Pragmatic design in randomized controlled trials.

At more than 10 years after the paper by Hotopf and colleagues regarding pragmatic trials in psychiatry, the field has evolved and is evolving further. There have been many developments in our understanding of what pragmatism really means, and excellent examples of truly pragmatic trials in psychiatry are currently available. Funders have helped encourage more emphasis on the need for such studies, but 'local' and trans-national regulations could help more. Consumers of the evidence should have a greater voice in generating the research agenda and, as this happens, the questions generated are more likely to be answered by a pragmatic approach to trials.

Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics.

Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel diagnostic tests to match individual schizophrenia patients to the most effective and safe medication. In this study, we use a genome-wide approach to detect genetic variation underlying individual differences in response to treatment with the antipsychotics olanzapine, quetiapine, risperidone, ziprasidone and perphenazine. Our sample consisted of 738 subjects with DSM-IV schizophrenia who took part in the Clinical Antipsychotic Trials of Intervention Effectiveness. Subjects were genotyped using the Affymetrix 500 K genotyping platform plus a custom 164 K chip to improve genome-wide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale. Our criterion for genome-wide significance was a prespecified threshold that ensures that, on an average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our prespecified threshold and involved a single-nucleotide polymorphism (SNP) in an intergenic region on chromosome 4p15. In addition, SNPs in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing Protein 1B (ANKS1B) and in the Contactin-Associated Protein-Like 5 gene (CNTNAP5), which mediated the effects of olanzapine and risperidone on Negative symptoms, were very close to our threshold for declaring significance. The most significant SNP in CNTNAP5 is nonsynonymous, giving rise to an amino-acid substitution. In addition to highlighting our top results, we provide all P-values for download as a resource for investigators with the requisite samples to carry out replication. This study demonstrates the potential of genome-wide association studies to discover novel genes that mediate the effects of antipsychotics, which could eventually help to tailor drug treatment to schizophrenic patients.

Gender and genetic control of resistance to intestinal amebiasis in inbred mice.

Resistance to the establishment of intestinal Entamoeba histolytica infection is dependent on the inbred mouse strain. In this work we used the inbred strains B6 (resistant), CBA (susceptible), B6CBAF(1) and a backcross of B6CBAF(1) to CBA to further examine the genetic basis of resistance. Mouse genotype was assessed with single nucleotide polymorphism and microsatellite markers and infection assessed by culture 9 days after intracecal E. histolytica challenge. The backcross population showed a male predisposition to culture positivity (P<0.002). F1 genotype at two loci on chromosomes 1 and 2 exhibited suggestive linkage with resistance to infection (P=0.0007 and 0.0200). Additional suggestive quantitative trait locus were observed on chromosomes 1, 9 and 13 for cecal parasite antigen load and histologic evidence of inflammation. Infection in C3H x B6 recombinant inbred mice supported the mapping data. Candidate B6 genes on chromosomes 1 and 2 were examined by microarray analysis of epithelial tissues from B6 vs CBA mice. This work shows a male predisposition to intestinal amebiasis and suggests that relatively few B6 loci can confer resistance in inbred mice. Future identification of regional candidate genes has implications for understanding the human variability to amebic infection.

Risperidone versus olanzapine for schizophrenia.

