New 1,2,3-triazolo[1,5-a]quinoxalines: synthesis and binding to benzodiazepine and adenosine receptors. II

On pursuing research about 1,2,3-triazolo[1,5-a]quinoxalines, in this paper we report synthesis and binding assays toward the benzodiazepine and A(1) and A(2A) adenosine receptors, of a new series of derivatives, bearing some structural changes (introduction of fluorine and trifluoromethyl in the seventh position, amino substituents in the fourth position, benzyl group in the fifth position and aroyl substituents in the third position). The biological tests have shown that only the 7-fluorosubstituted compounds 3a and 4a and the N-benzyl derivative 7 have a good affinity toward the benzodiazepine receptors, while only the 7-trifluoromethyl substituted compound 3b presents a moderate affinity with low selectivity toward the A(1) adenosine receptors. The other structural modifications strongly decreased biological activity.     

Assessment of Anxiety and Depression in Adolescents with Mental Retardation

This report examines the concurrent validity of different informant and self-report assessment instruments of psychopathology, both general and specific for anxiety and/or depression, in referred mentally retarded adolescents with a depressive and anxiety disorders, according to DSM IV criteria. A consecutive, unselected sample of 50 mildly and moderate mentally retarded adolescents (29 males and 21 females, aged 11.8 to 18 years, mean age 15.1) were assessed using standardized assessment techniques: Psychopathology Instrument for Mentally Retarded Adults (PIMRA) (informant version) (total score, affective and anxiety subscales), Child Behavior Checklist (CBCL) (informant version) (total score, internalizing and externalizing scores, anxiety-depression scale), Zung Self-Rating Depression Scale and Zung Self-Rating Anxiety Scale. Patterns of correlation among measures were calculated. PIMRA and CBCL total scores were closely intercorrelated. Internalizing and externalizing scores of CBCL were not intercorrelated, but they both correlated with CBCL and PIMRA total scores. Anxiety measures were positively correlated; they correlated with PIMRA and CBCL total scores, as well as with the internalizing score of CBCL. Depression measures were not correlated; their correlation with more general measures of psychopathology was weak. Clinical implications of these findings are discussed.     

Attachment and panic disorder

A dysfunctional relationship between parents and children can influence cognitive and emotional development and contribute to the development of psychiatric disorders, particularly panic disorder (PD). With the aim of exploring childhood experiences of parenting in PD patients, we compared subjectively perceived climate and objective recall by administering the Parental Bonding Instrument and 10 adjunctive items to 22 out-patients and 22 matched controls. Our analysis showed that DSM-III-R-diagnosed PD patients reported their parents to be significantly less caring than did the control group, while there was no significant difference in objective recall of parenting experiences.     

Effect of heparan sulphate on kidney tissue expression of TGF-beta,rhoA, laminin and fibronectin in subtotally nephrectomized rats

BACKGROUND: Different mitogens are involved in the pathogenesis of kidney damage after subtotal nephrectomy. One of them, TGF-beta, controls mesangial cell proliferation and interstitial fibrosclerosis. The transduction of the TGF-beta signal is controlled by intracellular signalling molecules such as Ras G monomeric proteins. Renal damage after subtotal nephrectomy (5/6 Nx) can be prevented by heparins, but so far no immunohistochemical correlation between TGF-beta, TGF-beta induced matrix molecules and Rho proteins has been investigated. Since the Ras transduction pathway has recently been associated with progression of renal damage, we evaluated the effect of heparan sulphate (HS) on the expression of TGF-beta, laminin, fibronectin and a Ras protein, RhoA, in the rat remnant kidney model. METHODS: The immunoperoxidase technique was employed to reveal the antigens on 18 remnant kidneys from 5/6 nephrectomized rats, nine untreated and nine treated with oral HS, and on seven normal kidneys from sham-operated rats. Data were semiquantitatively analyzed by an image analyzer (Quantimet, Leica). RESULTS: The expression of the antigens was significantly higher in the remnant kidneys than in normals. The high TGF-beta, laminin, fibronectin and RhoA expression observed in subtotally nephrectomized rats suggests a role for these molecules in the pathogenesis of progressive renal damage. However, apart from RhoA, HS-treated rats had significantly lower levels of the antigens than the untreated rats. CONCLUSIONS: HS treatment is associated with significantly lower renal expression of TGF-beta, laminin and fibronectin, but not of RhoA. This suggests that the renal-protective effect of HS may be obtained by modulating the TGF-beta pathway, independently of RhoA-mediated transduction.     

