Predictors and moderators of the response of adults with intellectual disabilities and depression to behavioural activation and guided self-help therapies.

BACKGROUND: No previous studies have reported predictors and moderators of outcome of psychological therapies for depression experienced by adults with intellectual disabilities (IDs). We investigated baseline variables as outcome predictors and moderators based on a randomised controlled trial where behavioural activation was compared with guided self-help. METHODS: This study was an exploratory secondary data analysis of data collected during a randomised clinical trial. Participants (n = 161) were randomised to behavioural activation or guided self-help and followed up for 12 months. Pre-treatment variables were included if they have previously been shown to be associated with an increased risk of having depression in adults with IDs or have been reported as a potential predictor or moderator of outcome of treatment for depression with psychological therapies. The primary outcome measure, the Glasgow Depression Scale for Adults with Learning Disabilities (GDS-LD), was used as the dependant variable in mixed effects regression analyses testing for predictors and moderators of outcome, with baseline GDS-LD, treatment group, study centre and antidepressant use as fixed effects, and therapist as a random effect. RESULTS: Higher baseline anxiety (mean difference in outcome associated with a 1 point increase in anxiety 0.164, 95% confidence interval [CI] 0.031, 0.297; P = 0.016), lower performance intelligence quotient (IQ) (mean difference in outcome associated with a 1 point increase in IQ 0.145, 95% CI 0.009, 0.280; P = 0.037) and hearing impairment (mean difference 3.449, 95% CI 0.466, 6.432; P = 0.024) were predictors of poorer outcomes, whilst greater severity of depressive symptoms at baseline (mean difference in outcome associated with 1 point increase in depression -0.160, 95% CI -0.806, -0.414; P < 0.001), higher expectation of change (mean difference in outcome associated with a 1 point increase in expectation of change -1.013, 95% CI -1.711, -0.314; p 0.005) and greater percentage of therapy sessions attended (mean difference in outcome with 1 point increase in percentage of sessions attended -0.058, 95% CI -0.099, -0.016; P = 0.007) were predictors of more positive outcomes for treatment after adjusting for randomised group allocation. The final model included severity of depressive and anxiety symptoms, lower WASI performance IQ subscale, hearing impairment, higher expectation of change and percentage of therapy sessions attended and explained 35.3% of the variance in the total GDS-LD score at 12 months (R2  = 0.353, F4, 128  = 17.24, P < 0.001). There is no evidence that baseline variables had a moderating effect on outcome for treatment with behavioural activation or guided self-help. CONCLUSIONS: Our results suggest that baseline variables may be useful predictors of outcomes of psychological therapies for adults with IDs. Further research is required to examine the value of these potential predictors. However, our findings suggest that therapists consider how baseline variables may enable them to tailor their therapeutic approach when using psychological therapies to treat depression experienced by adults with IDs.

A randomized trial investigating the efficacy and safety of water soluble micellar paclitaxel (Paccal Vet) for treatment of nonresectable grade 2 or 3 mast cell tumors in dogs.

BACKGROUND: Effective treatments for dogs with advanced stage mast cell tumors (MCT) remain a pressing need. A micellar formulation of paclitaxel (paclitaxel [micellar]) has shown promise in early-phase studies. HYPOTHESIS/OBJECTIVES: The objective was to demonstrate greater activity for paclitaxel (micellar) compared with lomustine. The null hypothesis was µ(p) = µ(L) (ie, proportion of responders for the paclitaxel [micellar] and lomustine groups, respectively). ANIMALS: Two hundred and fifty-two dogs with advanced stage nonresectable grade 2 or 3 MCT. METHODS: Prospective multicenter randomized double-blind positive-controlled clinical trial. The primary endpoint was confirmed overall response rate (CORR) at 14 weeks. A secondary endpoint, biologic observed response rate (BORR), also was calculated. Safety was assessed by the characterization and grading of adverse events (AE). RESULTS: Overall CORR (7% versus 1%; P = .048) and BORR (23% versus 10%; P = .012) were greater for paclitaxel (micellar) compared with lomustine. Paclitaxel (micellar)-treated dogs were 6.5 times more likely to have a confirmed response and 3.1 times more likely to experience a biologic observed response. The majority of AE with paclitaxel (micellar) were transient and clinically manageable. Twenty-seven dogs (33%) receiving lomustine were discontinued because of hepatopathy compared with 3 dogs (2%) receiving paclitaxel (micellar) (P < .0001; odds ratio 26.7). CONCLUSIONS AND CLINICAL IMPORTANCE: Paclitaxel (micellar)'s activity and safety profile are superior to lomustine. The addition of an active and novel taxane to the veterinary armamentarium could fill a substantial need and, as its mechanism of action and AE profile do not overlap with currently available TKI, its availability could lead to effective combination protocols.

