Effects of Age-Dependent Hormonal Changes and Estrogen Supplementation on Voice in Girls with Anorexia Nervosa-Preliminary Report.

INTRODUCTION: Human development includes lots of physical and emotional changes. The human voice depends on age. Voice production is a complex physiological and acoustic phenomenon that depends on many factors such as structure, hormone level, degree of fatigue or nutrition and hydration of the body, systemic diseases, and emotional state. All these factors can be present in anorexia nervosa (AN), such as excessive weight loss, generated hydro-electrolytic changes, nutritional deficiencies, hormonal disturbances in the function of the hypothalamic-pituitary-adrenal axis, the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-ovarian axis, and emotional distress. The prevalence of AN ranges between 0.3% and 3%, and it is the third most common chronic disease affecting adolescent girls. However, voice changes related to AN have not been fully investigated. OBJECTIVE: The purpose of this study was to evaluate the impact of AN on age-related changes in the voice of adolescent women-before and after puberty, particularly through acoustic analysis. An additional objective was to evaluate estrogen substitution in female patients with AN in order to investigate their effect on voice condition. MATERIALS AND METHODS: 126 girls diagnosed with AN (15.32 ± 2.12 years, range 12-19, BMI = 14.38 ± 1.67), were assessed for the condition of the voice such as perceptual voice evaluation on the GRBAS scale, maximal phonation time (MPT), laryngoscopy, with special attention to voice acoustic analysis-Multi-Dimensional Voice Program (MDVP). The control group (B) included 93 girls without eating disturbances (aged 12-19, mean age 15.52 ± 2.40, BMI = 21.50 ± 1.54). Perceptual voice assessment, aerodynamic test MPT, and acoustic parameters were analyzed in age groups (≤16 years and >16 years). The human vocal tract is sensitive to sex hormones, so the analysis was carried out in the group up to the age of 16 and above 16 to check possible effects. RESULTS: GRBAS scale was higher in girls with AN compared to the control group for breathiness (B) (P = 0.0002) and asthenia (A) (P < 0.05). The median GRBAS scale for the older group of anorexic women was the highest (2.0). The mean MPT for group A was significantly lower (15.40 ± 3.51 seconds). Comparing age subgroups there was a prolongation of MPT in the healthy group (in groups ≤16 years and >16 years respectively 21.13 seconds versus 25.40 seconds) and a shortening in the anorectic group (≤16 years versus >16 years: 17.06 seconds versus 14.17 seconds). There was no difference between groups A and C up to 16 years of age, but above 16 years of age appeared (14.17 seconds versus 25.40 seconds). Acoustic analysis revealed lower F0 values in group A and C in older subgroups (215,85 Hz versus 236,01 Hz-statistically significant), as well as between subgroups both groups (A: 251,38 Hz versus 215,85 Hz; C: 248,20 Hz versus 236,01 Hz). A narrowing of the vocal range in girls over 16 years in group A was observed. There were no statistically significant differences in F0 between subgroups ≤16 years in groups A and C (251.38 Hz versus 248.20 Hz). The ENT study found that more than half of the girls (54.55%) over the age of 16 who took hormone supplementation manifested laryngeal structure that was normal for their age, there was no effect of hormone supplementation on any of the MDVP parameters between the drug-taking and non-drug-taking groups. CONCLUSIONS: The acoustic results of the voice in MDVP measurements in adolescent women with AN are not within the normal range and do not mimic the normal developmental changes of the voice. The most important acoustic characteristics of the voice are changes in the fundamental frequency F0 and the range of the voice tended to be more severe in anorectic women >16 years of age and to increase with age, indicating a possible cumulative effect of malnutrition-related disorders as well as hormonal dysfunctions. MDVP can be considered a simple, non-invasive method of assessing the voice organ in AN. MPT differentiated the study groups well: statistically significant differences were noted both between the groups, as well as between age groups. There was no significant effect of oral hormone supplementation on any parameters of the voice. In conclusion, body mass and fat volume in AN may be related to voice production/physiology, affecting voice quality, voice acoustic parameters, voice aerodynamics, and phonatory range in an age-dependent manner. Future studies are needed to assess the long-term efficacy of estrogen treatment in AN.

