Interactions between Cognitive, Affective, and Respiratory Profiles in Chronic Respiratory Disorders: A Cluster Analysis Approach.

This study conducted at Leamna Pulmonology Hospital investigated the interrelations among cognitive, affective, and respiratory variables within a cohort of 100 patients diagnosed with chronic respiratory conditions, utilizing sophisticated machine learning-based clustering techniques. Spanning from October 2022 to February 2023, hospitalized individuals confirmed to have asthma or COPD underwent extensive evaluations using standardized instruments such as the mMRC scale, the CAT test, and spirometry. Complementary cognitive and affective assessments were performed employing the MMSE, MoCA, and the Hamilton Anxiety and Depression Scale, furnishing a holistic view of patient health statuses. The analysis delineated three distinct clusters: Moderate Cognitive Respiratory, Severe Cognitive Respiratory, and Stable Cognitive Respiratory, each characterized by unique profiles that underscore the necessity for tailored therapeutic strategies. These clusters exhibited significant correlations between the severity of respiratory symptoms and their effects on cognitive and affective conditions. The results highlight the benefits of an integrated treatment approach for COPD and asthma, which is personalized based on the intricate patterns identified through clustering. Such a strategy promises to enhance the management of these diseases, potentially elevating the quality of life and everyday functionality of the patients. These findings advocate for treatment customization according to the specific interplays among cognitive, affective, and respiratory dimensions, presenting substantial prospects for clinical advancement and pioneering new avenues for research in the domain of chronic respiratory disease management.

Digging in real-word electronic database for assessing CDK 4/6 inhibitors adherence in breast cancer patients from Romania.

Introduction: It is imperative for patients to respect the prescribed treatments to achieve the anticipated clinical outcomes, including the outpatients receiving oral anti-cancer drugs such as selective cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). With the introduction of three CDK 4/6i drugs in the Romanian pharmaceutical market in 2018, our study aimed to evaluate medication adherence and the influencing factors among patients undergoing treatment with palbociclib, ribociclib, or abemaciclib for advanced or metastatic breast cancer. Methods: Medication adherence was assessed using the Proportion of Days Covered (PDC) method, and Spearman correlation analysis was conducted to explore the relationships between adherence, age, gender, and follow-up duration. Results: The study enrolled 330 breast cancer patients, with an average follow-up period of 14.6 ± 12.5 months for palbociclib, 10.6 ± 7.1 months for ribociclib, and 8.6 ± 6.4 months for abemaciclib-treated patients. A small proportion of patients demonstrated non-adherence: 12.8% for palbociclib, 14.6% for ribociclib, and 14.7% for abemaciclib. Among patients receiving palbociclib, there was no significant correlation between adherence, age (rho = 0.07, p = 0.35), or gender (rho = -0.144, p = 0.054). However, a significant correlation was found with the duration of follow-up (rho = -0.304, p < 0.0001). Similar results were observed for patients receiving ribociclib or abemaciclib. Most patients received combination therapy with letrozole (46%) and exemestane (13%) for palbociclib, letrozole (48%) and fulvestrant (19%) for ribociclib, and fulvestrant (39%) and letrozole (27%) for abemaciclib, Discussion: High adherence rates were observed among patients treated with CDK 4/6i drugs, with no significant differences noted among the three drugs in this class. However, the collected patient data was limited, lacking information on adverse reactions that could potentially lead to treatment discontinuation, as determined by the oncologist's decision not to prescribe. Consequently, a comprehensive understanding of all factors contributing to the low adherence levels is hindered.

Epigenetics of Ageing and Psychiatric Disorders.

Both classic epigenetic modifications and microRNAs can impact a range of bodily processes, from metabolism to brain function, and may contribute to the development of diseases such as cancer, cardiovascular disorders, and psychiatric disorders. Numerous studies suggest a connection between epigenetic changes and mood disorders. In this study, we performed a comprehensive search using PubMed and Google for the terms "epigenetics", "ageing", "miRNA", "schizophrenia", and "mood disorders" in the titles and abstracts of articles. Epigenetic changes during early life may play a crucial role in triggering severe mental disorders and shaping their clinical trajectory. Although these alterations can take place at any age, their impact may not be immediately evident or observable until later in life. Epigenetic modifications play a crucial role in the ageing process and challenge the prevailing belief that mutations are the primary driver of ageing. However, it is plausible that these epigenetic changes are a consequence of the disorder rather than its root cause. Moreover, both the disorder and the epigenetic alterations may be influenced by shared environmental or genetic factors. In the near future, we might be able to replace chronological age with biological age, based on the epigenetic clock, with the promise of providing greater therapeutic benefits. A wide range of epigenetic drugs are currently under development at various stages. Although their full effectiveness is yet to be realized, they show great potential in the treatment of cancer, psychiatric disorders, and other complex diseases.

