Sustainable bioenergy for climate mitigation: developing drought-tolerant trees and grasses.

BACKGROUND AND AIMS: Bioenergy crops are central to climate mitigation strategies that utilize biogenic carbon, such as BECCS (bioenergy with carbon capture and storage), alongside the use of biomass for heat, power, liquid fuels and, in the future, biorefining to chemicals. Several promising lignocellulosic crops are emerging that have no food role - fast-growing trees and grasses - but are well suited as bioenergy feedstocks, including Populus, Salix, Arundo, Miscanthus, Panicum and Sorghum. SCOPE: These promising crops remain largely undomesticated and, until recently, have had limited germplasm resources. In order to avoid competition with food crops for land and nature conservation, it is likely that future bioenergy crops will be grown on marginal land that is not needed for food production and is of poor quality and subject to drought stress. Thus, here we define an ideotype for drought tolerance that will enable biomass production to be maintained in the face of moderate drought stress. This includes traits that can readily be measured in wide populations of several hundred unique genotypes for genome-wide association studies, alongside traits that are informative but can only easily be assessed in limited numbers or training populations that may be more suitable for genomic selection. Phenotyping, not genotyping, is now the major bottleneck for progress, since in all lignocellulosic crops studied extensive use has been made of next-generation sequencing such that several thousand markers are now available and populations are emerging that will enable rapid progress for drought-tolerance breeding. The emergence of novel technologies for targeted genotyping by sequencing are particularly welcome. Genome editing has already been demonstrated for Populus and offers significant potential for rapid deployment of drought-tolerant crops through manipulation of ABA receptors, as demonstrated in Arabidopsis, with other gene targets yet to be tested. CONCLUSIONS: Bioenergy is predicted to be the fastest-developing renewable energy over the coming decade and significant investment over the past decade has been made in developing genomic resources and in collecting wild germplasm from within the natural ranges of several tree and grass crops. Harnessing these resources for climate-resilient crops for the future remains a challenge but one that is likely to be successful.

Recent treatment advances in Hodgkin lymphoma: a concise review.

The majority of patients with Hodgkin lymphoma enjoy durable remissions following front-line treatment. This typically involves combination chemotherapy with or without radiotherapy. A significant minority of patients experience relapsed/refractory disease, of whom only approximately half can be 'salvaged' with conventional second-line treatments. Until recently, for those patients either failing or who are not fit for salvage, there have been few curative alternatives. Furthermore, there is a significant risk of delayed treatment complications to conventional therapies, including secondary malignancies and cardiac disease. However, novel targeted therapies are producing excellent results in clinical trials. They provide additional treatment options for those with relapsing/refractory disease; they may have potential in front-line therapy. The anti-CD30 antibody brentuximab vedotin (BV) has been tested as monotherapy and in combination in a variety of clinical settings, including in relapsed/refractory patients and as consolidative therapy following standard second-line therapy. Nivolumab and pembrolizumab, currently used in other malignancies that are known to utilise the programmed death pathway for survival, have shown outstanding results when used as single agents in heavily pre-treated (including BV refractory) patients. Individualising and adapting a patient's treatment course, whether augmenting or rationalising therapy, based on an interim positron emission tomography/computed tomography response is an important strategy currently under exploration to minimise toxicity while maximising response. Further work is needed to explore clinical and biological factors associated with improved outcomes. Knowledge of these factors combined with the movement of novel therapies into the front-line setting will enable individualised therapy to enhance clinical responses and minimise toxicities.

Haploidentical bone marrow transplants for haematological malignancies using non-myeloablative conditioning therapy and post-transplant immunosuppression with cyclophosphamide: results from a single Australian centre.

