The effects of ketamine and classic hallucinogens on neurotrophic and inflammatory markers in unipolar treatment-resistant depression: a systematic review of clinical trials.

Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n = 587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine's and classical hallucinogens' antidepressant effect. The PROSPERO ID for this study is CRD42021249089.

Health resource utilization and cost before versus after initiation of second-generation long-acting injectable antipsychotics among adults with schizophrenia in Alberta, Canada: a retrospective, observational single-arm study.

BACKGROUND: Long-acting injectable (LAI) antipsychotics, along with community treatment orders (CTOs), are used to improve treatment effectiveness through adherence among individuals with schizophrenia. Understanding real-world medication adherence, and healthcare resource utilization (HRU) and costs in individuals with schizophrenia overall and by CTO status before and after second generation antipsychotic (SGA)-LAI initiation may guide strategies to optimize treatment among those with schizophrenia. METHODS: This retrospective observational single-arm study utilized administrative health data from Alberta, Canada. Adults (≥ 18 years) with schizophrenia who initiated a SGA-LAI (no use in the previous 2-years) between April 1, 2014 and March 31, 2016, and had ≥ 1 additional dispensation of a SGA-LAI were included; index date was the date of SGA-LAI initiation. Medication possession ratio (MPR) was determined, and paired t-tests were used to examine mean differences in all-cause and mental health-related HRU and costs (Canadian dollars), comprised of hospitalizations, physician visits, emergency department visits, and total visits, over the 2-year post-index and 2-year pre-index periods. Analyses were stratified by presence or absence of an active CTO during the pre-index and/or post-index periods. RESULTS: Among 1,211 adults with schizophrenia who initiated SGA-LAIs, 64% were males with a mean age of 38 (standard deviation [SD] 14) years. The mean overall antipsychotic MPR was 0.39 (95% confidence interval [CI] 0.36, 0.41) greater during the 2-year post-index period (0.84 [SD 0.26]) compared with the 2-year pre-index period (0.45 [SD 0.40]). All-cause and mental health-related HRU and costs were lower post-index versus pre-index (p < 0.001) for hospitalizations, physician visits, emergency department visits, and total visits; mean total all-cause HRU costs were $33,788 (95% CI -$38,993, -$28,583) lower post- versus pre-index ($40,343 [SD $68,887] versus $74,131 [SD $75,941]), and total mental health-related HRU costs were $34,198 (95%CI -$39,098, -$29,297) lower post- versus pre-index ($34,205 [SD $63,428] versus $68,403 [SD $72,088]) per-patient. Forty-three percent had ≥ 1 active CTO during the study period; HRU and costs varied according to CTO status. CONCLUSIONS: SGA-LAIs are associated with greater medication adherence, and lower HRU and costs however the latter vary according to CTO status.

Using Machine Learning to Predict Remission in Patients With Major Depressive Disorder Treated With Desvenlafaxine.

BACKGROUND: Major depressive disorder (MDD) is a common and burdensome condition that has low rates of treatment success for each individual treatment. This means that many patients require several medication switches to achieve remission; selecting an effective antidepressant is typically a sequential trial-and-error process. Machine learning techniques may be able to learn models that can predict whether a specific patient will respond to a given treatment, before it is administered. This study uses baseline clinical data to create a machine-learned model that accurately predicts remission status for a patient after desvenlafaxine (DVS) treatment. METHODS: We applied machine learning algorithms to data from 3,399 MDD patients (90% of the 3,776 subjects in 11 phase-III/IV clinical trials, each described using 92 features), to produce a model that uses 26 of these features to predict symptom remission, defined as an 8-week Hamilton Depression Rating Scale score of 7 or below. We evaluated that learned model on the remaining held-out 10% of the data (n = 377). RESULTS: Our resulting classifier, a trained linear support vector machine, had a holdout set accuracy of 69.0%, significantly greater than the probability of classifying a patient correctly by chance. We demonstrate that this learning process is stable by repeatedly sampling part of the training dataset and running the learner on this sample, then evaluating the learned model on the held-out instances of the training set; these runs had an average accuracy of 67.0% ± 1.8%. CONCLUSIONS: Our model, based on 26 clinical features, proved sufficient to predict DVS remission significantly better than chance. This may allow more accurate use of DVS without waiting 8 weeks to determine treatment outcome, and may serve as a first step toward changing psychiatric care by incorporating clinical assistive technologies using machine-learned models.