Bruns syndrome in a patient with intraventricular subependymoma: a case report.

Purpose: Subependymoma is a slow-growing benign brain neoplasm, classified by the World Health Organization (WHO) as a grade I tumor, which typically presents in middle-aged male adults. Case description: A case of Bruns syndrome and an intraventricular subependymoma in a 49-year-old patient who presented with intractable headache and vertigo is discussed in this paper. Imaging revealed a well-delimited cystic and solid mass near the lateral ventricle. Comment: Complete surgical excision of the tumor resulted in the restoration of normal cerebrospinal fluid pathway and resolution of clinical symptoms with no signs of tumor recurrence in the 4-year follow-up period.

Acoustics Features of Voice in Adolescent Females With Anorexia Nervosa.

INTRODUCTION: The process of human voice production is a complex physiological and acoustic phenomenon that depends on many structural, physical, and hormonal factors, systemic diseases as well as emotional states. All these factors can be present in eating disorders. However, studies on eating disorders and voice problems have usually been evaluated in terms of bulimia. Chronic starvation and emotional problems in the course of anorexia nervosa (AN) appear to be under-researched, despite various biochemical, metabolic, and hormonal changes. OBJECTIVE: The purpose of this study was to evaluate voice quality, specifically acoustic analysis, in adolescent female with AN from the point of view of the possible influence on the function and structure of the larynx, low body mass accompanying AN, as well as energy deficiency, hormonal and emotional disturbances. MATERIALS AND METHODS: A total of 84 girls diagnosed with AN (Gr.A) (15.32 years, SD = 2.12; range 12-19, BMI = 14.11 ± 1.72) were assessed for the condition of the voice such as perceptual voice evaluation on the GRBAS scale, maximal phonation time (MPT), laryngoscopy, with special attention to voice acoustic analysis - Multi-Dimensional Voice Program (MDVP). The control group (Gr.C) included 62 girls without eating disturbances (aged 12-19, mean age 15.41 ± 2.40, BMI = 21.60 ± 1.92). Perceptual voice assessment, aerodynamic test MPT, and acoustic parameters were analyzed according to girls' age. RESULTS: Total GRBAS scale was higher in girls with AN compared to the control group mainly for two parameters: breathiness (B) (P = 0.00015) and asthenia (A) (P < 0.05). The MPT for Gr.A was significantly shorter compared to Gr.C (15.40 ± 3.51 seconds vs. 23.19 ± 5.17 seconds) (P < 0.001), and a correlation of MPT values with the age of the adolescent female was observed: Spearman's coefficient for Gr.A = (-)0.5378, for Gr.C = 0.5516 (P = 0.0012). Acoustic analysis revealed the decrease in the basic frequency F0 in Gr.A compared to Gr.C (231.08 Hz vs. 242.30 Hz), and narrowing of the voice scale was observed, resulting mainly from a reduction in the upper limit. Significant differences were found for measures of frequency perturbations (Jita, Jitter, RPA, PPQ, sPPR), with Gr.A scoring significantly higher than Gr.C (P < 0.05 for all). Significant changes in voice acoustic analysis parameters were found with age. Negative correlations were found for measures of F0 for Gr.A to a much greater extent compared to Gr.C. Positive correlations were found with measures of tremor assessment (SPI, FTRI, ATRI) for Gr.A.

Arginase 1/2 Inhibitor OATD-02: From Discovery to First-in-man Setup in Cancer Immunotherapy.

Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with cancer. SIGNIFICANCE: We have developed an orally available, small-molecule intracellular arginase 1 and 2 inhibitor as a potential enhancer in cancer immunotherapy. Because of its favorable pharmacologic properties shown in nonclinical studies, OATD-02 abolishes tumor immunosuppression induced by both arginases, making it a promising drug candidate entering clinical trials.

Dietary effects on antiseizure drug metabolism and management of epilepsy.

In recent years, there has been growing interest in the influences of food-drug interactions on the metabolism of antiseizure medications (ASM) and the management of epilepsy. Studies have proven the effectiveness of the ketogenic diet (KD) in controlling refractory epilepsy. However, dietary interventions such as the KD or its variants may induce significant changes in serum drug concentrations which counteracts the anticonvulsive effects of ASMs, leading to an increased risk of developing seizures. Interactions with enzymes within the cytochrome P450 system may also explain the dietary influences on serum concentrations of antiseizure drugs. The bioavailability of ASMs is also affected by several foods and nutritional supplements. Nevertheless, more studies are warranted to explore the mechanisms underlying food-drug interactions and the risks and benefits of combined drug-diet therapy.

The alterations of cerebrospinal fluid TNF-alpha and TGF-beta2 levels in early relapsing-remitting multiple sclerosis.

AIM OF THE STUDY: This study aimed to analyze serum and cerebrospinal fluid (CSF) concentrations of proinflammatory and anti-inflammatory cytokines produced by T regulatory (Treg) cells in early RRMS according to the 2017 McDonald criteria. CLINICAL RATIONALE FOR THE STUDY: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with the cytokine network playing an important role. However, there is a continual lack of data regarding the immunopathogenesis of early RRMS, especially according to the 2017 McDonald criteria. MATERIALS AND METHODS: The study groups included early RRMS patients during relapse (n = 18), remission (n = 14), and the control group. The MS diagnosis was established according to the 2017 McDonald criteria. Patients were studied up to 1 year after diagnosis was made. A quantitative test kit based on ELISA was used for cytokine measurement in the serum and CSF. Comparative and correlation analyses between the levels of TNF-α, TGF-ß2, IgG index, and relapse duration were performed. RESULTS: Significantly higher CSF concentrations of TNF-α in both RRMS-relapse and RRMS-remission groups were found compared to the controls (p < 0.01). The CSF levels of TGF-ß2 in the RRMS-relapse group were significantly lower in comparison to the control group (p = 0.01). CONCLUSIONS AND CLINICAL IMPLICATIONS: An inappropriate inflammatory response seems to occur in early RRMS and includes the production of TNF-α and a decrease in TGF-ß2 release suggesting a significant Treg cells role. Further studies on the topic may contribute to developing new disease-modifying drugs and biochemical markers of the disorder.

Genetic diseases mimicking multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disorder manifesting as gradual or progressive loss of neurological functions. Most patients present with relapsing-remitting disease courses. Extensive research over recent decades has expounded our insights into the presentations and diagnostic features of MS. Groups of genetic diseases, CADASIL and leukodystrophies, for example, have been frequently misdiagnosed with MS due to some overlapping clinical and radiological features. The delayed identification of these diseases in late adulthood can lead to severe neurological complications. Herein we discuss genetic diseases that have the potential to mimic multiple sclerosis, with highlights on clinical identification and practicing pearls that may aid physicians in recognizing MS-mimics with genetic background in clinical settings.

Musical hallucinations in cerebrovascular disease.

