Emerging Strategies in Drug Development and Clinical Care in the Era of Personalized and Precision Medicine.

In the ever-changing landscape of modern medicine, we face an important moment where the interplay of disease, drugs, and patients defines a new paradigm [...].

Circadian Rhythms, Chrononutrition, Physical Training, and Redox Homeostasis-Molecular Mechanisms in Human Health.

A multitude of physiological processes, human behavioral patterns, and social interactions are intricately governed by the complex interplay between external circumstances and endogenous circadian rhythms. This multidimensional regulatory framework is susceptible to disruptions, and in contemporary society, there is a prevalent occurrence of misalignments between the circadian system and environmental cues, a phenomenon frequently associated with adverse health consequences. The onset of most prevalent current chronic diseases is intimately connected with alterations in human lifestyle practices under various facets, including the following: reduced physical activity, the exposure to artificial light, also acknowledged as light pollution, sedentary behavior coupled with consuming energy-dense nutriments, irregular eating frameworks, disruptions in sleep patterns (inadequate quality and duration), engagement in shift work, and the phenomenon known as social jetlag. The rapid evolution of contemporary life and domestic routines has significantly outpaced the rate of genetic adaptation. Consequently, the underlying circadian rhythms are exposed to multiple shifts, thereby elevating the susceptibility to disease predisposition. This comprehensive review endeavors to synthesize existing empirical evidence that substantiates the conceptual integration of the circadian clock, biochemical molecular homeostasis, oxidative stress, and the stimuli imparted by physical exercise, sleep, and nutrition.

Intermittent Fasting on Human Health and Disease.

Chronic non-communicable diseases (NCDs) are the leading cause of morbidity and mortality worldwide, but most of all in industrialized countries, and are fundamentally correlated to improper nutrition and impaired lifestyle behaviours [...].

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine.

This review presents current updates of pancreatic enzyme replacement therapy in children with cystic fibrosis based on literature published in the last decade and some special considerations regarding pancreatic enzyme replacement therapy in the era of new therapies, such as cystic fibrosis transmembrane conductance regulator modulator therapies. Few articles evaluate the efficacy of pancreatic enzyme replacement therapy in the pediatric population, and most studies also included children and adults with cystic fibrosis. Approximately 85% of cystic fibrosis patients have exocrine pancreatic insufficiency and need pancreatic enzyme replacement therapy. Fecal elastase is the most commonly used diagnostic test for exocrine pancreatic insufficiency, although this value can fluctuate over time. While it is used as a diagnostic test, it cannot be used for monitoring the effectiveness of pancreatic enzyme replacement therapy and for adjusting doses. Pancreatic enzyme replacement therapy, the actual treatment for exocrine pancreatic insufficiency, is essential in children with cystic fibrosis to prevent malabsorption and malnutrition and needs to be urgently initiated. This therapy presents many considerations for physicians, patients, and their families, including types and timing of administration, dose monitoring, and therapy failures. Based on clinical trials, pancreatic enzyme replacement therapy is considered effective and well-tolerated in children with cystic fibrosis. An important key point in cystic fibrosis treatment is the recent hypothesis that cystic fibrosis transmembrane conductance regulator modulators could improve pancreatic function, further studies being essential. Pancreatic enzyme replacement therapy is addressed a complication of the disease (exocrine pancreatic insufficiency), while modulators target the defective cystic fibrosis transmembrane conductance regulator protein. Exocrine pancreatic insufficiency in cystic fibrosis remains an active area of research in this era of cystic fibrosis transmembrane conductance regulator modulator therapies. This new therapy could represent an example of personalized medicine in cystic fibrosis patients, with each class of modulators being addressed to patients with specific genetic mutations.

Clinical and Electrophysiological Changes in Pediatric Spinal Muscular Atrophy after 2 Years of Nusinersen Treatment.

