Treatment outcome of patients with synchronous oligometastatic non-small cell lung cancer in the immunotherapy era: Analysis of a real-life intention-to-treat population.

The standard first-line treatment for non-oncogene driven metastatic non-small cell lung cancer (NSCLC) is an immune checkpoint inhibitor (ICI) based strategy. Although guidelines increasingly advise adding local radical treatment (LRT) to patients with synchronous oligometastatic (sOMD) NSCLC responding to systemic therapy, this recommendation is based on the studies without ICI. Furthermore, the majority of published oligometastatic studies were not on an intention-to-treat basis, resulting in selection bias. Moreover, staging Positron Emission Tomography-Computed Tomography (PET-CT) and brain imaging were often not mandatory and definitions of oligometastatic were heterogeneous. Therefore, this study focused on a single centre retrospective series, including all adequately staged patients with sOMD NSCLC according to the European Organisation for Research and Treatment of Cancer definition (maximum of 5 metastases in 3 organs) that were treated with induction (chemo)-ICI and compared outcomes to those treated with chemotherapy only, with and without LRT. The primary end-points were median progression-free survival (PFS) and overall survival (OS) for patients treated with induction (chemo)-ICI versus chemotherapy. Out of 68 included patients, 38 (56%) eventually received LRT. With a median follow-up of 26.7 months, the median PFS was 19.0 months for (chemo)-ICI (n = 18) versus 6.8 for chemotherapy-only (n = 50) (HR 0.5, p = 0.03), the median OS was 19.3 versus 15.7 months, respectively (HR 0.8, p = 0.4). In patients having received LRT, median PFS was 19.0 months for (chemo)-ICI versus 8.3 for chemotherapy-only (HR 0.6, p = 0.2). In conclusion, an ICI-based systemic treatment is feasible and may result in superior survival outcomes. This should be investigated in prospective trials. Strategies to improve response rates to systemic treatment are also needed.

Response of TRPM2 Channel to Hypercapnic Acidosis and Role of Zn, Se, and GSH.

Hypercapnia can increase the production of reactive oxygen species (ROS) by inducing oxidative stress in cells. Transient receptor potential melastatin 2 (TRPM2) channel activation that is realized by ROS plays a critical role in the cellular mechanism. It was shown that antioxidants such as zinc (Zn), selenium (Se), and glutathione (GSH) can partake in the structures of enzymes and create a protective effect against oxidative stress. This study revealed the relationship between TRPM2 channel and hypercapnia, and the interaction of zinc, selenium, and glutathione. In our study, normoxia, hypercapnia, hypercapnia + Zn, hypercapnia + Se, and hypercapnia + GSH were created, in transfected HEK293 cells. The cells were exposed to normoxia or hypercapnia gasses in two different times (30 min and 60 min), while Zn, Se, and GSH were applied to the cells in the other groups before being exposed to the gas mixtures. The statistical evaluation showed a significant increase in lipid peroxidation (LPO) level and lactate dehydrogenase (LDH)% in the hypercapnia 30 min and 60 min groups, compared to the normoxia 30 min and 60 min groups, and an increase in LPO level and LDH% in the hypercapnia groups that Zn, Se, and GSH were applied. It was determined that in comparison with the normoxia 30 min and 60 min groups, the amount of inward Ca+2 current across TRPM2 channels and mean current density increased in the groups that were exposed to hypercapnia for 30 min and 60 min, while the same values significantly decreased in the hypercapnia groups that Zn, Se, and GSH were applied. Also, it was shown that oxidative stress rose as the duration of hypercapnia exposure increased. It was concluded that hypercapnia increased oxidative stress and caused cellular membrane damage, while the addition of Zn, Se, and GSH could protect the cell membrane from these damaging effects.

Effect of methylphenidate at different doses on new bone formation with rapid maxillary expansion: A micro-CT and histomorphometric study in rats.