Mononitrate Isosorbide as an Adjunctive Therapy in Schizophrenia: A Randomized Controlled Crossover Trial.

BACKGROUND: Schizophrenia is a complex disabling mental disorder, and many patients present poor response to available treatments. Accumulating evidence about the role of the glutamate/nitric oxide pathway in mediating the positive and negative symptoms of schizophrenia suggests potential benefits of drugs that modulate this system. The aim of this study was to test the efficacy of isosorbide mononitrate (ISMN) as an adjunctive therapy for symptomatic outpatients with schizophrenia. METHODS: This was a 2-month randomized, double-blind, placebo-controlled trial with 24 schizophrenia patients. Participants were treated with ISMN 50 mg for 1 month and placebo for another month in a crossover design. The Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, Global Assessment of Functioning, and MATRICS Cognitive Consensual Battery were used for symptom assessment and arterial spin labeling was used to assess brain activation patterns. RESULTS: We found significant differences in the total, general, and positive subscales of the PANSS, Global Assessment of Functioning scores, and Clinical Global Impression scores during treatment with ISMN relative to placebo. No treatment effects were found comparing scores in the MATRICS Cognitive Consensual Battery and the negative subscale of the PANSS between the active and placebo conditions. A post hoc analysis of neuroimaging data showed reduced activity in the thalamus in subgroup of patients with severe psychopathology. CONCLUSIONS: Schizophrenia patients with persistent symptoms showed significant improvement after 4 weeks of treatment with ISMN 50 mg/d compared with placebo. Isosorbide mononitrate added beneficial effects to antipsychotic treatment in terms of positive symptoms and functioning.

Incubation of neural alcohol cue reactivity after withdrawal and its blockade by naltrexone.

During the first weeks of abstinence, alcohol craving in patients may increase or "incubate." We hypothesize that Naltrexone (NTX) blocks this incubation effect. Here, we compared NTX effects on neural alcohol cue reactivity (CR) over the first weeks of abstinence and on long-term clinical outcomes to standard treatment. Male alcohol-dependent patients (n = 55) and healthy controls (n = 35) were enrolled. Participants underwent baseline psychometric testing and functional magnetic resonance imaging (fMRI) assessment of mesolimbic alcohol CR. Patients participated in a standard treatment program with the option of adjuvant NTX. They received another scan after 2 weeks of treatment. We found higher CR in several brain regions in patients versus healthy controls. CR significantly increased over 2 weeks in the standard treatment group (n = 13) but not in the NTX group (n = 22). NTX significantly attenuated CR in the left putamen and reduced relapse risk to heavy drinking within 3 months of treatment. Additionally, increased CR in the left putamen and its course over time predicted both NTX response and relapse risk. Carrier status for the functional OPRM1 variant rs1799971:A > G was considered but had no effect on NTX efficacy. In conclusion, NTX was most effective in patients with high CR in the left putamen. While the results from our naturalistic study await further confirmation from prospective randomized trials, they support a potential role of neural CR as a biomarker in the development of precision medicine approaches with NTX.

Neuroimmunological antibody-mediated encephalitis and implications for diagnosis and therapy in neuropsychiatry.

The past decade has seen a surge of reports and investigations into cases of autoimmune-mediated encephalitis. The increasing recognition of these disorders is especially of relevance to the fields of neurology and psychiatry. Autoimmune encephalitis involves antibodies against synaptic receptors, neuronal cell surface proteins and intracellular targets. These disorders feature prominent symptoms of cognitive impairment and behavioural changes, often associated with the presence of seizures. Early in the clinical course, autoimmune encephalitis may manifest as psychiatric symptoms of psychosis and involve psychiatry as an initial point of contact. Although commonly associated with malignancy, these disorders can present in the absence of an inciting neoplasm. The identification of autoimmune encephalitis is of clinical importance as a large proportion of individuals experience a response to immunotherapy. This review focuses on the current state of knowledge on n-methyl-d-aspartate (NMDA) receptor-associated encephalitis and limbic encephalitis, the latter predominantly involving antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the γ-aminobutyric acid (GABA)B receptor and leucine-rich glioma-inactivated 1 (LGI1) protein. In addition, we briefly describe anti-dopamine D2 receptor encephalitis. A summary of the literature will focus on common clinical presentations and course, diagnostic approaches and response to treatment. Since a substantial proportion of patients with autoimmune encephalitis exhibit symptoms of psychosis, the relevance of this disorder to theories of psychosis and schizophrenia will also be discussed.

