Febuxostat attenuates aluminum chloride-induced hepatorenal injury in rats with the impact of Nrf2, Crat, Car3, and MNK-mediated apoptosis.

Aluminum (Al) is a ubiquitous xenobiotic with known toxicity for both humans and animals. Our study was conducted to investigate the protective role of febuxostat (Feb) against aluminum chloride (AlCl3)-induced hepatorenal injury in rats. Hepatorenal injury was induced by oral administration of AlCl3 (40 mg/kg b.w.), for 2 months. Twenty-four male Sprague-Dawley rats were randomly allocated into four groups (six rats/group). The first group received the vehicle thought the experiment. The second group was considered as a control positive group. The third and fourth groups received oral treatment of Feb (10 mg/kg.b.w.) and (15 mg/kg.b.w.), respectively with AlCl3, concurrently for 2 months. Twenty-four hours, after the last treatment, serum biochemical, molecular, histopathology, and immunohistochemical studies were evaluated. Our findings showed that rats intoxicated with Alcl3 had disturbed biochemical picture. In addition, intoxication with AlCl3 increased oxidative stress and apoptosis, as demonstrated by an increase in malodialdeyde (MDA), carnitine o-acetyltransferase (Crat), and carbonic anhydrase (Car3) with a decrease in glutathione (GSH), MAP kinase-interacting serine/threonine kinase (MNK) and nuclear factor-erythroid 2-related factor 2 (Nrf2) mRNA expression. Furthermore, the levels of tumor necrosis factor-alpha (TNF-α) and the levels of caspase-3 were elevated with sever hepatic and renal pathological changes. Conversely, Feb (15 mg/kg.b.w.) could improve the serum biochemical indices and repressed MDA, Crat, and Car3 levels, whereas it increased GSH, MNK, and Nrf2 levels. Feb inhibited the apoptotic effect of AlCl3 in the liver and kidney by decreasing caspase-3 and TNF-α expression. The protective effect of Feb against AlCl3 toxicity was confirmed by histopathological findings. Moreover, molecular docking studies supported the anti-inflammatory effect of Feb due to its significant binding interactions with cyclooxygenase-1 (COX-1), NF-kappa-B-inducing kinase (NIK), and mitogen-activated protein kinases-p38 (MAPK-p38). The findings suggest that Feb system Feb can avert Alcl3-induced hepatotoxicity and nephrotoxicity by enhancing the antioxidant defense system, and inhibiting the inflammatory cascade and apoptosis.

The Prevalence and Associated Predictors for Diabetes Mellitus in Adult Patients With Thyroid Nodules.

Background: Diabetes mellitus (DM) and thyroid nodules (TNs) with the risk of malignancy are increasing globally. Hence, we conducted this study to evaluate the prevalence and the associated predictors for DM among adult patients with TNs in Royal Commission Hospital, Kingdom of Saudi Arabia (KSA). Methods: A retrospective study was conducted between January 1, 2015 and December 31, 2021. Patients with documented TNs based on the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) were recruited. Then the prevalence and associated risk factors for DM were assessed. Result: Three hundred ninety-one patients who had TNs were recruited. The median (interquartile range (IQR)) age was 46.00 (20.0) years, and 332 (84.9%) of the patients were females. There was a high prevalence of DM (24.0%) among adult patients with TNs. In the univariate analysis, there were significant associations between diagnosed DM among adult patients with TNs and age, gender, 25-hydroxyvitamin D (25(OH)D) level, hypertension, bronchial asthma, free triiodothyronine (FT3), white blood cell count, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides. In the multivariate analysis, there were significant associations between diagnosed DM among adult patients with TNs and age (odds ratio (OR) 1.037 (95% confidence interval (CI) 1.012 - 1.062)), hypertension (OR 0.374 (95% CI 0.203 - 0.689)), FT3 level (OR 0.635 (95% CI 0.412 - 0.980)), LDL (OR 0.643 (95% CI 0.456 - 0.907)) and HDL (OR 0.654 (95% CI 0.465 - 0.919)). Conclusion: There was a high prevalence of DM among patients with TNs. Age, hypertension, FT3, LDL and HDL were significantly associated with DM and TNs.