BACKGROUND: Antipsychotic medication is a mainstay of treatment for schizophrenia. Risperidone and olanzapine are popular choices among the new generation drugs. OBJECTIVES: To determine the clinical effects, safety and cost effectiveness of risperidone compared with olanzapine for treating schizophrenia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (Sept 2005) which is based on regular searches of, amongst others, BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were inspected for further trials. We also contacted relevant pharmaceutical companies for additional information. SELECTION CRITERIA: We included all clinical randomised trials comparing risperidone with olanzapine for schizophrenia and schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For homogenous dichotomous data we calculated random effects, relative risk (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat/harm (NNT/H) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). MAIN RESULTS: We found no difference for the outcome of unchanged or worse in the short term (n=548, 2 RCTs, RR 1.00 CI 0.88 to 1.15). One study favoured olanzapine for the outcome of relapse/rehospitalisation by 12 months (n=279, 1 RCT, RR 2.16 CI 1.31 to 3.54, NNH 7 CI 3 to 25). Most mental state data showed the two drugs to be as effective as each other (n=552, 2 RCTs, RR 'no <20% decrease PANSS by eight weeks' 1.01 CI 0.87 to 1.16). Both drugs commonly cause adverse events: 75% given either drug experience an adverse event; 20% anticholinergic symptoms; both groups experienced insomnia although it was more frequent with risperidone (n=1588, 5 RCTs, RR 1.41 CI 1.15 to 1.72, NNH 15 CI 9 to 41); about 30% experienced sleepiness (n=1713, 6 RCTs, RR 0.92 CI 0.79 to 1.07). People given either drug often experienced some extrapyramidal symptoms (n=893, 3 RCTs, RR 1.18 CI 0.75 to 1.88); 25% of people using risperidone required medication to alleviate these symptoms (n=419, 2 RCTs, RR 1.76 CI 1.25 to 2.48, NNH 8 CI 4 to 25). People allocated to risperidone were less likely to gain weight compared with those given olanzapine and the weight gain was often considerable and of quick onset (n=984, 2 RCTs, RR gain more than 7% of their baseline weight in short term 0.47 CI 0.36 to 0.61, NNH 7 CI 6 to 10). Risperidone participants were less likely to leave the study due to metabolic side effects and weight gain compared with olanzapine (n=667, 1RCT, RR 0.19 CI 0.08 to 0.45). Patients on risperidone were more likely to experience abnormal ejaculation (n=370, 2 RCTs, RR 4.36 CI 1.38 to 13.76, NNH 20 CI 6 to 176). Both drugs are associated with high attrition rates; in the long term consistent findings show that 66% of those allocated risperidone left the study early compared with 56% given olanzapine (n=1440, 5 RCTs, RR 1.17 CI 1.08 to 1.27, NNH 11 CI 7 to 23). AUTHORS' CONCLUSIONS: We know very little of the effects of these drugs regarding service outcomes, general functioning and behaviours, engagement with services and treatment satisfaction from evaluative studies. There was generally a high rate of attrition in the trials and there appears to be little to differentiate between risperidone and olanzapine except on issues of adverse effects. Both drugs are associated with a reduction in psychotic symptoms but both commonly cause unpleasant adverse effects.

Amino acid sequence of rabbit carbonic anhydrase II.

The amino acid sequence of the high activity form of erythrocyte carbonic anhydrase, carbonic anhydrase II, purified from rabbit erythrocytes has been determined. This sequence was determined primarily from the cyanogen bromide and tryptic peptides through use of automated Edman degradation procedures. The ordering of the peptides from rabbit carbonic anhydrase II was based on the high degree of homology between the rabbit enzyme and the homologous enzymes derived from sheep, bovine, and human erythrocytes. The function of certain residues is discussed in the context of these three known sequences and the previously reported three-dimensional structure of human carbonic anhydrase II. Possible microheterogeneity of rabbit carbonic anhydrase II is also discussed.

Paclitaxel in combination chemotherapy with radiotherapy in patients with unresectable stage III non-small-cell lung cancer.

