Correlation between depression scores and serum NF-ĸB/NLRP3 axis, biotinidase, and HMGB1 after treatment with isotretinoin in patients with acne vulgaris.

BACKGROUND: Acne vulgaris (AV) is an inflammatory skin disorder leading to scars and discomfort, its intensity has major psychological consequences such as depression. AIM: To investigate the effect of isotretinoin (ISO) on NF-κB/NLRP3, biotinidase, and HMGB and correlation with depression. PATIENTS AND METHODS: This was a case-control study that involved two groups. Group 1 is 20 healthy control, and group 2 is 20 patients diagnosed with AV according to Global Acne Grading System (GAGS) and received 20 mg ISO for 2 months. Before and after therapy, the Hamilton Depression Rating Scale (HDRS) was applied to assess each participant's level of depression. Nuclear factor kappa B (NF-ĸB), biotinidase, high mobility group box protein (HMGB1), nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP-3) were measured in serum samples. RESULTS: There was no significant difference in all measured markers of healthy group before and after 2 months. Regarding group 2, there was a statistically significant decrease in all measured markers after 2 months of treatment and significant correlations between GAGS, NF-ĸB, HMGB1, NLRP3, biotinidase, and depression score. CONCLUSION: Increased GAGS, HMGB1, NLRP3, and biotinidase were associated with depression severity in AV patients and ISO treatment significantly reduced these parameters and reduced depressive symptoms.

Effect of a high dose atorvastatin as added-on therapy on symptoms and serum AMPK/NLRP3 inflammasome and IL-6/STAT3 axes in patients with major depressive disorder: randomized controlled clinical study.

Background: Neuroinflammation pathways have been associated with the development of major depressive disorders (MDD). The anti-inflammatory characteristics of statins have been demonstrated to have significance in the pathophysiology of depression. Aim: To investigate the mechanistic pathways of high dose atorvastatin in MDD. Patients and methods: This trial included 60 patients with MDD who met the eligibility requirements. Two groups of patients (n = 30) were recruited by selecting patients from the Psychiatry Department. Group 1 received 20 mg of fluoxetine plus a placebo once daily. Group 2 received fluoxetine and atorvastatin (80 mg) once daily. All patients were assessed by a psychiatrist using the Hamilton Depression Rating Scale (HDRS). A HDRS score of ≤7 indicates remission or partial remission [HDRS<17 and>7]. Response was defined as ≥ 50% drop in the HDRS score. The serum concentrations of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP-3), interleukin-6 (IL-6), adenosine monophosphate activated protein kinase (AMPK), and signal transducer and activator of transcription factor-3 (STAT-3) were measured. Results: The atorvastatin group showed a significant reduction in the levels of all measured markers along with a statistical increase in the levels of AMPK when compared to the fluoxetine group. The atorvastatin group displayed a significant decrease in HDRS when compared to its baseline and the fluoxetine group. The response rate and partial remission were higher in the atorvastatin group than fluoxetine (p = 0.03, and p = 0.005), respectively. Conclusion: These results imply that atorvastatin at high doses may be a promising adjuvant therapy for MDD patients by altering the signaling pathways for AMPK/NLRP3 and IL-6/STAT-3. Clinical Trial Registration: clinicaltrials.gov, identifier NCT05792540.

Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments.

Herein, modifications to the previously reported BIBR1591 were conducted to obtain bioisosteric candidates with improved activities. The % inhibition of the newly afforded candidates against the telomerase target was investigated. Notably, 6f achieved superior telomerase inhibition (63.14%) compared to BIBR1532 and BIBR1591 (69.64 and 51.58%, respectively). In addition, 8a and 8b showed comparable promising telomerase inhibition with 58.65 and 55.57%, respectively, which were recorded to be frontier to that of BIBR1591. 6f, 8a, and 8b were tested against five cancer cell lines related to the lung and liver subtypes. Moreover, 6f was examined on both cell cycle progression and apoptosis induction in HuH7 cancer cells. Furthermore, the in vivo antitumor activity of 6f was further assessed in female mice with solid Ehrlich carcinoma. In addition, molecular docking and molecular dynamics simulations were carried out. Collectively, 6f, 8a, and 8b could be considered potential new telomerase inhibitors to be subjected to further investigation and/or optimization.

