Nucleophilic Selenocyclization Reaction of Benzodiynes Promoted by Sodium Selenide: Synthesis of Isoselenochromenes.

We describe here the synthesis of isoselenochromenes via a nucleophilic selenocyclization reaction of benzodiynes with sodium selenide. The central parameters that affect this cyclization reaction were studied, and the best reaction conditions were applied to different substrates to determine the scope of the method. The results indicated that isoselenochromenes were obtained in higher yields when the reactions were performed by the addition of NaBH4 (3 equiv), at room temperature, under nitrogen atmosphere, to a solution of elemental selenium (2 equiv) in dimethylformamide (2 mL). After 1 h, a benzodiynes (0.25 mmol) solution in EtOH (3 mL) was added at room temperature. The reaction was stirred at 75 °C until the starting material was consumed. The best conditions were applied to benzodiynes having electron-rich, electron poor aromatic rings, and alkyl groups directly bonded to the alkynes. The same reaction condition was extended to isothiochromene derivatives but failed to prepare isotelurochromenes. The isoselenochromenes were easily transformed into three new classes of organoselenium compounds using classical methods available in the literature. We also conducted several control experiments to propose a reaction mechanism.

AOP Report: Glutathione Conjugation Leading to Reproductive Dysfunction via Oxidative Stress.

We propose an adverse outcome pathway (AOP) for reproductive dysfunction via oxidative stress (OS). The AOP was developed based on Organisation for Economic Co-operation and Development (OECD) Guidance Document 184 and on the specific considerations of the OECD users' handbook supplement to the guidance document for developing and assessing AOPs (no. 233). According to the qualitative and quantitative experimental data evaluation, glutathione (GSH) conjugation is the first upstream key event (KE) of this AOP to reproductive dysfunction triggering OS. This event causes depletion of GSH basal levels (KE2 ). Consequently, this drop of free GSH induces an increase of reactive oxygen species (KE3 ) generated by the natural cellular metabolic processes (cellular respiration) of the organism. Increased levels of these reactive species, in turn, induce an increase of lipid peroxidation (KE4 ). This KE consequently leads to a rise in the amount of toxic substances, such as malondialdehyde and hydroxynonenal, which are associated with decreased quality and competence of gamete cell division, consequently impairing fertility (KE5 and adverse outcome). The overall assessment of the general biological plausibility, the empirical support, and the essentiality of KE relationships was considered as high for this AOP. We conclude that GSH conjugation is able to lead to reproductive disorder in fishes and mammals, via OS, but that the amount of stressor needed to trigger the AOP differs between stressors. Environ Toxicol Chem 2023;42:2519-2528. © 2023 SETAC.

Synthesis, characterization, solution chemistry and anticancer activity of [NiCl2(Ph2P-N(R)-PPh2)] (R = 2-CH2Py, CH2Ph and p-tol) complexes.

In this work three Ni2+ complexes with general formula [NiCl2(Ph2P-N(R)-PPh2)], R = 2-CH2Py (Py = pyridine) - 1, CH2Ph (Ph = phenyl) - 2 and p-tol (p-tol = p-tolyl) - 3, were synthesized and characterized. These complexes were obtained in high yield by the reaction of NiCl2.6H2O and the corresponding diphenylphosphinoamine ligand (Ph2P-N(R)-PPh2) in CH2Cl2/MeOH (1:1) solution, at room temperature (∼25 °C), and characterized by 1H and 31P {1H} NMR, vibrational spectroscopy in the infrared region, electronic spectroscopy in the UV-Vis regions, elemental analysis (%C, %H, %N) and single-crystal X-ray diffraction. The solution chemistry was studied in CDCl3/dmso-d6 (dimethylsulfoxide) or neat dmso-d6 using complex 2 as a model. The complexes were evaluated as cytotoxic agents against two cancer cells lines, A549 (lung cancer cells), B16F10 (melanoma cells) and the health cells HaCaT (human epithelial keratinocytes).

Molecular and clinical diversity in primary central nervous system lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.

Electrophile-Promoted Nucleophilic Cyclization of 2-Alkynylindoles to Give 4-Substituted Oxazinoindolones.