AIMS: To demonstrate safety and efficacy of haploidentical bone marrow transplantation with non-myeloablative conditioning and high-dose post-transplant cyclophosphamide in adult patients with leukaemia or lymphoma. BACKGROUND: Human leukocyte antigen haploidentical bone marrow transplantation is a treatment option in patients with haematological malignancies who have no available human leukocyte antigen-matched donor but is limited by conditioning regimen toxicity, graft failure, relapse and graft-versus-host disease (GvHD). METHODS: Twelve patients, median age of 51 years, underwent transplantation with T cell replete bone marrow from a haplotype-matched relative. The conditioning regimen consisted of cyclophosphamide, fludarabine and low-dose total body irradiation. Post-transplant immunosuppression consisted of a single dose of cyclophosphamide 50 mg/kg on day 3, followed by oral tacrolimus and mycophenolate mofetil. Outcomes reported are overall survival, engraftment and chimerism, toxicity, and clinical outcome. RESULTS: All patients had neutrophil recovery (median 14.5 days), and 11 of 12 had platelet engraftment (median 17 days). Two patients had autologous reconstitution. Seven of nine assessable patients had complete donor chimerism. Four patients had grades II-III GvHD, and none had grade IV GvHD. Four patients developed limited stage chronic GvHD. Five patients with acute myeloid leukaemia relapsed. Two patients died of nonrelapse causes, both from other malignancies, and five patients remain alive and relapse free. Median overall survival was 324 days (range 88-1163). CONCLUSION: This regimen is feasible and well tolerated in older patients with high-risk leukaemia or lymphoma, with minimal short-term toxicity and low rates of GvHD. The proportion of disease-free survivors indicates a graft-versus-malignancy effect is present in survivors.

A risk score for early cytomegalovirus reactivation after allogeneic stem cell transplantation identifies low-, intermediate-, and high-risk groups: reactivation risk is increased by graft-versus-host disease only in the intermediate-risk group.

BACKGROUND: This retrospective study was aimed at establishing a clinical score to stratify the risk of cytomegalovirus (CMV) reactivation in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in order to direct strategies for post-transplant CMV monitoring and therapy. PATIENTS AND METHODS: In total, 335 adult patients undergoing HSCT were analyzed and divided into a training set (n = 235) and a validation set (n = 100). Logistic regression analysis on the training set identified recipient and donor CMV seropositivity, acute graft-versus-host disease (GVHD), and use of anti-thymocyte globulin or alemtuzumab as significant risk factors for CMV reactivation. Weighted scores were assigned to each factor. A weighted score (CMV scoring index [CSI]) was calculated for each patient using the scores of all risk factors except for GVHD. The index was collapsed into 3 risk groups - low risk (score of 0-2), intermediate risk (score of 3-5), and high risk (score of 6-7) - and reactivation rates were calculated. In the training set, CMV reactivation occurred in 5.8% in the low-risk group, 44.8% in the intermediate-risk group, and 67.7% in the high-risk group. RESULTS: In patients with an intermediate CSI only, significantly higher reactivation rates were seen in the presence of corticosteroid treatment for GVHD (57.8% vs. 24.5%, P < 0.01). These findings were similar in the validation set with reactivation rates of 0% in the low-risk, 46% in the intermediate-risk, and 68.4% in the high-risk groups. As seen in the training set, the presence of GVHD was associated with higher CMV reactivation rates only in the intermediate-risk group (64% vs. 28% in the absence of GVHD, P = 0.02). CONCLUSIONS: Identification of these 3 risk groups in association with the presence or absence of GVHD will help transplant units to make pre-transplant policy decisions about prophylactic, pre-emptive, or experimental CMV prevention strategies in groups of patients undergoing HSCT, as well as in those developing GVHD post transplant.

Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy.