Prevalence and Associated Predictors of Hypertension in Adult Patients with Thyroid Nodules at the Royal Commission Hospital, Kingdom of Saudi Arabia.

Background: Hypertension and thyroid nodules (TNs) are common medical problems that are increasing in prevalence globally. Hence, we conducted this study to assess the prevalence and associated predictors of hypertension in adult patients with TNs at the Royal Commission Hospital, Kingdom of Saudi Arabia (KSA). Methods: A retrospective study was conducted between 1 January 2015 and 31 December 2021. Patients with documented TNs based on the Thyroid Imaging Reporting and Data System (TI-RADS) were recruited to assess the prevalence and associated risk factors for hypertension. Result: Three hundred ninety-one patients with TNs were recruited for this study. The median (interquartile range, IQR) age was 46.00 (20.0) years, and 332 (84.9%) of the patients were females. The median (IQR) body mass index (BMI) was 30.26 (7.71) kg/m2. There was a high prevalence of hypertension (22.5%) in adult patients with TNs. In the univariate analysis, there were significant associations between diagnosed hypertension in patients with TNs and age, sex, diabetes mellitus (DM), bronchial asthma, triiodothyronine (FT3), total cholesterol and high-density lipoprotein (HDL). In the multivariate analysis, age (OR = 1.076 [95% CI 1.048 - 1.105]), sex (OR = 2.28 [95% CI 1.132 - 4.591]), DM (OR = 0.316 [95% CI 0.175 - 0.573]) and total cholesterol levels (OR = 0.820 [95% CI 0.694 - 0.969]) were significantly associated with hypertension. Conclusion: There is a high prevalence of hypertension in patients with TNs. Age, female sex, DM and elevated total cholesterol are significant predictors of hypertension in adult patients with TNs.

BAAE-AgNPs Improve Symptoms of Diabetes in STZ-induced Diabetic Rats.

OBJECTIVES: Nanoparticles can be employed to improve the therapeutic activity of natural products. Type 2 diabetes mellitus is a serious health condition that has spread like a "modern pandemic" worldwide. In the present study, we developed silver nanoparticles, Ag-NPs, with an aqueous extract from Balanites aegyptiaca to investigate their antioxidant and anti-inflammatory activity in STZ-induced diabetic rats. METHODS: Aqueous extracts of Balanites aegyptiaca seeds (BAAE) were used in the synthesis of BAAE-AgNPs, which were characterized using FTIR and TEM. Different doses of BAAE-AgNP (1/50 LD50; 29.4 mg/kg b.w. and 1/20 LD50: 73.5 mg/kg b.w.) were administered to STZ-induced diabetic rats to evaluate their potential antidiabetic activity. RESULTS: FTIR spectral data indicated the presence of flavonoids and polyphenols in BAAEAgNPs. The size of the BAAE-AgNPs, determined by TEM examination, was 49.33 ± 7.59 nm, with a zeta potential of +25.37. BAAE-AgNPs were characterized by an LD50 value of 1470 mg/kg b.w. In diabetic rats, the daily oral administration of both doses of BAAE-AgNPs (29.4 and 73.5 mg/kg b.w.) for 12 weeks resulted in a significant improvement in body weight, insulin homeostasis, HbA1c, HDL-C, MDA, and pancreatic SOD, CAT, and GSH. They reduced plasma glucose, cholesterol, and triglycerides. This treatment also resulted in a significant decrease in pancreatic IL-6, p53, and TNF-α in diabetic rats. Furthermore, BAAE-AgNPs down-regulated pancreatic TGF-ß1 and Akt gene expression in diabetic rats and resulted in a significant decrease in the regulation of hepatic GLUT-2, as well as an increase in the regulation of hepatic GK and pancreatic B-cl2 gene expression. The histopathological results obtained indicated that BAAEAgNPs improved pancreatic tissue metabolism by enhancing antioxidant enzymes, suppressing inflammatory cytokines, and scavenging free radicals. CONCLUSION: The findings implied that similar to the glibenclamide-treated groups, in the BAAEAgNPs treated group, the compromised antioxidant status normalized in STZ-induced diabetes. By scavenging free radicals, BAAE-Ag-NPs protected against lipid peroxidation while reducing the risk of complications from diabetes. Compared to the daily dose of 29.4 mg, the impact was more prominent at 73.5 mg.