An Overview of Animal Models Related to Schizophrenia.

Schizophrenia is a heterogeneous psychiatric disorder that is poorly treated with current therapies. In this brief review, we provide an update regarding the use of animal models to study schizophrenia in an attempt to understand its aetiology and develop novel therapeutic strategies. Tremendous progress has been made developing and validating rodent models that replicate the aetiologies, brain pathologies, and behavioural abnormalities associated with schizophrenia in humans. Here, models are grouped into 3 categories-developmental, drug induced, and genetic-to reflect the heterogeneous risk factors associated with schizophrenia. Each of these models is associated with varied but overlapping pathophysiology, endophenotypes, behavioural abnormalities, and cognitive impairments. Studying schizophrenia using multiple models will permit an understanding of the core features of the disease, thereby facilitating preclinical research aimed at the development and validation of better pharmacotherapies to alter the progression of schizophrenia or alleviate its debilitating symptoms.

Deep grey matter iron accumulation in alcohol use disorder.

PURPOSE: Evaluate brain iron accumulation in alcohol use disorder (AUD) patients compared to controls using quantitative susceptibility mapping (QSM). METHODS: QSM was performed retrospectively by using phase images from resting state functional magnetic resonance imaging (fMRI). 20 male AUD patients and 15 matched healthy controls were examined. Susceptibility values were manually traced in deep grey matter regions including caudate nucleus, combined putamen and globus pallidus, combined substantia nigra and red nucleus, dentate nucleus, and a reference white matter region in the internal capsule. Average susceptibility values from each region were compared between the patients and controls. The relationship between age and susceptibility was also explored. RESULTS: The AUD group exhibited increased susceptibility in caudate nucleus (+8.5%, p=0.034), combined putamen and globus pallidus (+10.8%, p=0.006), and dentate nucleus (+14.9%, p=0.022). Susceptibility increased with age in two of the four measured regions - combined putamen and globus pallidus (p=0.013) and combined substantia nigra and red nucleus (p=0.041). AUD did not significantly modulate the rate of susceptibility increase with age in our data. CONCLUSION: Retrospective QSM computed from standard fMRI datasets provides new opportunities for brain iron studies in psychiatry. Substantially elevated brain iron was found in AUD subjects in the basal ganglia and dentate nucleus. This was the first human AUD brain iron study and the first retrospective clinical fMRI QSM study.

Dietary supplementation with low-dose omega-3 fatty acids reduces salivary tumor necrosis factor-α levels in patients with chronic periodontitis: a randomized controlled clinical study.

BACKGROUND AND OBJECTIVE: Recent studies have demonstrated the beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) on physiological processes and on a variety of chronic inflammatory diseases, including periodontal diseases. In this study, we evaluated the impact of omega-3 PUFAs in conjunction with scaling and root planing (SRP) on salivary markers in patients with chronic periodontitis. MATERIAL AND METHODS: Thirty systemically healthy subjects with chronic periodontitis were enrolled and randomly allocated into two groups. The control group (n = 15) was treated with SRP + placebo whereas the test group was treated with SRP and dietary supplementation of low-dose omega-3 PUFAs (6.25 mg eicosapentaenoic acid and 19.19 mg docosahexaenoic acid). Clinical parameters were taken at baseline, 1, 3 and 6 mo following therapy. Saliva samples were obtained at the same time intervals and analyzed for tumor necrosis factor-α (TNF-α) and superoxide dismutase (SOD). RESULTS: Both groups showed significant changes in clinical parameters in response to treatment compared to baseline with no significant difference between groups. Salivary TNF-α levels showed a statistically significant decrease in the test group at 6 mo compared to the control group. Salivary SOD levels increased significantly at 3 and 6 mo in the test group and at 6 mo in placebo groups compared to baseline with no statistically significant differences between the groups. CONCLUSION: The results demonstrated that dietary supplementation with low-dose omega-3 PUFAs improves salivary TNF-α without any significant impact on clinical parameters in patients with chronic periodontitis, suggesting that the systemic benefits of dietary omega-3 PUFAs may not be translated to periodontal health. (ClinicalTrials.gov ID NCT02719587).