Between January 2001 and June 2008, 315 adult patients (median age 43 years, range 16-65) including 203 males and 112 females undergoing hematopoietic stem cell transplantation (HSCT) had serial monitoring for cytomegalovirus (CMV) followed by initiation of preemptive therapy. The majority (62.1%) had a conventional myeloablative transplant with 116 (36.9%) having a reduced-intensity conditioning (RIC) transplant, using either matched sibling/family (63.3%) or unrelated donors (36.7%). Graft source was peripheral blood stem cells in 257 (81.5%), bone marrow in 41 (13.1%), and cord blood in 16 (5.4%). T-cell depletion with anti-thymocyte globulin or alemtuzumab was used in 35%. Based upon CMV serostatus, patients were classified into low risk (donor [D]-/recipient [R]-), intermediate risk (D+/R-), or high risk (D-/R+ or D+/R+). Serial weekly monitoring for CMV viremia was performed using a qualitative polymerase chain reaction (PCR) and when positive, quantification was done using either pp65 antigen or a quantitative PCR. CMV reactivation was seen in 123 patients (39.1%) at a median of 50 days post HSCT (range 22-1978). CMV serostatus was the most important risk factor with incidence of 53% in the high-risk group (53.3%) compared with 10.2% in the intermediate risk and 0% in the low-risk group (P<0.0001). Other significant risk factors identified included use of alemtuzumab during conditioning (P=0.03), RIC transplants (P=0.06), and the presence of acute graft-versus-host disease (GVHD) (P<0.0001). On a multivariate analysis, CMV serostatus, RIC transplants, and acute GVHD remained independent predictors of CMV reactivation. All were treated with antiviral therapy with responses seen in 109 (88.6%). Sixteen patients (13%) developed CMV disease at a median of 59 days post HSCT (range 26 days-46 months), 8 of whom died. At a median follow up of 43 months (range 6-93), 166 patients (52.6%) are alive with a significantly higher survival among patients without CMV reactivation (57.2%) as compared with patients with CMV reactivation (45.5%; P=0.049). CMV reactivation and disease remains a major problem in high-risk patients undergoing allogeneic HSCT. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this specific group of patients.

Single versus double unrelated umbilical cord blood units for allogeneic transplantation in adults with advanced haematological malignancies: a retrospective comparison of outcomes.

BACKGROUND: Unrelated umbilical cord blood has emerged as an alternative stem cell source for allogeneic transplantation for patients with haematological malignancies, but in adults is limited by the low number of stem cells present in banked cord blood units. We report our experience with double cord blood transplants for adult patients. The aim of the study was to compare the outcomes of double unrelated cord blood transplants in adults with poor prognosis haematological diseases with single cord blood transplants. METHODS: Eleven patients, median age 27 years and median weight 69 kg, received transplants of two partially matched unrelated cord blood units after myeloablative conditioning therapy. RESULTS: Neutrophil recovery to 0.5 x 10(9)/L was seen by median day 32 (18-53), and platelet recovery to 50 x 10(9)/L by day 91 (56-381). These results were not significantly different from those reported in patients receiving single cord blood transplants. Acute graft-versus-host disease of grades II-IV was seen in four patients, but no chronic graft-versus-host disease occurred. Transplant-related complications were responsible for the deaths of five patients in the first 3 months post-transplant, whereas two patients died of relapse of their haematological malignancy. Four patients survive, disease free, 17-33 months post-transplant. CONCLUSION: Transplantation using two partially matched unrelated cord blood units did not appear to result in improvements either in engraftment or survival, as compared with a previous cohort of patients receiving single cord blood units. Further strategies appear to be needed to reduce the duration of severe neutropenia and reduce the high transplant-related mortality in these patients.

Oral health and dental morbidity in long-term allogeneic blood and marrow transplant survivors in Australia.

BACKGROUND: Oral and dental disease is a major cause of long-term morbidity following allogeneic blood and marrow transplantation (Allo-BMT). This study aimed to describe the extent and range of oral and dental complications in BMT recipients and to identify gaps in service provision provided to this high-risk group. METHODS: Participants were Allo-BMT recipients, aged >18 years, and received transplants between 2000 and 2012 in NSW. They completed seven surveys, the purpose-designed Sydney Post-BMT Study survey and six other validated instruments. RESULTS: Of 441 respondents, many reported dry mouth (45.1%), dental caries (36.7%), mouth ulcers (35.3%), oral GVHD (35.1%), gingivitis (16.2%), tooth abscess (6.1%) and oral cancer (1.5%). Regular dental visits were reported by 66.2% of survivors. Middle-high income, older age and geographic location showed a positive association with regular dental visits. Of those who did not visit the dentist regularly, 37% stated they did not feel it necessary, 36% reported cost and 20% stated it was not advised by the treating team. CONCLUSION: Despite oral complications commonly occurring after Allo-BMT, many survivors receive inadequate dental care. These results emphasize the need for improved oral health education, the importance of regular dental checks and improvement in the delivery of dental health services for BMT survivors.