Preliminary evidence for biologic activity of toceranib phosphate (Palladia(®)) in solid tumours.

The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia®, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.

L-selectin is dispensable for T regulatory cell function postallogeneic bone marrow transplantation.

In murine models, the adoptive transfer of CD4(+) /CD25(+) regulatory T cells (T(regs) ) inhibited graft-versus-host disease (GvHD). Previous work has indicated a critical role for the adhesion molecule L-selectin (CD62L) in the function of T(regs) in preventing GvHD. Here we examined the capacity of naive wild-type (WT), CD62L(-/-) and ex vivo expanded CD62L(Lo) T(regs) to inhibit acute GvHD. Surprisingly, we found that CD62L(-/-) T(regs) were potent suppressors of GvHD, whereas CD62L(Lo) T(regs) were unable to inhibit disease despite being functionally competent to suppress allo T cell responses in vitro. Concomitant with improved outcomes, WT and CD62L(-/-) T(regs) significantly reduced liver pathology and systemic pro-inflammatory cytokine production, although CD62L(-/-) T(regs) were less effective in reducing lung pathology. While accumulation of CD62L(-/-) T(regs) in GvHD target organs was equivalent to WT T(regs) , CD62L(-/-) T(regs) did not migrate as well as WT T(regs) to peripheral lymph nodes (PLNs) over the first 2 weeks posttransplantation. This work demonstrated that CD62L was dispensable for T(reg) -mediated protection from GvHD.

Widespread divergence between incipient Anopheles gambiae species revealed by whole genome sequences.

The Afrotropical mosquito Anopheles gambiae sensu stricto, a major vector of malaria, is currently undergoing speciation into the M and S molecular forms. These forms have diverged in larval ecology and reproductive behavior through unknown genetic mechanisms, despite considerable levels of hybridization. Previous genome-wide scans using gene-based microarrays uncovered divergence between M and S that was largely confined to gene-poor pericentromeric regions, prompting a speciation-with-ongoing-gene-flow model that implicated only about 3% of the genome near centromeres in the speciation process. Here, based on the complete M and S genome sequences, we report widespread and heterogeneous genomic divergence inconsistent with appreciable levels of interform gene flow, suggesting a more advanced speciation process and greater challenges to identify genes critical to initiating that process.

Basic surgical training in the era of the European Working Time Directive: what are the problems and solutions?

BACKGROUND AND AIMS: Imposed reductions in working hours will impact significantly on the ability of surgical trainees to achieve competency. The objective of this study was to obtain the opinions of Scottish surgical trainees concerning the training they receive, in order to inform and guide the development of future, high-standard training programmes. METHODS: An anonymous questionnaire was sent to basic surgical trainees on the Edinburgh, Aberdeen and Dundee Basic Surgical Rotations commencing after August 2002. RESULTS: Thirty six questionnaire responses were analysed. Very few of the returned comments were complimentary to the existing training structure; indeed, most comments demonstrated significant trainee disappointment. Despite "regular" exposure to operative sessions, training tutorials and named consultant trainers, the most common concern was a perceived lack of high-quality, structured, operative exposure and responsibility. Textbooks and journals remain the most frequently utilised learning tools, with high-tech systems such as teleconferencing, videos, CD-ROMS, and DVDs being poorly exploited. CONCLUSIONS: Current surgical training is not meeting the expectation of the majority of its trainees. To solve this problem will require extensive revision of attitudes and current educational format. A greater emphasis on the integration of 21st century learning tools in the training programme may help bridge this gap.

Clinical and molecular delineation of the 17q21.31 microdeletion syndrome.

BACKGROUND: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. AIM: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. RESULTS: We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)). CONCLUSION: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

The use of a Giardia vaccine as an immunotherapeutic agent in dogs.

Dogs (n = 13), which had failed to be cured of giardiosis following chemotherapeutic measures, were treated with a Giardia vaccine (2-3 injections). Clinical signs resolved between 16 and 42 days postvaccination and cessation of fecal cyst shedding was between 21 and 70 days. Vaccination is a potential method of treating giardiosis in dogs.