Gingival crevicular fluid tissue/blood vessel-type plasminogen activator and plasminogen activator inhibitor-2 levels in patients with rheumatoid arthritis: effects of nonsurgical periodontal therapy.

BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the effect of nonsurgical periodontal therapy on clinical parameters and gingival crevicular fluid levels of tissue/blood vessel-type plasminogen activator (t-PA) and plasminogen activator inhibitor-2 (PAI-2) in patients with periodontitis, with or without rheumatoid arthritis (RA). MATERIAL AND METHODS: Fifteen patients with RA and chronic periodontitis (RA-P), 15 systemically healthy patients with chronic periodontitis (H-P) and 15 periodontally and systemically healthy volunteers (C) were included in the study. Plaque index, gingival index, probing pocket depth, clinical attachment level, bleeding on probing, gingival crevicular fluid t-PA and PAI-2 levels, erythrocyte sedimentation rate, serum C-reactive protein and disease activity score were evaluated at baseline and 3 mo after mechanical nonsurgical periodontal therapy. RESULTS: All periodontal clinical parameters were significantly higher in the RA-P and H-P groups compared with the C group (p < 0.001) and decreased significantly after treatment (p < 0.001). Pretreatment t-PA levels were highest in the RA-P group and significantly decreased post-treatment (p = 0.047). Pre- and post-treatment PAI-2 levels were significantly lower in controls compared with both periodontitis groups (p < 0.05). Gingival crevicular fluid volume and the levels of t-PA and PAI-2 were significantly correlated. CONCLUSION: In patients with periodontitis and RA, nonsurgical periodontal therapy reduced the pretreatment gingival crevicular fluid t-PA levels, which were significantly correlated with gingival crevicular fluid PAI-2 levels. The significantly higher t-PA and PAI-2 gingival crevicular fluid levels in periodontal patients, regardless of systemic status, suggest that the plasminogen activating system plays a role in the disease process of periodontitis.

Randomized controlled pilot trial of supportive text messages for patients with depression.

BACKGROUND: Depression is projected to be the primary cause of disability worldwide by 2030. In a recent survey, the most commonly cited unmet need among 42.4% of depressed Albertans was the lack of sufficient, accessible, and affordable counselling. Our aim was to test the efficacy of a supportive text messaging mobile health intervention in improving treatment outcomes in depressed patients. METHODS: We performed a single-rater-blinded randomized trial involving 73 patients with Major Depressive Disorder. Patients in the intervention group (n = 35) received twice-daily supportive text messages for 3 months while those in the control group (n = 38) received a single text message every fortnight thanking them for participating in the study. The primary outcome of this study was: "Mean changes in the BDI scores from baseline". RESULTS: After adjusting for baseline BDI scores, a significant difference remained in the 3 month mean BDI scores between the intervention and control groups: (20.8 (SD = 11.7) vs. 24.9 (SD = 11.5), F (1, 60) = 4.83, p = 0.03, ηp2 = 0.07). The mean difference in the BDI scores change was significant with an effect size (Cohen's d) of 0.67. Furthermore, after adjusting for baseline scores, a significant difference remained in the 3 month mean self-rated VAS scores (EQ-5D-5 L scale) between the intervention and control groups, 65.7 (SD = 15.3) vs. 57.4 (SD = 22.9), F (1, 60) =4.16, p = 0.05, ηp2 = 0.065. The mean difference in change mean self-rated VAS scores was also statistically significant with an effect size (Cohen's d) of 0.51. CONCLUSIONS: Our findings suggest that supportive text messages are a potentially useful psychological intervention for depression, especially in underserved populations. Further studies are needed to explore the implications of our findings in larger clinical samples. TRIAL REGISTRATION: ClinicalTrials.gov NCT02327858 . Registered 24 December 2014.

Characterization and toxicity of hospital wastewaters in Turkey.