In the new therapeutic era, disease-modifying treatment (nusinersen) has changed the natural evolution of spinal muscular atrophy (SMA), creating new phenotypes. The main purpose of the retrospective observational study was to explore changes in clinical evolution and electrophysiological data after 2 years of nusinersen treatment. We assessed distal compound motor action potential (CMAP) on the ulnar nerve and motor abilities in 34 SMA patients, aged between 1 and 16 years old, under nusinersen treatment, using specific motor scales for types 1, 2 and 3. The evaluations were performed at treatment initiation and 26 months later. There were registered increased values for CMAP amplitudes after 2 years of nusinersen, significantly correlated with motor function evolution in SMA type 1 patients (p < 0.005, r = 0.667). In total, 45% of non-sitters became sitters and 25% of sitters became walkers. For SMA types 1 and 2, the age at the treatment initialization is highly significant (p < 0.0001) and correlated with treatment yield. A strong negative correlation (r = −0.633) was observed for SMA type 1 and a very strong negative correlation (r = −0.813) for SMA type 2. In treated SMA cases, the distal amplitude of the CMAP and motor functional scales are important prognostic factors, and early diagnosis and treatment are essential for a better outcome.

Polypharmacy in the Management of Arterial Hypertension-Friend or Foe?

Background and Objectives: Polypharmacy is associated with drug-drug or food-drug interactions that may pose treatment difficulties. The objective of the study was to investigate the use of polypharmacy in hypertensive patients hospitalized in the Internal Medicine Clinic of a European referral hospital. Materials and Methods: We conducted a retrospective chart review study on patients identified by a database search of discharge diagnoses to assess the use of polypharmacy and identify potential drug-drug and food-drug interactions. Results: In total, 166 hypertensive patients (68.46 ± 12.70 years, range 42-94 years) were compared to 83 normotensive subjects (67.82 ± 14.47 years, range 22-94 years) who were hospitalized in the clinic during the same period. Polypharmacy was more common in hypertensive versus normotensive subjects (p = 0.007). There were no differences in terms of age, as well as major (0.44 ± 0.77 versus 0.37 ± 0.73 interactions/patient, p = 0.52) and minor (1.25 ± 1.50 versus 1.08 ± 1.84 interactions/patient, p = 0.46) drug-drug interactions between patients with and without hypertension. The mean number of drug-drug interactions (6.55 ± 5.82 versus 4.93 ± 5.59 interactions/patient, p = 0.03), moderate drug-drug interactions (4.94 ± 4.75 versus 3.54 ± 4.17, p = 0.02) and food-drug interactions (2.64 ± 1.29 versus 2.02 ± 1.73, p = 0.00) was higher in patients with hypertension versus their counterparts. Conclusions: The present study reinforces that polypharmacy is a serious concern in hypertensive patients, as reflected by the high number of potentially harmful drug-drug or food-drug interactions. We recorded higher numbers of comorbidities, prescribed drugs, and moderate drug-drug/food-drug interactions in hypertensive versus normotensive patients. A strategy to evaluate the number of discharge medications and reduce drug-drug interactions is essential for the safety of hypertensive patients.

Clinical significance of serum melatonin in predicting the severity of oral squamous cell carcinoma.

Melatonin, the primary hormone produced by the pineal gland, is intensely assessed for its anticancer properties. This study aimed to reveal the clinical significance of serum melatonin levels in predicting the severity of oral squamous cell carcinoma (OSCC). For this purpose, 40 male patients with OSCC and 30 healthy subjects were enrolled in this study. The serum levels of melatonin were determined by ELISA. The results revealed that the melatonin concentrations were significantly lower in the patients with OSCC compared with the controls (18.2 vs. 47.6 pg/ml, P<0.001). In addition, the serum melatonin levels had a high predictive accuracy for discriminating patients with OSCC with T-depth of invasion (DOI) II from the healthy controls (89.1%), as well as in discriminating patients with OSCC with nodal metastasis from those without nodal metastasis (83.8%). On the whole, the findings of this study suggest that the serum melatonin concentrations are closely related to the severity of OSCC and may thus be used to assess the different stages of oral cancer objectively and accurately. The present study also supports the conclusion that melatonin may be a potential therapeutic agent for use in the treatment of patients with OSCC.

Adverse and hormetic effects in rats exposed for 12 months to low dose mixture of 13 chemicals: RLRS part III.

