A time averaged semiclassical approach to IR spectroscopy.

We propose a new semiclassical approach to the calculation of molecular IR spectra. The method employs the time averaging technique of Kaledin and Miller upon symmetrization of the quantum dipole-dipole autocorrelation function. Spectra at high and low temperatures are investigated. In the first case, we are able to point out the possible presence of hot bands in the molecular absorption line shape. In the second case, we are able to reproduce accurate IR spectra as demonstrated by a calculation of the IR spectrum of the water molecule, which is within 4% of the exact intensity. Our time averaged IR spectra can be directly compared to time averaged semiclassical power spectra as shown in an application to the CO2 molecule, which points out the differences between IR and power spectra and demonstrates that our new approach can identify active IR transitions correctly. Overall, the method features excellent accuracy in calculating absorption intensities and provides estimates for the frequencies of vibrations in agreement with the corresponding power spectra. In perspective, this work opens up the possibility to interface the new method with the semiclassical techniques developed for power spectra, such as the divide-and-conquer one, to get accurate IR spectra of complex and high-dimensional molecular systems.

The first HyDRA challenge for computational vibrational spectroscopy.

Vibrational spectroscopy in supersonic jet expansions is a powerful tool to assess molecular aggregates in close to ideal conditions for the benchmarking of quantum chemical approaches. The low temperatures achieved as well as the absence of environment effects allow for a direct comparison between computed and experimental spectra. This provides potential benchmarking data which can be revisited to hone different computational techniques, and it allows for the critical analysis of procedures under the setting of a blind challenge. In the latter case, the final result is unknown to modellers, providing an unbiased testing opportunity for quantum chemical models. In this work, we present the spectroscopic and computational results for the first HyDRA blind challenge. The latter deals with the prediction of water donor stretching vibrations in monohydrates of organic molecules. This edition features a test set of 10 systems. Experimental water donor OH vibrational wavenumbers for the vacuum-isolated monohydrates of formaldehyde, tetrahydrofuran, pyridine, tetrahydrothiophene, trifluoroethanol, methyl lactate, dimethylimidazolidinone, cyclooctanone, trifluoroacetophenone and 1-phenylcyclohexane-cis-1,2-diol are provided. The results of the challenge show promising predictive properties in both purely quantum mechanical approaches as well as regression and other machine learning strategies.

A Ketogenic Diet in Combination with Gemcitabine Mitigates Pancreatic Cancer-Associated Cachexia in Male and Female KPC Mice.

Cancer-associated cachexia (CAC) is a critical contributor to pancreatic ductal adenocarcinoma (PDAC) mortality. Thus, there is an urgent need for new strategies to mitigate PDAC-associated cachexia; and the exploration of dietary interventions is a critical component. We previously observed that a ketogenic diet (KD) combined with gemcitabine enhances overall survival in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. In this study, we investigated the effect and cellular mechanisms of a KD in combination with gemcitabine on the maintenance of skeletal muscle mass in KPC mice. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD), a KD, a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. We observed that a KD or a KG-mitigated muscle strength declined over time and presented higher gastrocnemius weights compared CD-fed mice. Mechanistically, we observed sex-dependent effects of KG treatment, including the inhibition of autophagy, and increased phosphorylation levels of eIF2α in KG-treated KPC mice when compared to CG-treated mice. Our data suggest that a KG results in preservation of skeletal muscle mass. Additional research is warranted to explore whether this diet-treatment combination can be clinically effective in combating CAC in PDAC patients.

Acute liver injury following turmeric use in Tuscany: An analysis of the Italian Phytovigilance database and systematic review of case reports.

