Error-related brain activity in adolescents with obsessive-compulsive disorder and major depressive disorder.

BACKGROUND: The error-related negativity (ERN) is a negative deflection in the event-related potential following a mistake that is often increased in patients with obsessive-compulsive disorder (OCD). The relationship of the ERN to comorbid major depressive disorder (MDD) has not been examined in adolescents with OCD. This study compared ERN amplitudes in OCD patients with MDD (OCD + MDD), OCD patients without MDD (OCD - MDD), MDD patients, and healthy controls (HC). METHOD: The ERN, correct response negativity, and accuracy were measured during a flanker task to assess performance monitoring in 53 adolescents with a lifetime diagnosis of OCD, 36 adolescents with a lifetime diagnosis of MDD, and 89 age-matched HC of 13-18 years. Fourteen OCD patients had a history of MDD. RESULTS: ERN amplitude was significantly increased in OCD patients compared to HC and significantly correlated in OCD patients with age at OCD symptom onset, particularly in the OCD - MDD patients. The ERN was significantly enlarged in OCD + MDD patients compared to HC, but not in MDD patients compared to HC. There was a trend for an increased ERN amplitude in OCD - MDD patients compared to HC. OCD patients were significantly less accurate than either MDD patients or HC. CONCLUSIONS: An enlarged ERN is a neural correlate of adolescent OCD that is associated with age at OCD symptom onset. Adolescents with OCD may have impaired cognitive control on a flanker task. Follow-up studies with larger samples may determine whether an enlarged ERN in adolescents with OCD is associated with a higher risk for MDD.

Constitutive abnormal expression of RasGRP-1 isoforms and low expression of PARP-1 in patients with systemic lupus erythematosus.

OBJECTIVE: Defective expression of Ras guanil releasing protein-1 (RasGRP-1) and increased apoptosis have been reported in lymphocytes from SLE patients. Whether these aberrations are correlated and linked to disease activity has not been elucidated. METHODS: Expression of normal 90 kDa RasGRP-1, its most prevalent 86 kDa isoform and full PARP-1 116 kDa and its cleavage fragment 84 kDa were determined in whole protein lysates of peripheral blood mononuclear cells (PBMC) in correlation with mitogen activated protein kinase (MAPK) activity and SLE clinical status in a large group of SLE patients during 1 year follow-up. RESULTS: Expression of normal 90 kDa RasGRP-1 was comparable in patients and controls. However, SLE patients demonstrated a constitutively increased 86 kDa/90 kDA ratio (p < 0.01) and decreased full poly (ADP-ribose) polymerase protein-1 (PARP-1) expression (p < 0.002) compared with controls who were disease-independent. A remission in disease activity was associated with decreased RasGRP-1 expression. Expression of 84 kDa PARP-1 cleavage fragment was found in 15% of patients but in none of the controls. In addition, expression of PARP-1 correlated positively with normal 90 kDa RasGRP-1 expression and negatively with the RasGRP-1 86 kDa/90 kDA ratio. CONCLUSIONS: These data suggest that constitutive aberrant expression of PARP-1 and RasGRP-1 ratio may act in concert to impair survival of lymphocytes in SLE patients.

Increased ERK and JNK activities correlate with disease activity in patients with systemic lupus erythematosus.

BACKGROUND: Aberrant signalling along the p21ras/MAP kinase pathway has been demonstrated in systemic lupus erythematosus (SLE). OBJECTIVE: To determine whether expression and activity of the MAP kinases ERK and JNK reflect disease activity in patients with SLE. METHODS: Blood samples of 42 outpatients with SLE were prospectively collected during four consecutive visits. The control group included 20 healthy subjects. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Expression of total ERK and JNK kinases and their active forms (pERK and pJNK) was determined in whole protein lysates of peripheral blood mononuclear cells. RESULTS: The mean levels of the active kinases pERK and pJNK were significantly increased in patients with active disease (SLEDAI 4-20) as compared with patients with inactive disease (SLEDAI 0-3), p = 0.04, as well as with healthy controls, p = 0.03 and p = 0.003 for pERK and pJNK, respectively. The percentage of activated forms of ERK and JNK of the total expression of these MAP kinases was also gradually increased, reaching 50% for pERK and >40% for pJNK in patients with SLE with moderate-to-severe disease (SLEDAI 7-20), p = 0.005, p = 0.005 and p = 0.02, p = 0.05 as compared with controls and inactive patients, respectively. A decrease of more than three SLEDAI points was associated with a significant reduction in the expression of both total and activated forms of ERK and JNK, p = 0.03, p = 0.01, respectively. CONCLUSIONS: The results show that ERK and JNK activity reflects disease activity in patients with SLE. These MAP kinases may serve as additional tools for the evaluation of disease activity and management of these patients.