Frequency of RAS and p53 Mutations in Acute Promyelocytic Leukemias

The frequency of RAS and p53 mutations was investigated in 30 acute promyelocytic leukemias by single strand conformation polymorphism analysis and direct sequencing of ge-nomic DNA. Only two cases bore N-RAS codon 12 mutations and none had p53 mutations responsible for aminoacid substitutions. It would, therefore, seem that neither RAS nor p53 are involved in acute promyelocytic leukemogenesis.     

Effects of different degrees of sympathetic antagonism on cytokine network in patients with ischemic dilated cardiomyopathy

BACKGROUND: The proinflammatory cytokines have been implicated in the pathogenesis of heart failure. Recent studies have shown that beta-adrenergic blockade can modulate cytokine production. This study investigates the different impact of different degrees of sympathetic antagonism on circulating levels of cytokines in patients with heart failure resulting from ischemic dilated cardiomyopathy (IDC). METHODS AND RESULTS: Thirty-five patients with IDC were randomly assigned to receive metoprolol or carvedilol in an open-label study. Echocardiographic measurements and circulating levels of tumor necrosis (TNF)-alpha and interleukin (IL)-1beta and IL-6 were obtained at baseline and after 3 months of treatment. The 2 beta-blockers significantly improved the left ventricular ejection fraction and reduced end-diastolic and end-systolic volume. The magnitude of these changes was greater with carvedilol than with metoprolol (respectively P < .001, P < .05, and P < .05). Both treatments induced a significant decrease in the levels of cytokines (for all P < .01), but the decrease in TNF-alpha and IL-1beta was more consistent in the carvedilol group ( P < .01). CONCLUSION: Our results support the hypothesis that a more complete block of sympathetic activity by carvedilol induces a greater decrease in the circulating levels of proinflammatory cytokines that could explain, at least in part, the better improvement in the left ventricular remodelling and systolic function in patients with IDC.     

Visual evoked potentials may be recorded simultaneously with fMRI scanning: A validation study

Integrating electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data may help to optimize anatomical and temporal resolution in the investigation of cortical function. Successful removal of fMRI scanning artifacts from continuous EEG in simultaneous recordings has been reported. We assessed the feasibility of recording reliable visual evoked potentials (VEPs) during fMRI scanning using available artifact removing procedures. EEG during administration of visual stimuli was recorded using MRI-compatible 32-channel equipment in nine normal subjects (mean age, 23.9 +/- 2.5 years), with and without fMRI acquisition. fMRI scanning and cardioballistographic artifacts were removed after subtraction of averaged artifact waveforms. Consistency between VEPs waveforms and of P1 and N1 peak latencies and amplitudes in the two conditions was assessed. Good correlation was found between VEP waveforms (Pearson's correlation coefficient: r(P) between 0.76-0.94 across subjects; P < 0.0001) and between latency or amplitude of P1 and N1 peaks (latencies: r = 0.7, P < 0.035; amplitudes: r > 0.65, P < 0.05; Spearman rank correlation coefficient) in the two recording conditions. No significant differences were found between P1 and N1 parameters in the two conditions (Wilcoxon signed rank test). Consistent VEP waveforms, latencies, and amplitudes with and without fMRI scanning indicate that reliable VEPs may be obtained simultaneously with fMRI recording. This possibility might be helpful by shortening recording times and reducing variability from learning, habituation, and fatigue phenomena from separate recordings for the integration of event-related EEG and fMRI data.     