A method for the synthesis of 4-organoselanyl oxazinoindolone derivatives by the cascade cyclization of N-(alkoxycarbonyl)-2-alkynylindoles using iron(III) chloride and diorganyl diselenides as promoters was developed. This protocol was applied to a series of N-(alkoxycarbonyl)-2-alkynylindoles containing different substituents. The reaction conditions also tolerated a variety of diorganyl diselenides having both electron donating and electron withdrawing groups. However, the reaction did not work for diorganyl disulfides and ditellurides. The reaction mechanism seems to proceed via an ionic pathway and the cooperative action between iron(III) chloride and diorganyl diselenides is crucial for successful cyclization. We also found that using the same starting materials, by simply changing the electrophilic source to iodine, led to the formation of 4-iodo-oxazinoindolones. The high reactivity of Csp2 -Se and Csp2 -I bonds were tested under cross-coupling conditions leading to the preparation of a new class of functionalized indole derivatives. In addition, the absorption, emission and electrochemical properties of 4-organoselanyl oxazinoindolones showed an important relationship with the substituents of the aromatic rings. The advantages of the methodology include the use of electrophilic to promote the cyclization reaction and functionalization of the indole ring, and the electronic properties presented by the prepared compounds can be exploited as probes, analyte detectors and optical materials.

Ozone use in the treatment of subclinical mastitis in dairy cows.

This research communication paper addresses the hypothesis that the use of therapeutic alternatives for mastitis, such as intramammary ozone, can cure the disease with lower costs and without harmful residues for human consumption and without formation of microbial resistance like the ones caused by indiscriminate use of antibiotics in dairy farms. The study was performed in 36 mammary quarters from 12 dairy cows with subclinical mastitis grade three. The experimental units were randomly assigned into four groups and each group received a treatment. Treatments comprised (a) 20 µg/ml ozone gas; (b) 40 µg/ml ozone gas; (c) negative control treatment of 12.5 µg/ml ozonated saline and (d) positive control treatment of 100 mg of cephalexin + 100 mg of neomycin + 10 mg of prednisolone, all by intramammary injection. In all quarters, milk was collected before and after the application of treatments for California mastitis test and evaluation of milk composition, somatic cell count, and bacterial cultures. The results indicated that the use of intramammary ozone did have a therapeutic effect, and whilst this was less than that of antibiotics, ozone does confer some advantages. Treated milk had a good composition, the treatment cost was low, milk withdrawal may not be necessary and there is no risk of antibiotic resistance.

Different protocols for piglet creep feeding in the farrowing stage and residual effects in the nursery phase.

This study was aimed at the effects of different Creep-feeding protocols on piglet performance and its residual effects during the nursery phase. Experimental design used was five groups: WC (without creep); DCF (dry creep feeding); WCF (wet creep feeding); LD (additional liquid creep with automatic feed dispenser plus DCF); and LLF (additional liquid creep with linear feeder plus DCF). Ten litters per treatment were selected a total 50 sows and 645 piglets. During the first two weeks of lactation, the LD treatment (2.61 and 4.20 kg) promoted greater body weight (P <0.001) than the DCF (2.55 and 3.93 kg), (WFS) (2.43 and 3.69 kg) and LLF (2.50 and 4.00 kg) treatments, but did not differ from the WC treatment (2.68 and 4.09 kg). At weaning, the WC (5.22 kg), LD (5.32 kg) and LLF (5.27 kg) treatments gave higher body weights (P <0.001) when compared to the DCF (4.97 kg) and WCF (4.69 kg) treatments. We concluded that there was no change in the behavior of the piglets, and the use of dry feed with liquid supplements did not improve weight gain. The different creep feeding systems did not influence the weight and performance of the piglets in the nursery phase.

Potassium tert-Butoxide-Promoted Tandem Cyclization of Organoselenium Alkynyl Aryl Propargyl Ethers.