PURPOSE: The addition of combination chemotherapy to standard radiation therapy has improved treatment for locally unresectable non-small-cell lung cancer. In this phase II study, we evaluated the toxicity and efficacy of a novel chemotherapy regimen that included paclitaxel, cisplatin, and etoposide plus concurrent radiation therapy in this group of patients. PATIENTS AND METHODS: Thirty-three patients with previously untreated, unresectable stage III non-small-cell lung cancer (stage IIIA, 11 patients; stage IIIB, 22 patients) initially received two courses of chemotherapy, which included paclitaxel 135 mg/m2 by 1-hour infusion on day 1, cisplatin 60 mg/m/ intravenously (i.v.) on day 2, and etoposide 100 mg/m2 i.v. on days 1, 2 and 3. On week 6, radiation therapy (60 Gy in 30 fractions) was initiated in conjunction with two additional courses of chemotherapy: paclitaxel 135 mg/m2 i.v. by 1-hour infusion on day 1, cisplatin 5 mg/m2 i.v. on days 2- to 10, and etoposide 25 mg/m2 on days 1 to 10. RESULTS: This combined modality program was feasible and well tolerated by most patients. During the two courses of induction chemotherapy, grade 3 or 4 myelosuppression occurred in only six patients (18%). Esophagitis was common during combined modality therapy (grade 3, 10 patients; grade 4 five patients). Forty-two percent of patients had partial response after two courses of induction therapy, and 82% of patients had an objective response at completion of therapy. Twelve patients (36%) had a complete response. Nineteen patients remain progression-free at a median of 8 months; the median survival time has not been reached. CONCLUSION: This paclitaxel-containing combined modality therapy is feasible and highly active in patients with inoperable stage III lung cancer. Esophagitis is the most common severe toxicity with this program. Further studies with paclitaxel-containing combination regimens in patients with stage III non-small-cell lung cancer are indicated.

Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: comparison of sequential phase II trials using different dose-intensities.

PURPOSE: In two sequential phase II studies, we evaluate the feasibility and efficacy of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of small-cell lung cancer. PATIENTS AND METHODS: One hundred seventeen patients with small-cell lung cancer were treated between June 1993 and July 1996. The first 38 patients received a lower-dose regimen: paclitaxel 135 mg/m2 by 1-hour infusion, carboplatin at an area under the concentration-time curve (AUC) of 5.0, and etoposide 50 mg alternating with 100 mg orally on days 1 to 10. When only mild myelosuppression was observed, doses of paclitaxel and carboplatin were increased in the subsequent 79 patients (paclitaxel 200 mg/m2 by 1-hour infusion and carboplatin at an AUC of 6.0). All patients received four courses of treatment, administered at 21-day intervals. Patients with limited-stage small-cell lung cancer also received thoracic radiation therapy (1.8 Gy/d; total dose, 45 Gy) administered concurrently with courses 3 and 4 of chemotherapy. RESULTS: Seventy-two of 79 patients (91%) who receive the higher-dose regimen had major responses. Thirty-two of 38 (84%) with extensive-stage disease responded (21% complete response rate); median survival was 10 months for this group. With limited-stage disease, the overall response rate was 98%, with 71% complete responses; the median survival time has not been reached at 16 months. Median survival in extensive-stage patients was longer in patients who received the higher-dose regimen (10 months) than in the previous group treated with lower doses (7 months; P = .008). The higher-dose regimen was well tolerated, with myelosuppression being the major toxicity. Compared with the lower-dose regimen, grade 3/4 neutropenia increased from 8% to 38% of courses, but the incidence of hospitalization for neutropenia and fever did not increase. Other nonhematologic toxicities were uncommon, and did not increase substantially with the higher-dose regimen. CONCLUSION: Paclitaxel can be added at full dose (200 mg/m2) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Median survival times in both extensive- and limited-stage patients compare favorably with other reported regimens. This regimen merits further investigation, and a randomized trial to compare this regimen with a standard carboplatin/etoposide combination is underway.

Paclitaxel by 1-hour infusion in combination chemotherapy of stage III non-small cell lung cancer.

We report our preliminary phase II experience with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a I-hour infusion with cisplatin, etoposide, and concurrent radiotherapy to patients with unresectable stage IIIA or IIIB non-small cell lung cancer. Twenty-three patients have been started on therapy, with 15 thus far completing treatment. Eight of 15 patients have achieved complete or "near complete" responses, and five more patients have had partial responses. No patients experienced disease progression. The combined-modality regimen was well tolerated, with the exception of grade 3 or 4 esophagitis, which usually occurred during the last 2 weeks of radiation therapy (eight patients). It is hoped the results of these and other studies will help clarify the role of paclitaxel in multimodality therapy for lung cancer.

Small cell lung cancer. Complete remission and improved survival.