Antidepressant drug consumption and public health indicators in Italy, 1955 to 2000

OBJECTIVE: This study investigated the impact of the increasing consumption of selective serotonin reuptake inhibitors (SSRIs) and newer anti-depressants on the following public health indicators: (1) suicide rates, (2) proportion of completed suicides by poisoning with solid or liquid substances, and (3) hospital admissions for depression and proportion of admissions for depression that were first admissions. METHOD: Data collected by IMS Health on antidepressants dispensed in Italy from 1983 to 2000 were obtained from the Italian Ministry of Health, while data on suicide deaths from 1955 to 2000 were obtained from the Italian National Institute of Statistics. RESULTS: In Italy from 1983 to 2000, the use of tricyclic antidepressants remained substantially stable, and the use of SSRIs and newer agents dramatically increased. In contrast, suicide rates for males decreased from 1955 to 1974 and subsequently increased, reaching a peak in 1985 and then declining. In females, suicide rates remained substantially stable until 1978. A subsequent increase occurred up to 1985, followed by a steady decline. Suicide by poisoning using solids or liquids dropped by nearly 50% from 1986 to 2000. Admissions to the hospital for depression showed an erratic pattern; however, no decline was observed. No change was observed in the rate of first admissions for depression. CONCLUSION: Despite a reduction in suicides by poisoning using solids or liquids, the analysis of long-term trends in suicide did not suggest that increases in antidepressant prescribing lie behind recent reductions in population suicides. Furthermore, in Italy, newer antidepressants had no impact on the total number of admissions for depression or on the proportion of all admissions that were first admissions.     

Barriers to caregiver administration of pain medication in hospice care

Barriers to adequate pain management in hospice and palliative care settings are an important area of investigation. In this study, a Caregiver Pain Medicine Questionnaire (CPMQ) was developed and psychometrically tested. The CPMQ is a 22-item self-report instrument that measures concern about reporting pain, concern about administering analgesics, and difficulty administering analgesics. One hundred fifty-one caregivers of patients admitted to three Chicagoland hospice agencies participated; these individuals were family members, hired caregivers in the home, or staff nurses in skilled care facilities. While only a small percentage of the caregivers expressed concern about communicating information about the patient's pain, more than a quarter were concerned about addiction, tolerance, and side effects from medications. A fourth of the caregivers had difficulty administering medications because of fear of doing something wrong and difficulty deciding which or what amount of medications to give. Male caregivers and hired caregivers had greater concerns, both about reporting information about the patient's pain and administering medications. Greater concerns were also evident among less educated caregivers, caregivers who worked in blue-collar jobs, and caregivers who were homemakers or retired. Concerns of caregivers in the home were significantly greater than staff nurse caregivers in skilled care facilities only in the belief that pain could not be controlled and concern about addiction. Caregivers who had greater concern about addiction and tolerance, and more difficulty administering medications, rated the patient's pain as less completely controlled. These findings remind hospice staff members of the importance of assessing specific caregiver concerns about medication administration and devising appropriate strategies to address them.     

Type II Benign Osteopetrosis (Albers-Schönberg Disease) Caused by a Novel Mutation in CLCN7 Presenting with Unusual Clinical Manifestations

A 16-year-old male patient with type II autosomal dominant benign osteopetrosis (ADO) was genotyped and found to harbor a novel mutation in exon 25 of the gene encoding for the osteoclast-specific chloride channel, CLCN7, inherited from the father, who was asymptomatic. The patient had normal biochemical findings and acid-base balance, except for increased serum levels of creatine kinase, lactic dehydrogenase, and the bone formation markers bone alkaline phosphatase isoenzyme, osteocalcin and N-terminal type I collagen telopeptide/creatinine ratio. Unusual generalized osteosclerosis was observed together with a canonical increase in vertebral and pelvis bone mass. An affected first grade cousin presented with normal biochemical findings and a milder osteosclerotic pattern of the pelvis. At the cellular level, cultured osteoclasts from the patient showed increased motility, with lamellipodia, membrane ruffling and motile pattern of podosome distribution, all of which could have contributed to functional impairment of bone resorption. The present report documents a novel mutation of the CLCN7 gene causing osteopetrosis in a radiologically uncertain form of the diseases, with apparent incomplete penetrance.