Base-promoted cyclization of 3-organoselenyl-methylene-2-alkynyl aryl propargyl ethers has been developed for the synthesis of 3-butylselanyl-methylene benzofurans, 3-methyl-2-alkynyl-benzofurans, and 4-iodo-benzo[b]furan-fused selenopyrans. Under potassium tert-butoxide as the base and tetrahydrofuran as the solvent, at room temperature, 3-organoselenyl-methylene-2-alkynyl aryl propargyl ethers were converted into 3-butylselanyl-methylene benzofurans via a 5-exo-dig mode. Using the same substrate, changing the solvent to dimethylsulfoxide, 3-methyl-2-alkynyl-benzofurans were selectively obtained in good yields. From 3-butylselanyl-methylene benzofurans, 4-iodo-benzo[b]furan-fused selenopyrans were prepared through a nucleophilic cyclization promoted by molecular iodine. The optimization of the reaction conditions showed that the solvents governed the regioselectivity of this cyclization and the initial formation of the dimsyl anion by the reaction of dimethylsulfoxide with potassium tert-butoxide was crucial for the 3-methyl-2-alkynyl-benzofuran preparation. We also proposed the mechanism for the formation of the products, demonstrated that the methodology can be scaled up, and showed the application of the prepared compounds as substrate in further transformations.

Short-Term Efficacy Outcomes of Tenecteplase versus Alteplase for Acute Ischemic Stroke: A Meta-Analysis of 5 Randomized Trials.

Tenecteplase (TNK) has been shown to be noninferior to Alteplase (ALT) for long term efficacy and safety outcomes. Whether this also applies to short term efficacy outcomes such as early clinical improvement and recanalization is unknown. To compare TNK and ALT regarding the short term efficacy outcomes: early neurological improvement and recanalization. The PRISMA was used to conduct a meta analysis, adapted to noninferiority analysis. The primary outcome was early (24-72 h) neurological improvement, defined as either NIHSS score 0 or reduction of at least 8 points compared to baseline. Recanalization was a secondary outcome. The noninferiority margin was set at 6.5%. Search strategy yielded 5 randomized clinical trials (1585 patients: 828 TNK, 757 ALT). Mean age was 70.8, 58.8% were men, mean baseline NIHSS was 7, and mean onset to treatment time was 148 min. Patients in intervention group received TNK at doses of 0.1 mg/kg (6.8%), 0.25 mg/kg (24.6%), and 0.4 mg/kg (68.6%), while all ALT patients received 0.9 mg/kg. In random effects meta analysis, TNK was noninferior to ALT for the primary outcome, early major neurological improvement (risk difference 8% in favor of TNK, 95% CI 1%-15%). Recanalization was also noninferior for the TNK compared to the ALT group (risk difference 9% in favor of TNK, 95% CI 6% to 23%). Fixed effects models yielded similarly noninferior results and signaled for a possible TNK superiority for both early neurological improvement and recanalization. TNK is noninferior to ALT at the short term efficacy outcomes: early neurological improvement and recanalization.

A case series of mucormycosis after covid infection in two hospitals.

This paper aims to discuss clinical aspects of mucormycosis. This case series was conducted in two services, comprising six mucormycosis cases during COVID-19 pandemic. About gender, there are 4 (66.7%) males and 2 (33.3%) females with mean age (48.7 ± 9.4) years. All cases presented complaints of pain and swelling in oral cavity and had an aggressive clinical presentation. Five patients had diabetes and one had a nasal non-Hodgkin lymphoma. Histologically, large, branched, hyphae associated with necrotic areas were observed, confirming microscopically such as mucormycosis through PAS and GMS stains. In four cases, treatment consisted in surgical debridement associated with antifungal therapy. All patients were submitted to debridement and received antifungal treatment (amphotericin B). Five patients were followed up without clinical recurrence, but unfortunately one patient died. Diagnosis of mucormycosis should be early because it is related to high mortality. The treatment consists of surgical debridement associated with antifungal therapy.

Neutralizing Effect of Synthetic Peptides toward SARS-CoV-2.

The outbreak caused by SARS-CoV-2 has taken many lives worldwide. Although vaccination has started, the development of drugs to either alleviate or abolish symptoms of COVID-19 is still necessary. Here, four synthetic peptides were assayed regarding their ability to protect Vero E6 cells from SARS-CoV-2 infection and their toxicity to human cells and zebrafish embryos. All peptides had some ability to protect cells from infection by SARS-CoV-2 with the D614G mutation. Molecular docking predicted the ability of all peptides to interact with and induce conformational alterations in the spike protein containing the D614G mutation. PepKAA was the most effective peptide, by having the highest docking score regarding the spike protein and reducing the SARS-CoV-2 plaque number by 50% (EC50) at a concentration of 0.15 mg mL-1. Additionally, all peptides had no toxicity to three lines of human cells as well as to zebrafish larvae and embryos. Thus, these peptides have potential activity against SARS-CoV-2, making them promising to develop new drugs to inhibit cell infection by SARS-CoV-2.