The aim of the current study was to evaluate the effects of a mixture of thirteen common chemicals on rats, after a one-year exposure to doses around the acceptable daily intake (ADIs), using blood and urinary tests. The influence of low doses of the mixture on weight gain, water consumption, feed consumption and feed efficiency, biochemistry parameters, haematological parameters, blood lymphocytes subsets, serum inflammation profile and urine parameters was evaluated. Our mixture caused a moderate monotonic increase of the males' appetite and a non-monotonic increase of anabolism and a monotonic increase of appetite for the females. Regarding biochemical parameters, the exposure to the test mixture caused non-monotonic increases of AST and ALT, a decrease of PChE in males and plausibly a monotonic biliary obstruction in both sexes. Monocytes significantly increased in low dose groups of both sexes. A significant decrease of all the lymphocytes subclasses and an increased expression of TNF-α protein associated with an increased expression of IFN-γ protein observed in various groups. It became apparent that after twelve months of exposure very low doses of the tested mixture had both non-monotonic and monotonic harmful effects on different levels on rats.

Cardiovascular risk assessment in osteoporotic patients using osteoprotegerin as a reliable predictive biochemical marker.

Osteoprotegerin (OPG), a member of the tumour necrosis factor receptor (TNFR) superfamily of proteins known to be involved in a large number of biological systems, plays a pivotal role in bone remodelling. In addition to the roles of OPG in bone metabolism, it has been reported to be associated with a high cardiovascular risk in patients with metabolic syndrome. In most cases, the exact functions of OPG remain to be established; however, the widespread expression of OPG suggests that this molecule may have multiple biological activities, mainly in the cardiometabolic environment. The aim of this study was to evaluate the value of OPG as a predictive marker for cardiovascular and metabolic risk in osteoporotic patients. The study group comprised patients with osteoporosis, in order to evaluate the association between OPG serum levels and cardiovascular pathology. Our results revealed significant correlations between classical biochemical bone and metabolic parameters, such as osteocalcin and parathyroid hormone with lipid and glucose biomarkers, sustaining the crosstalk between calcium and bone parameters and cardiovascular risk. The OPG serum level proved to have a significant and independent predictive value for metabolic syndrome (MetS) as a cardiovascular risk standard in osteoporotic patients. The OPG serum levels were increased in patients with MetS as a protective response against the atherosclerotic lesions. The serum levels of 25­hydroxy vitamin D had significant and independent predictive value for cardiovascular and metabolic risk in our subjects, sustaining the active role of vitamin D beyond the area of bone metabolism.

Antimicrobial resistance development following surgical site infections.

Surgical site infections (SSIs) determine an increase in hospitalization time and antibiotic therapy costs. The aim of this study was to identify the germs involved in SSIs in patients from the Clinical Emergency County Hospital of Craiova (SCJUC) and to assess their resistance to antimicrobials, with comparisons between surgical wards and the intensive care unit (ICU). The biological samples were subjected to classical bacteriological diagnostics. Antibiotic resistance was tested by disc diffusion. We used hierarchical clustering as a method to group the isolates based upon the antibiotic resistance profile. The most prevalent bacterial species isolated were Staphylococcus aureus (S. aureus; 50.72%), followed by Escherichia coli (E. coli; 17.22%) and Pseudomonas aeruginosa; 10.05%). In addition, at lower percentages, we isolated glucose-non-fermenting, Gram-negative bacteria and other Enterobacteriaceae. The antibiotic resistance varied greatly between species; the most resistant were the non-fermenting Gram­negative rods. E. coli exhibited lower resistance to third generation cephalosporins, quinolones and carbapenems. By contrast, Klebsiella was resistant to many cephalosporins and penicillins, and to a certain extent to carbapenems due to carbapenemase production. The non-fermenting bacteria were highly resistant to antibiotics, but were generally sensitive to colistin. S. aureus was resistant to ceftriaxone (100%), penicillin (91.36%), amoxicillin/clavulanate (87.50%), amikacin (80.00%) and was sensitive to levofloxacin, doxycycline, gentamycin, tigecycline and teicoplanin. The Enterobacteriaceae resistance was only slightly higher in the ICU, particularly to carbapenems (imipenem, 31.20% in the ICU vs. 14.30% in the surgical wards; risk ratio = 2.182). As regards Staphylococcus species, but for non-fermenting bacteria, even if the median was almost the same, the antibiotic resistance index values were confined to the upper limit in the ICU. The data gathered from this study may help infection control teams to establish effective guidelines for antibiotic therapies in various surgical procedures, in order to minimize the risk of developing SSIs by the efficient application of the anti-infection armamentarium.

