Computer-aided psychotherapy: revolution or bubble?

Research into computer-aided psychotherapy is thriving around the world. Most of it concerns computer-aided cognitive-behavioural therapy (CCBT). A recent narrative review found 97 computer-aided psychotherapy systems from nine countries reported in 175 studies, of which 103 were randomised controlled trials. The rapid spread of the mass delivery of psychotherapy through CCBT, catalysed in the UK by the National Institute for Health and Clinical Excellence's recommendation of two CCBT programmes and the Department of Health's CCBT implementation guidance, seems unprecedented. This editorial is a synopsis of the current status of CCBT and its future directions.

The effectiveness of computerized cognitive behavioural therapy in routine care.

OBJECTIVES AND DESIGN: The efficacy of a Computerized Cognitive Behavioural Therapy (CCBT) package, Beating the Blues, has been demonstrated in a large randomized controlled trial. The current study tests the generalizability of this finding in a naturalistic non-randomized trial. METHOD: 219 patients with anxiety and/or depression were recruited to receive CCBT in routine care. The Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) and Work and Social Adjustment scale (WSA) were administered pre-treatment, immediately on completing treatment and at 6 months post-treatment. Single-item self-report measures of anxiety and depression were also collected during each treatment session. RESULTS: Completer and intention-to-treat analysis demonstrated statistically and clinically significant improvements on the CORE-OM, WSA and in self-reported anxiety and depression. Intention-to-treat analysis indicated an average 0.29-point drop on the CORE-OM, equating to an uncontrolled pre-post effect size of 0.50. Research completers achieved an average 0.61-point drop equating to an uncontrolled pre-post size of 1.00 on the same measure. Where data was available (18%), these benefits were maintained at week 32 (6 months follow-up). CONCLUSION: CCBT can be an effective first line tool within a stepped care framework for the management of common mental health problems.

Computerized cognitive-behaviour therapy for anxiety and depression: a practical solution to the shortage of trained therapists.

Computerized cognitive-behaviour therapy (CCBT) programmes have been developed to help meet the enormous need for evidence-based psychological treatment of common mental health problems in the context of a severe shortage of trained therapists to meet that need. Randomized controlled trials have confirmed the efficacy of such programmes. We present the experience of a community mental health team (CMHT) resource centre with one such programme, Beating the Blues, together with outcome data on a small sample of its clients. We conclude that experience and data, taken together, demonstrate the practical benefits of CCBT in routine practice.

The effect of mood and arousal on UCS expectancy biases.

This paper reports two studies investigating the role of mood and arousal on the development of UCS expectancy biases to fear-relevant and fear-irrelevant stimuli. Experiment 1 found that, compared with a neutral control condition, individuals in both experimentally-induced positive and negative moods significantly overestimated the possibility of aversive outcomes following all types of stimuli in a hypothetical thought' conditioning experiment. Experiment 2 found that this UCS expectancy bias produced by both positive and negative mood could not be explained by the effect that these mood states might have on arousal independently of the valency of the mood. The findings appear to be explained best by emotional response categorisation theory (Psychol. Rev. 106 (1999) 337-361), which predicts that individuals would be more likely to view emotionally valenced stimuli as similar when in an emotional state. It is argued that, while negative mood may be a genuine vulnerability factor for the development of anxiety-relevant threat-outcome expectancies, the effects found with positive mood in the current studies may have less ecological relevance to real-world aetiologies.

The use of stimulus dimensions in judgement making in spider fearful and nonfearful individuals.

This study uses a multidimensional scaling approach to investigate the hypothesis that spider fearful individuals give priority to a threat-safety dimension when making judgments. The results show that when making judgments about stimuli, spider fearful individuals (1) placed significantly greater comparative weighting on a threat-relevant dimension than on a non-emotive dimension (colour), and (2) tended to rate threatening pairs of stimuli and safe pairs of stimuli as more similar than did the nonfearful group. This prioritised dimensional processing suggests a mechanism by which phobics can exhibit what initially appear to be paradoxical tendencies to give priority to both threat and safety information.