Withdrawn/Depressed Behaviors and Error-Related Brain Activity in Youth With Obsessive-Compulsive Disorder.

OBJECTIVE: The pathophysiology of obsessive-compulsive disorder (OCD) involves increased activity in corticostriatal circuits connecting the anterior cingulate cortex with other brain regions. The error-related negativity (ERN) is a negative deflection in the event-related potential after an incorrect response that is believed to reflect anterior cingulate cortex activity. This study examined the relation of the ERN to OCD symptom dimensions and other childhood symptom dimensions. METHOD: The ERN, correct response negativity, and accuracy were measured during a flanker task to assess performance monitoring in 80 youth with a lifetime diagnosis of OCD and 80 matched healthy comparison participants ranging from 8 to 18 years old. The relation of the ERN to OCD symptom dimension scores and Child Behavior Checklist Syndrome Scale scores was examined in multiple linear regression analyses. RESULTS: Accuracy was significantly decreased and ERN amplitude was significantly increased in patients compared with controls. ERN amplitude in patients was significantly correlated with accuracy, but not with OCD symptom dimensions, severity, comorbidity, or treatment. In a multiple linear regression analysis using age, accuracy, OCD, and Child Behavior Checklist Syndrome Scale scores as predictors of ERN amplitude, the ERN had significant associations only with Withdrawn/Depressed Scale scores and accuracy. CONCLUSION: An enlarged ERN is a neural correlate of pediatric OCD that is independent of OCD symptom expression and severity. The finding of lower accuracy in pediatric cases requires replication. The relation between an enhanced ERN and withdrawn/depressed behaviors warrants further research in youth with OCD and other internalizing disorders.

Characterization of a short unique sequence in the yeast HO gene promoter that regulates HO transcription in a SIN1 dependent manner.

Recently it has become clear that general chromatin proteins as well as sequence-specific DNA binding proteins are important in the control of gene expression. SIN1 in Saccharomyces cerevisiae is a chromatin component that regulates the transcription of a family of genes. Previously, we identified a 32 bp unique sequence (here termed XBS) in the promoter of one of those genes, HO, which specifically binds a protein that interacts with SIN1. We also found that this sequence can function as a weak UAS in a heterologous promoter that is dependent on the presence of SIN1. Here we report a relationship between the level of HO expression and the presence of the short sequence in situ in the HO gene. By comparing the expression of HO from wild type or XBS deleted HO promoters, we concluded that XBS serves as a weak UAS in situ in the HO gene, that it influences HO transcription via the SWI/SNF complex, and that sequences other than the XBS mediate the effect of SIN1 on HO transcription. In addition, we show that a portion of the SIN1 protein that has sequence similarity to mammalian HMG1 preferentially binds the XBS.

Association of yeast SAP1, a novel member of the 'AAA' ATPase family of proteins, with the chromatin protein SIN1.

The yeast SIN1 protein is a nuclear protein that together with other proteins behaves as a transcriptional repressor of a family of genes. In addition, sin1 mutants are defective in proper mitotic chromosome segregation. In an effort to understand the basis for these phenotypes, we employed the yeast two-hybrid system to identify proteins that interact with SIN1 in vivo. Here, we demonstrate that SAP1, a novel protein belonging to the 'AAA' family of ATPases, is able to directly interact with SIN1. Furthermore, we show, using recombinant molecules in vitro, that a short 27 amino acid sequence near the N-terminal of SIN1 is sufficient to bind SAP1. Previous experiments defined different domains of SIN that interact with other proteins and with DNA. The C-terminal domain of SIN1 was shown to be responsible for interaction with a protein that binds the regulatory region of HO, a gene whose transcription is repressed by SIN1. The central 'HMG1-like region' of SIN1 binds DNA, while the N-terminal of SIN1 can bind CDC23, a protein that regulates chromosome segregation. These data, taken together with the results presented here, suggest that SIN1 is a multifunctional chromatin protein that can interact with a number of different proteins that are involved in several different cellular functions.