Purpose: Musical hallucinations (MH) are a subset of complex auditory hallucinations in which individuals perceive music in the absence of an external auditory stimulus. It is a rare phenomenon, first described by Ballinger in 1846, with diverse presentations from familiar childhood melodies to a simple pitch which evolved into the harmonies Robert Schumann incorporated in his sole Violin Concerto. Views: This uncommon phenomenon has diverse etiologies, including psychiatric and neurological backgrounds, which guide its classification and methods of treatment. The pathophysiological basis of MH remains understood incompletely, potentially resulting from lesions anywhere along the auditory pathway, from the external auditory canal to the auditory cortex. The strong association between MH and hearing impairment has led researchers to hypothesize that MH represent a "release phenomenon," in which sensory deprivation, eliminating the afferent input to the auditory sensory network, instigates spontaneous activity within a system - comparable to the Charles Bonnet syndrome, in which visual impairment precipitates the development of visual hallucinations (so called auditory Charles Bonnet syndrome), and phantom limb syndrome, in which amputees experience sensations in a limb that is not no longer there. In this paper, we report on six cases of MH in patients with cerebrovascular disease, who presented to the neurology department at the Poznan University of Medical Sciences from 2015 to 2018. Conclusions: We discuss the findings of computed tomography and magnetic resonance imaging of six cases of MH in patients with cerebrovascular disease, and the treatment leading to its resolution. We briefly review the literature on MH in patients with cerebrovascular diseases, discussing their suggested pathophysiology, clinical presentations and response to medical treatment.

Subjective and Objective Assessments of Post-traumatic Olfactory Dysfunction.

Introduction: Traumatic brain injuries are the most common cause of olfactory dysfunction. Deficits in olfaction may be conductive or neurosensory in nature, with varying degrees of impairment resulting in a diminished quality of life and an increased risk for personal injury among patients. The aim of this research is to evaluate the results of the subjective and objective quantitative examinations of olfactory function in a group of patients with post-traumatic anosmia in order to predict its value in identifying olfactory deficits in clinical practice. Materials and Methods: The present study included 38 patients who reported anosmia or hyposmia caused by a traumatic head injury, and a group of 31 age- and sex-matched controls without olfactory dysfunction or prior history of head injury. The comparison of odor perception and identification of two oils (mint and anise) was assessed with the use of blast olfactometry with cortical olfactory event-related potentials. Results: Subjective olfactory tests revealed anosmia or hyposmia in 94% of patients with head injury-related olfactory dysfunction. Objective tests revealed olfactory event-related potentials from cranial nerve I produced by the stimulation with both mint and anise in 20 patients (52.6%). Olfactory event-related potentials from cranial nerve V produced by the stimulation with mint were registered in 26 patients (68.4%). The lack of any responses, from both cranial nerve I and V, was found in 12 patients (32% of cases). Conclusions: Findings from our study indicate the application of both subjective and objective examinations in the evaluation of patients with olfactory impairment. In the diagnosis of post-traumatic anosmia or hyposmia, objective examinations are particularly useful when the patients' level of cognition may be impaired or when subjects may be exaggerating their olfactory defects for a secondary gain. The diagnosis of damage to the olfactory system, specifically in the receptive part of the olfactory pathway, can be established in patients who showed reduced amplitudes or absent cortical responses in addition to absent odor identification and perception threshold in the subjective examination.

"A case report: Co-occurrence of cerebral amyloid angiopathy and multiple sclerosis".

Cerebral amyloid angiopathy (CAA) is a chronic pathological condition characterized by progressive accumulation of amyloid protein in the wall of cerebral blood vessels, both leptomeningeal and cortical. That may result in the development of such conditions as microaneurysms, hemorrhagic, ischaemic brain injury and contribute to cognitive impairment. We herein report a case of Iowa-type hereditary cerebral amyloid angiopathy (CAA) mutation diagnosed with MS. The family of the reported patient had performed genetic testing due to the history of intracerebral hemorrhage. Sequence analysis of exon 17 of the APP gene showed the presence of the D694N g.275272 G > A (c.2080 G > A) mutation, which caused the substitution of aspartate for aspargine at position 694 of APP. Alike the discussed patient, this mutation has been found in other family members in an autosomal dominant pattern of inheritance. Contrary to the rest of the family, the reported patient has been diagnosed with multiple sclerosis based on McDonald criteria. Recent studies shed light on the possible link between the APP accumulation and MS progression. It has been indicated that amyloid can prove a vital role in neuroimmunology, whereas the accumulation of APP in the CNS has been suggested to be a potential biomarker for the progression of MS. Moreover, the amyloid positron-emission tomography (amyloid-PET) has been demonstrated to serve as a diagnostic tool for establishing the degree of demyelination and remyelination in MS. Even though, one swallow does not make a summer, this finding would be another step forward in the understanding of pathological processes underlying the pathogenesis of MS.