Biocompatibility and Surface Roughness of Different Sustainable Dental Composite Blocks: Comprehensive In Vitro Study.

The study purposed to investigate the biocompatibility and sustainability of two computer-aided design/computer-aided manufacturing (CAD/CAM) resin-based composites compared to a resin-modified ceramic in terms of surface roughness, biofilm formation, cytotoxicity, genotoxicity, and cellular changes observed under transmission electron microscopy (TEM). Three CAD/CAM blocks were used, two resin-based composites [Brilliant Crios (BC) and Cerasmart, (CS) and one hybrid ceramic (Vita Enamic (EN)]. Each block was sectioned into 10 × 12 × 2 mm specimens, followed by finishing and polishing. Each specimen was evaluated for surface roughness using 3D optical profilometry and scanned by scanning electron microscopy. Biofilm formation and its relation to surface roughness have been investigated for all tested materials. A Hep-2 cell line was used to investigate the viability through MTT assay. The cytotoxicity of the materials was measured at 24, 48, and 168 h. The activity of P53, caspase 3, and cytochrome C was evaluated to detect the genotoxicity of different groups, followed by TEM tracking of the cellular changes. Statistical analysis was implemented by utilizing a one-way analysis of variance test. The significance was set at P ≤ 0.05. With regard to the surface roughness, no statistically significant differences were shown between groups. BC possessed the highest biofilm formation value, followed by EN and CS, with no significance between them. No correlation between surface roughness of tested materials and biofilm formation was shown. Considering viability, the highest values were recorded for EN, whereas BC showed the lowest values. P53-fold changes in EN were significantly the lowest, indicating less genotoxicity. Within the current study's limitations, BC showed the highest biofilm formation. However, no significant surface roughness difference or correlation with biofilm formation was observed in tested materials. EN showed the lowest cytotoxicity and the highest viability. EN revealed the best compatibility performance among tested materials. On the contrary, the BC exhibited fewer preferences.

Downregulation of TLR4-NF-?B-p38 MAPK Signalling in Cholestatic Rats Treated with Cranberry Extract.

<b>Background and Objective:</b> Cholestasis is a liver disease that occurs when bile flow is restricted or blocked. Estrogen-induced cholestasis is marked by a reduction in bile flow and the accumulation of bile acids in the liver as well as liver damage. The aim was to evaluate the hepatoprotective effect on EE-induced cholestasis in rats of Cranberry Water Extract (CWE). <b>Materials and Methods:</b> Adult albino rats weighing approximately 150±10 g were divided into six groups of six animals each. As control groups, three groups (I, II and IV) and three experimental groups were used (III, V, VI). <b>Results:</b> Oral administration for 15 days of CWE (150 mg kg¹ b.wt.) in EE-treated rats (100 µg kg¹ 5 days b.wt.) improved serum cholesterol, bile acid and TBIL as well as hepatic SOD and GPx significantly. Also, CWE inhibited ALP, ALT, γ-GT activity as well as levels of TNF-α, NO, MMP-2 and MMP-9 and MDA in comparison with the EE treatment rats. On the other hand, the liver TLR4, NF-κB and p38MAPK gene expression was down regulated group of rats administrated with cranberry extract when compared with the EE-treated rats. CWE's prophylactic action II is more pronounced than prophylactic one. The hepatoprotective effects of cranberry in restoring normal liver functional ability were also supported by histopathological examination of liver tissues. <b>Conclusion:</b> The results show clearly that cranberry extract has a strong prophylactic effect in EE-induced cholestasis by normalizing the levels of TLR4, NF-κB and p38MAPK gene expression.

