Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol

The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation.     

No Effect of Serotoninergic Gene Variants on Response to Interpersonal Counseling and Antidepressants in Major Depression

Objective

Gene variants within the serotonin pathway have been associated with major depressive disorder (MDD) treatment outcomes, however a possible different modulation on pharmacological or psychological treatments has never been investigated.

Methods

One hundred sixty MDD patients were partially randomized to either inter-personal counseling (IPC) or antidepressants. The primary outcome was remission at week 8. Five serotonergic polymorphisms were investigated (COMT rs4680, HTR1A rs6295, HTR2A rs2224721, HTR2A rs7997012 and SLC6A4 rs421417).

Results

IPC (n=43) and antidepressant (n=117) treated patients did not show any difference in remission rates at week 8 (corrected for baseline severity, age and center). None of the studied gene variants impacted on response and remission rates at week 8 neither in the IPC nor in the antidepressant group. An analysis of the whole sample showed a trend of association between rs7997012 AA genotype and a better treatment outcome.

Conclusion

Our study confirms that IPC is an effective psychological intervention comparable to antidepressants in mild-moderate MDD. Polymorphisms related to the serotonin system did not exert a major effect on clinical outcomes in none of the treatment groups.     

Genetic Variants Within Key Nodes of the Cascade of Antipsychotic Mechanisms: Effects on Antipsychotic Response and Schizophrenia Psychopathology in a Naturalistic Treatment Setting in Two Independent Korean and Italian Samples

Introduction

Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. Genetic factors play an important role in both SCZ liability and its treatment outcome. In the present paper, we investigated the effects of several single nucleotide polymorphisms (SNPs) within ten strong candidate genes involved with antipsychotics (APs) mechanisms of action.

Methods

Two independent samples were investigated in the present study. Totals of 176 SCZ subjects and 326 controls of Korean ancestry, and 83 SCZ subjects and 194 controls of Italian ancestry were recruited and genotyped. SCZ risk and other parameters were also investigated.

Results

Concerning APs response, only a nominal association with HOMER1 rs3822568 in the Korean sample was found. In the haplotype analysis, rs9801117 C–rs12668837 C–rs4621754 A haplotype within ESYT2 and NCAPG2 genes was associated with APs response in the same sample. As for secondary outcomes, rs7439 within PKDCC and rs12668837 within NCAPG2 were associated with SCZ risk in the Italian sample. In the haplotype analysis, rs2788478 G–rs2657375 T–rs1039621 A within the region between WDR60 and ESYT genes and rs2013 C (ESYT2)–rs6459896 A (NCAPG2) haplotypes were associated with SCZ in the same sample. No association was found in the Korean sample. Finally, our exploratory data suggest a possible modulation of HOMER1, ARC, BDNF, TXNRD2, WDR60, and ESYT2 genes in the APs response to specific symptom clusters.

Conclusion

Our results did not support a primary role for the genes investigated in the APs response. On the other hand, our secondary results suggest a possible involvement of NACPG2 and PKDCC in SCZ liability. Finally, our exploratory findings may deserve further investigations in specific studies.

     

Cytochrome Oxidase and Lactate Dehydrogenase Activities in Peroxidized Rabbit Epididymal Spermatozoa/Cytochromoxydase- und Lactatdehydrogenase-Aktivität bei peroxydierten Kaninchen Spermatozoen aus dem Nebenhoden

We report a quantitative cytochemical study on cytochrome oxidase and lactate dehydrogenase activities on rabbit epididymal spermatozoa during spontaneous lipid peroxidation. Our data show that during aerobic incubation both in NTP and KTP media the sperm cytochrome oxidase activity undergoes a significant decrease. The lactate dehydrogenase activity shows different cytochemical patterns in comparison between the two media considered. Such activity significantly increases in rabbit spermatozoa suspended in NTP medium from the first until the sixteenth hour of incubation time. At the following times the lactate dehydrogenase activity significantly declines showing yet until the later times of incubation integrated optical density values fairly high. During the whole period of the aerobic incubation, the spermatozoa suspended in medium KTP show lactate dehydrogenase integrated optical density values which not significantly differ from those of the control in spite of an initial enhancement from the first until the thirteenth hour of the experimental treatment.     

Endogenous adrenergic modification of exercise-induced asthma

To determine if endogenous adrenergic activity could modify the obstructive response to exercise in subjects with asthma, we had 10 subjects undergo two bouts of cycle ergometry under controlled inspired air conditions while peak expiratory flow rates and plasma catecholamines were serially recorded. The second challenge of each pair was timed to coincide with the height of the bronchospasm induced by the first. A similar protocol was undertaken with isocapnic hyperventilation to serve as a control. The initial exercise produced bronchodilatation followed by bronchoconstriction when exercise ceased. During the second challenge, the obstruction resolved totally, only to recur once more when the subjects stopped work. Plasma concentrations of norepinephrine exactly mirrored the fluctuations in pulmonary mechanics, rising with bronchodilatation and falling with bronchoconstriction. The pattern with hyperventilation differed from exercise in that there was no significant increase in norepinephrine during the challenges. To determine if norepinephrine could abolish the bronchial narrowing produced by exercise, and, as a result, possibly account for the changes in mechanics that we observed, we performed a second study in which eight subjects were administered an aerosol of this compound to inhale during an episode of exercise-induced asthma. As with the endogenous elevation, exogenously administered norepinephrine also totally abolished the attack. These data demonstrate that the sympathoadrenal activity that occurs with repetitive exercise in subjects with asthma can materially influence the severity of exercise-induced asthma.     