The addition of residue from pruning of yerba mate (Ilex paraguariensis) in laying hens modulates fatty acid profile and incorporates chlorogenic acid in the egg.

This study aimed to determine whether the addition of Ilex paraguariensis residue to the basal diet of laying hens improves bird health, production, fatty acids, egg quality, and transfer of chlorogenic acids to the egg. One hundred twenty birds of the Hy-line lineage were used, divided into five groups with six replicates and four birds per replicate, as follows: T0 (control group, without IPPR supplementation), T0.5 (basal diet plus 0.5% of IPPR), T1 (basal diet plus 1% IPPR), T1.5 (basal diet plus 1.5% IPPR), and T2 (basal diet plus 2% IPPR), for two consecutive cycles of 21 days each. The productive performance of the birds, physicochemical composition of eggs, fatty acid profile, the concentration of chlorogenic acids in eggs, leukocyte count, serum biochemistry, oxidant and antioxidant status, total bacterial count in eggs, and feces were evaluated at 21 and 42 days of the experiment. The addition of IPPR to the birds' diet no-change eggs production and feed conversion. In the egg yolks of birds that consumed IPPR, there were chlorogenic acids. There was a reduction in the total bacterial count in the feces and eggshells of the birds that received 2% of the IPPR. IPPR intake also reflected a reduction in total saturated fatty acid levels and increased monounsaturated fatty acids. These findings suggest that IPPR is a compelling alternative for laying hens; however, its ingestion also has negative effects that are discussed in below. Chlorogenic acids in the egg are desirable, as these phenolics have nutraceutical effects in humans.

Bis-triazolylchalcogenium-Functionalized Benzothiadiazole Derivatives as Light-up Sensors for DNA and BSA.

A range of bis-triazolylchalcogenium-BTD 3 was synthesized by a copper-catalyzed azide-alkyne cycloaddition of azido arylchalcogenides 1 and 4,7-diethynylbenzo[c][1,2,5]thiadiazole 2. Eight new compounds were obtained in moderate to good yields using 1 mol % of copper(II) acetate monohydrate under mild reaction conditions. In addition, the synthesized bis-triazolylchalcogenium-BTD 3a-3h were investigated regarding their photophysical, electrochemical, and biomolecule binding properties in solution. In general, compounds presented strong absorption bands at the 250-450 nm region and cyan to green emission properties. The redox process attributed to the chalcogen atom was observed by electrochemical analysis (CV techniques). In addition, spectroscopic studies by UV-vis, steady-state emission fluorescence, and molecular docking calculations evidenced the ability of each derivative to establish interactions with calf-thymus DNA (CT-DNA) and bovine serum albumin (BSA). The behavior presented for this new class of compounds makes them a promising tool as optical sensors for biomolecules.

Microencapsulated phytogenic in dog feed modulates immune responses, oxidative status and reduces bacterial (Salmonella and Escherichia coli) counts in feces.

Improving the health and immunity of pets is a concern of the guardians, while maintaining the health of the animals directly impacts the owners' health and public health. The objective of this study was to produce a dog feed containing a microencapsulated phytogenic blend, as well as determine the impact of the additive on animal health and its intestinal microbiota. The composition included microencapsulated thymol, carvacrol, and cinnamaldehyde, at 300 mg/kg of feed. Ten male beagle dogs were divided into two groups, identified as follows: the control group (C; ingested the feed without the additive) and the treated group (T; consumed feed containing the phytogenic blend). The dogs received 300 g of feed/day divided into two meals. Greater neutrophil counts in group T and lymphocyte counts were observed at the end of the experiment, as well as levels of α2-globulins and γ-globulin, while ß1 and ß2-globulins levels were lower in group T. Serum nitrogen oxide levels were higher in group T. Levels of reactive oxygen species were lower in group T at days 30 and 45, unlike activity of glutathione peroxidase that was higher. We found less bacterial contamination in the feces of dogs in group T, i.e., total bacterial count, total coliform counts, and counts of Salmonella and Escherichia coli were lower on days 30 and 45. Phytogenic blend intake reduces bacterial counts in stool and improves antioxidant/oxidative status and immune responses.