OBJECTIVES: This study aimed to evaluate the effect of systemically administered methylphenidate hydrochloride (MPH) on new bone formation in premaxillary suture after rapid maxillary expansion (RME). SETTING AND SAMPLE POPULATION: Thirty-three Wistar rats were divided into four groups: Group 1 (high dose, 30/60 mg/kg MPH), Group 2 (low dose, 4/10 mg/kg MPH), Group 3 (positive control) and Group 4 (negative control). METHODS: RME was applied on the 70th day of the study. A 5-day RME period was followed by a 12-day retention period. The experiment was terminated on the 87th day. Micro-CT for radiological evaluation, haematoxylin-eosin and Masson's trichrome staining methods were used for histomorphometric evaluation. RESULTS: Among experimental groups with RME, the lowest number of osteoblasts and capillaries in Group 1 (P < .05). New bone formation, fibrous callus formation, distal osteotomy line, proximal osteotomy union and cortex remodelling were observed to be lower in Group 1 and Group 2 than Group 3 (P < .05). There was a statistically significant difference between Group 4 and each of the other groups (P = .000) in the evaluation of the results for bone mineral density, bone volume, bone volume percentage, trabecular thickness and trabecular number. CONCLUSIONS: MPH reduces cellular activity for new bone formation in suture in RME groups. Before performing rapid maxillary expansion in patients using MPH, the use of the drug should be postponed after a multidisciplinary decision process or clinical doses should be lowered.

Effects of plasma-emulating light-emitting diode (LED) versus conventional LED on cytotoxic effects and polymerization capacity of orthodontic composites.

OBJECTIVES: The aim of this study was to evaluate, the cytotoxicity of orthodontic composites in vitro as a function of degree of conversion (DC) and the light curing units (LCU) employed on mouse fibroblast (L929). MATERIALS AND METHODS: Cured samples of the composites Light bond (Reliance Orthodontic Products, Itasca, Illinois, USA), Ortho bracket paste (Bisco, Schaumburg, Illinois, USA), Opal bond MV (OPAL, South Jordan, Utah, USA), and Transbond XT (3M, Monrovia, California, USA) were prepared. Polymerization was performed with two LCUs: VALO Ortho (Ultradent, South Jordan, Utah, USA) is a third-generation LCU and Elipar S10 (3M, USA) is a second-generation LCU. Four samples were immersed in cell culture medium to obtain composite extracts. After incubation of L929 cell cultures with the extracts obtained, cytotoxicity was determined using the methyl tetrazolium test. Fourier transform infrared spectroscopy (FTIR) was used to evaluate DC for five samples. A multivariate analysis of variance (ANOVA), two-way ANOVA, and Tukey's honestly significant difference test were utilized for statistical analyses. RESULTS: Cytotoxicity and DC of all tested composites (p < 0.001) and the interaction between composites and LCUs (p < 0.01) were significantly different. LCUs had no significant influence on the cytotoxicity and DC of composite materials (p > 0.05). The correlations between cell viability and DC were positive for three composites but statistically insignificant. CONCLUSION: Composites and LCUs must be matched with one another to result in satisfactory maximal biocompatibility and DC. Opal Bond plasma light-emitting diode combination was a better choice for cell viability. Three composites showed a positive correlation between cytotoxicity and DC. Therefore high-intensity LCUs can be said to efficiently affect polymerization, and so, higher DC rates may achieve higher cell viability rates.

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update: [review]

Growing consistent evidence indicates that hypofunction of N-methyl-D-aspartate (NMDA) transmission plays a pivotal role in the neuropathophysiology of schizophrenia. Hence, drugs which modulate NMDA neurotransmission are promising approaches to the treatment of schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the NMDA receptor (NMDA-R). This review also includes a discussion and translation of neuroscience into schizophrenia therapeutics. Although the precise mechanism of action of minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of NMDA antagonists and may exert a differential effect on NMDA signaling pathways. We, therefore, hypothesize that the effects of minocycline on the brain may be partially modulated by the NMDA-R or related mechanisms. Thus, we have included a review of minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of glycine and D-cycloserine trials were conflicting regarding effectiveness on the negative and cognitive symptoms of schizophrenia. D-serine and D-alanine showed a potential effect on negative symptoms and on cognitive deficits. Sarcosine data indicated a considerable improvement as adjunctive therapy. Finally, minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with schizophrenia. The differential modulation of NMDA-R neurosystems, in particular synaptic versus extrasynaptic NMDA-R activation and specific subtypes of NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of schizophrenia.

Glutamate-N-methyl-D-aspartate receptor modulation and minocycline for the treatment of patients with schizophrenia: an update.