Antibiotic-induced epileptic seizures: mechanisms of action and clinical considerations.

In recent years, there has been growing interest in the development of epileptic seizures as an adverse effect of antibiotic therapy. The most commonly accepted mechanisms underlying the development of antibiotic-induced seizures include direct- and indirect gamma-aminobutyric acid (GABA) antagonism, inhibition of GABA synthesis, and glutaminergic N-methyl-D-Aspartate (NMDA) receptor agonistic activity. Inhibitory pathway inhibition leads to increased neuronal excitability and lowered seizure threshold. Blockage of myoneural presynaptic acetylcholine release, mitochondrial dysfunction, interference of neural protein synthesis, and oxidative stress caused by the generation of neurotoxic radicals also contributes to the development of neurotoxicity. Patients with pre-existing risk factors such as renal or hepatic insufficiency, central nervous system pathology, neurological diseases, history of epilepsy or seizures, critical illness, and increased age are more susceptible to seizure development as a consequence of antibiotic therapy. Administration of antibiotics, together with antiseizure drugs, may also lead to enhanced seizure risk due to drug interactions, which predisposes to alterations in drug metabolism and therapeutic efficacy.

Cardiovascular complications of epileptic seizures.

Seizure disorders are associated with multisystem complications. Cardiovascular complications account for a significant proportion of morbidity and mortality in these patients. As such, particular attention must be paid to the incidence of cardiovascular complications especially in populations at increased risk. The background for cardiac dysfunction lies in the interplay of genetic/molecular, autonomic, and iatrogenic factors that contribute to its onset. The purpose of this review was to summarize the state of literature in the last decade with regard to cardiac complications of epileptic seizures in order to increase awareness of short- and long-term debilitating cardiac complications as well as facilitate informed clinical decision-making. Taken together, the evidence provided in this review suggests that cardiac dysfunction following seizures should not be viewed as a separate entity but as an important complication of epileptic seizures. Appropriate cardiac therapy should be instituted in the postictal medical management of epileptic seizures. In acute states, postictal cardiac troponinemia (elevated cTn) should be worked up. Longer-term, monitoring for the development of cardiac structural and functional abnormalities is prudent.

Metastases to the central nervous system: Molecular basis and clinical considerations.

BACKGROUND: Metastatic tumors are the most common malignancies of the central nervous system (CNS) in adults. CNS metastases are associated with unfavorable prognosis, high morbidity and mortality. Lung cancer is the most common source of brain metastases, followed by breast cancer and melanoma. Rising incidence is primarily due to improvements in systemic control of primary malignancies, prolonged survival and advances in cancer detection. PURPOSE: To provide an overview of the metastatic cascade and the role of angiogenesis, neuroinflammation, metabolic adaptations, and clinical details about brain metastases from different primary tumors. METHODS: A review of the literature on brain metastases was conducted, focusing on the pathophysiology and clinical aspects of the disease. PubMed was used to search for relevant articles published from January 1975 through December 2019 using the keywords brain metabolism, brain metastasis, metastatic cascade, molecular mechanisms, incidence, risk factors, and prognosis. 146 articles met the criteria and were included in this review. DISCUSSION: Some primary tumors have a higher tendency to metastasize to the CNS. Establishing a suitable metastatic microenvironment is important in maintaining tumor cell growth and survival. Magnetic resonance imaging (MRI) is a widely used tool for diagnosis and treatment monitoring. Available treatments include surgery, radiotherapy, stereotactic radiosurgery, chemotherapy, immunotherapy, and systemic targeted therapies. CONCLUSIONS: Prevention of metastases to the CNS remains a difficult challenge. Advances in screening of high-risk patients and future development of novel treatments may improve patient outcomes.