Cerebrolysin Use in Patients with Liver Damage-A Translational Study.

The treatment of acute life-threatening events in patients suffering from chronic pathologies is problematic, as physicians need to consider multisystemic drug effects. Regarding Cerebrolysin, a Sonic Hedgehog signaling pathway amplifier and one of the few approved neurotrophic treatments for stroke patients, concerns of excessive Hedgehog pathway activation that could accelerate NAFLD progression to cirrhosis seem valid. We investigated stroke patients treated with Cerebrolysin that presented elevated levels of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT). We also investigated the efficiency of Cerebrolysin in reversing the neurogenesis inhibition within the hippocampus in a mouse model of NAFLD by evaluating behavior and histological outcomes. NeuN, BrdU and Iba1 positive signals in the cortex and hippocampus of the animals were also observed. Clinically, Cerebrolysin improved AST levels in a majority of stroke patients with hepatic damage. The same treatment in an experimental setup was able to reverse anxiety-like behavior in MCD mice, reducing their freezing time from 333.61 ± 21.81 s in MCD animals to 229.17 ± 26.28 in treated ones. The use of Cerebrolysin did not improve short-term memory nor rescued cell multiplication in the hippocampus after MCD food intake. Understanding the neuroprotective and neurotrophic effects that drugs have on NAFLD patients can significantly contribute to a suitable therapeutic approach.

Therapeutic Use and Chronic Abuse of CNS Stimulants and Anabolic Drugs.

The available evidence suggests that affective disorders, such as depression and anxiety, increase risk for accelerated cognitive decline and late-life dementia in aging individuals. Behavioral neuropsychology studies also showed that cognitive decline is a central feature of aging impacting the quality of life. Motor deficits are common after traumatic brain injuries and stroke, affect subjective well-being, and are linked with reduced quality of life. Currently, restorative therapies that target the brain directly to restore cognitive and motor tasks in aging and disease are available. However, the very same drugs used for therapeutic purposes are employed by athletes as stimulants either to increase performance for fame and financial rewards or as recreational drugs. Unfortunately, most of these drugs have severe side effects and pose a serious threat to the health of athletes. The use of performance-enhancing drugs by children and teenagers has increased tremendously due to the decrease in the age of players in competitive sports and the availability of various stimulants in many forms and shapes. Thus, doping may cause serious health-threatening conditions including, infertility, subdural hematomas, liver and kidney dysfunction, peripheral edema, cardiac hypertrophy, myocardial ischemia, thrombosis, and cardiovascular disease. In this review, we focus on the impact of doping on psychopathological disorders, cognition, and depression. Occasionally, we also refer to chronic use of therapeutic drugs to increase physical performance and highlight the underlying mechanisms. We conclude that raising awareness on the health risks of doping in sport for all shall promote an increased awareness for healthy lifestyles across all generations.

Identification of transcriptome alterations in the prefrontal cortex, hippocampus, amygdala and hippocampus of suicide victims.

