Combining pharmacotherapy and psychotherapy or monotherapy for major depression? A meta-analysis on the long-term effects.

BACKGROUND: The present meta-analysis aimed to examine to what extent combined pharmacotherapy with psychotherapy results in a different response to treatment compared to psychotherapy or pharmacotherapy alone in adults with major depression at six months or longer postrandomization. METHODS: A systematic literature search resulted in 23 randomized controlled trials with 2184 participants. Combined treatment was compared to either psychotherapy or anti-depressant medication alone in both the acute phase and the maintenance phase. Odds ratios of a positive outcome were calculated for all comparisons. RESULTS: In acute phase treatment, combined psychotherapy with antidepressants outperformed antidepressants alone at six months or longer postrandomization in patients with major depressive disorder (OR=2.93, 95%CI 2.15-3.99, p<0.001). Heterogeneity was zero (95%CI 0-57%, p>0.05). However, combined therapy resulted in equal response to treatment compared to psychotherapy alone at six months or longer postrandomization. As for the maintenance treatment, combined maintenance psychotherapy with antidepressants resulted in better-sustained treatment response compared to antidepressants at six months or longer postrandomization (OR=1.61, 95%CI 1.14-2.27, p<0.05). Heterogeneity was zero (95%CI 0-68%, p>0.05). CONCLUSIONS: Combined therapy results in a superior enduring effect compared to antidepressants alone in patients with major depression. Psychotherapy is an adequate alternative for combined treatment in the acute phase as it is as effective as combined treatment in the long-term.

Electroconvulsive stimulation reverses anhedonia and cognitive impairments in rats exposed to chronic mild stress.

Electroconvulsive therapy remains the most effective treatment for depression including a fast onset of action. However, this therapeutic approach suffers from some potential drawbacks. In the acute phase this includes amnesia. Electroconvulsive stimulation (ECS) has previously been shown to reverse a depression-like state in the chronic mild stress model of depression (CMS), but the effect of ECS on cognition has not previously been investigated. In this study the CMS model was used to induce a depressive-like condition in rats. The study was designed to investigate the acute effect of ECS treatment on working memory and the chronic effect of repeated ECS treatments on depression-like behavior and working memory. The results indicated that, in the acute phase, ECS treatment induced a working memory deficit in healthy controls unexposed to stress, while repeated treatments reversed stress-induced decline in working memory, as well as recovering rats submitted to the CMS paradigm from the anhedonic-like state. Like in the clinical setting, a single ECS exposure was ineffective in inducing remission from a depression-like state.

Decreased cell proliferation in the dentate gyrus does not associate with development of anhedonic-like symptoms in rats.

Depressive disorders have been proposed to be caused by stress-induced down-regulation of hippocampal neurogenesis. Nevertheless, several reports have recently pointed out that, in rodent models of depression, suppression of generation of new hippocampal neurons is not by itself sufficient to induce the development of depression-related symptoms. In the present study, we used the cell proliferation blocker methylazoxymethanol (MAM) and the rat chronic mild stress (CMS) model of depression to challenge the neurogenic theory of depression. In order to achieve a comparable reduction in hippocampal cytogenesis, rats were either chronically treated with MAM for 2 weeks, or subjected to an 8 week regime of chronic mild stress. Consumption of a palatable sucrose solution was monitored once a week to assess the development of anhedonic behavior. Prior to terminal perfusion, the animals were injected with bromodeoxyuridine, a marker of proliferating cells. The number of proliferating cells and total cell number and volume were estimated for the granule cell layer of the ventral hippocampal formation. Unlike CMS, chronic injections with MAM did not induce anhedonia-like symptoms in rats. Both MAM-treated and CMS-exposed groups of rats showed a comparable significant reduction in cell proliferation in the granular cell layer of the ventral hippocampal formation. However, the total cell number was reduced for CMS-exposed rats only while the granule cell layer volume was conserved for both groups. Our results show that suppression of cell proliferation in the hippocampal formation is not an absolute factor for induction of an anhedonia-like state in rats. However, it may still represent an important causal factor for vulnerable subjects.

Distribution of ATPase and ATP-to-ADP phosphate exchange activities in magnesium chelatase subunits of Chlorobium vibrioforme and Synechocystis PCC6803.