Resveratrol: A Potential Protector Against Benzo[a]pyrene- Induced Lung Toxicity.

<b>Background and Objective:</b> Benzo[a]pyrene (B[a]P), a major component of lipophilic pollutants then can be translated to diffluent substances. The aim of t he present article was to investigate protective activity of resveratrol against lung toxicity induced by B[a]P. Material and Methods: Male Sprague-Dawley rats were randomly assigned to 6 groups (6 animals/group): 3 negative control groups, control positive, B[a]P (20 mg kg¹ b.wt., resveratrol (50 mg kg¹ b.wt.)-B[a]P and vitamin C (1 g kg¹ b.wt.)-B[a]P groups. <b>Results:</b> The daily oral administration of the resveratrol (50 mg kg¹ b.wt.) and vitamin C (1 g kg¹ b.wt.) for 30 days to rats treated with B[a]P (20 mg kg¹ b.wt.) resulted in a significant improve plasma cholesterol, triglyceride and HDL-C as well as serum TNF-α, TBARS, IL-2,IL-6, haptoglobin, histamine, IgA, Ig E,Ig G and Ig M in B[a]P treated rats. On the other hand oral administration of resveratrol elevated the SOD, GPx and GR gene expression in lung rats treated with B[a]P. Furthermore, resveratrol and vitamin C nearly normalized these effects in lung histoarchitecture. <b>Conclusion:</b> The obtained biochemical, molecular biology and histological results of this study proved the lung protective activity of resveratrol against B[a]P induced lung toxicity in rats.

Radiotherapy of the Hepatocellular Carcinoma in Mice Has a Time-Of-Day-Dependent Impact on the Mouse Hippocampus.

Chronic liver diseases including hepatocellular carcinoma (HCC) create a state of chronic inflammation that affects the brain via the liver-brain axis leading to an alteration of neurotransmission and cognition. However, little is known about the effects of HCC on the hippocampus, the key brain region for learning and memory. Moreover, radiotherapy used to treat HCC has severe side effects that impair patients' life quality. Thus, designing optimal strategies, such as chronotherapy, to enhance the efficacy and reduce the side effects of HCC treatment is critically important. We addressed the effects of HCC and the timed administration of radiotherapy in mice on the expression of pro-inflammatory cytokines, clock genes, markers for glial activation, oxidative stress, neuronal activity and proliferation in the hippocampal neurogenic niche. Our data showed that HCC induced the upregulation of genes encoding for pro-inflammatory cytokines, altered clock gene expressions and reduced proliferation in the hippocampus. Radiotherapy, in particular when applied during the light/inactive phase enhanced all these effects in addition to glial activation, increased oxidative stress, decreased neuronal activity and increased levels of phospho(p)-ERK. Our results suggested an interaction of the circadian molecular clockwork and the brain's innate immune system as key players in liver-brain crosstalk in HCC and that radiotherapy when applied during the light/inactive phase induced the most profound alterations in the hippocampus.

Antioxidant and Antiapoptotic Effects of a Turraea fischeri Leaf Extract on Cryopreserved Goat Sperm.

