Predictive tissue markers in testicular germ cell tumors: Immunohistochemical expression of MLH1 and REV-7 proteins.

PURPOSE: Testicular Germ Cell Tumors (TGCTs) are the most frequent solid malignancies in young adult men. Regardless of differences in their cell of origin, all TGCTs are considered highly curable malignancies. However, approximately 3-5% of all TGCTs do not respond to platinum-based chemotherapies. The purpose of our paper is to investigate whether immunohistochemical expression of MLH1 and REV-7 can be used as predictive tissue markers for TGCTs. MATERIAL AND METHODS: The main demographic and clinicopathological characteristics of 64 male patients with TGCTs who underwent orchiectomy from 2007 to 2022 were retrospectively obtained from two large Oncology Clinics in Greece. Both patients with chemosensitive and chemoresistant disease were included. Immunohistochemical staining for MLH1 and REV-7 proteins was applied in specimens of these patients. RESULTS: 31 seminomas and 33 non-seminomas were included. 48 patients had chemosensitive disease, while 16 had chemoresistant disease. 53 specimens showed preserved MLH1 expression, while 11 specimens had lost MLH1 expression. Expression of MLH1 was only significantly associated with patients' age. 16 specimens showed positive REV-7 expression, while 48 specimens were REV-7 negative. Interestingly, 50% of patients with chemoresistant disease and 16,7% of patients with chemosensitive disease were REV-7 positive. This difference was statistically significant. Moreover, REV-7 positivity was significantly associated with chemoresistance, various clinicopathological parameters and patients' prognosis and survival. CONCLUSION: Loss of MLH1 expression was only found to be significantly associated with lower patients' age. Positive immunohistochemical REV-7 expression was significantly associated with various clinicopathological parameters, while it was also associated with significantly lower survival and greater hazard. REV-7 positive percentages were significantly higher in patients with chemoresistant disease. Our findings imply that immunohistochemical staining for REV-7 could potentially be used as a predictive tissue marker for TGCT tumors. Moreover, targeting of REV-7 protein, could represent a potential therapeutic strategy for chemoresistant TGCT cases. The implementation of well-designed studies on a larger scale is of utmost importance, in order to draw safer conclusions. Additional studies are needed so as to draw safer conclusions.

Effect of Heme Oxygenase-1 Depletion on Complement Regulatory Proteins Expression in the Rat.

Heme oxygenase has been implicated in the regulation of various immune responses including complement activation. Using a transgenic rat model of HO-1 depletion, the present study assessed the effect of HO-1 absence on the expression of complement regulatory proteins: decay accelerating factor (DAF), CR1-related gene/protein Y (Crry) and CD59, which act to attenuate complement activation. Protein expression was assessed by immunohistochemistry in kidney, liver, lung and spleen tissues. DAF protein was reduced in all tissues retrieved from rats lacking HO-1 (Hmox1-/-) apart from spleen tissue sections. Crry protein was also reduced, but only in Hmox1-/- kidney and liver tissue. C3b staining was augmented in the kidney and spleen from Hmox1-/- rats, suggesting that the decrease of DAF and Crry was sufficient to increase C3b deposition. The observations support an important role of HO-1 as a regulator of the complement system.

Obsessive compulsive symptoms are associated with better functioning independently of cognition in schizophrenia.

OBJECTIVES: Although the relationship of obsessive-compulsive symptoms (OCSs) with both cognition and social functioning (SF) has already been the focus of research in schizophrenia, the moderation of the relationship of OCSs with SF by cognition has not been explored to date. We investigated the association of OCSs with SF and its interaction with cognition in schizophrenia. METHODS: We recruited 110 schizophrenia patients and assessed OCSs (Yale-Brown Scale), schizophrenia symptoms (Positive and Negative Syndrome Scale), SF (Strauss-Carpenter Scale) and cognition. 51 patients had one obsessive-compulsive symptom or more, whereas 59 patients had no obsessive compulsive-symptom, according to the Yale-Brown Scale. We mainly investigated: a) the predictive effect of OCSs on SF, controlling for cognition, illness duration and symptoms' severity and b) the moderating effect of cognition on the OCSs-SF relationship. RESULTS: The mean score of OCSs for patients having at least one symptom was 13.43 (SD=8.32). Higher OCSs predicted increased SF (B=0.98, t=2.41, df=88, p=0.018). This relationship was driven by the association of compulsions with job functioning (B=0.074, t=2.029, df=88, p=0.046). Patients without OCSs demonstrated worse functioning compared with those having at least one obsessive-compulsive symptom (mean difference=2.496, t=3.732, df=88, p<0.001). We failed to find evidence that cognition moderates the effect of OCSs on SF. CONCLUSION: There may be a beneficial effect of OCSs on SF in patients with schizophrenia which is independent of their cognitive performance.

Episodic Visual Learning/Memory and Attentional Flexibility in Patients With Major Depressive Disorder After Clinically Effective Electroconvulsive Therapy.