Insertion of magnesium into protoporphyrin IX is a complex ATP-dependent reaction catalysed by the enzyme Mg-chelatase. Three separate proteins (Mg-chelatase subunits), designated as D, H and I, are involved in the chelation reaction. The genes encoding the Mg-chelatase subunits of the green sulfur bacterium Chlorobium vibrioforme and of the cyanobacterium Synechocystis strain PCC6803 were expressed in Escherichia coli. The recombinant proteins were purified, tested for ATPase and phosphate exchange activities, and compared with the activities of the corresponding subunits of Rhodobacter sphaeroides. The Synechocystis strain PCC6803 I subunit and the C. vibrioforme H and I subunits hydrolysed ATP at the rates of 2.0, 1.8 and 0.16 nmol (mg protein)-1 min-1, respectively. The ATPase activity of the C. vibrioforme H subunit was similar to that reported for the R. sphaeroides H subunit. The Synechocystis strain PCC6803 H subunit failed to hydrolyse ATP. The I subunit of Synechocystis strain PCC6803 and C. vibrioforme catalysed a transfer of PO4 from ATP to ADP (exchange activity) at the rate of 1.75 +/- 0.15 nmol (mg protein)-1 min-1. This exchange rate was 300-fold lower than that reported for the R. sphaeroides I subunit. The PO4 exchange activities were correlated with the presence of the sequence GXRGTGKSTXVRALA in the primary structure of the three I subunits. Mg-chelatase activity was reconstituted by combining the three subunits of the same bacterium [rates of 41-89 pmol Mg-deuteroporphyrin (mg protein)-1 min-1]. Heterologous subunit combinations resulted in low or no Mg-chelatase activity.

Reconstitution of an active magnesium chelatase enzyme complex from the bchI, -D, and -H gene products of the green sulfur bacterium Chlorobium vibrioforme expressed in Escherichia coli.

Magnesium-protoporphyrin chelatase, the first enzyme unique to the (bacterio)chlorophyll-specific branch of the porphyrin biosynthetic pathway, catalyzes the insertion of Mg2+ into protoporphyrin IX. Three genes, designated bchI, -D, and -H, from the strictly anaerobic and obligately phototrophic green sulfur bacterium Chlorobium vibrioforme show a significant level of homology to the magnesium chelatase-encoding genes bchI, -D, and -H and chlI, -D, and -H of Rhodobacter sphaeroides and Synechocystis strain PCC6803, respectively. These three genes were expressed in Escherichia coli; the subsequent purification of overproduced BchI and -H proteins on an Ni2+-agarose affinity column and denaturation of insoluble BchD protein in 6 M urea were required for reconstitution of Mg-chelatase activity in vitro. This work therefore establishes that the magnesium chelatase of C. vibrioforme is similar to the magnesium chelatases of the distantly related bacteria R. sphaeroides and Synechocystis strain PCC6803 with respect to number of subunits and ATP requirement. In addition, reconstitution of an active heterologous magnesium chelatase enzyme complex was obtained by combining the C. vibrioforme BchI and -D proteins and the Synechocystis strain PCC6803 ChlH protein. Furthermore, two versions, with respect to the N-terminal start of the bchI gene product, were expressed in E. coli, yielding ca. 38- and ca. 42-kDa versions of the BchI protein, both of which proved to be active. Western blot analysis of these proteins indicated that two forms of BchI, corresponding to the 38- and the 42-kDa expressed proteins, are also present in C. vibrioforme.

Structure and organization of a 25 kbp region of the genome of the photosynthetic green sulfur bacterium Chlorobium vibrioforme containing Mg-chelatase encoding genes.