AIMS: Several cases of acute non-infectious cholestatic hepatitis recently appeared in Italy following consumption of Curcuma longa-containing dietary supplements. The aim of this research was to describe the Tuscan (Italy) cases of acute hepatitis and to compare them with similar cases of hepatotoxicity published in the literature by performing a systematic review. METHODS: Records of Tuscan cases of acute hepatitis were obtained from the Italian Phytovigilance system. Each spontaneous report was analysed in order to collect all relevant clinical information of patients and information concerning the Curcuma longa-containing dietary supplement. Moreover, both the RUCAM and WHO-UMC systems were used to evaluate the causal relationship between the use of dietary supplement and acute hepatitis. A systematic literature review was performed in MEDLINE and Embase and all case-reports and case-series published in English were included. RESULTS: Seven cases of acute hepatitis occurring in Tuscany up to September 2019 are described. In all cases, hepatotoxicity was associated with Curcuma longa formulations with high bioavailability and high dosage of curcumin/curcuminoids. The causal relationship was also supported by the positive dechallenge observed in most cases. In the 23 cases identified through the systematic review, the majority of patients were concomitantly exposed to at least one other medication and 16 of them experienced a positive dechallenge. CONCLUSIONS: Within the frame of poorly controlled and regulated products, such as dietary supplements, the evaluation of Italian cases of Curcuma longa-induced acute hepatitis and the systematic review of literature confirmed the association between Curcuma longa and liver injury.

Role of Histamine H3 Receptor Antagonists on Intraocular Pressure Reduction in Rabbit Models of Transient Ocular Hypertension and Glaucoma.

Intraocular pressure (IOP) has a tendency to fluctuate throughout the day, reaching its peak in the early morning in healthy subjects or glaucoma patients. Likewise, histamine tone also fluctuates over time, being lower at nighttime. Numerous studies have demonstrated a correlation between short-term IOP fluctuation and glaucoma progression; however, it has not yet been determined whether histamine plays a role in IOP fluctuations. The aim of this research was to establish the distribution of the histamine receptor proteins and respective mRNAs in the eye by western blot, immunohistochemistry and RT-PCR in New Zealand rabbits. Furthermore, we used a transient ocular hypertension (OHT) model induced by injection of 50 µL of 5% hypertonic saline into the vitreous and a stable OHT model (100 µL 0.1% carbomer in the anterior chamber) to address the potential IOP-lowering ability of H3 receptor (H3R) antagonists (ciproxifan, DL76 and GSK189254). IOPs were performed with a Tono-Pen at baseline and 60, 120 and 240 min post treatment after transient OHT induction and, every day for 12 days in the stable OHT model. All histamine receptor subtypes were localized in the rabbit retina and ciliary body/trabecular meshwork. All the treatments lowered IOP in a dose-dependent fashion between 0.3% and 1%. More specifically, the effects were maximal with ciproxifan at 60 min post-dose (IOP60 change = -18.84 ± 4.85 mmHg, at 1%), remained stable until 120 min (IOP120 change = -16.38 ± 3.8 mmHg, at 1%) and decayed thereafter to reach baseline values at 240 min. These effects were highly specific and dependent on histamine release as pre-treatment with imetit (H3R agonist, 1%) or pyrilamine (H1R antagonist, 1%) largely blocked ciproxifan-mediated effects. Color Doppler ultrasound examination was performed to evaluate changes in ophtalmic artery resistivity index (RI) before and after repeated dosing with DL 76, GSK189254, ciproxifan and timolol. Chronic treatments with H3R antagonists and timolol improved the vascular performance of ophthalmic arteries and reduced retinal ganglion cell death. Oxidative stress was also reduced and measured 8-Hydroxy-2'-deoxyguanosine (8OHdG) expression, and by dihidroethydium (DHE) staining. These results demonstrated that the histamine system participates in IOP regulation and that H3R antagonists could represent a future promising therapy for glaucoma. Further studies should be focused on the long-term IOP circadian fluctuations.

Phenolic metabolites in plasma and tissues of rats fed with a grape pomace extract as assessed by liquid chromatography-tandem mass spectrometry.