Growing consistent evidence indicates that hypofunction of N-methyl-D-aspartate (NMDA) transmission plays a pivotal role in the neuropathophysiology of schizophrenia. Hence, drugs which modulate NMDA neurotransmission are promising approaches to the treatment of schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the NMDA receptor (NMDA-R). This review also includes a discussion and translation of neuroscience into schizophrenia therapeutics. Although the precise mechanism of action of minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of NMDA antagonists and may exert a differential effect on NMDA signaling pathways. We, therefore, hypothesize that the effects of minocycline on the brain may be partially modulated by the NMDA-R or related mechanisms. Thus, we have included a review of minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of glycine and D-cycloserine trials were conflicting regarding effectiveness on the negative and cognitive symptoms of schizophrenia. D-serine and D-alanine showed a potential effect on negative symptoms and on cognitive deficits. Sarcosine data indicated a considerable improvement as adjunctive therapy. Finally, minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with schizophrenia. The differential modulation of NMDA-R neurosystems, in particular synaptic versus extrasynaptic NMDA-R activation and specific subtypes of NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of schizophrenia.

Cannabidiol for the treatment of psychosis in Parkinson's disease.

The management of psychosis in Parkinson's disease (PD) has been considered a great challenge for clinicians and there is a need for new pharmacological intervention. Previously an antipsychotic and neuroprotective effect of Cannabidiol (CBD) has been suggested. Therefore, the aim of the present study was to directly evaluate for the first time, the efficacy, tolerability and safety of CBD on PD patients with psychotic symptoms. This was an open-label pilot study. Six consecutive outpatients (four men and two women) with the diagnosis of PD and who had psychosis for at least 3 months were selected for the study. All patients received CBD in flexible dose (started with an oral dose of 150 mg/day) for 4 weeks, in addition to their usual therapy. The psychotic symptoms evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire showed a significant decrease under CBD treatment. CBD did not worsen the motor function and decreased the total scores of the Unified Parkinson's Disease Rating Scale. No adverse effect was observed during the treatment. These preliminary data suggest that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.

Nickel adsorption on the modified pine tree materials.

Removal of nickel ions from aqueous solutions containing 1-100 mg l(-1), using pine tree (Pinus nigra) materials modified with HCl, was investigated on a laboratory scale. For this purpose, two natural adsorbents such as the modified pine bark (MPB) and the modified pine cone (MPC) materials with HCl solution were studied. At first, the required concentration level of the HCl solution for the modification was observed, and then this was followed by the determinations of optimum levels of adsorbent amount, stirring rate, contact time and pH values. Various adsorption isotherms were also obtained by using different concentrations of the heavy metal cations tested in the experiment. As a result, the maximum removal efficiency levels obtained were as follows; 97% for the modified pine bark at pH 8 and 80% for the modified pine cone at pH 8.

Effect of MnSO4 on the chromium removal from the leather industry wastewater.

Chromium (VI) is one of the heavy metals in water and wastewater that has the most toxic characteristic. Consequently, it is dangerous for human and environmental health. Various methods are used for removal of the chromium from wastewater, and new methods have been developed in recent years. Recent studies and investigations on the removal of environmental pollution selected methods that were economical, of optimum efficiently and could be carried out easily. In this study, the removal of Cr6+ in the leather industry wastewater is investigated using MnSO4 that was used easily and economically. Experimental studies are performed in two phases. In the first phase, the optimum MnSO4 dose for removal of Cr6+ was determined. In the second phase, the optimum pH was studied. About 96% removal of chromium was launched with 530 mg l(-1) MnSO4 dose at pH value 9 in the wastewater sample.

Aripiprazole in schizophrenia: consensus guidelines.

Schizophrenia is a chronic disabling disease which in the majority of cases requires long-term treatment with antipsychotic medication. Before the development of atypical antipsychotics, treatment choice was restricted to conventional (or typical) antipsychotics, which are known to cause a range of side effects including extrapyramidal symptoms. Although atypical agents provide a favourable alternative (advocated by the National Institute of Clinical Excellence in the UK), they are associated with side effects. These differ between agents, but can include weight gain, sedation and hyperprolactinaemia. Aripiprazole is a newly available atypical antipsychotic for the treatment of schizophrenia. With the apparent imitations of currently available medications, aripiprazole provides clinicians with another treatment option. The purpose of these guidelines is to outline the consensus reached by the Schizophrenia Innovation Working Group on best practice in prescribing and appropriate use of aripiprazole in the UK.