A region comprising approximately 25 kbp of the genome of the strictly anaerobic and obligate photosynthetic green sulfur bacterium Chlorobium vibrioforme has been mapped, subcloned and partly sequenced. Approximately 15 kbp have been sequenced in it's entirety and three genes with significant homology and feature similarity to the bchI, -D and -H genes and the chlI, -D and -H genes of Rhodobacter and Synechocystis strain PCC6803, respectively, which encode magnesium chelatase subunits, have been identified. Magnesium chelatase catalyzes the insertion of Mg2+ into protoporphyrin IX, and is the first enzyme unique to the (bacterio)chlorophyll specific branch of the porphyrin biosynthetic pathway. The organization of the three Mg-chelatase encoding genes is unique to Chlorobium and suggests that the magnesium chelatase of C. vibrioforme is encoded by a single operon. The analyzed 25 kbp region contains five additional open reading frames, two of which display significant homology and feature similarity to genes encoding lipoamide dehydrogenase and genes with function in purine synthesis, and another three display significant homology to open reading frames with unknown function in distantly related bacteria. Putative E. coli sigma 70-like promoter sequences, ribosome binding sequences and rho-independent transcriptional stop signals within the sequenced 15 kbp region are related to the identified genes and orfs. Southern analysis, restriction mapping and partial sequencing of the remaining ca. 10 kbp of the analyzed 25 kbp region have shown that this part includes the hemA, -C, -D and -B genes (MOBERG and AVISSAR 1994), which encode enzymes with function in the early part of the biosynthetic pathway of porphyrins.

Expression of the chlI, chlD, and chlH genes from the Cyanobacterium synechocystis PCC6803 in Escherichia coli and demonstration that the three cognate proteins are required for magnesium-protoporphyrin chelatase activity.

Magnesium-protoporphyrin chelatase catalyzes the first step unique to chlorophyll synthesis: the insertion of Mg2+ into protoporphyrin IX. Genes from Synechocystis sp. PCC6803 with homology to the bchI and bchD genes of Rhodobacter sp. were cloned using degenerate oligonucleotides. The function of these genes, putatively encoding subunits of magnesium chelatase, was established by overexpression in Escherichia coli, including the overexpression of Synechocystis chlH, previously cloned as a homolog of the Rhodobacter bchH gene. The combined cell-free extracts were able to catalyze the insertion of Mg2+ into protoporphyrin IX in an ATP-dependent manner and only when the products of all three genes were present. The ChlH, ChlI, and ChlD gene products are therefore assigned to the magnesium chelatase step in chlorophyll a biosynthesis in Synechocystis PCC6803. The primary structure of the Synechocystis ChlD protein reveals some interesting features; the N-terminal half of the protein shows 40-41% identity to Rhodobacter BchI and Synechocystis ChlI, whereas the C-terminal half displays 33% identity to Rhodobacter BchD. This suggests a functional as well as an evolutionary relationship between the "I" and "D" genes.

Structural genes for Mg-chelatase subunits in barley: Xantha-f, -g and -h.

Barley mutants in the loci Xantha-f, Xantha-g and Xantha-h, when fed with 5-aminolevulinate in the dark, accumulate protoporphyrin IX. Mutant alleles at these loci that are completely blocked in protochlorophyllide synthesis are also blocked in development of prolamellar bodies in etioplasts. In contrast to wild type, the xan-f, -g and -h mutants had no detectable Mg-chelatase activity, whereas they all had methyltransferase activity for synthesis of Mg-protoporphyrin monomethyl ester. Antibodies recognising the CH42 protein of Arabidopsis thaliana and the OLIVE (OLI) protein of Antirrhinum majus immunoreacted in wild-type barley with 42 and 150 kDa proteins, respectively. The xan-h mutants lacked the protein reacting with antibodies raised against the CH42 protein. Two xan-f mutants lacked the 150 kDa protein recognised by the anti-OLI antibody. Barley genes homologous to the A. majus olive and the A. thaliana Ch-42 genes were cloned using PCR and screening of cDNA and genomic libraries. Probes for these genes were applied to Northern blots of RNA from the xantha mutants and confirmed the results of the Western analysis. The mutants xan-f27, -f40, -h56 and -h57 are defective in transcript accumulation while -h38 is defective in translation. Southern blot analysis established that h38 has a deletion of part of the gene. Mutants xan-f10 and -f41 produce both transcript and protein and it is suggested that these mutations are in the catalytic sites of the protein. It is concluded that X an-f -h genes encode two subunits of the barley Mg-chelatase and that X an-g is likely to encode a third subunit. The XAN-F protein displays 82% amino acid sequence identity to the OLI protein of Antirrhinum, 66% to the Synechocystis homologue and 34% identity to the Rhodobacter BchH subunit of Mg-chelatase. The XAN-H protein has 85% amino acid sequence identity to the Arabidopsis CH42 protein, 69% identity to the Euglena CCS protein, 70% identity to the Cryptomonas BchA and Olisthodiscus CssA proteins, as well as 49% identity to the Rhodobacter BchI subunit of Mg-chelatase. Identification of the barley X an-f and X an-h encoded proteins as subunits required for Mg-chelatase activity supports the notion that the Antirrhinum OLI protein and the Arabidopsis Ch42 protein are subunits of Mg-chelatase in these plants. The expression of both thet X an-f and -h genes in wild-type barley is light induced in leaves of greening seedlings, and in green tissue the genes are under the control of a circadian clock.