This study evaluated the efficacy of Turraea fischeri leaf extract for maintaining the viability of cryopreserved goat sperm. Ejaculated semen was collected from 5 mature Baladi bucks (50-60 kg, 2-4 years of age) and those samples with mass motility ≥ 70% and sperm concentration ≥ 2.5 × 109/mL were selected, pooled, and divided into 4 aliquots. Each aliquot was diluted in Tris-citric-soybean lecithin extender containing a different concentration of T. fischeri leaf extract (0, 125, 250, or 375 µg/mL). Treated semen samples were cooled to 5 °C, transferred to 0.25-mL French straws, and stored in liquid nitrogen (LN2) at -196 °C. After thawing, membrane integrity was examined by transmission electron microscopy, apoptotic activity by Annexin/propidium iodide staining and flow cytometry, and both enzyme activities and antioxidant capacity by spectroscopic assays. The leaf extract at 375 µg/mL significantly improved semen quality as indicated by enhanced total antioxidant capacity, reduced H2O2 concentration, a greater proportion of structurally intact motile sperm, and concomitant reductions in apoptosis and necrosis. The extract also significantly increased the proportion of sperm with a contiguous plasma membrane and intact acrosome (p < 0.05). Furthermore, LC-MS revealed numerous secondary metabolites in the extract that may contribute to sperm cryopreservation.

Does timing matter in radiotherapy of hepatocellular carcinoma? An experimental study in mice.

This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on non-tumoral liver (NTL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were analyzed in irradiated and nonirradiated animals by detection of Ki67 and γ-H2AX. Prior to whole animal experiments, organotypic slice cultures were investigated to determine the dosage to be used in whole animal experiments. Irradiation was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on NTL were minimal at ZT20. As compared with NTL, nonirradiated HCC revealed disruption in daily variation and downregulation of all investigated clock genes except Per1. Irradiation affected rhythmic clock gene expression in NTL and HCC at all ZTs except at ZT20 (late activity phase). Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice at which the ratio between efficacy of tumor treatment and toxic side effects was maximal. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.

P2Y2 deficiency impacts adult neurogenesis and related forebrain functions.

Adult neurogenesis occurs particularly in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. This continuous addition of neurons to pre-existing neuronal networks is essential for intact cognitive and olfactory functions, respectively. Purinergic signaling modulates adult neurogenesis, however, the role of individual purinergic receptor subtypes in this dynamic process and related cognitive performance is poorly understood. In this study, we analyzed the role of P2Y2 receptor in the neurogenic niches and in related forebrain functions such as spatial working memory and olfaction using mice with a targeted deletion of the P2Y2 receptor (P2Y2-/- ). Proliferation, migration, differentiation, and survival of neuronal precursor cells (NPCs) were analyzed by BrdU assay and immunohistochemistry; signal transduction pathway components were analyzed by immunoblot. In P2Y2-/- mice, proliferation of NPCs in the SGZ and the SVZ was reduced. However, migration, neuronal fate decision, and survival were not affected. Moreover, p-Akt expression was decreased in P2Y2-/- mice. P2Y2-/- mice showed an impaired performance in the Y-maze and a higher latency in the hidden food test. These data indicate that the P2Y2 receptor plays an important role in NPC proliferation as well as in hippocampus-dependent working memory and olfactory function.

Evaluation of the Cytotoxicity and apoptotic effect of Nano triple antibiotic paste with Nano anti-inflammatory drug as an intracanal medicament.

OBJECTIVE: The aim of this study is to compare the cytotoxicity of triple antibiotic paste (TAP) with an antiinflammatory drug (TAP+Catafast-TAPC) in nano and regular formulations versus calcium hydroxide as intracanal medicaments. METHODS: The TAPC drugs extraction were made in cell culture media MEM-E (Eagle's minimal essential medium) using concentration of 10 mg/mL of each sample for seven days. Inhibitory concentrations (IC50 values) were determined for each extract. A human fibroblasts cell line was used to evaluate the cytotoxicity of different concentrations (10, 0.625 and 0.07 mg/mL) using MTT essay. The cell viability was measured after 24 h, 48 h and 7 days for all concentrations of the drugs. Flow cytometry analysis was carried out to identify the effect of materials on apoptosis/necrosis. Statistical analysis for the obtained results was done by one-way ANOVA. RESULTS: The results revealed that cell viability was inversely proportional to the duration of treatment in all of the groups. Calcium hydroxide (Control group) demonstrated a significantly greater cytotoxic effect, followed by Nano Triple Antibiotic Paste with Catafast as an anti-inflamatory drug (Nano TAPC), while Triple Antibiotic Paste with Catafast (TAPC) had the least cytotoxic effect. Nano TAPC has the greatest apoptotic value, while TAPC had the least when compared with the reference group, with no significant difference between groups (P<0.05). CONCLUSION: The cytotoxic effect of Nano TAPC was lower than that of calcium hydroxide and higher than that of TAPC. Although Nano TAPC has the highest apoptotic value when compared to TAPC and calcium hydroxide but still there is no statistically significant difference between them.