The aim of the study was to present first preliminary characterization of Turkish hospital wastewaters, their environmental risk, and a method for toxicity assessment. The hospital wastewater samples were collected from two of the largest medical faculty hospitals and a training and research hospital in Istanbul, Turkey. The samples from the selected hospitals were taken as grab samples on March 2014. Overall, 55 substances including pharmaceuticals and their metabolites, pesticides, and corrosion inhibitors were analyzed in all hospital wastewaters. Analysis of toxicity and the antibiotic resistance bacteria were investigated in addition to the chemical analysis in the wastewater of one hospital. Hazard quotients (HQs) and toxic units (TUs) were calculated as basis of the environmental risk assessment. Fourteen pharmaceuticals in hospital wastewater (HWW) were classified as "high risk" with HQ > 10. HQHWW values higher than 100 were determined for five antibiotics and one analgesic, namely, ofloxacin, clarithromycin, ciprofloxacin, sulfapyridine, trimethoprim, and diclofenac. Ofloxacin with an HQHWW of 9090 was observed to be the most hazardous compound. HQ and TU values of the wastewater treatment plant (WWTP) effluent dropped significantly due to dilution in the sewer. Further elimination by biological degradation or adsorption was observed only in some cases. However, the decreased HQWWTPeffluent values do not the change environmental load significantly. Therefore, advanced treatment processes should be applied to remove the persistent compounds. In combination with the results on antibiotic resistance, we would prefer on-site treatment of hospital wastewater. Toxicological assessment was performed using cytotoxic and mutagenic screening tests. The results of the Ames assay showed that the native hospital wastewaters had strongly mutagenic activity with a ≤10-fold increase relative to negative controls. The mutagenic potentials of the samples were generally concentration and metabolic activation dependent. Multiple antibiotic resistances were demonstrated with the tested isolates to ciprofloxacin, trimethoprim, and ceftazidime. This study demonstrates that the hospital wastewaters in Istanbul exhibit strong environmental and toxicological risks, as well as high multiple drug resistance to commonly used antibiotics.

The effects of periodontal therapy on gingival crevicular fluid matrix metalloproteinase-8, interleukin-6 and prostaglandin E2 levels in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this study was to evaluate the effects of non-surgical periodontal therapy on gingival crevicular fluid levels of matrix metalloproteinase-8 (MMP-8), interleukin-6 (IL-6) and prostaglandin E2 (PGE2 ) in patients with rheumatoid arthritis (RA) with periodontal disease. MATERIAL AND METHODS: Twenty-seven patients with gingivitis and periodontitis with RA, 26 patients with gingivitis and periodontitis that were systemically healthy and 13 periodontally and systemically healthy volunteers (control group) were included in this study. RA activity was assessed by disease activity score test. The clinical periodontal parameters, fasting venous blood and gingival crevicular fluid samples were obtained and gingival crevicular fluid MMP-8, IL-6 and PGE2 levels were evaluated at baseline and at 3 mo follow-up after non-surgical periodontal treatment. RESULTS: Gingival crevicular fluid MMP-8, PGE2 and IL-6 levels were higher in all groups than the control group. Following periodontal therapy, there were significant decreases in gingival crevicular fluid MMP-8, PGE2 and IL-6 levels from patients with RA with periodontitis (p < 0.05). Plaque index, gingival index and bleeding on probing were significantly correlated with IL-6 and PGE2 at baseline and at 3 mo follow-up after non-surgical periodontal treatment. CONCLUSION: Non-surgical periodontal therapy of patients with RA with periodontitis may provide beneficial effects on local inflammatory control via decreases in gingival crevicular fluid MMP-8, PGE2 and IL-6 levels.

Cross-sectional survey evaluating Text4Mood: mobile health program to reduce psychological treatment gap in mental healthcare in Alberta through daily supportive text messages.

BACKGROUND: To complement the oversubscribed counselling services in Alberta, the Text4Mood program which delivers daily supportive text messages to subscribers was launched on the 18th of January, 2016. This report presents an evaluation of self-reports of the impact of the program on the mental wellbeing of subscribers. METHODS: An online link to a survey questionnaire was created by an expert group and delivered via text messages to mobile phones of all 4111 active subscribers of the Text4Mood program as of April 11, 2016. RESULTS: Overall, 894 subscribers answered the survey (overall response rate 21.7 %). The response rate for individual questions varied and is reported alongside the results. Most respondents were female (83 %, n = 668), Caucasian (83 %, n = 679), and diagnosed with a psychiatric disorder (38 %, n = 307), including Depression (25.4 %, n = 227) and Anxiety (20 %, n = 177). Overall, 52 % (n = 461) signed up for Text4Mood to help elevate their mood and 24.5 % (n = 219) signed up to help them worry less. Most respondents felt the text messages made them more hopeful about managing issues in their lives (81.7 %, n = 588), feel in charge of managing depression and anxiety (76.7 %, n = 552), and feel connected to a support system (75.2 %, n = 542). The majority of respondents felt Text4Mood improved their overall mental well-being (83.1 %, n = 598). CONCLUSION: Supportive text messages are a feasible and acceptable way of delivering adjunctive psychological interventions to the general public with mental health problems. Given that text messages are affordable, readily available, and can be delivered to thousands of people simultaneously, they present an opportunity to help close the psychological treatment gap for mental health patients in Alberta and elsewhere.