Sudden cardiac death prevention in the era of novel heart failure medications.

Sudden cardiac death (SCD) occurs unexpectedly and is usually a result of ventricular arrhythmia in patients with structural heart disease. The implantable cardioverter-defibrillator (ICD), with or without biventricular pacing, has been proven to be protective for heart failure patients with reduced ejection fraction of <35 % (HFrEF). This device therapy prevents SCD, with additional optimal medications, namely angiotensin-converting enzyme-inhibitors, angiotensin-II receptor-blockers, beta-blockers and mineralocorticoid receptor-antagonists. HFrEF patients present the majority of SCD incidents, as they are characterized by cardiac fibrosis, the main arrhythmogenic element. The introduction of angiotensin-receptor-neprilysin inhibitors, sodium-glucose co-transporter-2 inhibitors and guanylate-cyclase stimulators was associated with reduction of SCD. Additionally, clinical trials have evaluated the improved outcome of these new medications on left ventricular ejection fraction, arrhythmias and HFrEF. These beneficial effects could possibly lead to important changes in decision-making on ICD implantation for primary prevention in patients with HFrEF and reduce the need for device therapy. In this review, we highlight the pathophysiological mechanisms of the new drug agents, and evaluate the possible effect they could have on the role of device therapy as a primary prevention of SCD.

Total Parenteral and Enteral Nutrition in the ICU: Evolving Concepts.

Appropriate nutrition in the hospital setting, particularly in critically ill patients, has long been tied to improving clinical outcomes. During critical illness, inflammatory mediators and cytokines lead to the creation of a catabolic state to facilitate the use of endogenous energy sources to meet increased energy demands. This process results in increasing the likelihood of overfeeding. The literature has revealed exponential advances in understanding the molecular basis of nutritional support and evolution of clinical protocols aimed at treating artificial nutritional support as a therapeutic intervention, preventing loss of lean body mass and metabolic deterioration to improve clinical outcomes in the critically ill.

Pain Control in the Presence of Drug Addiction.

Drug addiction is present in a significant proportion of the population in the USA and worldwide. Drug addiction can occur with the abuse of many types of substances including cocaine, marijuana, stimulants, alcohol, opioids, and tranquilizers. There is a high likelihood that clinicians will encounter patients with substance abuse disorders on a regular basis with the prevalence of the use of illicit substances and the high rate of abuse of prescription drugs. The use of abuse deterrent formulations of prescription opioid agents, pill counts, and urine drug abuse screenings are all useful strategies. Optimum pain management of patients with addiction in the outpatient and inpatient setting is essential to minimize pain states. Careful selection of medications and appropriate oversight, including drug agreements, can reduce drug-induced impairments, including sleep deficits and diminished physical, social, and sexual functioning. This review, therefore, discusses the prevalence of illicit and prescription drug addiction, the challenges of achieving optimum pain control, and the therapeutic approaches to be considered in this challenging population. More research is warranted to develop improved therapies and routes of treatments for optimum pain relief and to prevent the development of central sensitization, chronic pain, and impaired physical and social functioning in patients with drug addiction.

Perceptions of communication in the operating room: a pilot survey study.

BACKGROUND: An operating room (OR) environment is challenging and complicated. At any given time, several vital tasks are being performed by skilled individuals, including physicians, nurses, and ancillary staff. There is a potential for multifactorial mistakes; many arise because of communication issues. METHODS: To evaluate the current state of perceptions of interdisciplinary communication in an OR setting, a survey was developed and administered to four academic residency training departments of anesthesiology in a single U.S. state. RESULTS: The results of this survey show that perceived poor communication within the OR leads to a lack of emphasis on a multidisciplinary approach to patient care in the OR. CONCLUSIONS: Survey data can be used internally to identify shortcomings in communication at a facility, to stress the importance of communication, and to serve as a powerful education tool to potentially improve patient care. Through this type of survey, which emphasizes communication in the OR, stakeholders can work more effectively to improve patient care and decrease adverse outcomes in the hospital environment.