Partial lipodystrophy, mesangiocapillary glomerulonephritis, and complement dysregulation. An autoimmune phenomenon.

Partial lypodistrophy (PLD) is a rare disease in which, there is loss of fat usually from the upper part of the body. The disease is frequently associated with mesangiocapillary (membranoproliferative) glomerulonephritis Type II (MCGN II). In the early 1970s, it was noticed that MCGN II and/or PLD was sometimes associated with dysfunction of the complement system as reported in several case descriptions and studies. Subsequently, an IgG autoantibody was detected-C3 nephritic factor (C3NeF). The target of this autoantibody is the alternative pathway C3 convertase-C3bBb. There are sporadic case reports that linked PLD, MCGNII, and C3NeF with autoimmune diseases. This association may be more than a coincidence. The complement deficiency may lead to perturbation of the immune system, which may trigger some of the autoimmune diseases. This article will be focused on the association among PLD, MCGN II and C3NeF.

Solitary eosinophilic granuloma of sternum: case report with review of the literature.

A solitary lesion in the distal sternum in a 30-year-old woman caused by eosinophilic granuloma (EG) is reported. Bone scan with 99Tcm was negative. Laboratory tests were completely normal. Although EG bone lesions have been discussed extensively in the literature only one similar case of solitary EG of the sternum has been published to date. A comprehensive summary of the literature is presented.

Hepatitis in a family infected by Chlamydia psittaci.

Hepatic involvement is considered a rare complication of psittacosis. Occurrence of icteric hepatitis as the cardinal manifestation of the disease has been rarely reported. We describe two members of a family infected by psittacosis, in whom icteric hepatitis was the prominent expression of the disease. The diagnosis of psittacosis was confirmed by isolation of the pathogen and by detection of serum antibodies to Chlamydia species. No serological evidence for acute TWAR infection was found. Chlamydia psittaci was also isolated from the family's parrot.

Multisystem presentation of eosinophilic fasciitis.

A 20-year-old man experienced the onset of progressive scleroderma-like skin changes with eosinophilia and hypergammaglobulinaemia after strenuous military activity. A biopsy showed faciitis. Concomitant splenomegaly, polysynovitis, restrictive lung function, myositis, decrease hepatic clotting factors and proteinuria were documented. He responded well to corticosteroids, relapse upon their discontinuation and had a complete remission of both skin and systemic features while on penicillamine and azathioprine. He is new in good health and has received no medication for the past two years.

Should acute gold overdose be invariably treated?

Acute gold overload is rare and its clinical and pathophysiological consequences are not well delineated. Consequently the therapeutic approach has not been formulated. We describe 2 patients with rheumatoid arthritis in whom an acute gold overload was inadvertently administered. Their subsequent course, without specific treatment, was benign and uneventful. We suggest that with similar cases a conservative approach of watchful expectancy be adopted.

SIN1 interacts with a protein that binds the URS1 region of the yeast HO gene.

Evidence has recently been mounting suggesting that a number of chromatin components previously thought to primarily or exclusively have structural function, also have a regulatory role in eukaryotic transcription. Notably, in yeast, histone H4 N-terminal sequence has been shown to be required for promoter activation of certain genes in vivo, and mutations in histone H3 (SIN2) or in SIN1 (which has some sequence similarity to HMG1) are able to suppress swi1, swi2, and swi3 mutations, restoring transcription to HO as well as a number of other genes. In this paper we report the identification of a novel protein or protein complex that specifically binds a short sequence in the HO regulatory region on the one hand, and on the other somehow appears to contact the SIN1 protein. We have shown that the DNA binding activity itself does not contain SIN1, since extracts from sin1 delta strains retain the activity. Interestingly, extracts made from cells carrying the dominant sin1-2 point mutation lack the binding activity. Furthermore, bacterially produced sin1-2 protein can dissociate a DNA/protein complex while a similarly produced SIN1 protein has no effect on the complex at similar concentrations. When the DNA sequence to which the protein complex binds is placed in a CYC1 promoter lacking a UAS (upstream activating sequence), it can serve as a weak UAS in a SIN1 dependent way. Our data imply that a sequence specific DNA binding protein(s) may mediate between the SIN1 protein and the basal transcription apparatus transcribing HO.

