CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study

Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Among our group of CCM Italian patients, we selected a cohort of sporadic cases negative for mutations in CCM genes. In this cohort, five variants in CCM2 gene were detected, which proved to be the known polymorphisms in intronic regions (IVS2-36A>G and IVS8 +119 C>T) and in coding sequence (c.157 G>A in exon 2, c.358 G>A in exon 4 and c.915 G>A in exon 8). Therefore, we undertook a case-control study to investigate the possible association of these polymorphisms with sporadic CCMs. The five polymorphisms were identified in 91 CCM sporadic patients and in 100 healthy controls by direct sequencing methods using lymphocyte DNA. Polymorphisms IVS2-36A>G and c.915 G>A showed statistically significant differences in frequencies between patients and controls [(χ2, 6.583; P<0.037); (χ2, 14.205; P<0.001)]. The prevalence of the wild-type genotype was significantly lower in the CCM group than in the control sample. Patients with the A/G and G/G genotypes (IVS2-36A>G) had a significant increase for CCM risk (OR, 3.08; 95% CI, 1.5-5.9 and OR, 4.3; 95% CI, 1.4-22.6) and the same was observed for the polymorphism c.915 G> A (genotype G/A OR, 6.1; 95% CI, 3.0-12.6 and genotype A/A OR, 2.79). In addition, the polymorphisms c.358 G>A in exon 4 (χ2, 15.977; P<0.04) and c.915 G>A in exon 8 (χ2, 18.109; P<0.02) were significantly associated with different types of symptoms. Haplotype analysis, performed only on polymorphisms c.358 G>A (p.Val120Ile), c.915 G>A (p.Thr305 Thr) and IVS2-36A>G, shows that haplotype GAG (+--) significantly increased among CCM sporadic patients compared to the control group. Significant differences between patients and controls were observed only for IVS2-36A>G and c.915 G>A polymorphisms indicating their possible association with sporadic CCMs and an increased risk of CCM. On the other hand, polymorphisms c.358 G>A and c.915 G>A were associated with a more benign course of the disease. These data were confirmed by the haplotype GAG (+--) frequencies.     

Clinical differences between first and recurrent episodes in depressive patients

Background

Depressive disorder is one of the most common mental disorders in primary care. Depression is often a chronic disorder with recurrent episodes. Little is known about the differences in clinical profile between first and recurrent episodes. The aim of the study is to analyze the differences between clinical presentation of first and subsequent episodes of depressive disorders in primary care patients.

Method

A cross-sectional epidemiologic study in primary care centers in Spain was designed. A total of 10?257 primary care patients having a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depressive episode were analyzed. Clinical symptoms were measured using the Montgomery Asberg Depression Scale. Patient Health Questionnaire was used to assess somatic symptoms.

Results

There were 40.6% of patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for recurrent depression. Compared with those diagnosed of their first major depressive disorder, recurrent patients had greater rates and severity of depressive (t = −7.85, P < .001) and somatic symptoms (t = 5.64, P < .001). The severity of symptoms also increases with number of episodes (F = 40.2, P < .001, for depressive symptoms; F = 27.8, P < .001, for somatic symptoms). First-episode patients were more likely to experience reduced appetite (adjusted odds ratio, 1.2) and suicidal thoughts (adjusted odds ratio, 1.2).

Conclusion

There are differences in the clinical profile of initial and recurrent episodes in primary care depressive patients. Each recurrent depressive episode seems to have a greater impact on symptoms and well-being. The identification of a specific depression symptom profile in first or recurrent episodes is needed to improve the long-term management of major depressive episode patients in primary care settings.     

Long-term outcomes after uncomplicated mild traumatic brain injury: a comparison with trauma controls

The question as to whether mild traumatic brain injury (mTBI) results in persisting sequelae over and above those experienced by individuals sustaining general trauma remains controversial. This prospective study aimed to document outcomes 1 week and 3 months post-injury following mTBI assessed in the emergency department (ED) of a major adult trauma center. One hundred and twenty-three patients presenting with uncomplicated mTBI and 100 matched trauma controls completed measures of post-concussive symptoms and cognitive performance (Immediate Post-Concussion Assessment and Cognitive Testing battery; ImPACT) and pre-injury health-related quality of life (SF-36) in the ED. These measures together with measures of psychiatric status (the Mini-International Neuropsychiatric Interview [MINI]) pre- and post-injury, the Hospital Anxiety and Depression Scale, Visual Analogue Scale for Pain, Functional Assessment Questionnaire, and PTSD Checklist-Specific, were re-administered at follow-up. Participants with mTBI showed significantly more severe post-concussive symptoms in the ED and at 1 week post-injury. They performed more poorly than controls on the Visual Memory subtest of the ImPACT at 1 week and 3 months post-injury. Both the mTBI and control groups recovered well physically, and most were employed 3 months post-injury. There were no significant group differences in psychiatric function. However, the group with mild TBI was more likely to report ongoing memory and concentration problems in daily activities. Further investigation of factors associated with these ongoing problems is warranted.     

An introduction to recursive neural networks and kernel methods for cheminformatics

The aim of this paper is to introduce the reader to new developments in Neural Networks and Kernel Machines concerning the treatment of structured domains. Specifically, we discuss the research on these relatively new models to introduce a novel and more general approach to QSPR/QSAR analysis. The focus is on the computational side and not on the experimental one.     