A liquid-stable reagent for lactic acid levels. Application to the Hitachi 911 and Beckman CX7.

We evaluated the use of a new lactate oxidase-based reagent for the determination of serum and plasma lactic acid levels with the Hitachi 911 (Roche Diagnostics, Indianapolis, IN) and the Beckman CX7 (Beckman Instruments, Brea, CA). Evaluation studies demonstrated on-board stability of at least 3 months and a calibration stability of more than 5 months. Within- and between-day imprecision of this reagent was less than 2% for both applications. The reagent is free of the deleterious effects of triglyceride up to levels of 1,400 mg/dL (15.8 mmol/L), bilirubin to concentrations of 24.6 mg/dL (420 mumol/L), and hemoglobin, from lysed erythrocytes, to levels of more than 0.3 g/dL (3.0 g/L). When used on the Hitachi 911 for the determination of plasma lactate concentrations, the reagent correlates with the Dade aca III (Dade International, Deerfield, IL). When applied to the Beckman CX7 for the determination of serum lactate levels, the method correlates with the Beckman method.

UCS expectancy biases in spider phobics: underestimation of aversive consequences following fear-irrelevant stimuli.

This paper reports the results of two studies investigating judgements made by spider phobics about the potential threatening consequences (unconditioned stimulus, UCS, expectancies) associated with their phobic stimulus, fear-relevant (FR) stimuli, and fear-irrelevant (FI) stimuli. Using a 'thought experiment' UCS expectancy paradigm, the studies reported found that (1) spider phobics reported significantly higher UCS expectancies to spider stimuli than nonphobics, (2) spider phobics consistently underestimated the probability of aversive consequences following FI stimuli and (3) this underestimation of UCS expectancies to FI stimuli in phobics was not the result of a contrast effect resulting from sequential FR and FI judgements. This differential effect may have important implications for the kind of mechanism which mediates judgements about phobic consequences. These findings suggest that the dimensions on which phobic stimuli are categorised may be 'stretched' in the case of phobics and that this gives rise to the comparative underestimation of threat associated with FI stimuli but also makes phobics more vulnerable to acquiring other phobias.

Caprine mucopolysaccharidosis IIID: a preliminary trial of enzyme replacement therapy.

Mucopolysaccharidosis type IIID (MPS IIID) is a lysosomal storage disorder resulting from lack of activity of the lysosomal hydrolase N-acetylglucosamine 6-sulfatase (6S) (EC 3.1.6.14). The syndrome is associated with systemic and central nervous system (CNS) heparan sulfate glycosaminoglycan (HS-GAG) accumulation, secondary storage of lipids, and severe, progressive dementia. In this investigation, caprine MPS IIID, established as a large animal model for the human disease, was used to evaluate the efficacy of enzyme replacement therapy (ERT). Recombinant caprine 6S (rc6S) (1 mg/kg/dose) was administered intravenously to one MPS IIID goat kid at 2, 3, and 4 wks of age. Five days after the last dose, the uronic acid (UA) content and the composition of uncatabolized HS-GAG fractions in the brain of the ERT-treated MPS IIID kid were similar to those from a control, untreated MPS IIID animal. However, hepatic uronic acid levels in the treated MPS IIID kid were approximately 90% lower than those in the untreated MPS IIID control; whereas the composition of the residual hepatic HS-GAG was identical to that in the untreated animal. Marked reduction of lysosomal storage vacuoles in hepatic cells of the treated MPS IIID kid was observed, but ERT had no effect on CNS lesions. No residual 6S activity was detected in brain or liver. This preliminary investigation indicates that other treatment regimens will be necessary to ameliorate MPS III-related CNS lesions.

Caprine mucopolysaccharidosis-IIID: clinical, biochemical, morphological and immunohistochemical characteristics.