Reconstruction with rectus abdominis myocutaneous free flap after orbital exenteration in children.

OBJECTIVE: To present a 1-stage technique for orbital reconstruction after exenteration with the use of myocutaneous rectus abdominis free flap in children. SURGICAL TECHNIQUE: After orbital exenteration, a myocutaneous rectus abdominis free flap with long vascular pedicle is harvested from the abdomen. The flap is transferred to the orbit and the vascular pedicle is passed through an opening made in the lateral orbital wall, where it is anastomosed to superficial temporal vessels. The skin of the flap is trimmed to correspond to the eyelid defect and the incisions are closed. METHODS: After informed consent was obtained, 2 children, 3 and 8 years old, underwent orbital reconstruction with a rectus abdominis free flap after exenteration for orbital rhabdomyosarcoma and orbital osteosarcoma in the setting of retinoblastoma. RESULTS: This technique allowed easy postoperative wound care. Viability of the flap was excellent. The technique provided sufficient volume to fill the orbit, with improved aesthetic results and minimal donor site deformity. CONCLUSIONS: The postoperative care and aesthetic outcome in patients with rectus abdominis free flap after exenteration are much improved over those provided with traditional surgical techniques. This primary reconstruction is recommended for any patient requiring orbital exenteration, but particularly for pediatric patients who tolerate debridement of traditional exenteration sites poorly.

Surveying Saccharomyces genomes to identify functional elements by comparative DNA sequence analysis.

Comparative sequence analysis has facilitated the discovery of protein coding genes and important functional sequences within proteins, but has been less useful for identifying functional sequence elements in nonprotein-coding DNA because the relatively rapid rate of change of nonprotein-coding sequences and the relative simplicity of non-coding regulatory sequence elements necessitates the comparison of sequences of relatively closely related species. We tested the use of comparative DNA sequence analysis to aid identification of promoter regulatory elements, nonprotein-coding RNA genes, and small protein-coding genes by surveying random DNA sequences of several Saccharomyces yeast species, with the goal of learning which species are best suited for comparisons with S. cerevisiae. We also determined the DNA sequence of a few specific promoters and RNA genes of several Saccharomyces species to determine the degree of conservation of known functional elements within the genome. Our results lead us to conclude that comparative DNA sequence analysis will enable identification of functionally conserved elements within the yeast genome, and suggest a path for obtaining this information.

A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms.

We describe a map of 1.42 million single nucleotide polymorphisms (SNPs) distributed throughout the human genome, providing an average density on available sequence of one SNP every 1.9 kilobases. These SNPs were primarily discovered by two projects: The SNP Consortium and the analysis of clone overlaps by the International Human Genome Sequencing Consortium. The map integrates all publicly available SNPs with described genes and other genomic features. We estimate that 60,000 SNPs fall within exon (coding and untranslated regions), and 85% of exons are within 5 kb of the nearest SNP. Nucleotide diversity varies greatly across the genome, in a manner broadly consistent with a standard population genetic model of human history. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy.

Quality of life with functional pharyngeal preservation in advanced carcinomas of the base tongue complex using an integrated trimodality approach.

Standard management of advanced carcinoma arising from the base of the tongue or infiltrating that region from contiguous areas (henceforth referred to as base of tongue complex [BTC] tumors) with radical surgery and postoperative radiation therapy results in extensive loss of function affecting deglutition, speech, and physical appearance. From January 1995, 16 patients with advanced stage BTC tumors were entered in this phase II study. Eleven patients (74%) had N2-3 neck disease. To optimize neck control, those with clinical N+ nodes at presentation had neck dissection. This was followed by hyperfractionated radiotherapy at 120 cGy twice daily to a median dose of 7,320 cGy to the primary and 6,240 cGy to areas with pathologically positive nodes. Concomitant chemotherapy was administered during weeks 1 and 4 of the radiation therapy using bolus cisplatin 75 to 100 mg/m2 on day 1 and continuous infusional 5-fluorouracil 750 to 1,000 mg/m2/d from days 1 to 4 of each chemotherapy cycle. Survival curves were plotted for various events, using actuarial life table methods. A functional assessment was made at least 1 year after completion of treatment using a previously validated Head/Neck Performance Status Scale. The median follow-up period was 23 months. There was a 100% complete response to the treatment at the primary site. The actuarial 4-year local (primary site) control was 100%, locoregional control (including nodes) was 69%, and disease-specific survival was 70% at 4 years. The predominant acute toxicity (63% incidence) was reversible grade III mucositis resulting in a median of 9 days' interruption in treatment. All of the patients were able to complete the prescribed treatment course, and there were no treatment-related deaths. Quality of Life assessment after treatment examined all facets of oropharyngeal function. Of note, none of the patients required long-term tube feedings. For the nine patients who responded to the functional assessment questionnaire, the results were excellent (score >75). The mean score for ability to eat in public was 75, mean of 76 for normalcy of diet, and 91 for understandability of speech. Concomitant hyperfractionated chemoradiation therapy produced excellent functional preservation with good long-term control in this patient group with historically poor prognosis. A 4-year actuarial local control rate of 69% was obtained, which is comparable to results of radical surgery and adjuvant radiation therapy. Further studies with modifications of fractionation and use of newer chemotherapy agents/radioprotectors will improve on these gains while reducing toxicity.