Structure and expression of a nitrite reductase gene from bean (Phaseolus vulgaris) and promoter analysis in transgenic tobacco.

A structural gene encoding nitrite reductase (NiR) in bean (Phaseolus vulgaris) has been cloned and sequenced. The NiR gene is present as a single copy encoding a protein of 582 amino acids. The bean NiR protein is synthesized as a precursor with an amino-terminal transit peptide (TP) consisting of 18 amino acid residues. The bean NiR transit peptide shows similarity to the TPs of other known plant NiRs. The NiR gene is expressed in trifoliate leaves and in roots of 20-day old bean plants where transcript accumulation is nitrate-inducible. Gene expression occurs in a circadian rhythm and induced by light in leaves of dark-adapted plants. A particular 100 bp sequence is present in the promoter and in the first intron of the NiR gene. Several copies of this 100 bp sequence are present in the bean genome. Comparisons between the promoter of the bean NiR gene and of two bean nitrate reductase genes (NR1 and NR2) show a limited number of conserved motifs, although the genes are presumed to be co-regulated. Comparisons are also made between the bean NiR promoter and the spinach NiR promoter. Transformation of tobacco plants with the bean NiR promoter fused to the GUS reporter gene (beta-glucuronidase) shows that the bean NiR promoter is nitrate-regulated and that the presence of the 100 bp sequence influences the level of GUS activity. NiR-coding sequences are not required for nitrate regulation but have a quantitative effect on the measured GUS activity.

A cDNA clone encoding a 10.8 kDa photosystem I polypeptide of barley.

A cDNA clone encoding the barley photosystem I polypeptide which migrates with an apparent molecular mass of 16 kDa on SDS-polyacrylamide gels has been isolated. The 634 bp sequence of this clone has been determined and contains one large open reading frame coding for a 15,457 Da precursor polypeptide. The molecular mass of the mature polypeptide is 10,821 Da. The amino acid sequence of the transit peptide indicates that the polypeptide is routed towards the stroma side of the thylakoid membrane. The hydropathy plot of the polypeptide shows no membrane-spanning regions.

No fallacies in the formulation of the paternity index.

In a recent publication, Li and Chakravarti claim to have shown that the paternity index is not a likelihood ratio. They present a method of estimating the prior probability of paternity from a sample of previous court cases on the basis of exclusions and nonexclusions. They propose calculating the posterior probability on the basis of this estimated prior and the test result expressed as exclusion/nonexclusion. Their claim is wrong--the paternity index is a likelihood-ratio, that is, the ratio of the likelihood of the observation conditional on the two mutually exclusive hypotheses. Their proposed method of estimating the prior has been long known, has been applied to several samples, and is inferior (in terms of variance of the estimate) to maximum likelihood estimation based on all the phenotypic information available. Their proposed "new method" of calculating a posterior probability is based on the use of a less informative likelihood ratio 1/(1-PE) instead of Gürtler's fully informative paternity index X/Y (Acta Med Leg Soc Liege 9:83-93, 1956), but is otherwise identical to the Bayesian approach originally introduced by Essen-Möller in 1938.

Atopic dermatitis. A genetic-epidemiologic study in a population-based twin sample.