Thirty-two patients with limited-stage small cell lung cancer were treated with combined supervoltage radiotherapy and a combination of cyclophosphamide, doxorubicin and vincristine chemotherapy. The goal of obtaining a complete remission, the necessary step which precedes improved survival, was successful in 26 of 27 of completely re-evaluated patients. Fiberoptic bronchoscopy was useful in substantiating complete remission status. Seventeen of the 32 patients remain alive from 8+ to 28+ months (median 16+ months). Ten patients are alive and relapse-free from 12+ to 28+ months (median 19+ months). Transient granulocytopenia (mean nadir 650 cells/mm3) during induction therapy and the associated risk of infection were the most serious toxicities encountered. This therapy produces complete remission on roentgenography and bronchoscopy, symtomatic improvement and improved survival in the majority of patients with limited-stage small cell lung cancer. A portion of these patients may have their disease eradicated.

Characterization of a variant erythrocyte surface antigen (VESA1) expressed by Babesia bovis during antigenic variation.

Babesia bovis, an intraerythrocytic, protozoal parasite of cattle, undergoes clonal antigenic variation (Allred DR, Cinque RM, Lane TJ, Ahrens KP. Infect Immun 1994;62:91-98). This ability could provide a mechanism by which the parasite escapes host immune defenses to establish chronic infection. Previous work identified two parasite-derived antigens of Mr 128,000 and 113,000 that were present on the surface of the infected erythrocyte and appeared to be associated with clonal antigenic variation (Allred DR, Cinque RM, Lane TJ, Ahrens KP. Infect Immun 1994;62:91 98). Two monoclonal antibodies (mAbs), 3F7.1H11 and 4D9.1G1, which recognize the variant erythrocyte surface antigen (VESA1) have been identified. These mAbs react only with the surface of erythrocytes infected with the B. bovis C9.1 clone in live-cell immunofluorescence assays. In both conventional and surface immunoprecipitations, the mAbs precipitate a variant antigen doublet that matches in mass the infected red blood cell (IRBC) surface antigens precipitated with bovine serum. In contrast, Western blot analysis revealed that only the Mr 128,000 polypeptide is recognized by the mAbs. Neither mAb recognizes antigenically variant progenitor or progeny parasite clones in any of the immunoassays, confirming the involvement of this antigen in rapid clonal antigenic variation. Failure to label this antigen with [9,10(n)-3H]myristic acid, [9,10(n)-3H]palmitic acid or D-[6-3H]glucosamine indicates that these polypeptides are neither N-glycosylated nor fatty acylated. Identity of the variant antigen recognized by the mAbs with that putatively identified with immune serum was confirmed by comparison of partial proteolytic digestion products. Unambiguous identification of the VESA1 antigen as a component of antigenic variation will facilitate characterization of the events leading to antigenic variation on the B. bovis-infected erythrocyte surface and its significance to parasite survival during chronic infection.

Testicular infiltrate in childhood acute lymphocytic leukemia. The need for biopsy in suspected relapse.

The testicle is a prime initial target for infiltration during relapse in male children with acute lymphocytic leukemia. Herein wer report our experience with management of this entity in 8 childre. It is stressed that a biopsy is essential to the diagnosis. The differential diagnosis is usually straightforward. One is admonished not to make presumptive diagnosis by palpation. Orchiectomy is unwarranted. The treatment of choice is testicular radiation with 2,000 rads in ten fractions in a twelve-day course plus reinsstitution of high-dose adjunctive chemotherapy in those children off chemotherapy, or reinduction therapy for children who relapse while still on chemotherapy. Prognosis of male children who undergo a bout of testicular infiltration is guarded.

Semi-empirical model for depth dose distributions of megavoltage x-ray beams.