Sarcoid nephrocalcinotic renal failure reversed by sodium cellulose phosphate.

A case of renal failure due to sarcoidosis with hypercalciuria and nephrocalcinosis is described. Prolonged treatment with inorganic absorbable phosphate significantly deteriorated the patient's renal function. After a sodium cellulose phosphate treatment, renal failure was completely reversed. We suggest that sodium cellulose phosphate is the treatment of choice in sarcoidotic renal failure induced by nephrocalcinosis.

The C-terminal domain of SIN1 in yeast interacts with a protein that binds the URS1 region of the yeast HO gene.

A protein or protein complex has previously been identified in Saccharomyces cerevisiae which both binds a short DNA sequence in URS1 of HO and interacts with SIN1. SIN1, which has some sequence similarity to mammalian HMG1, is an abundant chromatin protein in yeast and is thought to participate in the transcriptional repression of a specific family of genes. SIN1 binds DNA weakly, though it has no DNA binding specificity. Here we address the nature of the interaction between SIN1 and the specific DNA binding protein(s) to HO DNA. We show that the isolated C-terminal region of SIN1 can interact in vitro with the DNA binding protein, causing a supershift in a gel mobility shift assay. Interestingly, inclusion of the region in SIN1 which contains two acidic sequences, precludes the binding of recombinant protein to the DNA/protein complex.

Association of yeast SIN1 with the tetratrico peptide repeats of CDC23.

The yeast SIN1 protein is a nuclear protein that together with other proteins behaves as a transcriptional repressor of a family of genes. In addition, sin1 mutants are defective in proper mitotic chromosome segregation. In an effort to understand the basis for these phenotypes, we employed the yeast two-hybrid system to identify proteins that interact with SIN1 in vivo. Here we demonstrate that CDC23, a protein known to be involved in sister chromatid separation during mitosis, is able to directly interact with SIN1. Furthermore, using recombinant molecules in vitro, we show that the N terminal of SIN1 is sufficient to bind a portion of CDC23 consisting solely of tetratrico peptide repeats. Earlier experiments identified the C-terminal domain of SIN1 to be responsible for interaction with a protein that binds the regulatory region of HO, a gene whose transcription is repressed by SIN1. Taken together with the results presented here, we suggest that SIN1 is a chromatin protein having at least a dual function: The N terminal of SIN1 interacts with the tetratrico peptide repeat domains of CDC23, a protein involved in chromosome segregation, whereas the C terminal of SIN1 binds proteins involved in transcriptional regulation.

Schistosomiasis, helminth infection and health education in Tanzania: achieving behaviour change in primary schools.

Over a period of one school year a study was carried out into the feasibility and effectiveness of introducing active teaching methods into primary schools in Tanzania with a view to enhancing health education. The Lushoto Enhanced Health Education Project had as a focus personal hygiene with reference to the control of schistosomiasis and helminth infections. When a randomly selected group of children were compared with a comparison group there was evidence of changes in both knowledge and health-seeking behaviour. The passing of messages from children to the community met with mixed results. The observed changes were still evident over 1 year after the project had ended.

Heavy schistosomiasis associated with poor short-term memory and slower reaction times in Tanzanian schoolchildren.

Cross-sectional studies of the relationship between helminth infection and cognitive function can be informative in ways that treatment studies cannot. However, interpretation of results of many previous studies has been complicated by the failure to control for many potentially confounding variables. We gave Tanzanian schoolchildren aged 9-14 a battery of 11 cognitive and three educational tests and assessed their level of helminth infection. We also took measurements of an extensive range of potentially confounding or mediating factors such as socioeconomic and educational factors, anthropometric and other biomedical measures. A total of 272 children were moderately or heavily infected with Schistosoma haematobium, hookworm or both helminth species and 117 were uninfected with either species. Multiple regression analyses, controlling for all confounding and mediating variables, revealed that children with a heavy S. haematobium infection had significantly lower scores than uninfected children on two tests of verbal short-term memory and two reaction time tasks. In one of these tests the effect was greatest for children with poor nutritional status. There was no association between infection and educational achievement, nor between moderate infection with either species of helminth and performance on the cognitive tests. We conclude that children with heavy worm burdens and poor nutritional status are most likely to suffer cognitive impairment, and the domains of verbal short-term memory and speed of information processing are those most likely to be affected.