Relationship between locomotor activity rhythm and corticosterone levels during HCC development, progression, and treatment in a mouse model.

Cancer-related fatigue (CRF) and stress are common symptoms in cancer patients and represent early side effects of cancer treatment which affect the life quality of the patients. CRF may partly depend on disruption of the circadian rhythm. Locomotor activity and corticosterone rhythms are two important circadian outputs which can be used to analyze possible effects on the circadian function during cancer development and treatment. The present study analyzes the relationship between locomotor activity rhythm, corticosterone levels, hepatocellular carcinoma (HCC) development, and radiotherapy treatment in a mouse model. HCC was induced in mice by single injection of diethylnitrosamine (DEN) and chronic treatment of phenobarbital in drinking water. Another group received chronic phenobarbital treatment only. Tumor bearing animals were divided randomly into four groups irradiated at four different Zeitgeber time points. Spontaneous locomotor activity was recorded continuously; serum corticosterone levels and p-ERK immunoreaction in the suprachiasmatic nucleus (SCN) were investigated. Phenobarbital treated mice showed damped corticosterone levels and a less stable 24 hours activity rhythm as well as an increase in activity during the light phase, reminiscent of sleep disruption. The tumor mice showed an increase in corticosterone level during the inactive phase and decreased activity during the dark phase, reminiscent of CRF. After irradiation, corticosterone levels were further increased and locomotor activity rhythms were disrupted. Lowest corticosterone levels were observed after irradiation during the early light phase; thus, this time might be the best to apply radiotherapy in order to minimize side effects.

Predictors of clinically relevant differences between noninvasive versus arterial blood pressure.

OBJECTIVE: Blood pressure (BP) measurements are important for managing patients with hypertensive emergencies (HE). Previous studies showed that there was significant difference between IABP and NIBP but no information whether these differences changed management. Our study investigated the factors associated with the differences affecting BP management of patients with HE. METHODS: This was a retrospective study involving adult patients admitted to a resuscitation unit. We screened all patients who received IABP upon admission between 06/01/2017 and 12/31/2017 as sample size calculation recommended 64 patients. Primary outcome was the clinical relevance of the difference of IABP vs. NIBP, which was defined as having both: a) difference of 10 mm of mercury (mmHg), and b) resulting in possible change of blood pressure managements according to treatment guidelines. We performed backward stepwise multivariable logistic regression to measure associations. RESULTS: We analyzed 147 patients whose mean age was 69 (±16) years and included 69 (47%) patients with spontaneous intracerebral hemorrhage (sICH). Mean difference between IABP and NIBP was 21 (±16) mmHg while 41 (28%) patients who had difference affecting managements. In multivariable regression, sICH (Odd Ratios 13.5, 95%CI 2.3-79.5, p-value < 0.001) was significantly associated with clinically relevant difference between the two modalities of BP monitoring. CONCLUSIONS: There was a large difference between IABP and NIBP among patients with hypertensive emergencies. Up to 30% of patients had clinically relevant differences. Patients with sICH were more likely to have differences affecting BP management. Further studies are needed to confirm our observation.

Early Predictors of Near-Shore Spinal Injuries Among Emergency Department Patients.