High sensitivity detection of salivary 8-hydroxy deoxyguanosine levels in patients with chronic periodontitis.

BACKGROUND: Inflammation is associated with hydroxyl radical damage to DNA as a result of oxidative stress. 8-Hydroxy deoxyguanosine (8-OHdG) is a marker of this process and its levels in saliva could be linked to the severity of periodontal inflammation. The aim of this study was to test the sensitivity of liquid chromatography with tandem mass spectrometry (LC-MS/MS) in comparison to enzyme-linked immune sorbent assay (ELISA) for the detection of 8-OHdG in saliva in patients with chronic periodontitis before and after periodontal treatment. METHODS: Saliva samples were collected from 23 patients (eight females and 15 males; 46.1 ± 5.1 years of age) with generalized chronic periodontitis and 25 (15 females and 10 males; 44.9 ± 6.8 years of age) periodontally healthy individuals. Patients received initial periodontal treatment consisting of scaling and root planing and were evaluated at baseline and after 6 wk of completion of non-surgical therapy. Salivary 8-OHdG levels were measured using ELISA and LC-MS/MS before and after the treatment. Clinically, plaque index, gingival index, clinical attachment level, bleeding on probing, gingival recession and probing pocket depth were measured at baseline and after 6 wk. RESULTS: Salivary levels of 8-OHdG decreased significantly after the non-surgical periodontal treatment (p < 0.001). Statistically significant positive correlations were observed between plaque index, gingival index, probing pocket depth, clinical attachment level, bleeding on probing values and LC-MS/MS and ELISA levels of 8-OHdG (p < 0.001). CONCLUSION: LC-MS/MS is a reliable and sensitive method for evaluating salivary 8-OHdG levels to monitor the treatment response of periodontitis.

Evaluation of gingival crevicular fluid levels of tissue plasminogen activator, plasminogen activator inhibitor 2, matrix metalloproteinase-3 and interleukin 1-ß in patients with different periodontal diseases.

OBJECTIVES: The purpose of this study was to evaluate the gingival crevicular fluid levels of interleukin-1beta (IL-1ß), matrix metalloproteinases-3 (MMP-3), tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor 2 (PAI-2) in patients with chronic periodontitis, aggressive periodontitis (AgP) and healthy individuals (controls). MATERIAL AND METHODS: Systemically healthy (21 chronic periodontitis, 23 AgP and 20 controls) subjects were included in this study. Plaque index, gingival index, probing pocket depth and clinical attachment level were recorded and gingival crevicular fluid samples were collected. Assays for IL-1ß, MMP-3, t-PA and PAI-2 levels in gingival crevicular fluid were carried out by an enzyme-linked immunosorbent assay. The one-sample Kolmogorov-Smirnov test, Mann-Whitney U test and Spearman correlation coefficient were used for data analyses. RESULTS: Gingival crevicular fluid levels of t-PA and IL-1ß were significantly higher in chronic periodontitis and AgP groups than in the control group (p < 0.001). MMP-3 levels in gingival crevicular fluid were detected as significantly higher in the chronic periodontitis and AgP groups compared with the control group (p < 0.05). The t-PA/PAI-2 rate of patients with chronic periodontitis and AgP were significantly higher than the control group (p < 0.05). The positive correlations were found among the PAI-2, t-PA, IL-1ß and MMP-3 levels in gingival crevicular fluid. The volume of the gingival crevicular fluid correlated with all of the clinical parameters (p < 0.001). There were positive correlations between the gingival crevicular fluid levels of PAI-2 and the probing pocket depth and between gingival crevicular fluid levels of PAI-2 and the clinical attachment level (p < 0.01). Similarly, significant correlations were found between t-PA levels and probing pocket depth and between t-PA levels and clinical attachment level measurements (p < 0.001). CONCLUSION: The present data showed that gingival crevicular fluid levels of IL-1 ß, MMP-3 and t-PA increased in periodontal disease regardless of the periodontitis type and played a part in tissue destruction.