Antiganglioside antibodies in neurological diseases.

Gangliosides are sialylated glycosphingolipids, highly abundant in our nervous system. Antibodies targeting gangliosides are usually developed as a consequence of molecular mimicry following infections. Antiganglioside antibodies are implicated in many neurological disorders such as acute and chronic polyradiculoneuropathies which includes different variants of Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy. Presence of such antibodies in paraneoplastic peripheral neuropathy, neurodegenerative disorders, multiple sclerosis, myasthenia gravis and amyotrophic lateral sclerosis have also been reported. Recent evidence supports a role of antiganglioside antibodies in the pathogenesis of acute vestibular syndrome. Binding of antibodies to gangliosides on axonal membranes, nodes of Ranvier, myelin sheath components, Schwann cells, neuromuscular junctions or other neural cell surfaces may elicit inflammatory damage through complement-dependent and independent mechanisms, resulting in nerve conduction blocks and subsequent axonal degeneration. Gangliosides are essential for proper cell signaling, transduction and influences neuroplasticity, all of which are affected by autoimmune mediated damage. Better insight into the pathophysiological role of antiganglioside antibodies in different neurological diseases may improve their utility as diagnostic and prognostic biomarkers.

Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders.

Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification. Using exome sequencing and family based rare variant analyses, we identified a homozygous variant (c.997C>T [p.Arg333Cys]) in TUBGCP2, encoding gamma-tubulin complex protein 2 (GCP2), in two individuals from a consanguineous family; both individuals presented with microcephaly and developmental delay. GCP2 forms the multiprotein γ-tubulin ring complex (γ-TuRC) together with γ-tubulin and other GCPs to regulate the assembly of microtubules. By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes including a homozygous variant (c.1843G>C [p.Ala615Pro]) in two families and compound heterozygous variants consisting of one missense variant (c.889C>T [p.Arg297Cys]) and one splice variant (c.2025-2A>G) in another family. Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration. Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder, and our data implicate GCP2 as a core component of γ-TuRC in neuronal migrating cells.

Role of B cells and antibodies in multiple sclerosis.

Multiple sclerosis (MS) is a chronically progressive auto-immune mediated inflammatory demyelinating disease of the central nervous system (CNS) which manifests as disturbances in sensorimotor function and cognitive impairment. Although believed to be a T-cell mediated disease, the role of B cells has recently become a central issue in MS pathogenesis. Both antibody dependent and independent theories have been suggested to play a role in the initiation of inflammatory demyelination. Antibody dependent mechanisms include formation of autoantibodies targeting specific tissues in the CNS and B cell antigen presentation to T cells, leading to subsequent activation and cytokine secretion. Antibody independent mechanisms entail formation of ectopic lymphoid structures, cytokine production and secretion of neurotoxic factors. Moreover, breach of peripheral tolerance mechanisms due to disturbances in regulatory T cell functioning has also been described. B cell depletion through anti-CD20 monoclonal antibody utilization and other immunomodulatory therapies have been promising in reducing episodes of relapse and slowing progression, further strengthening the concept that B cells and antibodies are significant players in formation of brain lesions in MS.

Safety, tolerability and pharmacokinetics of oral nafithromycin (WCK4873) after single or multiple doses and effects of food on single-dose bioavailability in healthy adult subjects.

Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, Phase 1 studies. In the first-in-human study, single-ascending oral doses of nafithromycin (100 to 1200 mg) were administered to subjects under fasted or fed condition, with effects of food on bioavailability of nafithromycin studied at the dose levels of 400 and 800 mg. In the second study, multiple-ascending oral doses of 600, 800, or 1000 mg of nafithromycin were administered once daily for 7 days under a fed condition. Nafithromycin was generally well tolerated at all doses. No serious or severe adverse events were observed. The mean maximum plasma concentration (Cmax) ranged from 0.099 to 1.742 mg/L, and the area under the concentration-time curve from time zero to time t (AUC0-t ) ranged from 0.54 to 22.53 h⋅mg/L. Nafithromycin plasma AUC0-t increased approximately 1.2-fold under fed compared to fasted condition. In the multiple-dose study, the Day 7 nafithromycin Cmax ranged from 1.340 to 2.987 mg/L and the AUC over the final dosing interval (AUC0-24) ranged from 13.48 to 43.46 h⋅mg/L. The steady state was achieved after 3 days for the 600 mg and 800 mg dose cohorts and after 4 days for the 1000 mg cohort. Under both single- and multiple-dosing regimens, plasma exposure to nafithromycin appeared to increase more than dose-proportionally. Nafithromycin showed moderate accumulation on Day 7 of dosing. The human pharmacokinetic profile, safety and tolerability data support further development of nafithromycin.

Alzheimer's dementia: pathogenesis and impact of cardiovascular risk factors on cognitive decline.

Alzheimer's disease (AD) is the most common form of dementia manifesting as alterations in cognitive abilities, behavior, and deterioration in memory which is progressive, leading to gradual worsening of symptoms. Major pathological features of AD are accumulations of neuronal amyloid plaques and neurofibrillary tangles, with early lesions appearing primarily in the hippocampus, the area of the brain involved in memory and learning. Cardiovascular-related risk factors are believed to play a crucial role in disease development and the acceleration of cognitive deterioration by worsening cerebral perfusion, promoting disturbances in amyloid clearance. Current evidence supports hypertension, hypotension, heart failure, stroke and coronary artery diseases as potential factors playing a role in cognitive decline in patients with Alzheimer's dementia. Although dementia due to cardiovascular deficits is more strongly linked to the development of vascular dementia, a stepwise decline in cognition, recent researches have also discovered its deleterious influence on AD development.

Infectious Etiologies of Parkinsonism: Pathomechanisms and Clinical Implications.

Extensive research in recent decades has expanded our insights into the pathogenesis of Parkinson's disease (PD), though the underlying cause remains incompletely understood. Neuroinflammation have become a point of interest in the interconnecting areas of neurodegeneration and infectious diseases. The hypothesis concerning an infectious origin in PD stems from the observation of Parkinson-like symptoms in individuals infected with the influenza virus who then developed encephalitis lethargica. The implications of infectious pathogens have later been studied in neuronal pathways leading to the development of Parkinsonism and PD, through both a direct association and through synergistic effects of infectious pathogens in inducing neuroinflammation. This review explores the relationship between important infectious pathogens and Parkinsonism, including symptoms of Parkinsonism following infectious etiologies, infectious contributions to neuroinflammation and neurodegenerative processes associated with Parkinsonism, and the epidemiologic correlations between infectious pathogens and idiopathic PD.

Advances in the Potential Biomarkers of Epilepsy.

Epilepsy is a group of chronic neurological disorders characterized by recurrent, spontaneous, and unpredictable seizures. It is one of the most common neurological disorders, affecting tens of millions of people worldwide. Comprehensive studies on epilepsy in recent decades have revealed the complexity of epileptogenesis, in which immunological processes, epigenetic modifications, and structural changes in neuronal tissues have been identified as playing a crucial role. This review discusses the recent advances in the biomarkers of epilepsy. We evaluate the possible molecular background underlying the clinical changes observed in recent studies, focusing on therapeutic investigations, and the evidence of their safety and efficacy in the human population. This article reviews the pathophysiology of epilepsy, including recent reports on the effects of oxidative stress and hypoxia, and focuses on specific biomarkers and their clinical implications, along with further perspectives in epilepsy research.