Grape pomace extract (GPE) is a rich and relatively low-cost source of phenolic compounds. However, little is known about the main GPE metabolites in mammals, which could help explain the observed health-promoting effects. This study investigated the presence of parent compounds from flavanol, flavonol and stilbene families and their metabolites in rat plasma and tissues after an acute intake of GPE in doses of 300 and 600 mg kg/body weight. The measurement of free compounds and their metabolites was performed by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Results showed the presence of epicatechin, epicatechin methyl-glucuronide, epicatechin methyl-sulphate, catechin, catechin-glucuronide, quercetin methyl-glucuronide, resveratrol-3-glucuronide, resveratrol-4-glucuronide and resveratrol-3-sulphate in plasma, which was dose dependent. The most abundant measured compound in plasma was epicatechin-glucuronide. The presence of glucuronidated and methyl-glucuronidated forms of catechin were observed in the liver at both doses, while epicatechin-glucuronide and methyl-glucuronide were detected only upon intake of 600 mg GPE/kg body weight. At this dose epicatechin-glucuronide and methyl-glucuronide were also detected in muscle, and catechin methyl-glucuronide in adipose tissue. Results show the main GPE metabolites present in rat tissues after oral consumption, contributing to better understand the health benefits of GPE and its potential utilization as a functional ingredient.

Methadone Dose Adjustments, Plasma R-Methadone Levels and Therapeutic Outcome of Heroin Users: A Randomized Clinical Trial.

AIMS: We aimed to improve the retention in treatment and therapeutic outcome of methadone maintenance treatment (MMT) patients by adjusting the oral methadone dose in order to reach a "target" plasma R-methadone level (80-250 ng/mL). METHODS: A multicenter randomized controlled trial was organized. RESULTS: The intention-to-treat statistical analysis showed that repeated dose adjustments performed in order to obtain therapeutic plasma R-methadone levels did not improve retention in treatment of heroin-dependent patients. However, patients having plasma methadone levels in the "target range" at the beginning of the study had a better retention in treatment than controls. Furthermore, patients succeeding in keeping plasma R-methadone target levels (per protocol analysis) remained in treatment and improved their social scores better than controls. -Conclusion: Although the primary endpoint of this study was not demonstrated, a post hoc and a per protocol analysis suggested that patients in MMT with plasma R-methadone concentrations in the target range have a better therapeutic outcome than controls.

HYDAMTIQ, a selective PARP-1 inhibitor, improves bleomycin-induced lung fibrosis by dampening the TGF-ß/SMAD signalling pathway.

Idiopathic pulmonary fibrosis is a severe disease characterized by excessive myofibroblast proliferation, extracellular matrix and fibrils deposition, remodelling of lung parenchyma and pulmonary insufficiency. Drugs able to reduce disease progression are available, but therapeutic results are unsatisfactory; new and safe treatments are urgently needed. Poly(ADP-ribose) polymerases-1 (PARP-1) is an abundant nuclear enzyme involved in key biological processes: DNA repair, gene expression control, and cell survival or death. In liver and heart, PARP-1 activity facilitates oxidative damage, collagen deposition and fibrosis development. In this study, we investigated the effects of HYDAMTIQ, a potent PARP-1 inhibitor, in a murine model of lung fibrosis. We evaluated the role of PARP on transforming growth factor-ß (TGF-ß) expression and TGF-ß/SMAD signalling pathway in lungs. Mice were intratracheally injected with bleomycin and then treated with either vehicle or different doses of HYDAMTIQ for 21 days. Airway resistance to inflation and lung static compliance, markers of lung stiffness, were assayed. Histochemical and biochemical parameters to evaluate TGF-ß/SMAD signalling pathway with alpha-smooth muscle actin (αSMA) deposition and the levels of a number of inflammatory markers (tumour necrosis factor-α, interleukin-1ß, iNOS and COX-2) were performed. Bleomycin administration increased lung stiffness. It also increased lung PARP activity, TGF-ß levels, pSMAD3 expression, αSMA deposition and content of inflammatory markers. HYDAMTIQ attenuated all the above-mentioned physiological, biochemical and histopathological markers. Our findings support the proposal that PARP inhibitors could have a therapeutic potential in reducing the progression of signs and symptoms of the disease by decreasing TGF-ß expression and the TGF-ß/SMAD transduction pathway.