Medication errors in anesthesia.

Medication errors represent one of the most common causes of morbidity and mortality in hospitalized patients. Anesthesia has specific medication-related risks; providers must administer many potent intravenous medications quickly, often with minimal to no supervision. Well-described reasons for medication administration errors in anesthesia include medication ampoules with similar appearance and packaging, clinician inattention, ineffective communication, fatigue, and haste. Technologies that are used widely in other parts of the hospital, such as barcoding, are a challenge to implement in anesthesia, and systemic approaches, including color-coding of syringe labels and barcoding technology of syringes, have been evaluated with mixed results. Emphasis should be placed on implementing forcing functions when possible, utilizing technology, standardization, and education about the need for awareness in specific situations. More studies need to be done to define the epidemiology of medication errors in anesthesia, and more importantly, to assess interventions for preventing them.

Novel improvements in perioperative sterility.

Operative sterility is a critical factor with regard to infection in the postoperative period. In recent years, techniques and devices have been developed to reduce the potential for exposure to pathogens. This brief review details the SteriCup, a unique product that has the potential to reduce the risk of healthcare-acquired infections. The SteriCup provides a designated sterile area to store suction catheters and removed endotracheal tubes and allows for their simple and safe disposal. Devices such as the SteriCup have the potential to improve operating room systems and minimize potential for operative infection.

Lumbosacral plexus delineation, dose distribution, and its correlation with radiation-induced lumbosacral plexopathy in cervical cancer patients.

BACKGROUND: To evaluate the dose distribution to the lumbosacral plexus (LSP) and its correlation with radiation-induced lumbosacral plexopathy (RILSP) in patients with cervical cancer treated with intensity-modulated radiotherapy (IMRT) and high-dose-rate brachytherapy. MATERIALS AND METHODS: After meeting eligibility criteria, 50 patients with cervical cancer were selected who were treated with IMRT and high-dose-rate brachytherapy, and the LSP was contoured. Mean volume; percentages of LSP volume absorbing 40, 50, 55, and 60 Gy (V30, V40, V50, V55, and V60) and point doses (P1, P2, P3, P4, P5, P6, P7, P8, P9, and P10); and RILSP incidence were calculated. RESULTS: At 60 months of follow-up, four patients (8%) were found to have grade 2/3 RILSP. The mean maximal LSP dose in patients with RILSP was 59.6 Gy compared with 53.9 Gy in patients without RILSP (control; P=0.04). The mean values of V40, V50, V55, and V60 in patients with RILSP versus control were 61.8% versus 52.8%, 44.4% versus 27.7%, 8.0% versus 0.3% and 1.8% versus 0%, respectively (P=0.01, 0.001, 0.001, and 0.001, respectively). CONCLUSION: The delineation of the LSP during IMRT planning may reduce the risk for RILSP. The mean values of V40, V50, V55, and V60 for LSP should be less than 55%, 30%, 5%, and 0.5%, respectively; however, further studies are warranted.

Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model.

BACKGROUND: This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia. METHODS: Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules. RESULTS: The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 µg m(-2) tri-weekly, is G-CSF, 300 µg, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m(-2), is optimally supported by the slightly less cost-effective G-CSF 300 µg, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per µl) under Doc, 100-150 mg m(-2) tri-weekly. CONCLUSIONS: The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.

Molecular ecology meets remote sensing: environmental drivers to population structure of humpback dolphins in the Western Indian Ocean.