Hemophilus Influenzae Infections with Abscess Formation in Adults: a Retrospective Study Covering an Eleven-Year Period.

BACKGROUND: The aim of this study was to investigate the presence of Haemophilus influenzae in abscesses in adults and to determine their antibiotic resistance patterns. METHODS: H. influenzae strains isolated from abscesses during an eleven-year period were determined retrospectively and the stored strains were tested for ampicillin, amoxicillin/calvulanic acid, cefuroxime, cefotaxime, ceftriaxone, ciprofloxacin, azithromycin, tetracycline, and imipenem resistance by broth microdilution method. The production of ß-lactamase was detected using the nitrocefin disc test and real-time PCR. RESULTS: A total of 26 H. influenzae isolated strains were found. According to ampicillin resistance and ß-lactamase production, 2 strains were determined as BLPAR, 1 strain BLNAR, 1 strain BLPACR, and 22 strains as BLNAS. Cefuroxime resistance was detected in 4 strains, tetracycline resistance was detected in 4 strains, and no resistance to cefotaxime, ceftriaxone, imipenem, azithromycin and levofloxacin was detected. CONCLUSIONS: H. influenzae should be taken into account for the proper management of abscesses.

The Gut-Brain Axis and the Microbiome in Anxiety Disorders, Post-Traumatic Stress Disorder and Obsessive-Compulsive Disorder.

A large body of research supports the role of stress in several psychiatric disorders in which anxiety is a prominent symptom. Other research has indicated that the gut microbiome-immune system- brain axis is involved in a large number of disorders and that this axis is affected by various stressors. The focus of the current review is on the following stress-related disorders: generalized anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder and obsessivecompulsive disorder. Descriptions of systems interacting in the gut-brain axis, microbiome-derived molecules and of pro- and prebiotics are given. Preclinical and clinical studies on the relationship of the gut microbiome to the psychiatric disorders mentioned above are reviewed. Many studies support the role of the gut microbiome in the production of symptoms in these disorders and suggest the potential for pro- and prebiotics for their treatment, but there are also contradictory findings and concerns about the limitations of some of the research that has been done. Matters to be considered in future research include longer-term studies with factors such as sex of the subjects, drug use, comorbidity, ethnicity/ race, environmental effects, diet, and exercise taken into account; appropriate compositions of pro- and prebiotics; the translatability of studies on animal models to clinical situations; and the effects on the gut microbiome of drugs currently used to treat these disorders. Despite these challenges, this is a very active area of research that holds promise for more effective, precision treatment of these stressrelated disorders in the future.

What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia.

Schizophrenia is a frequently debilitating and complex mental disorder affecting approximately 1% of the global population, characterized by symptoms such as hallucinations, delusions, disorganized thoughts and behaviors, cognitive dysfunction, and negative symptoms. Traditional treatment has centered on postsynaptic dopamine antagonists, commonly known as antipsychotic drugs, which aim to alleviate symptoms and improve functioning and the quality of life. Despite the availability of these medications, significant challenges remain in schizophrenia therapeutics, including incomplete symptom relief, treatment resistance, and medication side effects. This opinion article explores advancements in schizophrenia treatment, emphasizing molecular mechanisms, novel drug targets, and innovative delivery methods. One promising approach is novel strategies that target neural networks and circuits rather than single neurotransmitters, acknowledging the complexity of brain region interconnections involved in schizophrenia. Another promising approach is the development of biased agonists, which selectively activate specific signaling pathways downstream of receptors, offering potential for more precise pharmacological interventions with fewer side effects. The concept of molecular polypharmacy, where a single drug targets multiple molecular pathways, is exemplified by KarXT, a novel drug combining xanomeline and trospium to address both psychosis and cognitive dysfunction. This approach represents a comprehensive strategy for schizophrenia treatment, potentially improving outcomes for patients. In conclusion, advancing the molecular understanding of schizophrenia and exploring innovative therapeutic strategies hold promise for addressing the unmet needs in schizophrenia treatment, aiming for more effective and tailored interventions. Future research should focus on these novel approaches to achieve better clinical outcomes and improve the functional level and quality of life for individuals with schizophrenia.