The dose distribution due to absorption of photon energy fluence in a homogeneous water phantom irradiated by megavoltage x-ray beams has been analyzed with a semiempirical model. The method generalizes an analytical formalism for the scattering component of dose within a water phantom which was developed recently for monoenergetic photon beams. Contributions to dose via Compton interaction and pair creation form the essential structure of the secondary component formula. Both the central-axis percent depth dose and off-central-axis ratios can be determined for beams of different sizes, used at any value of source to surface distance. The input data include the values of linear attenuation and energy-absorption coefficients in water at energies between 10 keV and the equivalent energy of the beam. Predicted values of the central-axis percent depth dose and the off-central-axis ratios are compared with the measured data for 2, 4, 6, 8, 10, 14, 20, 35, 45, and 70 MVp x-ray beams. For the central-axis percent depth dose, agreement is within 3% for fields of sizes between 5 X 5 and 20 X 20 cm2, and 5% for larger fields, for beams of MVp up to 20. For higher energy beams, comparison was made only for the 10 X 10 cm2 fields and the discrepancies were within 3%. For the off-central-axis ratios, agreement between the predicted and measured values is within 5% over the umbra region but worsens in the penumbra region and geometrical shadow. This formalism requires large computer storage for generating data for all realistic beams irradiating normal-size phantoms.

Evaluation of tissue-air ratios and tissue-maximum ratios with the photon energy-fluence absorption dose model.

Values of tissue-air ratio (TAR) and tissue-maximum ratio (TMR) have been calculated with the photon energy-fluence absorption dose model, at depths d greater than dn (depth of dose normalization) in a homogeneous water phantom, for Co-60 gamma-ray, and 4, 6, 10, 14, and 45 MVp x-ray beams of EQS (the side of the equivalent square) up to 20 cm. It has been found that by (i) slightly altering the formula for the depth modification factor so that it depends on the difference (d -- dn) rather than d alone; and (ii) permitting E, the effective energy of the beam, to vary with EQS for some x-ray beams, it is possible for the model to reproduce within 2.5% the measured data at depths d greater than dn, on TAR, TMR and PDD (the central axis percent depth dose), for any source to surface distance.

Physical approach to depth dose distributions in a water phantom irradiated by a teleisotope photon beam.

The physical basis of deposition of radiation dose within a homogeneous phantom irradiated by a monoenergetic photon beam has been studied in terms of photon attenuation and energy-absorption properties of the phantom material. A semi-empirical model based on the Klein-Nishina formula for Compton scattering, and the ratio of multiply scattered to singly scattered photon fluences, has been developed for the scatter dose component within a realistic phantom to determine the central-axial percent depth dose (PDD) and off-central-axis ratios (OCR). Differences between the predicted and measured values of PDD and OCR for cobalt-60 and cesium-137 beams are less than 3% for fields of equivalent-square-side less than 20 cm, and less than 5% for larger fields. Beam profiles of all field sizes can be well simulated by this model and reasonable agreement has been found between the predicted and tabulated values of scatter functions and the backsetter factor for cobalt-60 beams. This formulation involves no variable parameters, and is valid for all values of the source-to-surface distance, field length and width, and field shape. However, the algorithm developed is not suitable for routine multiple-field treatment planning because it requires large computer memory size.

Comparing provider perceptions of access and utilization management in full-risk and no-risk Medicaid programs for adults with serious mental illness.

This article compares provider perceptions of access to services and utilization management (UM) procedures in two Medicaid programs in the same state: a full-risk capitated managed care (MC) program and a no-risk, fee-for-service (FFS) program. Survey data were obtained from 198 mental health clinicians and administrators. The only difference found between respondents in the FFS and MC sites was that outpatient providers in the MC site reported significantly lower levels of access to high-intensity services than did providers in the FFS site (p < .001). Respondents in the two sites reported similar attitudes toward UM procedures, including a strong preference for internal over external UM procedures. These findings support the conclusion that through diffusion of UM procedures, all care in the Medicaid program for persons with a serious mental illness is managed, regardless of risk arrangement. Implications for mental health services and further research are discussed.

Laparoscopic and percutaneous cryotherapy for renal neoplasms.