Genetic analyses of population structure can be placed in explicit environmental contexts if appropriate environmental data are available. Here, we use high-coverage and high-resolution oceanographic and genetic sequence data to assess population structure patterns and their potential environmental influences for humpback dolphins in the Western Indian Ocean. We analyzed mitochondrial DNA data from 94 dolphins from the coasts of South Africa, Mozambique, Tanzania and Oman, employing frequency-based and maximum-likelihood algorithms to assess population structure and migration patterns. The genetic data were combined with 13 years of remote sensing oceanographic data of variables known to influence cetacean dispersal and population structure. Our analyses show strong and highly significant genetic structure between all putative populations, except for those in South Africa and Mozambique. Interestingly, the oceanographic data display marked environmental heterogeneity between all sampling areas and a degree of overlap between South Africa and Mozambique. Our combined analyses therefore suggest the occurrence of genetically isolated populations of humpback dolphins in areas that are environmentally distinct. This study highlights the utility of molecular tools in combination with high-resolution and high-coverage environmental data to address questions not only pertaining to genetic population structure, but also to relevant ecological processes in marine species.

Effect of different sprint training regimes on the oxygen delivery-extraction in elite sprinters.

AIM: The effects of sprint training regimes of varying distance schedules on the oxygen delivery-extraction relationship were investigated in 15 young (22+/-1 years) healthy males national-level sprinters. METHODS: During one session subjects performed four sprints, in a schedule of increasing distance order (100, 200, 300 and 400 m), and during the other session, in a schedule of decreasing distance order (400, 300, 200, and 100 m). All sprint bouts were performed on a treadmill at a speed of 22 km/h-1, which corresponds to 85% of subjects' maximal speeds. The order of the running sequences during sessions was balanced over subjects. RESULTS: During both sprint schedules, all variables except for oxygen extraction in the incremented training regime, increased significantly from rest to exercise. Training regimes were not different with regard to cardiac output and absolute oxygen uptake. However, the decreasing compared to the increasing scheme was characterized by significantly (P<0.05) higher mean values of heart rate (194.5+/-4.1 185.2+/-5.7 beats/min-1, respectively), oxygen extraction (54.3+/-3.8 and 47.1+/-3.4 mL/L-1, respectively) and lactate (10.6+/-0.5 and 9.2+/-0.7 mmol/L-1, respectively), while stroke volume was significantly (P<0.05) lower (100.4+/-4.5 and 109.7+/-4.4 mL, respectively). CONCLUSION: The present study indicates that in sprinters performing a similar distance at the same speed, but under different training regimes interplay exists between oxygen delivery and extraction, suggesting a link between the type of training scheme and physiological cardiovascular and skeletal muscle metabolic adaptations. This may explain the absence of differences between the conditions in absolute oxygen uptake and peak power output.

Acute incremental exercise to maximal performance does not cause alterations in serum oxidant levels of healthy young individuals.

AIM: This study was designed to analyze serum oxidative stress (OS) levels in healthy young individuals performing a routine maximal aerobic exercise and to evaluate the correlation between OS levels and physiological parameters. METHODS: Serum OS levels were studied by thermochemiluminescence (TCL) parameters at rest and following maximal aerobic exercise in 85 healthy young subjects. Levels were measured by a real time on line TCL assay (higher TCL-Ratio and TCL-H3 = lower OS level). RESULTS: Aerobic capacity had no effect on baseline OS levels. Post-exercise OS levels correlated with maximal oxygen uptake (V.O(2max)) (P<0.005), delta V.O(2) (V.O(2max)- V.O(2)rest) (P<0.005), anaerobic threshold (VTH) (P<0.01), and total oxygen uptake (especially O(2) after VTH), (P<0.005). TCL-Ratio was related to total running time (P<0.01), as well. Post-exercise OS levels for the whole study group did not vary from baseline values. However, individuals with higher fitness level (V.O(2max) >percentile 60) had significantly lower values of TCL-H3 (P=0.04) and tended to have lower TCL-Ratio, indicating they had elevated OS levels. In a multivariate analysis OS level was most affected by V.O(2) after VTH (anaerobic phase of the test) (P=0.003; adjusted odds ratio of 3.41, 95% confidence interval: 1.55-7.48). CONCLUSIONS: In conclusion, acute incremental exercise to maximal performance does not cause alterations in serum oxidant levels of healthy young individuals. In healthy individuals performing maximal aerobic exercise, OS levels correlate with maximal aerobic power.