Suicide is one of the leading causes of death globally for all ages, and as such presents a very serious problem for clinicians worldwide. However, the underlying neurobiological pathology remains to a large extent unknown. In order to address this gap, we have carried out a genome-wide investigation of the gene expression in the amygdala, hippocampus, prefrontal cortex and thalamus in post-mortem brain samples obtained from 20 suicide completers and 7 control subjects. By KEGG enrichment analysis indicated we identified novel clusters of downregulated pathways involved in antigen neutralization and autoimmune thyroid disease (amygdala, thalamus), decreased axonal plasticity in the hippocampus. Two upregulated pathways were involved in neuronal death in the hippocampus and olfactory transduction in the thalamus and the prefrontal cortex. Autoimmune thyroid disease pathway was downregulated only in females. Metabolic pathways involved in Notch signaling amino acid metabolism and unsaturated lipid synthesis were thalamus-specific. Suicide-associated changes in the expression of several genes and pseudogenes that point to various functional mechanisms possibly implicated in the pathology of suicide. Two genes (SNORA13 and RNU4-2) involved in RNA processing were common to all brain regions analyzed. Most of the identified gene expression changes were related to region-specific dysregulated manifestation of genetic and epigenetic mechanisms underlying neurodevelopmental disorders (SNORD114-10, SUSd1), motivation, addiction and motor disorders (CHRNA6), long-term depression (RAB3B), stress response, major depression and schizophrenia (GFAP), signal transduction at the neurovascular unit (NEXN) and inhibitory neurotransmission in spatial learning, neural plasticity (CALB2; CLIC6, ENPP1). Some of the differentially expressed genes were brain specific non-coding RNAs involved in the regulation of translation (SNORA13). One, (PARM1) is a potential oncogene and prognostic biomarker for colorectal cancer with no known function in the brain. Disturbed gene expression involved in antigen neutralization, autoimmunity, neural plasticity, stress response, signal transduction at the neurovascular unit, dysregulated nuclear RNA processing and translation and epigenetic imprinting signatures is associated with suicide and point to regulatory non-coding RNAs as potential targets of new drugs development.

Diagnostic and prognostic significance of hepatic steatosis in patients with chronic hepatitis C.

Knowing that hepatic steatosis (HS) is a common occurrence in patients with chronic hepatitis C (CHC), it is essential to establish what are the factors that predispose to its occurrence and what is the role of HS in the evolution and prognosis of patients with CHC who develop this feature. To achieve these aims, we performed a retrospective clinical study in 33 patients with CHC hospitalized, diagnosed, and monitored in the 2nd Medical Department of the Emergency County Hospital, Craiova, Romania, in a period of two years (2011-2012). Following clinical, hematological, biochemical, immunological, and pathological investigations of the 33 patients with CHC selected, only 14 patients showed pathological changes of the HS. The appearance of steatosis in patients with CHC results from a complex interaction between the particularities of the host and viral factors. The main risk factors of the host, which contributed to the appearance of HS were sex, age, body mass index (BMI), body weight, and personal history of pathology (obesity, metabolic syndrome). Virus-related factors involved in HS were viremia and viral genotype. In conclusion, HS is a common finding (42.42%) in patients with CHC, particularly genotypes 1 and 2. Early detection of HS by invasive or non-invasive methods is an important objective of monitoring patients with CHC, because HS is correlated with a high degree of fibrosis. Therefore, early correction of metabolic factors and early introduction of antiviral therapy are important targets for treating of patients with CHC.

Association between genetic variants and depression in a Romanian cohort.

Major depressive disorder (MDD) is beyond doubt a common, disabling, and costly condition. MDD associates hypothalamic-pituitary-adrenal (HPA) axis alterations. We sought to investigate two candidate variants which could have a role in the genetic susceptibility for stress or corticoid-induced MDD: glucocorticoid receptor (GR) - nuclear receptor subfamily 3 group C member 1 (NR3C1) rs41423247 and brain-derived neurotrophic factor rs6265 BDNF:c.442G>A Val66Met. We enrolled 82 Romanian subjects, 1:2 male to female ratio, 53.54±8.98 years old, diagnosed with an episode of major depression at the Clinical Neuropsychiatry Hospital in Craiova, Romania, and 286 healthy controls, 34.28±16.34 years old. All subjects were genotyped using specific ThermoFisher Scientific assays on a ViiA™ 7 real-time polymerase chain reaction (PCR) system. The impact of certain genetic variants may be ethnic-specific. In our Romanian cohort, rs41423247 NR3C1:c.1184+646C>G has a minor allele frequency of 29.2%, and rs6265 BDNF:c.442G>A of 22.2%. Neither reached significance in our study, under any of the association models - dominant, recessive, or allelic. Interpretation of our negative findings requires caution: literature provides arguably more evidence for the association between the analyzed polymorphisms; our study has sample size challenges, from which refined phenotyping limitations derive.

The Influence of Covid-19 Infection on Neurocognitive Disorders.