Role of histamine H4 receptor ligands in bleomycin-induced pulmonary fibrosis.

Fibrosis of lung tissue is a disease where a chronic inflammatory process determines a pathological remodelling of lung parenchyma. The animal model obtained by intra-tracheal administration of bleomycin in C57BL/6 mice is one of the most validated murine model. Bleomycin stimulates oxidative stress and the production of pro-inflammatory mediators. Histamine H4R have recently been implicated in inflammation and immune diseases. This study was focused to investigate the effects of H4R ligands in the modulation of inflammation and in the reduction of lung fibrosis in C57BL/6 mice treated with bleomycin. C57BL/6 mice were treated with vehicle, JNJ7777120 (JNJ, selective H4R antagonist) or ST-1006 (partial H4R agonist), ST-994 (H4R neutral antagonist) and ST-1012 (inverse H4R agonist) at equimolar doses, released by micro-osmotic pumps for 21days. Airway resistance to inflation was assayed and lung samples were processed to measure malondialdehyde (TBARS); 8-hydroxy-2'-deoxyguanosine (8OHdG); myeloperoxidase (MPO); COX-2 expression and activity as markers of oxidative stress and inflammation. Fibrosis and airway remodelling were evaluated throughout transforming growth factor-ß (TGF-ß), percentage of positive Goblet cells, smooth muscle layer thickness determination. Our results indicated that JNJ, ST-994 and ST-1012 decreased inflammation and oxidative stress markers, i.e. the number of infiltrating leukocytes evaluated as lung tissue MPO, COX-2 expression and activity, TBARS and 8OHdG production. They also reduced the level of TGF-ß, a pro-fibrotic cytokine, collagen deposition, thickness of smooth muscle layer, Goblet cells hyperplasia; resulting in a decrease of airway functional impairment. The results here reported clearly demonstrated that H4R ligands have a beneficial effect in a model of lung fibrosis in the mouse, thus indicating that H4R antagonists or inverse agonists could be a novel therapeutic strategy for lung inflammatory diseases.

Effects of salicylic acid-induced wine rich in anthocyanins on metabolic parameters and adipose insulin signaling in high-fructose fed rats.

We evaluated the effects of Syrah red wine treated with salicylic acid (RW SA) and its control red wine (RW) on metabolic parameters, systolic blood pressure and adipose tissue insulin signaling in high-fructose (F) fed rats. Grape treated with SA increased the anthocyanin (ANTs) levels in RW. F induced increased systolic blood pressure, dislipidemia and insulin resistance (HOMA:IR). F rats treated with RW significantly prevented these alterations while RW SA partially attenuated triglycerides levels and HOMA:IR without modifications in HDL cholesterol levels. F impaired the adipose tissue response to insulin. Supplementation with RW and RW SA partially attenuated these alterations. Rats supplemented with RW SA had lesser beneficial effects on metabolic alterations than control RW, while both RW and RW SA attenuated altered adipose response to insulin. More studies are necessary to deeply evaluate the effect on SA-induced RW rich in ANTs levels on metabolic alterations associated to MetS.

Histamine receptor expression in human renal tubules: a comparative pharmacological evaluation.