An individualised risk-adapted protocol of pre- and post transplant zoledronic acid reduces bone loss after allogeneic stem cell transplantation: results of a phase II prospective trial.

Bone loss occurs frequently following allogeneic haematopoietic stem cell transplantation (alloSCT). The Australasian Leukaemia and Lymphoma Group conducted a prospective phase II study of pretransplant zoledronic acid (ZA) and individualised post-transplant ZA to prevent bone loss in alloSCT recipients. Patients received ZA 4 mg before conditioning. Administration of post-transplant ZA from days 100 to 365 post alloSCT was determined by a risk-adapted algorithm based on serial bone density assessments and glucocorticoid exposure. Of 82 patients enrolled, 70 were alive and without relapse at day 100. A single pretransplant dose of ZA prevented femoral neck bone loss at day 100 compared with baseline (mean change -2.6±4.6%). Using the risk-adapted protocol, 42 patients received ZA between days 100 and 365 post alloSCT, and this minimised bone loss at day 365 compared with pretransplant levels (mean change -2.9±5.3%). Femoral neck bone loss was significantly reduced in ZA-treated patients compared with historical untreated controls at days 100 and 365. This study demonstrates that a single dose of ZA pre-alloSCT prevents femoral neck bone loss at day 100 post alloSCT, and that a risk-adapted algorithm is able to guide ZA administration from days 100 to 365 post transplant and minimise further bone loss.

Reduced-intensity allogeneic haemopoietic stem cell transplantation induces durable responses in patients with chronic B-lymphoproliferative disorders.

Thirty-six patients with chronic B-lymphoproliferative disorders (B-LPD) underwent reduced-intensity allogeneic transplantation (RIT) from HLA-identical related donors. Diagnoses included follicular (n=17), mantle cell (n=9) and small lymphocytic lymphoma (n=2), and chronic lymphocytic leukaemia (n=8). Median age at transplant was 51 years (range, 30-66) and time from diagnosis was 3.4 years (range, 0.3-9.5). At transplant, 28% were in CR, 36% were in PR and 36% were chemorefractory. Conditioning therapy included fludarabine and either cyclophosphamide (n=27) or melphalan (n=9). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin (CsA)/methotrexate (n=21), CsA/mycophenolate mofetil (n=13) or CsA alone (n=2). Eight patients died owing to acute GVHD (n=3), infection in association with chronic GVHD (n=4) and intra-abdominal bleeding (n=1). Treatment-related mortality was 8% at day 100, and 17 and 20% at one and two years, respectively. The cumulative incidence of grade II-IV acute GVHD was 58%, whereas limited and extensive chronic GVHD occurred in 25 and 56%, respectively. No patient has relapsed or progressed. At a median follow-up of 48 months, overall survival probability is 80% (95% CI, 67-93%). We confirm that RIT in chronic B-LPD can result in high and durable CR rates but with significant incidences of acute and chronic GVHD.

External quality assurance of molecular analysis of haemochromatosis gene mutations.

BACKGROUND: The Royal College of Pathologists of Australasia Quality Assurance Programs has conducted an external quality assurance programme for the testing of the haemochromatosis gene (HFE) mutations C282Y and H63D. METHODS: A total of 10 surveys have been undertaken over a period of 6 years from 2000 to 2005. RESULTS: Of the 3016 responses received, the overall success rate was found to be 99.47% (3000/3016). A total of 16 errors were found, 6 for C282Y and 10 for H63D. Only one sample was associated with more than one error, in which 2 of 23 respondents classified a normal sample as heterozygotic for H63D. Overall performance was observed to vary minimally between surveys, from a low of 91.3% correct (21/23 responses) for a normal sample to 100% correct in most (85/100) samples. Of the 10 complete surveys, four returned a 0% error rate. In one survey in 2004, seven incorrect responses were returned by one laboratory, all of which were secondary to transcriptional errors. Overall success rates per assay were 99.61% (1532/1538) for C282Y and 99.32% (1468/1478) for H63D. Over a period of 6 years from 2000 to 2005, the proportion of respondents using polymerase chain reaction (PCR) and restriction enzyme analysis fell from 85% to around 30%, whereas the proportion of laboratories using real-time PCR rose from 5% to around 55%, as indicated by the questionnaire surveys of methods used by participants. DISCUSSION: Encouraging levels of testing proficiency for two common genetic mutations are indicated by these data, but they also confirm the need for participation of molecular diagnostic laboratories in external quality assurance programmes to ensure the ongoing provision of high-quality genetic testing services.