The action of cisplatinum (cis-DDP) on the postnatal growth of the rat liver. Cytokinetics and ultrastructural studies

The early and late effects of cis-DDP treatment on liver cell kinetics were analyzed after its intraperitoneal injection into 17-day old rats. Frequency of binucleate hepatocytes, cellular DNA content distribution, 3H-thymidine labelling and ultrastructure of the nuclei were analyzed. Two days after treatment, a block of mononucleate hepatocytes in the S phase and in the G2 phase was demonstrated by the increase of intermediate 2c-4c and 4c DNA values in the absence of changes in 3H-thymidine labelling; 8c binucleate cells, which are essential for the formation of tetraploid mononucleate cells, were not found. In cell nuclei, large areas of more condensed chromatin appeared, perhaps providing further evidence for a G2 block. Seven days after treatment, there was a tendency to catch up with the normal situation, as shown by the unblocking of the S phase in mononucleate cells indicated by both cytophotometry and autoradiography. The presence of 8c binucleate cells and 4c-8c mononucleate cells indicates that 4c mononucleate hepatocytes are either diploid cells in the G2 phase or true tetraploid G1 cells. The decrease in the heterochromatin areas and the appearance of hypertrophic nucleoli demonstrate an increase in the metabolic activity of the nuclei. Thirty six days after treatment, the incidence of different DNA hepatocyte classes and the 3H-thymidine labelling were already similar in control and in treated rats.     

Biohumoral parameters and bone mineral content in the identification of high risk subjects for postmenopausal osteoporosis.

BACKGROUND: The aim of this study was to evaluate the possibility of identifying women with a high risk of postmenopausal osteoporosis by using computerised bone mineral analysis (CBMA) associated with markers of bone turnover in order to provide a valid and reliable screening test. METHODS: A total of 925 patients were evaluated, 252 of whom had already undergone a preliminary densitometric test six months earlier and were diagnosed as fast bone losers. 225 of them (89%) also showed altered bone turnover markers. CBMA was negative in the remaining 673 patients but 13 patients showed altered bone turnover markers and three of the latter then showed a positive CBMA 18 months later. The 673 patients who, after six months of study, were not fast bone losers were monitored over time. RESULTS: It emerges from these results that fast bone losers are characterised by higher levels of hydroxyprolinuria and calcium, lower levels of oestrone and estradiol, and reduced body weight compared to healthy subjects. CONCLUSIONS: This simplified method enabled 79% of the fast bone losers to be identified, whereas densitometry identified 87.5% of the high-risk subjects. The main advantage of our simplified method compared to the measurement of bone mineral content is that it identifies the majority of fast bone losers in the initial postmenopausal period, before a substantial reduction in BMC has taken place.     

Endometrial morphological changes in intrauterine device users

The diminution of the number of births seems to stem from a widespread use of voluntary abortions and only partially from a correct use of contraceptive methods. The IUD is not without clinical complications, such as hemorrhage, pelvic or endometrial inflammation, possibly ectopic pregnancy, perforation of the uterus, and loss of the IUD itself. In several out-patient clinics in the province of Novara Italy the morphological and/or morpho-functional alterations of the endometrium were analyzed histologically and evaluated on a percentage basis after removal of the IUD and examination of adhering endocervical or endometrial tissue fragments. The total sample comprised 50 patients between the ages of 20 and 46. Removal of the IUD was performed between the 1st and 3rd theoretical date of the menstrual cycle. In 60% of the patients sufficient endometrial material revealed, under the morphological aspect, that 50% had superficial inflammation and pseudodeciduation, 46% superficial dysplasia of the epithelium, 8% papillary formation, 4% superficial microthrombosis and 26% granular tissue and/or exudative material. Under the functional aspect, the endometrium was in the regular menstrual phase, as expected, for 20% of these patients, 18% in the proliferative and 18% in the secretory phase. The anomalous or phase-altering function and morphological alteration of the endometrium reacting to the presence of an extraneous device is probably one of the reasons for the contraceptive efficacy of the IUD. These well-documented endometrial and endocervical alterations do not contraindicate the use of the IUD but regular clinical and cytologic checkups are advised.     

Effect of adipose tissue thickness and tissue optical properties on the differential pathlength factor estimation for NIRS studies on human skeletal muscle

We propose a quantitative and systematic investigation of the differential pathlength factor (DPF) behavior for skeletal muscles and its dependence on different factors, such as the subcutaneous adipose tissue thickness (ATT), the variations of the tissue absorption (µ_a) and reduced scattering (µ′_s) coefficients, and the source-detector distance. A time domain (TD) NIRS simulation study is performed in a two-layer geometry mimicking a human skeletal muscle with an overlying adipose tissue layer. The DPF decreases when µ_a increases, while it increases when µ′_s increases. Moreover, a positive correlation between DPF and ATT is found. These results are supported by an in-vivo TD NIRS study on vastus lateralis and biceps brachii muscles of eleven subjects at rest, showing a high inter-subject and inter-muscle variability.