OBJECTIVE AND DESIGN: The aim of this study is to evaluate the expression of the histamine receptors, particularly focusing on the H4R in human renal tubules. MATERIAL: The ex vivo evaluation was carried on specimens from human renal cortex. Primary and immortalized tubular epithelial cells (TECs) and the HK-2 cell line were used as in vitro models. TREATMENT: Cells were pretreated for 10 min with chlorpheniramine maleate 10 µM (H1R antagonist), ranitidine 10 µM (H2R antagonist), GSK189254 1 µM (H3R antagonist) or JNJ7777120 10 µM (H4R antagonist), and then exposed to histamine (3 pM-10 nM) for 30 min. METHODS: The ex vivo evaluation on specimens from human renal cortex was performed by immunohistochemistry. The expression of histamine receptors on primary and immortalized TECs and the HK-2 cell line was evaluated at both gene (RT-PCR) and protein (immunocytofluorescence) levels. The pharmacological analysis was performed by TR-FRET measurements of second messenger (IP3 and cAMP) production induced by histamine with or without the selective antagonists. RESULTS: Our data revealed the presence of all histamine receptors in human tubules; however, only TECs expressed all the receptors. Indeed, histamine elicited a sigmoid dose-response curve for IP3 production, shifted to the right by chlorpheniramine maleate, and elicited a double bell-shaped curve for cAMP production, partially suppressed by the selective H2R, H3R and H4R antagonists when each added alone, and completely ablated when combined together. CONCLUSIONS: Herein, we report the identification of all four histamine receptors in human renal tubules.

Cyclodextrin complexation highly enhances efficacy of arylsulfonylureido benzenesulfonamide carbonic anhydrase inhibitors as a topical antiglaucoma agents.

Two new sulfonamides incorporating arylsulfonylureido moieties were complexed with gamma cyclodextrin (γ-CD), hydroxypropyl-gamma cyclodextrin (HPγ-CD), hydroxypropyl-beta cyclodextrin (HPß-CD) and hydroxyethyl-beta cyclodextrin (HEß-CD) in order to obtain drug formulations with effective topical intraocular pressure (IOP) lowering effects, in an animal model of glaucoma. The HPγ-CD was the best solubilizing agent for the two sulfonamides and its complexes were characterized in detail and administered to rabbits with eye hypertension of 45-50 mmHg. The peak IOP lowering was observed after 1h post-administration and was of 36-37 mmHg. A low IOP pressure (of around-35 mmHg) was then maintained for the next 24h post-administration, which has not been observed before with any IOP lowering drug.

Synthesis of a new series of dithiocarbamates with effective human carbonic anhydrase inhibitory activity and antiglaucoma action.

A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide.

Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment.

Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid-reactive substance and 8-hydroxy-2'-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-ß, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis.

Pharmacokinetics and local safety profile of propranolol eye drops in rabbits.

BACKGROUND: Oral propranolol, a nonselective ß-blocker, is able to reduce the progression of retinopathy of prematurity in newborns, but it appeared unsafe. This study aimed to find, in rabbits, a propranolol eye drop concentration able to induce lower plasma but higher retinal concentrations than those obtained after oral administration. METHODS: Male New Zealand white rabbits were treated with oral propranolol (0.25 mg/kg/6 h) for 5 d, and propranolol concentrations were measured after 1, 2, 3, and 6 h in plasma, aqueous humor, vitreous humor, and retina. These concentrations were compared with those obtained after the administration of one drop of 25 µl of propranolol 0.1% prepared in saline, applied every 6 h to both eyes for 5 d. A Draize eye test and histological analyses were performed to assess eye drop tolerability. RESULTS: The administration of eye drops produced retinal concentrations similar to, but plasma concentrations significantly lower than, those measured after oral administration. The local tolerability profile was excellent. CONCLUSION: Propranolol eye drops are able to ensure high retinal and low plasma concentrations of propranolol, and this finding opens the perspective of possible topical treatment with propranolol in newborns with retinopathy of prematurity.

Anthocyanins and their metabolites promote white adipose tissue beiging by regulating mitochondria thermogenesis and dynamics.