Behavioral and molecular effects of prenatal continuous light exposure in the adult rat.

Disruption of the maternal environment during pregnancy leads to behavioral changes and diseases in the adult offspring. To explore the influence of prenatal continuous light exposure (PCLE) on the adult offspring, we exposed pregnant Wistar rats to constant light during late gestation. Adult PCLE offspring showed an anxiety-like behavior and impairment of short-term memory in different tests. Measurements in the whole brain homogenates from newborn and adult offspring indicated decreased melatonin and serotonin levels and increased reactive oxygen species level in PCLE offspring. Further, we determined melatonin-, serotonin-, oxidative stress-, apoptosis-, and circadian system-related genes expression in different brain areas of adult offspring. The serotonin reuptaker Slc6a4 displayed a decreased expression in the prefrontal cortex of PCLE group. The circadian rhythm-related gene Rora was upregulated in the amygdala of PCLE offspring. Our results point to adverse behavioral effects of PCLE on adult offspring, involving serotonin and melatonin signaling dysregulation, increased chronic oxidative stress, and altered gene expression.

Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-kappaB in acute myeloid leukemia-derived predendritic KG-1 cells.

The leukemic cell line KG-1 was isolated from a patient with acute myeloid leukemia and is regarded a cellular model of human dendritic cell progenitors. The T helper type 1 cytokine interleukin (IL)-18 has been shown to induce the maturation of these cells towards a dendritic phenotype and, moreover, is able to mediate IFNgamma production in this model. Because T-box expressed in T cells (T-bet) is considered to be of paramount importance for dendritic cell function, the effects of IL-18 on this transcription factor have been investigated in the current study. Here, we show that activation of KG-1 cells by IL-18 induces T-bet mRNA and protein within 4 to 6 h of incubation. This hitherto unrecognized function of IL-18 was suppressed by the inhibition of p38 mitogen-activated protein kinase activity and nuclear factor-kappaB function. Blockage of translation by cycloheximide, usage of neutralizing antibodies, and the inability of IFNgamma to mediate significant p38 mitogen-activated protein kinase activation in KG-1 cells clearly revealed that activation of T-bet was not via autocrine IFNgamma. T-bet function was evaluated by short interfering RNA technology. Notably, specific suppression of T-bet induction impaired secretion of IFNgamma by KG-1 cells under the influence of IL-18. Therapeutic application of IL-18 has the potential to profoundly affect the biology of acute myeloid leukemia predendritic cells such as KG-1 cells. Under these conditions, activation of T-bet may play a key role in processes that have the potential to correct the T helper type 1 deficiency associated with leukemia-mediated immunosuppression.

[Canine tooth transposition study on a group of patients orthodontically treated]. / Studiu clinico-statistic despre transpozitia caninului pe un lot de pacienti tratati ortodontic.

The dental transposition is an eruption anomaly, which occurs in this process towards the final stage and that represents the switching of 2 teeth that are next to each other. The tooth that most often is involved in transposition is the canine tooth, most frequently the upper one, which switches places either with the first premolar either with the lateral incisor. Under a clinical aspect, the transposition can be total (complete) or partial (incomplete), the latter reported both for crowns and roots. The clinical manifestation of the anomaly imposes the characteristic signs and the individualized therapeutical attitude. The dental transposition must be differentiated within the eruption anomalies from the transmigration, which defines the displacement of a tooth inside the bone beyond the median line, this tooth usually being the lower canine. Our study, which was conducted on a small group of 34 patients, shows the results of the analysis of the anomaly versus the gender, the type of the transposition, the affected maxillary etc.