The selective cyclooxygenase-1 inhibitor SC-560 suppresses cell proliferation and induces apoptosis in human hepatocellular carcinoma cells

Two isoforms of cyclooxygenase (COX) are known, and to date most studies have implicated COX-2 in the development and progression of various human cancers. Increasing evidence suggests that COX-1 may also play a similar role. Indeed, we have recently observed that the dual COX-1/COX-2 inhibitor indomethacin induces apoptosis in human hepatocellular carcinoma (HCC) cell lines more effectively than the selective COX-2 inhibitors, possibly implicating COX-1 in HCC. In this study we investigated the expression of COX-1 in non-tumor and malignant human liver tissues, as well as the effects of the highly selective COX-1 inhibitor SC-560 on cell growth and apoptosis in human HCC cell lines. Expression of COX-1 was detected in nearly all the samples assayed, although with a high variability between non-tumoral (NT) and malignant tissues. The percentage of COX-1 positive cells was significantly higher in the NT tissues than in the tumors (p<0.0001). In well-differentiated HCC COX-1 expression was significantly higher than in the poorly-differentiated tissues (p<0.05). SC-560 showed a dose- and time-dependent inhibitory effect on HCC cell growth. The combination of the COX-1 inhibitor with nimesulide and CAY10404, two selective COX-2 inhibitors, resulted in additive effects on cell growth inhibition. SC-560 also inhibited colony formation in soft agar and induced apoptosis in HCC cells in a dose-dependent manner. Moreover, SC-560 decreased the levels of the anti-apoptotic proteins survivin and XIAP and activated caspase-3 and -7 in a dose- and time-dependent fashion. In conclusion, we report for the first time that the selective COX-1 inhibitor SC-560 exhibits anti-tumor and apoptotic effects in human HCC cells. Overall, our previous and present results suggest that both COX-1 and COX-2 inhibitors may have potential therapeutic implications in HCC patients.     

Detection of Signs of Brain Dysfunction in Epileptic Children by Recognition of Transient Changes in the Correlation of Seizure-Free EEG

Seizure-free EEG signals recorded from epileptic children were compared with EEG signals recorded from normal children. The comparison was based on the detection of transient events characterized by decrease in the correlation between different traces. For this purpose, a conceptually and mathematically simple method was applied. Two clear and remarkable phenomena, able to quantitatively discriminate between the two groups of subjects, were evidenced, with high statistical significance. In fact, it was observed that: (a) The number of events for the epileptic group was larger; (b) Applying restrictive criteria for event definition, the number of subjects in the epileptic group presenting events was larger. The results support the hypothesis of a decrease in brain correlation in children with epilepsy under treatment. This confirms the efficacy of the EEG signal in evaluating cortical functional differences not visible by visual inspection, independently of the cause (epilepsy or drugs), and demonstrate the specific effectiveness of the analysis method applied.     

Testosterone, social and sexual behavior of perinatally and lifelong calorie restricted offspring

Calorie restriction (CR) during sensitive perinatal periods has consistently been demonstrated to alter the development of a variety of physiological systems, which consequently affect behavior. This study compared the social behavior and sexual behavior of the adult male offspring of mothers administered a 25% CR at one of four times in the perinatal period: a brief period preconception, during gestation, during lactation, or a lifelong restriction (beginning at conception and continuing throughout life). Levels of serum testosterone were also determined in these animals. Social interaction increased in the gestation and lifelong CR groups. The lifelong group also exhibited more dominant type behaviors. CR during preconception and lactation resulted in offspring that displayed an enhanced and more efficient copulatory pattern compared to all other conditions. This was demonstrated by a reduced frequency of intromissions, shorter latency to ejaculation, and a greater frequency of ejaculations by the preconception and lactation group compared to some, if not all of the other CR groups and controls. Serum testosterone was significantly higher in the preconception group compared to controls. These findings indicate that CR during specific periods of development can differentially alter the social behavioral phenotype and hormone levels in adulthood.     

Help-seeking and coping with the psychosocial burden of chronic hepatitis C: a qualitative study of patient, hepatologist, and counsellor perspectives

BackgroundChronic hepatitis C affects millions of people worldwide, may have significant physical consequences, and patients are also at increased risk of psychiatric morbidity. However, it is currently unknown how patients cope with, and seek help for the psychosocial issues which contribute to this psychiatric morbidity.ObjectivesThis study aimed to qualitatively explore the biopsychosocial burden of chronic hepatitis C, patients’ subsequent coping and help-seeking, and the patient–health professional relationship from the different perspectives of patients, hepatologists, and counsellors.MethodsThirteen patients, five hepatologists, and two hepatitis C specific counsellors from South Australia participated in semi-structured interviews, which were audio-recorded, transcribed verbatim, and analysed thematically.ResultsAll groups perceived chronic hepatitis C as a severe disease involving inextricably intertwined biological, psychological, and social impacts. Negative factors included the impact of diagnosis, stigmatisation, and often unwarranted fears regarding transmission and disease progression. The key positive influences reported across the groups involved information provision and access to informal and formal support. However, a number of barriers were noted to accessing this support, particularly stigmatisation. All respondents highlighted the importance of the patient–health professional relationship. This relationship was perceived to be enhanced by empathetic, compassionate professionals who provided comprehensive information in a sensitive and timely manner. Key negative influences on this relationship included discrimination or inappropriate treatment from mainstream health professionals, time constraints of doctors, patient non-attendance, and discordant views regarding treatment decisions.ConclusionsReducing the psychosocial impact of chronic hepatitis C requires targeted information provision for patients, the general public, and mainstream health services. This may increase patient education, reduce the extent and impact of stigmatisation, remove barriers to help-seeking, and improve the patient–health professional relationship.