High-fat diet (HFD) consumption and excess nutrient availability can cause alterations in mitochondrial function and dynamics. We previously showed that anthocyanins (AC) decreased HFD-induced body weight gain and fat deposition. This study investigated: i) the capacity of AC to mitigate HFD-induced alterations in mitochondrial dynamics, biogenesis, and thermogenesis in mouse subcutaneous white adipose tissue (sWAT), and ii) the underlying mechanisms of action of cyanidin-3-O-glucoside (C3G), delphinidin-3-O-glucoside (D3G), and their gut metabolites on mitochondria function/dynamics in 3T3-L1 adipocytes treated with palmitate. Mice were fed control or HFD diets, added or not with 40 mg AC/kg body weight (BW). Compared to control and AC-supplemented mice, HFD-fed mice had fewer sWAT mitochondria that presented alterations of their architecture. AC supplementation prevented HFD-induced decrease of proteins involved in mitochondria biogenesis (PPARγ, PRDM16 and PGC-1α), and thermogenesis (UCP-1), and decreased AMPK phosphorylation. AC supplementation also restored the alterations in sWAT mitochondrial dynamics (Drp-1, OPA1, MNF-2, and Fis-1) and mitophagy (BNIP3L/NIX) caused by HFD consumption. In mature 3T3-L1, C3G, D3G, and their metabolites protocatechuic acid (PCA), 4-hydroxybenzaldehyde (HB), and gallic acid (GA) differentially affected palmitate-mediated decreased cAMP, PKA, AMPK, and SIRT-1 signaling pathways. C3G, D3G, and metabolites also prevented palmitate-mediated decreased expression of PPARγ, PRDM16, PGC-1α, and UCP1. Results suggest that consumption of select AC, i.e. cyanidin and delphinidin, could promote sWAT mitochondriogenesis and improve mitochondria dynamics in the context of HFD/obesity-induced dysmetabolism in part by regulating PKA, AMPK, and SIRT-1 signaling pathways.

Consensus Panel Recommendations for the Pharmacological Management of Breastfeeding Women with Postpartum Depression.

INTRODUCTION: Our consensus statement aims to clarify the use of antidepressants and anxiolytics during breastfeeding amidst clinical uncertainty. Despite recent studies, potential harm to breastfed newborns from these medications remains a concern, leading to abrupt discontinuation of necessary treatments or exclusive formula feeding, depriving newborns of benefits from mother's milk. METHODS: A panel of 16 experts, representing eight scientific societies with a keen interest in postpartum depression, was convened. Utilizing the Nominal Group Technique and following a comprehensive literature review, a consensus statement on the pharmacological treatment of breastfeeding women with depressive disorders was achieved. RESULTS: Four key research areas were delineated: (1) The imperative to address depressive and anxiety disorders during lactation, pinpointing the risks linked to untreated maternal depression during this period. (2) The evaluation of the cumulative risk of unfavorable infant outcomes associated with exposure to antidepressants or anxiolytics. (3) The long-term impact on infants' cognitive development or behavior due to exposure to these medications during breastfeeding. (4) The assessment of pharmacological interventions for opioid abuse in lactating women diagnosed with depressive disorders. CONCLUSIONS: The ensuing recommendations were as follows: Recommendation 1: Depressive and anxiety disorders, as well as their pharmacological treatment, are not contraindications for breastfeeding. Recommendation 2: The Panel advocates for the continuation of medication that has demonstrated efficacy during pregnancy. If initiating an antidepressant during breastfeeding is necessary, drugs with a superior safety profile and substantial epidemiological data, such as SSRIs, should be favored and prescribed at the lowest effective dose. Recommendation 3: For the short-term alleviation of anxiety symptoms and sleep disturbances, the Panel determined that benzodiazepines can be administered during breastfeeding. Recommendation 4: The Panel advises against discontinuing opioid abuse treatment during breastfeeding. Recommendation 5: The Panel endorses collaboration among specialists (e.g., psychiatrists, pediatricians, toxicologists), promoting multidisciplinary care whenever feasible. Coordination with the general practitioner is also recommended.

Hepatic safety profile of pancreatic cancer­bearing mice fed a ketogenic diet in combination with gemcitabine.