BACKGROUND: Spinal injuries (SIs) can pose a significant burden to patients and family; delayed surgical intervention, associated with interhospital transfer, results in worse outcomes. OBJECTIVE: This study aimed to identify early patient-centered factors associated with risk for near-shore SIs to assist clinicians with expeditious medical decision-making. METHODS: We performed a multicenter retrospective study of all adults transported from Ocean City, Maryland to two emergency departments (EDs) and one regional trauma center for evaluation of suspected SIs from 2006 to 2017. Outcomes were any SI and any spinal cord injury (SCI). Multivariable logistic regression was performed for association of environmental and clinical factors with outcomes. RESULTS: We analyzed 278 records, 102 patients (37%) were diagnosed with any SI and 41 (15%) were diagnosed with SCIs. Compared with patients without SI, patients with SI were more likely to be older (48 vs. 39 years), male (90% vs. 70%), with pre-existing spinal condition (62% vs. 33%), and injury caused by diving (11% vs. 2%). Multivariable logistic regression showed age (odd ratio [OR] 1.07; 95% confidence interval [CI] 1.04-1.11), diving (OR 3.5; 95% CI 3-100+), and wave height (OR 4.5; 95% CI 1.35-15.2) were associated with any SI, and a chief complaint of extremity numbness or tingling (OR 5.73; 95% CI 1.2-27.9) was associated with SCI. CONCLUSIONS: We identified older age, diving, and higher wave height as risk factors for any SI and symptoms of numbness and tingling were associated with SCIs. Clinicians should consider expediting these patients' transfers to a trauma center with neurosurgical capability.

Time-dependent changes in proliferation, DNA damage and clock gene expression in hepatocellular carcinoma and healthy liver of a transgenic mouse model.

Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time-of-day dependent changes of proliferation and DNA damage in HCC. Using transgenic c-myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ-H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev-erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ-H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time-of-day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.

A Polyphenol-Rich Extract From Entada abyssinica Reduces Oxidative Damage in Cryopreserved Ram Semen.

The Splinter bean, Entada abyssinica, is widely used in folk medicine. In the current work, we profiled the secondary metabolites from E. abyssinica bark extract using LC-MS and investigated its effect on cryopreserved ram semen. Twenty-eight compounds, including tannins and gallic acid derivatives that prevailed in the extract, were tentatively identified. Results showed that the quality of the post-thawed semen showed a significant improvement when the extract was added to the extender at a concentration of 375 µg/mL. The progressive motility and plasma membrane integrity of sperm cells were significantly increased in the post-thawed semen; however, the total antioxidant capacity (TAC) was insignificantly increased. A significant decrease in the concentration of hydrogen peroxide was detected as well. No significant changes were observed in activities of lactate dehydrogenase (LDH), alanine aminotransaminase (ALT), and aspartate transaminase (AST) within the treated samples. Intact sperm percentage was significantly increased, while apoptotic and necrotic sperm percentages were reduced significantly. Molecular docking of some individual components from the extract revealed their potential to interfere with the apoptosis cascade in which Bcl-2 is involved. In conclusion, Entada abyssinica appears to be useful for cryopreservation presumably owing to its polyphenol content that has potent antioxidant capacity scavenging reactive oxygen species (ROS), enhancing the endogenous antioxidant system and inhibiting lipid peroxidation.

Sedation Patterns and Hyperosmolar Therapy in Emergency Departments were Associated with Blood Pressure Variability and Outcomes in Patients with Spontaneous Intracranial Hemorrhage.