Subconjunctival carboplatin in retinoblastoma: impact of tumor burden and dose schedule.

OBJECTIVE: To evaluate the impact of tumor burden and chemotherapy dose scheduling on the response to subconjunctival carboplatin treatment in a murine transgenic retinoblastoma model. METHODS: Eighty simian virus 40 T antigen-positive mice were treated at age 5 or 10 weeks. Six control animals received placebo treatment. Twenty-four 5-week-old mice received 6 subconjunctival carboplatin injections at doses of 30 to 300 microg delivered at 72-hour intervals. Fifty 10-week-old mice received either 6 or 12 subconjunctival carboplatin injections at doses of 30 to 300 microg delivered at 72-hour intervals. All eyes were obtained at age 16 weeks for histopathologic examination. Eyes were graded as positive if any tumor was present. RESULTS: All simian virus 40 T antigen-positive control eyes contained large tumor foci throughout the retina. Subconjunctival carboplatin injections controlled tumors in a dose-dependent manner. Tumor control was observed in 50% of treated eyes at 138.3 microg for the 10-week-old 6-injection group, 94.3 microg for the 5-week-old 6-injection group, and 85.9 microg for the 10-week-old 12-injection group. CONCLUSION: Increased tumor burden requires an increase in subconjunctival carboplatin dose scheduling to maintain local tumor control in this murine model of retinoblastoma. CLINICAL RELEVANCE: This study documents the efficacy of subconjunctival carboplatin in the treatment of an animal model of retinoblastoma. These data establish a framework for further human clinical trials. Arch Ophthalmol. 2000;118:1549-1554

Increased accuracy of renal allograft rejection diagnosis using combined perforin, granzyme B, and Fas ligand fine-needle aspiration immunocytology.

BACKGROUND: Two major routes by which cytotoxic T lymphocytes induce apoptosis in target cells are the perforin-granzyme and the Fas ligand/Fas pathways. Intragraft expression of message for these immune activation genes has been shown to correlate very closely with clinical rejection. We have immunolabeled fine-needle aspiration biopsy samples using a panel of cytotoxic T-cell activation markers to evaluate the immunocytochemical identification of the protein products of these genes in the verification of human renal allograft rejection. METHODS: In this retrospective pilot study, 140 fine-needle aspiration biopsy samples from 50 human renal allografts were labeled using alkaline phosphatase/ anti-alkaline phosphatase immunocytochemistry incorporating monoclonal antibodies to perforin, granzyme B, and Fas ligand. Levels of positive labeling for these markers were compared with the original clinical diagnosis of rejection. RESULTS: An excellent correlation with clinical rejection was obtained when all three antibodies were positive. The false positive rate for each antibody was sufficient to make any one alone or in combination with one other unreliable for diagnosing rejection. When all three antibodies gave positive labeling, agreement with clinical rejection status was superior to using conventional morphological cytology. CONCLUSIONS: In addition to providing valuable morphological information regarding the composition of inflammatory leukocyte populations and the preservation status of renal parenchymal cells, fine-needle aspiration biopsy samples may be labeled using combined perforin, granzyme B, and Fas ligand immunocytochemistry to offer a safe and reliable method for diagnosing rejection with an excellent level of accuracy.

Siblings of retinoblastoma patients: are we underestimating their risk?