Expression profiles of acute lymphoblastic and myeloblastic leukemias with ALL-1 rearrangements.

The ALL-1 gene is directly involved in 5-10% of acute lymphoblastic leukemias (ALLs) and acute myeloid leukemias (AMLs) by fusion to other genes or through internal rearrangements. DNA microarrays were used to determine expression profiles of ALLs and AMLs with ALL-1 rearrangements. These profiles distinguish those tumors from other ALLs and AMLs. The expression patterns of ALL-1-associated tumors, in particular ALLs, involve oncogenes, tumor suppressors, antiapoptotic genes, drug-resistance genes, etc., and correlate with the aggressive nature of the tumors. The genes whose expression differentiates between ALLs with and without ALL-1 rearrangement were further divided into several groups, enabling separation of ALL-1-associated ALLs into two subclasses. One of the groups included 43 genes that exhibited expression profiles closely linked to ALLs with ALL-1 rearrangements. Further, there were evident differences between the expression profiles of AMLs in which ALL-1 had undergone fusion to other genes and AMLs with partial duplication of ALL-1. The extensive analysis described here pinpointed genes that might have a direct role in pathogenesis.

Pitch discrimination: are professional musicians better than non-musicians?

Musicians are typically considered to exhibit exceptional auditory skills. Only few studies, however, have substantiated this in basic psychoacoustic tasks. The purpose of the present investigation was to expand our knowledge on basic auditory abilities of musicians compared to non-musicians. Specific goals were: (1) to compare frequency discrimination thresholds (difference limen for frequency [DLF]) of non-musical pure tones in controlled groups of professional musicians and non-musicians; (2) to relate DLF performance to musical background; and (3) to compare DLF thresholds obtained with two threshold estimation procedures: 2- and 3- interval forced choice procedures (2IFC and 3IFC). Subjects were 16 professional musicians and 14 non-musicians. DLFs were obtained for three frequencies (0.25, 1 and 1.5 kHz) using the 3IFC adaptive procedure, and for one frequency (1 kHz) also using the 2IFC. Three threshold estimates were obtained for each frequency, procedure and subject. The results of the present study support five major findings: (a) mean DLFs for musicians were approximately half the values of the non-musicians; (b) significant learning for both groups during the three threshold estimations; (c) classical musicians performed better than those with contemporary musical background; (d) performance was influenced by years of musical experience; and (e) both groups showed better DLF in a 2IFC paradigm compared to the 3IFC. These data highlight the importance of short-term training on an auditory task, auditory memory and factors related to musical background (such as musical genre and years of experience) on auditory performance.

The Hebrew vowel system: raw and normalized acoustic data.

It is well known that different languages use different vowel systems in terms of variety and number. The Hebrew vowel system consists of five vowels /i, e, a, o, u/. The present research identified the acoustic features of the vowels produced by Hebrew speakers differing in age and sex. Ninety speakers (men, women, boys, and girls) were recorded. The vowels were presented in a nonword context that was placed in a meaningful Hebrew sentence. The data included measurements of F0, F1, F2, F3, F4, and vowel duration for the five different vowels produced by the four groups of participants. Conversion of the physical frequency measures of formants into a critical band (bark) scale was performed as well. The results indicated that the F2/F1 ratio is a distinctive feature of all five vowels, keeping with the findings of previous research in other languages. Nevertheless, the values of the F2/F1 ratios led to an overlap between different vowels produced by different groups of speakers. Applying the bark transformation as speaker normalization procedure succeeded in reducing speaker differences while increasing vowel differences.