Ketogenic diets (KDs) are actively being evaluated for their potential anticancer effects. Although KDs are generally considered safe, their safety profile when combined with chemotherapy remains unknown. It is known that a KD enhances the anticancer effect of gemcitabine (2',2'-difluoro-2'-deoxycytidine) in LSL-KrasLSL-G12D/+Trp53R172H/+Pdx-1-Cre (KPC) tumor-bearing mice. In the present study, whether a KD in combination with gemcitabine affected the liver safety profile in KPC mice was evaluated. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; % kcal: 20% fat, 65% carbohydrate, 15% protein) + gemcitabine [control plus gemcitabine group (CG)] or a KD (% kcal: 84% fat, 15% protein, 1% carbohydrate) + gemcitabine [ketogenic plus gemcitabine group (KG)] for two months. After two months of treatment, no significant differences in body weight were observed between CGs and KGs. Moreover, the KD did not significantly alter the serum protein expression levels of liver enzymes, including aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase. In addition, the KD did not alter markers of liver-lipid accumulation as well as serum cholesterol and triglyceride levels, compared with the CG-treated group. Upon histologic examination, steatosis was rare, with no notable differences between treatment groups. When examining liver fatty acid composition, KD treatment significantly increased the content of saturated fatty acids and significantly decreased levels of cis-monounsaturated fatty acids compared with the CG. Finally, the KD did not affect liver markers of inflammation and oxidative stress, nor the protein expression levels of enzymes involved in ketone bodies, such as 3-hydroxy-3-methylglutaryl-CoA lyase and hidroximetilglutaril-CoA sintasa, and glucose metabolism, such as hexokinase 2, pyruvate dehydrogenase and phosphofructokinase. In summary, a KD in combination with gemcitabine appears to be safe, with no apparent hepatotoxicity and these data support the further evaluation of a KD as an adjuvant dietary treatment for pancreatic cancer.

Exposures and Suspected Intoxications to Pharmacological and Non-Pharmacological Agents in Children Aged 0-14 Years: Real-World Data from an Italian Reference Poison Control Centre.

This study describes the exposures and suspected intoxications in children (0-14 years) managed by an Italian reference poison control center (PCC). A seven-year observational retrospective study was performed on the medical records of the Toxicology Unit and PCC, Careggi University Hospital, Florence (Italy). During the study period (2015-2021), a total of 27,212 phone call consultations were managed by the PCC, of which 11,996 (44%) involved subjects aged 0-14 years. Most cases occurred in males (54%) aged 1-5 years (73.8%), mainly at home (97.4%), and with an oral route of intoxication (93%). Cases mainly occurred involuntarily. Consultations were generally requested by caregivers; however, in the age group 12-14 years, 70% were requested by healthcare professionals due to voluntary intoxications. Cleaners (19.44%) and household products (10.90%) were the most represented suspected agents. Pharmacological agents accounted for 28.80% of exposures. Covariates associated with a higher risk of emergency department visit or hospitalization were voluntary intoxication (OR 29.18 [11.76-72.38]), inhalation route (OR 1.87 [1.09-3.23]), and pharmacological agents (OR 1.34 [1.23-1.46]), particularly central nervous system medications. Overall, consultations do not burden national and regional healthcare facilities, revealing the activity of PCCs as having a strategic role in reducing public health spending, even during the COVID-19 pandemic.

Oral and fecal microbiota perturbance in cocaine users: Can rTMS-induced cocaine abstinence support eubiosis restoration?

The effects of cocaine on microbiota have been scarcely explored. Here, we investigated the gut (GM) and oral (OM) microbiota composition of cocaine use disorder (CUD) patients and the effects of repetitive transcranial magnetic stimulation (rTMS). 16S rRNA sequencing was used to characterize GM and OM, whereas PICRUST2 assessed functional changes in microbial communities, and gas-chromatography was used to evaluate fecal short and medium chain fatty acids. CUD patients reported a significant decrease in alpha diversity and modification of the abundances of several taxa in both GM and OM. Furthermore, many predicted metabolic pathways were differentially expressed in CUD patients' stool and saliva samples, as well as reduced levels of butyric acid that appear restored to normal amounts after rTMS treatment. In conclusion, CUD patients showed a profound dysbiotic fecal and oral microbiota composition and function and rTMS-induced cocaine abstinence determined the restoration of eubiotic microbiota.