PURPOSE: To describe the clinical presentation of probable germ-line mosaicism in four retinoblastoma kindreds. METHODS: Review of 255 retinoblastoma patients and their family records in a University of California, San Francisco-Bascom Palmer database to identify those with potential germ-line mosaicism. Parents and siblings of retinoblastoma patients were given comprehensive ophthalmologic examinations. RESULTS: Four kindreds were identified, wherein retinoblastoma was diagnosed in two siblings and both parents demonstrated no evidence of retinoblastoma or retinocytoma. CONCLUSION: Clinical appearance of germ-line mosaicism is demonstrated in our retinoblastoma patient populations. We recommend routine clinical screening of all parents and siblings of retinoblastoma patients to provide more accurate genetic counseling and to allow earlier examination and treatment of children at presymptomatic disease stages. Germ-line mosaicism must be considered as a genetic transmission pattern in these patients, and genetic counseling should specifically recognize this possibility. If a parent is germ-line mosaic, the possibility of bearing a second child with retinoblastoma is clearly higher than conventionally believed.

Comparative genomic sequence analysis of the human and mouse cystic fibrosis transmembrane conductance regulator genes.

The identification of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in 1989 represents a landmark accomplishment in human genetics. Since that time, there have been numerous advances in elucidating the function of the encoded protein and the physiological basis of cystic fibrosis. However, numerous areas of cystic fibrosis biology require additional investigation, some of which would be facilitated by information about the long-range sequence context of the CFTR gene. For example, the latter might provide clues about the sequence elements responsible for the temporal and spatial regulation of CFTR expression. We thus sought to establish the sequence of the chromosomal segments encompassing the human CFTR and mouse Cftr genes, with the hope of identifying conserved regions of biologic interest by sequence comparison. Bacterial clone-based physical maps of the relevant human and mouse genomic regions were constructed, and minimally overlapping sets of clones were selected and sequenced, eventually yielding approximately 1.6 Mb and approximately 358 kb of contiguous human and mouse sequence, respectively. These efforts have produced the complete sequence of the approximately 189-kb and approximately 152-kb segments containing the human CFTR and mouse Cftr genes, respectively, as well as significant amounts of flanking DNA. Analyses of the resulting data provide insights about the organization of the CFTR/Cftr genes and potential sequence elements regulating their expression. Furthermore, the generated sequence reveals the precise architecture of genes residing near CFTR/Cftr, including one known gene (WNT2/Wnt2) and two previously unknown genes that immediately flank CFTR/Cftr.

Spontaneous regression of orbital Langerhans cell granulomatosis in a three-year-old girl.

PURPOSE: To report a case of spontaneous regression of orbital Langerhans cell granulomatosis. METHOD: Case report. A 3-year-old girl was initially examined with a 5-week history of slowly progressive blepharoptosis and periorbital swelling of the left eye. RESULTS: Computed tomographic scan showed a mass in the left orbit eroding into the left frontal bone; fine-needle aspiration confirmed diagnosis of Langerhans cell granulomatosis. After initial biopsy, the patient was treated by close observation alone. Six months after initial examination, the monostotic lesion had completely resolved. CONCLUSIONS: In some cases of monostotic Langerhans cell granulomatosis, initial biopsy followed by observation alone may allow for the spontaneous regression of the lesion. This conservative approach to treatment is an important therapeutic option that may spare the patient the adverse effects of surgical resection, radiation, or chemotherapy.

Perceived efficacy of pain clinics in the rehabilitation of injured workers.

OBJECTIVE: To assess the perceived efficacy of pain clinics in the rehabilitation of injured workers among four groups of professionals. DESIGN: A questionnaire was given to 351 subjects representing four professional groups: physicians, vocational rehabilitation counselors, staff at pain clinics, and employees of a workers compensation program. Subjects rated the effectiveness of pain clinics in eight specific functions, estimated the percentage of workers who return to work after pain clinic treatment, and indicated how soon after injury a worker should be referred to a pain clinic. RESULTS: Pain clinic staff consistently gave the most favorable ratings and workers compensation employees the least favorable ones. There was good agreement across professional groups regarding the need for early referral of injured workers to pain clinics and the specific functions that pain clinics carry out relatively well. Clinics were ranked as most effective in reducing workers' use of opiates, and as least effective in reducing workers' pain. Return-to-work estimates varied significantly across professional groups. Within professional groups, subjects with high estimates gave more favorable overall ratings to pain clinics. CONCLUSIONS: The results provide a profile of the perceived effectiveness of pain clinics in various functions and highlight the importance of getting accurate information about return to work rates following pain clinic treatment. They suggest that workers are not referred to pain clinics early enough.