BACKGROUND: Spontaneous intracranial hemorrhage (sICH) is associated with high mortality. Little information exists to guide initial resuscitation in the emergency department (ED) setting. However, blood pressure variability (BPV) and mechanical ventilation (MV) are known risk factors for poor outcome in sICH. OBJECTIVES: The objective was to examine the associations between BPV and MV in ED (EDMV) and between two ED interventions - post-MV sedation and hyperosmolar therapy for elevated intracranial pressure - and BPV in the ED and in-hospital mortality. METHODS: We retrospectively studied adults with sICH and external ventricular drainage who were transferred to a quaternary academic medical center from other hospitals between January 2011 and September 2015. We used multivariable linear and logistic regressions to measure associations between clinical factors, BPV, and outcomes. RESULTS: We analyzed ED records from 259 patients. There were 143 (55%) EDMV patients who had more severe clinical factors and significantly higher values of all BPV indices than NoEDMV patients. Two clinical factors and none of the severity scores (i.e., Hunt and Hess, World Federation of Neurological Surgeons Grades, ICH score) correlated with BPV. Hyperosmolarity therapy without fluid resuscitation positively correlated with all BPV indices, whereas propofol infusion plus a narcotic negatively correlated with one of them. Two BPV indices, i.e., successive variation of blood pressure (BPSV) and absolute difference in blood pressure between ED triage and departure (BPDepart - Triage), were significantly associated with increased mortality rate. CONCLUSION: Patients receiving MV had significantly higher BPV, perhaps related to disease severity. Good ED sedation, hyperosmolar therapy, and fluid resuscitation were associated with less BPV and lower likelihood of death.

Blood pressure management in emergency department patients with spontaneous intracerebral hemorrhage.

INTRODUCTION: Despite the well documented importance of blood pressure management in patients with spontaneous intracerebral hemorrhage (sICH), little is known about whether emergency departments (EDs) are able to achieve close monitoring and precise management. Our study characterizes ED monitoring and management of blood pressure in sICH patients. METHODS: This is a retrospective study of adults with sICH and elevated intracranial pressure. Patients who were admitted from any referring ED to our CCRU from 1 August 2013 to 30 September 2015 were included. We graphically assessed the association between average minutes between blood pressure measurements and average minutes between administration of antihypertensives. We also performed logistic regression to evaluate factors associated with close blood pressure monitoring and the achievement of goal blood pressure in patients with sICH who presented with hypertension. RESULTS: Of 115 patients, 73 presented to the ED with SBP above 160 mmHg. Length of stay in the ED was significantly associated with a longer period between blood pressure measurements. Longer periods between blood pressure measurements were a significant determinant of failure to achieve blood pressure goal in sICH patients. Longer periods between blood pressure measurements were significantly associated with longer periods between administration of antihypertensives. CONCLUSION: Our study suggests that blood pressure monitoring is related to the frequency of blood pressure interventions and achievement of adequate blood pressure control in patients with sICH. There is significant variability in EDs' achievement of the recommended close blood pressure monitoring and management in patients with sICH.

Impact of Targeted Deletion of the Circadian Clock Gene Bmal1 in Excitatory Forebrain Neurons on Adult Neurogenesis and Olfactory Function.

The circadian system is an endogenous timekeeping system that synchronizes physiology and behavior with the 24 h solar day. Mice with total deletion of the core circadian clock gene Bmal1 show circadian arrhythmicity, cognitive deficits, and accelerated age-dependent decline in adult neurogenesis as a consequence of increased oxidative stress. However, it is not yet known if the impaired adult neurogenesis is due to circadian disruption or to loss of the Bmal1 gene function. Therefore, we investigated oxidative stress and adult neurogenesis of the two principle neurogenic niches, the hippocampal subgranular zone and the subventricular zone in mice with a forebrain specific deletion of Bmal1 (Bmal1 fKO), which show regular circadian rhythmicity. Moreover, we analyzed the morphology of the olfactory bulb, as well as olfactory function in Bmal1 fKO mice. In Bmal1 fKO mice, oxidative stress was increased in subregions of the hippocampus and the olfactory bulb but not in the neurogenic niches. Consistently, adult neurogenesis was not affected in Bmal1 fKO mice. Although Reelin expression in the olfactory bulb was higher in Bmal1 fKO mice as compared to wildtype mice (Bmal1 WT), the olfactory function was not affected. Taken together, the targeted deletion of Bmal1 in mouse forebrain neurons is associated with a regional increase in oxidative stress and increased Reelin expression in the olfactory bulb but does not affect adult neurogenesis or olfactory function.