Neurocognitive disorders are a group of disorders characterized by an impaired cognition which has not been present since birth or very early life and represents a decline from a previous attained level of functioning. The case we studied is M.E., a 62 years female, married, from rural area, working as a tailor, without any psychiatric history. She develops psychiatric symptoms during Covid-19 infection and treatment, in November 2020. The patient has been admitted in psychiatric care, in that time, for about one month, for a persistent confusion state during and after this event. These symptoms diminish the patient's level of functioning and seemed to be related with the Covid-19 infection or treatment. Psychological investigation underlines a MMSE 14, severe impairment in attention, short-term and long-term memory. CT evaluation presents normal relation except a moderate general atrophy, according with patient's age. Differential diagnosis will be discussed. The treatment has proven its effectiveness, the patient regaining her ability to orientate, could do housework, good improvement in attention and short-term memory. We emphasize that there is correlation between the Covid-19 infection and confusive state and delirium in patients, as a comorbidity, followed in many cases by chronic progressive neurocognitive disorder, especially in elderly.

TSH and T4 Levels in a Cohort of Depressive Patients.

Depression is a significant contributor to the overall burden of disease on a global scale. Thyroid hormones thyroxine (T4) and triiodothyronine (T3) have been shown to play a critical role in the development and normal function of the brain. It has been suggested that dysregulation of thyroid function could be associated with depression, especially hypothyroidism, but not all studies support this hypothesis. We enrolled a cohort of 96 subjects with major depressive disorder and tested TSH and FT4 levels for 80 of them in order to assess the status of the hypothalamic-pituitary-thyroid axis (HPT). We found 7 cases (8.75% of the tested) of subclinical hyperthyroidism and 1 case (1.25%) of overt hyperthyroidism. While we did not find supporting evidence for association between TSH and FT4 levels and depression, our findings question whether screening depressive patients for HPT axis anomalies could be clinically relevant, if anything, in a regional context.

Circulating Cortisol in a Cohort of Depressive Patients.

It has long been suspected that the hypothalamic pituitary adrenal (HPA) axis plays a role in the pathophysiology of depression. Whether this association exists or not, and if it does, the degree of its significance, remain highly disputed. The issue is further complicated as no consensus currently exists on cortisol sampling timepoints or methods. Our study aimed to evaluate HPA functionality by evaluating plasma cortisol levels in a cohort of patients diagnosed with Major Depressive Disorder (MDD). We enrolled 96 subjects admitted for a major depressive episode and tested serum cortisol levels for 80 of them. We found that only 15 (12%) had values that were outside the normal reference range, with 14 of these being below the normal threshold. We also interviewed the patients and obtained self-reported information regarding previous depressive episodes, treatment administration, anxiety, suicidal ideas and suicidal gestures. Our study did not find a significant association between cortisol levels and the number of previous depressive episodes, the presence of feelings of anxiety, suicidal ideas or suicidal gestures. While our cohort did not find an association between cortisol levels and depression other authors have reported significantly different results and as such, more research is needed in order to establish or infirm this hypothesis.

Long-term treatment with spermidine increases health span of middle-aged Sprague-Dawley male rats.

Let alone calorie restriction, life span extension in higher organisms has proven to be difficult to achieve using simple drugs. Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. However, younger subjects (< 40 years of age) are infrequently prescribed nor self-medicating with antiaging drugs. Therefore, in the present study, we aimed at assessing the effect of long-term treatment with spermidine given in the drinking water on behavioral performance and longevity of male, middle-aged Sprague-Dawley rats. We report that spermidine given in the drinking water did not extend neither the median nor the maximum life span of the middle-aged male Sprague-Dawley rats. However, spermidine treatment had a beneficial effect on the body weight and the kidney tubules, liver, and heart morphology. Behaviorally, spermidine led to a reduction in anxiety and an increase in curiosity, as assessed by exploratory behavior. Moreover, long-term treatment with spermidine enhanced autophagy in the brain and led to a diminished expression of the inflammatory markers, Tgfb, CD11b, Fcgr1, Stat1, CR3, and GFAP mRNAs in several cortical region and hippocampus of the treated rats suggesting that one beneficial effect of the long-term treatment with spermidine is an attenuated proinflammatory state in the aged brain. Our results suggest that long-term treatment with spermidine increases health span of middle-aged rats by attenuating neuroinflammation and improving anxiety and exploratory behavior.