OBJECTIVES: This study is a follow-up of a previous one reporting that the neuropsychological profile of pharmacoresistant patients with major depressive disorder referred for electroconvulsive therapy (ECT, ECT group) contrasted with that of their pharmacorespondent counterparts (NECT group). The NECT group exhibited severe visuospatial memory and minor executive deficits; the ECT group presented the reverse pattern. In that same ECT group, the current follow-up study examined the effects of clinically effective ECT on both cognitive domains 2 months later. METHODS: Fifteen ECT patients were administered Hamilton Depression (HAMD-24), Hamilton Anxiety (HAMA), Mini-Mental State Examination Scales and 5 tests of Cambridge Neuropsychological Test Automated Battery at intake (pre-ECT), end of ECT course (post-ECT), and 2 months thereafter (follow-up). RESULTS: Electroconvulsive therapy was effective in relieving clinical depression. After a post-ECT decline, the patients exhibited significant improvement in both Cambridge Neuropsychological Test Automated Battery, paired associate learning, and Stockings of Cambridge. By contrast, their major pre-ECT deficit in intra/extradimensional set shifting remained virtually unaffected. CONCLUSIONS: Our findings suggest that attentional flexibility deficits may constitute a neuropsychological trait-like feature of pharmacoresistant, ECT-referred major depressive disorder patients. However, this deficit does not seem generalized, given patient improvement in episodic visual learning/memory and some indication of improvement in spatial planning after ECT.

COMT and MTHFR polymorphisms interaction on cognition in schizophrenia: an exploratory study.

The investigation of the catechol-O-methyltransferase (COMT-[rs4680]) and methylenetetrahydrofolate reductase (MTHFR-[rs1801133]) polymorphisms' interaction might shed light into the pathogenetic mechanisms of the cognitive dysfunction in schizophrenia. In an exploratory study, we hypothesized that the MTHFR 677T allele which has been related to a hypoactive MTHFR enzyme would augment the unfavorable effects of COMT Val158 homozygosity which has been associated with COMT enzyme hyperfunction. 90 schizophrenia patients and 55 healthy volunteers were assessed on psychomotor speed, pattern and spatial recognition memory (SRM), spatial working memory (SWM), attentional flexibility and planning (Stockings of Cambridge-SOC). IQ scores in a random subgroup of patients were also measured. A significant COMT×MTHFR interaction on SWM (p=0.048) and planning (p=0.026) was revealed in both groups. Among COMT-Val/Val participants, MTHFR-C/C made more SWM errors (p=0.033) and solved fewer SOC problems (p=0.025) than MTHFR-T carriers. In patients, there was a significant COMT×MTHFR interaction on full scale IQ (p=0.035): among COMT-Met carriers, MTHFR-T carriers performed significantly worse than MTHFR-C/C (p=0.021), which was driven by a COMT×MTHFR interaction involving performance IQ (p=0.047). In conclusion, COMT and MTHFR polymorphisms interacted on cognition, suggesting that the MTHFR enzyme activity might moderate the effects of the COMT enzyme. In contrast to our initial hypothesis, the MTHFR T-allele attenuated the cognitive effects of COMT Val homozygosity. In this preliminary study, we propose that dopaminergic and intracellular methylation mechanisms could interact on cognitive deficits in schizophrenia.

5-HT2C receptor involvement in the control of persistence in the reinforced spatial alternation animal model of obsessive-compulsive disorder.

OBJECTIVE: The serotonergic system is implicated in the pathophysiology of obsessive-compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD. METHODS: Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence. RESULTS: Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence. CONCLUSIONS: These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD.

Dopamine in anorexia nervosa: a systematic review.

Anorexia nervosa (AN) is a chronic relapsing psychiatric disorder with a largely unknown pathophysiology. Dopamine has been implicated in the pathophysiology of the disorder by preclinical and clinical evidence. Preclinical studies have examined two main characteristics of AN: reduction in food intake (diet restriction) and hyperactivity. Diet restriction has been associated with reduced dopamine levels in the hypothalamus, hippocampus, and the dorsal striatum. Animal hyperactivity following diet restriction has been linked to increased dopamine in the hypothalamus. Increased dopamine in the nucleus accumbens was associated with food administration, but not food expectation. Tyrosine and dopaminergic antagonists normalized anorexia-like behaviors in animal models of AN, but did not restore body weight. Clinical studies on the etiology of AN have produced contradictory findings. Cerebrospinal fluid concentrations of dopamine and its metabolites have been reported to be decreased or normal under conditions of low weight, whereas they tended to normalize when the weight was restored. Plasma and urinary levels of dopamine and its metabolites have been found to be normal, increased, and decreased. Neuroendocrine studies suggest that dopaminergic neurotransmission is increased in AN. However, recent neuroimaging studies lend support to the increase in binding of dopaminergic receptors in the striatum, which favors the opposite theory that intrasynaptic dopamine is indeed decreased. Genetic studies implicate dopamine D2 receptors, the dopamine transporter, and the enzyme COMT. There are promising results with respect to the use of atypical antipsychotics against symptoms of AN beyond weight gain, but further trials are required.

Doubtful association of antipsychotic polypharmacy and high dosage with cognition in chronic schizophrenia.

Despite consistent recommendations for antipsychotic monotherapy, antipsychotic polypharmacy (the use of two or more antipsychotic agents) and the administration of excessive doses (higher than 1000 mgr/day of chloropromazine equivalents) is a common practice in schizophrenia. The therapeutic and adverse effects of this practice are poorly studied, in particular with regards to the cognitive symptoms of the disease. In this cross-sectional study we investigated the cognitive effects of antipsychotic polypharmacy and excessive doses in 53 patients with chronic schizophrenia using non-verbal cognitive tasks involving speed of movement, memory and executive functions. No significant difference in performance scores was found between the groups under polypharmacy and monotherapy, or the groups receiving either excessive or normal doses of antipsychotics. Since these groups did not also differ in demographic, clinical, other pharmacologic parameters, in the relative anticholinergic potency of antipsychotics, or in intelligence scores, we raise doubts about the association of polypharmacy and excessive doses with non-verbal cognitive performance in chronic schizophrenia.