Several animal models have been developed for the mucopolysaccharidoses (MPSs), a group of lysosomal storage disorders caused by lysosomal hydrolase deficiencies that disrupt the catabolism of glycosaminoglycans (GAG). Among the MPS, the MPS-III (Sanfilippo) syndromes lacked an animal counterpart until recently. In this investigation of caprine MPS-IIID, the clinical, biochemical, morphological, and immunohistochemical studies revealed severe and mild phenotypes like those observed in human MPS III syndromes. Both forms of caprine MPS IIID result from a nonsense mutation and consequent deficiency of lysosomal N-acetylglucosamine 6-sulfatase (G6S) activity and are associated with tissue storage and urinary excretion of heparan sulfate (HS). Using special stains, immunohistochemistry, and electron microscopy, secondary lysosomes filled with GAG were identified in most tissues from affected goats. Primary neuronal accumulation of HS and the secondary storage of gangliosides were observed in the central nervous system (CNS) of these animals. In addition, morphological changes in the CNS such as neuritic expansions and other neuronal alterations that may have functional significance were also seen. The spectrum of lesions was greater in the severe form of caprine MPS IIID and included mild cartilaginous, bony, and corneal lesions. The more pronounced neurological deficits in the severe form were partly related to a greater extent of CNS dysmyelination. These findings demonstrate that caprine MPS IIID is a suitable animal model for the investigation of therapeutic strategies for MPS III syndromes.

Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics.

Mucopolysaccharidosis IIID (MPS IIID) is one of the rarest of the MPS-III syndromes. To date, the clinical manifestations of 10 patients have been reported, the deficient N-acetylglucosamine 6-sulfatase (G6S) enzyme has been purified, and the G6S gene has been cloned, sequenced and localized. However, morphological manifestations of this condition have not been reported and the pathogenesis of the severe neurological deficits remains an enigma. In this paper we describe and correlate the clinical, biochemical and pathological observations for 2 cases of MPS IIID. We used monoclonal antibodies against heparan sulfate (HS) and GM2-ganglioside, thin layer chromatography, mass spectrometry, and morphological techniques to demonstrate the nature and the distribution of the uncatabolized substrates. The majority of the cells in various tissues showed morphological changes expected with lysosomal storage of HS. The central nervous system (CNS) was most severely affected because of the secondary storage of GM2 and GM3 gangliosides in addition to the primary accumulation of HS. The extent as well as the distribution of the diverse storage materials varied within and among different neurons as observed in MPS-III A, B, and C syndromes. This study supports the hypothesis that the neurological dysfunction and neurodegeneration common to the Sanfilippo syndromes is, in part, due to the secondary metabolic perturbations induced by HS accumulation.

Caprine beta-mannosidase: sequencing and characterization of the cDNA and identification of the molecular defect of caprine beta-mannosidosis.

The complete sequence of the caprine beta-mannosidase cDNA coding region has been determined, and a mutation that is associated with caprine beta-mannosidosis has been identified. Reverse transcriptase-polymerase chain reactions were performed using primers based on bovine and, later, goat cDNA sequences to produce an overlapping series of amplicons covering the entire coding region. The composite cDNA codes for an 879-amino-acid peptide that has four potential N-glycosylation sites. Comparison of the caprine and bovine cDNAs reveals that 96.3% of the nucleotides and 95.2% of the deduced amino acids are identical. A single-base deletion at position 1398 of the coding sequence was identified in the cDNA isolated from a goat affected with beta-mannosidosis. This deletion results in a shift in the reading frame and a premature termination of translation, yielding a deduced peptide of 481 amino acids. An assay, developed to determine the presence or absence of this mutation, confirmed that animals affected with beta-mannosidosis were homozygous for the mutation and that obligate carriers in a caprine beta-mannosidosis colony were heterozygous. This assay accurately distinguished between mutation carrier and noncarrier goats and was used for prenatal diagnosis using DNA collected from fetal fluids. The assay also confirmed chimerism in a goat with an atypically mild beta-mannosidosis phenotype. Thus, this application enables assessment of the efficacy of engraftment of hematopoietic stem cells after prenatal transfer from donor sources.

