 days previously was conducted to assess drug use, criminal justice experience, medical co-morbidities, motivation for seeking treatment, and attitudes towards the C&C. Drug use was compared for the 30-day-period before C&C entry and the 30-day-period before the interview. RESULTS: Self-reported drug use levels decreased significantly among both inpatient and outpatient clients after enrolling in C&C treatment. Higher levels of past drug use, lower levels of social support, and more severe mental health issues were reported by participants who were previously imprisoned. Self-reported satisfaction with C&C treatment services was high. Conclusions/Importance: Preliminary evidence of reduced drug use and high levels of client satisfaction among C&C clients provide support for Malaysia's ongoing transition from compulsory drug detention centers (CDDCs) to these voluntary drug treatment centers. If C&C centers are successful, Malaysia plans to gradually transition away from CDDCs entirely.

Influence of Bovine Serum Lipids and Fetal Bovine Serum on the Expression of Cell Surface Markers in Cultured Bovine Preadipocytes.

To establish the influence of fetal bovine serum (FBS) and bovine serum lipids (BSL) on cell differentiation marker expression, bovine adipose-derived stem cells from subcutaneous tissue were incubated for 14 days in 4 types of differentiation media containing 10% FBS and 10 µL/mL BSL (TRT-1), no FBS and 10 µL/mL of BSL (TRT-2), 10% FBS and no BSL (TRT-3), or no supplements (TRT-4). Cells were subjected to Nile red staining, immunocytochemistry (CD73, CD90, CD105, DLK1, FabP4), and quantitative real-time PCR (CD73, CD90, CD105, FabP4). The number of cells presenting FabP4 and the percentage of mature adipocytes with large lipid droplets were increased in TRT-2, accompanied by a robust increase in FabP4 mRNA abundance and a decrease in DLK1-positive cells. In preadipocytes, CD73 was present around the nucleus and translocated towards cell membranes during differentiation. Although the percentage of CD73-positive cells was not different among treatments, its mRNA abundance, immunocytochemical staining intensity, and translocation towards cell membranes were decreased when the medium contained no FBS (TRT-2 and TRT-4). All cells showed a diffuse distribution of CD90 and CD105 and remained positive for these markers irrespective of the treatment. However, the CD90 and CD105 mRNA abundance was decreased in TRT-2 and TRT-4; i.e., in media containing no FBS. The presence of FBS increased the absolute number of cell nuclei as assessed by DAPI fluorescence. Our results suggest that bovine subcutaneous preadipocytes display typical stem cell markers. The differentiation into mature adipocytes is promoted by BSL, whereas FBS endorses cell proliferation.

Neuroticism and Fatigue 3 Months After Ischemic Stroke: A Cross-Sectional Study.

OBJECTIVE: To examine the relation between neuroticism and fatigue in Chinese patients with stroke. DESIGN: Cross-sectional study. SETTING: Acute stroke unit. PARTICIPANTS: Survivors of ischemic stroke (N=191) recruited from the acute stroke unit between May 1, 2010, and September 1, 2011. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The personality trait of neuroticism was measured with the neuroticism subscale of the Chinese version of the NEO Five-Factor Inventory. The level of fatigue was measured with the Fatigue Assessment Scale. The National Institutes of Health Stroke Scale, Geriatric Depression Scale, Barthel Index, and Mini-Mental State Examination were administered to obtain demographic and clinical information. RESULTS: Fatigue severity 3 months after stroke positively correlated with Geriatric Depression Scale and NEO Five-Factor Inventory neuroticism scores and negatively correlated with the Barthel Index score. CONCLUSIONS: Neuroticism, independent of depressive symptoms, is a predictor of fatigue severity 3 months after stroke. Interventions such as psychological screening programs are warranted for early detection of patients at high risk of poststroke depression.

An Extraordinary Manifestation of Nodular Cystic Fat Necrosis.

Nodular cystic fat necrosis (NCFN) is characterized by mobile subcutaneous nodules composed of necrotic adipocytes encapsulated by fibrous tissue. The classical presentation of NCFN is solitary or multiple, up to 40, discrete nodules scattered usually on the extremities or trunk. Here, the authors present an elderly woman who developed an unusual and striking clinical picture of NCFN, two months after a fall. The patient had a large indurated plaque and subcutaneous nodule with superposing necrotic ulcers. During debridement of the ulcers, nearly 100 small nodules popped up freely along with a brownish discharge. Deep in the ulcer, the authors discovered a dislocated nail that belongs to an old hip prosthesis. Histopathological findings of the nodules were compatible with NCFN.

Is it a sarcoidal foreign-body granuloma or a cutaneous sarcoidosis on a permanent eyebrow make-up?

Permanent make-up is a kind of cosmetic tattoo in which the colorants (pigments) are deposited in dermis after piercing the skin by tiny solid needles. It may cause some adverse effects such as local inflammation, infection, and allergic reactions on the skin and even systemic adverse effects such as sarcoidal reactions. Here the case of a 34-year-old woman who has some yellowish hard shiny papules on her eyebrows after having a permanent make-up is described. The histopathological examinations of the papules are diagnosed as sarcoidal foreign-body reactions. All the laboratory investigations were in normal limits except a mild elevation in angiotensin converting enzyme or ACE level. The lesions mostly improved after topical corticosteroid treatment. Sarcoidal foreign-body reaction due to permanent make-up is discussed with this presentation.