Incidence of renal cell carcinoma is increasing. There has been a shift towards utilization of nephron sparing surgery when feasible. Minimally invasive ablative treatments such as laparoscopic and percutaneous renal cryoablation aim to treat renal tumors with the two goals of cancer eradication and reduced morbidity compared to excisional surgical approaches. In this article, we review the basis of cryobiology and examine the current role of renal cryoablation and analyze the current literature focusing on laparoscopic and percutaneous approaches and discuss future directions and refinements in cryosurgical technology. While renal cryoablation is associated with higher local retreatment rates compared to radical or partial nephrectomy, emerging reports of intermediate-term oncological outcomes suggest disease-specific survival approaching that of extirpative surgery. Further follow up is needed to elucidate the long-term oncologic outcomes of and effects on renal function by renal cryoablation.

Persistence of Entamoeba histolytica infection in CBA mice owes to intestinal IL-4 production and inhibition of protective IFN-gamma.

The mechanisms whereby certain mouse strains develop persistent intestinal infection with Entamoeba histolytica remain unclear. In this work, we characterized the kinetic pattern of cytokine responses during the course of natural infection in CBA mice and showed that intracecal amebic infection led to a rapid and sustained upregulation of Th2 (IL-4, IL-5, IL-13) and Th17 cytokine responses while Th1 cytokines, IL-12p35 and interferon (IFN)-gamma, were suppressed. Depletion of IL-4 cleared infection by 14 days post-challenge, and this clearance correlated with and was mediated by IFN-gamma. The protective role for IFN-gamma was not strain-specific, as 129 background IFN-gammaR knockout mice exhibited a higher infection rate than their wild-type littermates. These studies indicate that IL-4 plays a critical pathogenic role in the persistence of E. histolytica infection through suppression of protective IFN-gamma and provide a possible explanation for why certain humans spontaneously clear amebiasis while others progress to invasive disease.

Entamoeba histolytica: genetic diversity of African strains based on the polymorphism of the serine-rich protein gene.

The polymorphism of the serine-rich Entamoeba histolytica protein (SREHP) among isolates obtained from different geographic regions was analyzed by a nested PCR followed by restriction analysis. Thirteen different profiles were generated from 23 E. histolytica isolates from Cameroon, Zimbabwe and South Africa while 20 others were generated from 38 E. histolytica PCR positive stool samples from South Africa. One of the profiles was common to isolates from Cameroon, Zimbabwe and South Africa and constituted the most prevalent (26.1%) of all the profiles. However, profiles unique to each country were also observed amongst the samples. A non-significant difference was observed between isolates from diarrheic and non-diarrheic samples. Of interest, of the five HIV positive stool samples three had the same profile indicating the possibility that some E. histolytica strains might be more common/pathogenic in immuno-compromised individuals. The results obtained showed that African isolates of E. histolytica may possess extremely complex genetic structures independent of geographic location. This study indicates that certain profiles might be responsible for the presentation of intestinal amoebic symptoms. However, more extended studies need to be performed in order to confirm these observations.

Bronchoalveolar neutrophils, interferon gamma-inducible protein 10 and interleukin-7 in AIDS-associated tuberculosis.

During advanced AIDS tuberculosis (TB) often presents atypically with smear-negative and non-cavitary disease, yet immune features associated with this change are poorly characterized. We examined the local immune response in a cohort of Tanzanian AIDS-associated TB patients who underwent bronchoalveolar lavage. TB infection was confirmed in bronchoalveolar lavage (BAL) fluid by culture, probe and polymerase chain reaction (PCR). Among TB patients CD4 count correlated positively with the extent of cavitary disease as well as BAL TB load (qPCR C(T)). TB patients had significantly higher granulocyte-macrophage colony-stimulating factor (GM-CSF) than non-TB patients, and those with non-cavitary TB had significantly higher BAL interferon gamma-inducible protein (IP-10) and interleukin (IL)-7 than those with cavities. BAL neutrophils were as prevalent as monocytes/macrophages or epithelial cells, and immunohistochemistry revealed that neutrophils, monocytes/macrophages, and epithelial cells were major sources of the IP-10 and IL-7. These data suggest a dysregulated cytokine profile may contribute to the TB of advanced AIDS.