Hepatic pathological features in naïve patients with chronic hepatitis C who have developed thyroid disorder.

Knowing the hepatic pathological features encountered in patients with chronic hepatitis C (CHC) and the fact that extrahepatic manifestations occur only in people with certain characteristics of the immune system, we tried to evaluate, qualitatively and semi-quantitatively, the liver pathological aspects encountered in 96 patients with CHC, previously untreated with Interferon (naïve), who showed or did not show signs of thyroid disorder (TD), hospitalized in the 2nd Medical Clinic of the Emergency County Hospital, Craiova, Romania, within a period of five years (2007-2012). Following hormonal, immunological, and thyroid ultrasound investigations, 14 (14.58%) of the 96 patients showed signs of TD. The main clinical forms of TD in the studied patients with CHC were autoimmune thyroiditis and subclinical hypothyroidism. In the patients with CHC with TD, we found mild chronic hepatitis in 14.28% of cases, the appearance of moderate chronic hepatitis was found in 71.42% patients, and the appearance of severe chronic hepatitis was found in 14.28% patients, while in the patients with CHC without TD we found chronic mild hepatitis in 62.19% of cases, the appearance of moderate chronic hepatitis was met in 32.92% patients, and the appearance of severe chronic hepatitis was found in 4.87% of patients. Mild and moderate fibrosis were found only in CHC patients without TD in a percentage of 25.6% and 65.85%, respectively, while severe fibrosis was found at 12.19% among CHC patients without TD and 92.85% among CHC patients with TD. The pathological aspect of liver cirrhosis was found only in those with TD (7.14%). In conclusion, the pathological features which define the liver necroinflammatory process, as encountered at the pathological examination in CHC patients with TD are the same as in any active chronic hepatitis, the differences being represented by the higher percentage of the periportal and the preseptal necrosis (piecemeal necrosis), as well as by the higher score of portal inflammation. In addition, the severe hepatic fibrosis and the histopathological appearance of the liver cirrhosis have only defined the cases of CHC with TD.

Multidisciplinary approach to patients with manifestations and pulmonary complications of cystic fibrosis.

Cystic fibrosis (CF) is a genetic disease, with autosomal recessive transmission, multisystemic, characterized by a remarkable clinical polymorphism and significant lethal prospective. Respiratory manifestations dominate the clinical picture, being present in all patients. The aim of the paper was to analyze the incidence of clinical manifestations, especially respiratory ones, as well as the contribution of interdisciplinary consultations to the positive diagnosis of CF, in a group of 16 patients who were hospitalized and treated in the IInd Pediatric Clinic and IInd Medical Clinic of the Emergency County Hospital, Craiova, Romania, in a period of 20 years. The 16 patients diagnosed with and treated of CF had all shown increased values of sweat chloride concentration of over 60 mmol∕L. The main symptoms and clinical signs encountered in these patients were cough (75%), sputum (62.5%), dyspnea (50%), wheezing (50%), stature hypotrophy (100%), pallor (37.5%), cyanosis (25%). All 16 patients had an acute exacerbation of chronic pulmonary disease. Of the total hospitalizations, the death was recorded only in the case of one female patient. The association of some clinical aspects specific with a positive result of the sweat test or the presence of the two pathological alleles made room for determining a positive diagnosis. The multisystemic nature of this disease requires a multidisciplinary approach to these patients. Histopathologically, there was a correspondence between lung morphological lesions and the results of imaging investigations.

Very Low Efficiency of Direct Reprogramming of Astrocytes Into Neurons in the Brains of Young and Aged Mice After Cerebral Ischemia.