Trihalomethane determination and removals from the main discharge channel of Konya City (Turkey).

Konya Main Discharge Channel is a very important environmental problem due to carrying the domestic waste water of Konya city centre as well as industrial waste water. Lowest flow rate of the channel was observed in October about 2 10(4) m3d(-1). In this period, channel water is not only waste water but includes more rain water coming from Gölyazi region. Discharge channel water can only reach to Tuz Lake for three months in a year. At other times of the year, water cannot reach the lake because of high evaporation, infiltration and usage of the water for irrigation. The land irrigated with the waste water tends to lose its productivity. In this study, water samples were collected and analysed from one hourly period for 2 days (24 x 2 = 48), daily period for 3 weeks (7 x 3 = 21) and monthly samples for a year (9 months). The samples were analysed as to whether these contained trihalomethanes or not, also results were compared with disinfection method that is used for drinking water, and samples were collected from ten different points on the channel. Pollution level of the channel water was controlled in accordance with the Turkish Water Pollution Control Law. In addition to trihalomethanes analysis, the effect of aeration on trihalomethanes was investigated. Collected samples (given above) were analysed for trihalomethanes compounds, and the relationship between disinfection type and dosage method on trihalomethanes formation was compared in this study.

Maintained improvement with minocycline of a patient with advanced Huntington's disease.

We present the case of a patient with advanced Huntington's disease treated with minocycline. Minocycline (but not tetracycline which does not cross the blood-brain barrier) appears to increase longevity in an animal model for Huntington's disease. The patient has been maintained on minocycline for more than 1 year with positive effects. Cessation of minocyclin for 3 weeks resulted in an exacerbation of symptoms. The animal studies have suggested that minocycline may prevent progression of Huntington's disease and other neurological disorders. By contrast, this present result suggests that minocycline may benefit those with advanced Huntington's disease and can be used safely in these patients.

The 'dalhousie serotonin cocktail' for treatment-resistant major depressive disorder.

We describe the successful treatment of five patients with treatment-resistant major depressive disorder (TR-MDD) with a combination pharmacotherapy of pindolol, tryptophan and nefazodone. Five TR-MDD outpatients who had previously not responded to at least four different antidepressant medication trials were initiated on 300 mg/day of nefazodone, 7.5 mg/day of pindolol and 1 g/day of tryptophan. Pindolol doses remained the same throughout the 20 weeks, while tryptophan and nefazodone dosages were gradually increased to 8 g/day and 450 mg/day, respectively. The Hamilton Depression Rating Scale (HAM-D) was used to evaluate outcome. By week 4, all cases demonstrated at least 50% decrease in HAM-D scores. At the end of the trial, the group mean HAM-D score had significantly decreased from 26.8 (+/- 1.9) to 1.8 (+/- 0.8) (p < 0.001). No significant adverse effects were reported. These results suggest that if serotonin availability and release is further enhanced by tryptophan in the presence of nefazodone and pindolol, an antidepressant effect may be produced in patients who are otherwise treatment-resistant. Due to limited sample size, an open design and an 'unusually' high successful efficacy rate of this preliminary study, controlled studies are required to confirm the efficacy of this treatment strategy.

Antidepressant discontinuation (withdrawal) symptoms presenting as 'stroke'.

We report two patients who developed a severe discontinuation (withdrawal) reaction following stoppage of paroxetine and venlafaxine, respectively. Neurological symptoms were prominent and neither patient could walk unaided. Both patients feared they had suffered a 'stroke' and arranged an emergency medical consultation. One patient was correctly diagnosed, the antidepressant was recommenced and symptoms resolved within 24 h. Failure to recognize the reaction resulted in the other patient being referred to a neurologist, undergoing a computed tomography brain scan and an electroencephalogram and remaining symptomatic for over 8 weeks. Relevant pharmacological issues are discussed. The cases illustrate the importance of patients and clinicians being familiar with antidepressant discontinuation symptoms.