Regional tracheal blood flow during conventional and high-frequency jet ventilation in suckling pigs.

OBJECTIVE: To determine whether intubation and ventilation with either conventional mechanical ventilation or high-frequency jet ventilation, using dry or humidified gas, could induce regional tracheal ischemia and serve as a basis for the tracheal necrosis observed clinically during ventilation. DESIGN: Prospective, multiple group, controlled experimental study. SETTING: Medical school research laboratory. SUBJECTS: Twenty, 3- to 5-wk-old suckling pigs. INTERVENTIONS: Anesthetized, closed-chest piglets were intubated and ventilated for 30 mins with conventional mechanical ventilation and then ventilated for 2 additional hrs with either conventional mechanical ventilation or high-frequency jet ventilation. Groups were also ventilated, using both modes of ventilation, with either 37 degrees C humidified gas or 25 degrees C dry gas. MEASUREMENTS AND MAIN RESULTS: Blood flow groups were compared during spontaneous breathing, conventional mechanical ventilation, high-frequency jet ventilation and both ventilation modes, using 37 degrees C humidified or 22 degrees C dry inspired gas. Groups were compared, using an analysis of variance with a Newman-Keul's post-test. Regional tracheal blood flow was measured, using radioactive microspheres. Cardiac output and organ blood flows were also monitored. Tracheal blood flow increased 10.3-fold within 30 mins after intubation, but there were no significant differences in regional or total tracheal blood flow between conventional mechanical ventilation and high-frequency jet ventilation, using 37 degrees C humidified gas. Tracheal blood flow was increased further using high-frequency jet ventilation and 25 degrees C dry gas but not conventional mechanical ventilation with dry gas. Although ventilation reduced cardiac output by approximately 30%, there were no significant differences in organ distribution between modes of ventilation. CONCLUSIONS: Acute tracheal hyperemia occurred with intubation and ventilation with both conventional mechanical ventilation and high-frequency jet ventilation but no differences were observed between ventilation modes. Hyperemia was further increased with cool, dry inspired gas, using high-frequency jet ventilation but not conventional mechanical ventilation. Although acute tracheal ischemia was not produced by high-frequency jet ventilation or conventional mechanical ventilation, factors which alter the balance between arterial supply and metabolic demand or induce inflammation may contribute to the tracheal necrosis reported during sustained ventilation.

Cloning and sequence analysis of caprine N-acetylglucosamine 6-sulfatase cDNA.

Mucopolysaccharidosis IIID results from the deficiency of N-acetylglucosamine 6-sulfatase activity. A Nubian goat with this lysosomal storage disease has been identified. As a first step in developing this animal model for testing treatment methods, we cloned and sequenced the caprine N-acetylglucosamine 6-sulfatase cDNA coding region. Overall there is 88% nucleotide homology between the goat and human sequence and 94% homology of the deduced amino acid sequence. The human and two ruminant species differ by the presence of an imperfect trinucleotide (CCG) repeat in the ruminant signal sequence.

Molecular cloning and characterization of bovine beta-mannosidase.

Deficiency of lysosomal beta-mannosidase activity results in a severe neurodegenerative disease in goats and cattle and a relatively milder phenotype in humans. A cDNA coding for the entire beta-mannosidase protein is described. Mixed oligonucleotides derived from bovine beta-mannosidase peptide sequences were used to screen a bovine thyroid cDNA library. Clones covering about 80% of the C-terminal region were recovered. The missing 5'-region was obtained using the technique of 5'-rapid amplification of cDNA ends. The composite cDNA contains 3852 nucleotides, encoding 879 amino acids. The N-terminal methionine is followed by 16 amino acids displaying the characteristics of a typical signal peptide sequence. The deduced amino acid sequence is colinear with all peptide sequences determined by protein microsequencing. Northern blot analysis demonstrates a single 4.2-kilobase transcript in various tissues from both normal and affected goats and calves. The mRNA level is decreased in tissues of affected beta-mannosidosis animals. The gene encoding beta-mannosidase is localized to human chromosome 4 as shown by Southern analysis of rodent/human somatic cell hybrids. This is the first report of cloning of lysosomal beta-mannosidase.