Atopic dermatitis is a multifactorial disease that seems both to rise in frequency and to be dependent on a genetic predisposition. In order to clarify these issues we encircled a representative twin series with atopic dermatitis from a total twin population of 592 like-sexed twin pairs. We found that the cumulative incidence rate (0-7 years) of atopic dermatitis in Denmark has increased significantly from 0.03 for the birth cohort 1960-1964 to 0.10 for the birth cohort 1970-1974, that monozygotic twin pairs are more often concordant for atopic dermatitis than dizygotic twin pairs, that monozygotic twins run a risk of 0.86 of having atopic dermatitis if the twin partner has the disease, whereas the disease risk of 0.21 run by dizygotic partners does not differ from the frequency seen in ordinary brothers and sisters. The results indicate that genetic factors play a decisive role in the development of atopic dermatitis and that widespread environmental factors are operating in genetically susceptible individuals.

Sequence of two genes in pea chloroplast DNA coding for 84 and 82 kD polypeptides of the photosystem I complex.

The genes encoding the two P700 chlorophyll a-apoproteins of the photosystem I complex were localized on the pea (Pisum sativum) chloroplast genome. The nucleotide sequence of the genes and the flanking regions has been determined. The genes are separated by 25 bp and are probably cotranscribed. The 5' terminal gene (psaA1) codes for a 761-residue protein (MW 84.1 kD) and the 3' terminal gene (psaA2) for a 734-residue protein (MW 82.4 kD). Both proteins are highly hydrophobic and contain eleven putative membrane-spanning domains. The homology to the corresponding polypeptides from maize are 89% and 95% for psaA1 and psaA2, respectively. A putative promoter has been identified for the psaA1 gene, and potential ribosome binding sites are present before both genes.

Divergence of chloroplast gene organization in three legumes: Pisum sativum, Vicia faba and Phaseolus vulgaris.

Isolated chloroplasts from Pisum sativum were found to contain at least 32 tRNA species. Hybridization of in vitro labeled, identified, chloroplast tRNAs to Pisum chloroplast DNA fragments revealed the locations of the tRNA genes on the circular chloroplast genome. Comparison of this gene map to the maps of Vicia faba and Phaseolus vulgaris showed that the chloroplast genomes of Pisum and Phaseolus are otherwise more closely related than either genome is to the chloroplast genome of Vicia. Furthermore, the results suggest how possible recombination events could be involved in the evolution of these three closely related, but divergent, chloroplast genomes.

Structure of a 3.2 kb region of pea chloroplast DNA containing the gene for the 44 kD photosystem II polypeptide.

The gene for the 44 kD chlorophyll a-binding photosystem II polypeptide has been localized on the pea (Pisum sativum) chloroplast genome. The nucleotide sequence of the gene and its flanking regions has been analyzed. The gene codes for a polypeptide of 473 amino acid residues and is possibly cotranscribed with the gene for the D2 photosystem II polypeptide with which it has 50 bp in common. The amino acid sequences of the 44 kD polypeptides from pea, spinach and maize are approximately 95% homologous. Within the 1 kb fragment 3' to the 44 kD gene a 93 bp tRNA-Ser (UGA) gene and an open reading frame of 62 codons (ORF 62) were identified. Both show high homology to corresponding genes 3' to the 44 kD genes from spinach, maize and barley. The 44 kD gene and ORF 62 are encoded in the same strand, and have putative promoter sequences, ribosome binding sites and transcription termination signals.

Familial cranial diabetes insipidus: a report of five families. Genetic, diagnostic and therapeutic aspects.

Five families were studied in which cranial diabetes insipidus occurred. In the pedigrees presented, the disease clearly followed an autosomal dominant mode of inheritance. Linkage analysis was performed in one large family by calculating lod scores for linkage between loci for cranial diabetes insipidus and 18 polymorphic markers and chromosome heteromorphisms. No significant genetic linkage was found and only one of the polymorphic markers gave a positive hint of linkage. A water deprivation test was performed in nine patients from three of the families and in healthy control subjects. The plasma concentration of arginine vasopressin was very low or undetectable in the patients, and unlike the control subjects did not increase significantly during water deprivation. Arginine vasopressin and serum osmolality (Sosm) were significantly positively correlated in the controls, but not in the patients. The results indicated that an arginine vasopressin-level lower than 2 pg/ml strongly suggests a diagnosis of cranial diabetes insipidus if at the same time Sosm is higher than 295 mosmol/kg. Studies with different intranasal dosages of 1-deamino-D-arginine-vasopressin (DDAVP) given once or twice a day showed that 20 micrograms effectively reduced urinary output and that administration once a day could be sufficient.