Dietary supplementation with curcumin-loaded nanocapsules in lambs: Nanotechnology as a new tool for nutrition.

Curcumin-containing nanocapsule powder formulations have not been used in ruminant feed to date, despite the fact that curcumin is known to be a functional food additive. The objective of this study was to determine whether ethyl polymethacrylate (Eudragit L-100) nanocapsules loaded with curcumin (N-CU) would improve health and growth of lambs. Thirty-two male Lacaune lambs (body weight [BW] = 16 ± 0.99 kg; 45 d of age) were randomly assigned to 1 of 4 treatments: T0, T1, T2 and T4, representing supplementation of curcumin at 0, 1, 2, and 4 mg/kg concentrate, respectively. The animals in each treatment were allocated in 4 pens of 2 lambs each (8 lambs per treatment). The experiment lasted 17 d, with samples and measurements collected on d 0, 7, 12, and 17. The T2 lambs had greater average daily gain than T0 lambs. Regression analysis showed that the ideal dose of N-CU to enhance weight gain was 1.89 mg/kg concentrate. There were significant interactions (P < 0.05) between treatments × time for hematological variables, particularly for increases in erythrocytes (T2) and reductions in counts of leukocytes, neutrophils, and lymphocytes in T1 and T2. There were significant interactions between treatment × time for total protein, globulin, urea, and triglyceride levels. Stimulation of the antioxidant system was also observed. There were increased levels of non-protein thiols (NPSH), as well as increased activities of superoxide dismutase (SOD) and glutathione S-transferase (GST) in the supplemented animals. Levels of reactive oxygen species (ROS) were lower in the serum of supplemented lambs. In general, the 4 mg/kg dose had no positive effects on growth or health. This was an unexpected result, given the known properties of curcumin. Taken together, these findings suggest that addition of low concentrations of nanoencapsulated curcumin (T1 and T2) in lamb feed improves health, minimizing oxidative stress and generates anti-inflammatory effects that may have contributed indirectly to greater weight gain. Nanocapsules potentiate the effects of curcumin and may emerge as a new tool in animal nutrition.

Anomalous aortic origin of the left main coronary artery associated with arterial compression-Case report.

BACKGROUND: Anomalous aortic origin of coronary artery is a rare finding, with varied presentation and symptomatology. Increasingly recognized by cardiac imaging, when found it raises questions about the appropriate approach and management. CASE PRESENTATION: We present a case of an 11-year-old female who presented with episodes of shortness of breath, angina, and syncope during exercise. Further investigation demonstrated episodes of nonsustained ventricular tachycardia on Holter and coronary angiotomography revealed that the left coronary artery had an anomalous origin from the right cusp with initial short intramural segment and significant external compression in its initial course between the aorta and the pulmonary artery. The patient was submitted to surgical correction with dissection of left coronary artery posterior to the pulmonary artery, coronary arteriotomy, roof ampliation with the autologous pericardium, and creation of neo-ostium in aorta. The patient had a satisfactory postoperative recovery, was discharged on the fifth-day post-op, and remains asymptomatic after 14 months of follow-up. Herein we present surgical video and postoperative echo and computed tomography scan.

Positive effects of biocholine powder dietary supplementation on milk production and quality, and antioxidant responses in lactating ewes: A new nutritional tool.

We determined whether the dietary supplementation with a commercial product (vegetable biocholine - VB) for Lacaune ewes at peak lactation would improve animal health and production as well as milk quality. We also determined the effects of VB as a feed additive. We used thirty Lacaune ewes at 30 days of lactation, allocated into three groups: T0 (control, without VB), T5 (5 g of VB/animal/day) and T10 (10 g of VB/animal/day). T10 sheep had greater milk yield during the experimental period. T10 ewes had also a significantly lower feed conversion ratio than the other groups. Total solids concentration of milk was higher in T10 than in the other groups on day 20. The somatic cell count in milk was lower in ewes that consumed VB in the highest dose (T10) than in the T0 and T5 in days 15 and 20. Lower levels of lipoperoxidation (LPO) and of reactive oxygen species (ROS) were observed in milk from ewes fed with the VB supplemented diet on day 20, associated with increased levels of total antioxidant capacity and superoxide dismutase activity in milk. In serum, we found that T5 and T10 animals had significantly higher levels of non-enzymatic antioxidants (non-protein thiols) associated with reduced LPO and ROS content. Higher levels of globulins were observed in T10 than in T0 sheep on day 20. These data suggest that VB dietary supplementation stimulates antioxidant responses and increases the concentration of globulins in a manner beneficial to sheep health. Milk production, feed conversion rate, and milk SCC were also improved.