Biochemical and histochemical analysis of lysosomal enzyme activities in caprine beta-mannosidosis.

Goats affected with beta-mannosidosis, an autosomal recessive disease of glycoprotein catabolism, have deficient tissue and plasma levels of the lysosomal enzyme beta-mannosidase. Pathological characteristics include cytoplasmic vacuolation in the nervous system and viscera, and myelin deficits that demonstrate regional variation. This study was designed to determine the correlation between beta-mannosidase activity in normal animals and the severity of lesions in affected goats, and to assess the regional changes in lysosomal enzyme activity in specific regions and cell types in affected animals. Although enzyme activity in normal organs (kidney, thyroid, brain) is correlated in general with the accumulation of uncatabolized substrate and with the extent of vacuolation, this correlation does not extend to assessment of specific regions of the central nervous system (CNS). In affected goats, the activities of alpha-mannosidase, alpha-fucosidase, and beta-hexosaminidase are elevated to a greater extent in all CNS regions than in organs. The results suggest cell-specific, organ-specific, and enzyme-specific regulation of changes in lysosomal enzyme activity in the presence of metabolic perturbations, such as deficiency of beta-mannosidase activity.

Possible beta-mannosidosis chimera. Altered expression of metabolic perturbations.

An aberrant beta-mannosidosis phenotype in a 5-month-old triplet goat kid was characterized by a late postnatal onset of mild neurological symptoms. Necropsy examination revealed relatively normal myelination; however, the distribution of cytoplasmic vacuolation in the kidney and brain was similar to that observed in neonatal beta-mannosidosis. Variable engraftment of donor stem cells, resulting from transplacental transfusion of stem cells from a normal sibling during the immunotolerant period, may have modified the expected severe beta-mannosidosis phenotype. This investigation was designed to determine the effects of a possible chimeric state on organ-specific metabolic perturbations. Residual beta-mannosidase enzyme activity was found in plasma, kidney, liver and spleen but not in brain. Other lysosomal enzyme activities were comparable to normal values. Immunoreactive beta-mannosidase was estimated to be less than 10% of normal levels. Kidney, brain grey matter and brain white matter contained 33%, 12% and 4%, respectively, of the oligosaccharides expected in the organs of beta-mannosidosis animals. There were no detectable oligosaccharides or cytoplasmic vacuolation in the liver or spleen. Studies of this possible chimera provided preliminary evidence for the efficacy of prenatal treatment of early-onset neurodegenerative disorders.

Bovine kidney beta-mannosidase: purification and characterization.

Lysosomal beta-mannosidase was purified 160,000-fold in 24% yield from bovine kidney by a four-step purification procedure, which included concanavalin A-Sepharose, immunoaffinity, TSK-butyl and h.p.l.c. cation-exchange chromatography. When analysed by SDS/PAGE and detected by Coomassie Blue or silver staining, the purified enzyme preparation consists of two prominent peptides (100 and 110 kDa) and a third minor peptide (84 kDa). These three peptides are immunologically related and are consistently associated with beta-mannosidase activity in all chromatographic steps. Removal of N-linked carbohydrate from the 84, 100 and 110 kDa peptides decreases their molecular sizes to 75, 86 and 91 kDa respectively. Bovine kidneys lacking beta-mannosidase, activity, acquired from calves affected with beta-mannosidosis, do not contain detectable quantities of the three beta-mannosidase peptides, as judged by monoclonal- and polyclonal-antibody reactivity.