After cerebral ischemia, the ratio between astroglial cells and neurons in the neurovascular unit is disrupted in the perilesional area. We hypothesized that restoring the balance within the neurovascular unit may lead to an improved neurorestoration after focal ischemia. Recently, an innovative technology has been invented to efficiently convert proliferating astroglial cells into neurons in the injured young brain. However, the conversion efficacy of this technology has not been explored in the post-stroke brains of the aged rodents. To this end, we used a retroviral delivery system encoding the transcription factor Ngn2 alone or in combination with the antiapoptotic factor Bcl-2 to target proliferating astrocytes in the neocortex of young and aged mice after cerebral ischemia. Successful direct in vivo reprogramming of reactive glia into neuroblasts and mature neurons was assessed by cellular phenotyping. We found that the conversion efficacy of proliferating astrocytes into neurons after cerebral ischemia in young and aged mice is disappointingly low, most likely because the therapeutic vectors carrying the conversion gene are engulfed by phagocytes shortly after intracortical administration. We conclude that other viral vectors and combinations of transcription factors should be employed to improve the efficacy of glia-to-neuron conversion after stroke in young and aged rodents.

Clinical and biological outcomes of prolonged treatment with haloperidol in schizophrenia.

Paranoid schizophrenia with long-term course is a challenge for the clinical and therapeutic research, particularly because chronic course is difficult to identify due to the high rate of mortality in this category of patients. The therapeutic stability on an antipsychotic molecule (haloperidol) is indeed an exception, since the current trend in the case of unfavorable course is based on therapeutic versatility and polypharmacy. Haloperidol is the first-generation antipsychotic that is referred in the therapeutic guidelines as the "golden standard" regarding its efficacy on positive symptoms. The research in fundamental and molecular psychopharmacology has shown the aggressivity of this molecule on the secondary and tertiary signaling chains, including mitochondrial alterations. On male patients with paranoid schizophrenia (positive symptoms) and a chronic course of more than 35 years who received exclusively haloperidol, our study demonstrated an negative outcome with the loss of social functioning, persistence of positive symptoms, chronic extrapyramidal symptoms and mild cognitive impairment. The neuroimaging evaluations have shown atrophy in the temporal poles, posterior ventriculomegaly, cerebellar atrophy and calcification on choroid plexus and pineal gland. The difference between the histological changes induced by haloperidol on animal model and the ones on the patients in our study is located in the frontal cortex, thus suggesting the presence of two neurobiological models of schizophrenia in men: fronto-striatal and temporal-limbic-striatal. The persistence of extrapyramidal symptoms during the treatment with haloperidol may be considered as a clinical marker of the risk for negative outcome and a potential indication for the therapeutic switch.

The microvascular alterations in frontal cortex during treatment with antipsychotics: a post-mortem study.

INTRODUCTION: Schizophrenia is the most severe psychiatric illness, with a biological support in the brain. There is evidence that the adequate dopamine balance in the frontal cortex is associated with a better outcome of the disorder, while the alteration of dopamine mechanism at this level may affect the vascular system leading to secondary neuronal alterations. Our study was conducted post-mortem and its objective was to identify the alterations in the neuronal architecture, in the integrity of the microvascular unit in the frontal cortex of patients treated with potent and excessive D2-blocking antipsychotics. MATERIALS AND METHODS: We studied post-mortem sections of the frontal cortex of three patients (two women and one man) diagnosed with schizophrenia or schizophrenia-spectrum disorders and treated with antipsychotics for the last 24 months. The slides were prepared according to the classical histopathological protocols. RESULTS: Various alterations were found at the neural and vascular levels in the frontal cortex. The most significant was the neural loss as the result of severe changes in the microvessels (diameter reduction, hyaline and collagen deposits, edema, pinocytosis and vacuolization). DISCUSSION: The evidences shown in our study highlight the fact that antipsychotics with potent antagonist action on D2 receptors may affect the neurovascular unit and small vessels in frontal cortex by altering the balance vasoconstriction-vasodilatation, thus reducing the blood flow and metabolism and generating structural microvascular changes proportional with the level of apoptosis at this level. The functional integrity of the dopaminergic system in frontal cortex depends on the vascular support and the capabilities of the neurovascular unit and any dysfunction increases the neuronal loss with clinically significant changes. CONCLUSIONS: The pathological data of our study raises the hypothesis for the pathogenic stages at the level of microvessels in the frontal cortex of the patients with schizophrenia or schizophrenia-spectrum disorders treated with D2-blocking antipsychotics: a stage with functional, reversible alterations that may be correlated with the impairments of working memory and presence of extrapyramidal symptoms and a lesional, irreversible stage with significant deterioration of cognition and global functioning. Further studies are needed to verify this hypothesis.