Effects of biocholine powder supplementation in ewe lambs: Growth, rumen fermentation, antioxidant status, and metabolism.

The objective of this study was to evaluate the effects of biocholine powder (BP) added to the concentrate of ewe lambs on growth, rumen fermentation, antioxidant status, and metabolism. Forty-eight Lacaune lambs were divided 3 treatments: T0, T4, and T8, representing 0, 4, and 8 g of BP per animal/day added to the concentrate, respectively. The T4 and T8 lambs had greater average daily gain from d 0-75 (0.22, 0.25, and 0.26 kg/d for T0, T4 and T8, respectively). T4 and T8 lambs had higher methylene blue test results (indicating microbiological activity), and the higher effects were detected for T8 lambs. The BP in lamb's diet increased the ruminal concentration of propionate (T4 and T8). The T8 lambs had greater serum activity of superoxide dismutase and glutathione transferase, and lower reactive oxygen species levels. We conclude that BP is a biotechnological additive with high nutritional potential.

Efficient synthesis and antitumor evaluation of 4-aminomethyl-N-arylpyrazoles: Discovery of potent and selective agents for ovarian cancer.

A new one-pot two-step sequential methodology for synthesis of novel 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives is reported. One-pot transformation of ß-enamino diketones and arylhydrazines generated 4-iminium-N-arylpyrazole salt intermediates in situ, which were easily transformed into 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives by NaBH3CN. The products could be isolated in the free or hydrochloride salt forms. Also, it was possible to obtain the products in the zwitterionic form by ester group hydrolysis. Furthermore, all synthesised compounds were evaluated in vitro against a panel of eight human tumor cell lines. The 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives were much more powerful than the hydrochloride and zwitterionic forms. Moreover, the results suggest that the N-aryl group at the pyrazole ring is vital for modulating antiproliferative activity. The 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-phenylpyrazoles 3a-g exhibited higher inhibitory activities against OVCAR-3, with GI50 values of 0.013-8.78 µM, and lower inhibitory activities against normal human cell lines. Molecular docking was performed to evaluate the probable binding mode of 3a into active site of CDK2.

Neuropathy and primary headaches affect different subgroups of inflammatory bowel disease patients.

BACKGROUND: Peripheral neuropathies (PN) and primary headaches (PH) are common comorbidities in inflammatory bowel disease (IBD) patients. We aimed to evaluate whether PN and PH affect the same subgroups of IBD patients. METHODS: Since 2004, we established a cohort study to evaluate neurological diseases in IBD patients. Over 2 years, all consecutive (N = 155) IBD patients (either Crohn's disease (CD) or ulcerative colitis (UC) were evaluated for the presence of PN and PH. PH were also evaluated in dyspeptic patients (N = 84) and IBD relatives (controls, N = 101). After neurological evaluation, symptomatic patients underwent skin wrinkling test to evaluate small fiber function and/or electromyography. RESULTS: Headaches and migraine were more prevalent in IBD than control patients: 52.3 and 34.2% vs. 40.6 and 20.8% (P < 0.05). Migraine was 2.6 times more common in CD patients than controls (CI = 1.34-5.129) and 8.6 times (13.3 times in the CD group) more common in men with IBD (P < 0.05). Headache and migraine were also more common in dyspeptic patients (P < 0.05). Chi-square, univariate, and multivariate regression analysis did not disclose any association between PN, headache, or PH (P > 0.05). Multivariate regression analysis disclosed that headaches were more prevalent in women, co-existing psychiatric disease, IBD, CD, and UC. After age, gender distribution, and prevalence of hypertension and psychiatric diseases were matched among the groups, there were still differences in the prevalence of headaches and migraine among IBD, CD, and UC versus control patients. CONCLUSION: In summary, PH and PN are common in IBD and do not affect the same subgroups of patients.