Unrelated umbilical cord blood transplantation for adults with haematological malignancies: results from a single Australian centre.

BACKGROUND: A number of haematological malignancies can be cured by allogeneic stem cell transplantation but only approximately 30% of Australians have a suitable histocompatible related donor. Matched donors can be found on international registries of unrelated volunteers for a proportion of the remaining patients. For those patients in need of an allogeneic transplant, but for whom a suitable matched related or unrelated adult donor cannot be found, the use of banked unrelated umbilical cord blood has emerged as a potential option. However, there is uncertainty about the applicability of this technique for the majority of adult patients as a result of limitations in the number of cells in banked cord blood units and the degree of mismatching for histocompatibility antigens. AIMS: The aim of this study was to define the feasibility of allogeneic stem cell transplantation using single unrelated cord blood units in a cohort of adults with poor prognosis leukaemia or lymphoma. METHODS: Nine patients with haematological malignancies (five with acute myeloid leukaemia, one with acute lymphoblastic leukaemia, one with Hodgkin lymphoma and two with non-Hodgkin lymphomas) received transplants of cryopreserved cord blood after conditioning therapy with high-dose cyclophosphamide, total body irradiation and antithymocyte globulin. Cord units contained a median 2.6 x 10(7) nucleated cells/kg recipient bodyweight and were matched for four (seven cases) or five (two cases) major histocompatibility complex class 1 and 2 antigens. Patients were given post-transplant immunosuppression with cycosporin and methylprednisolone. RESULTS: Neutrophil recovery to 0.5 x 10(9)/L was seen by median day 30 after transplant in all seven patients who survived more than 1 month post-transplant. Platelet recovery to 50 x 10(9)/L occurred by median day 81 in five evaluable patients. Acute graft versus host disease (GVHD) grades II-IV was seen in four of seven evaluable patients and limited chronic GVHD was seen in four of five. Infection was the most common complication. Four patients died before day 100 of infection (methicillin-resistant Staphylococcus aureus septicaemia, respiratory syncitial virus pneumonia), GVHD and multi-organ failure, and intracranial bleeding. Five patients survived 7-69 months post-transplant, without evidence of relapse of the underlying malignancy. CONCLUSION: Unrelated cord blood transplantation is feasible in adults with high-risk malignancy, with infection relating to immunocompromise being the major limitation.

The experience of survival following allogeneic haematopoietic stem cell transplantation in New South Wales, Australia.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) entails long-term morbidities that impair survivors' quality of life through broad physical and psychosocial sequelae. Current data and survival measurements may be inadequate for contemporary Australian allo-HSCT recipients. This study sought to comprehensively describe survivorship in an up-to-date, local setting through validated measurements and a novel questionnaire designed to complement and address limitations of current instruments. All adults who received an allo-HSCT between 2000 and 2012 in New South Wales were eligible and included, if alive, those literate and consenting to the study, which encompassed seven survey instruments. Four hundred and forty-three survivors participated, which is 76% of contactable (n=583) and 66% of eligible survivors (n= 669). Chronic GVHD (cGVHD) and co-morbidity rates were similar to published data. Noteworthy results include prevalent sexual dysfunction (66% females, 52% males), loss of income (low income increased from 21 to 36%, P<0.001) and employment (full-time employment fell from 64 to 33%, P<0.001), suboptimal vaccination (31% complete), and health screening (≈50%). Risk factors for poor vaccination and health screening were cGVHD, younger age, less education, rural/regional residence and transplantation <2 years. This study suggests that improvement in survivorship may necessitate structural changes in the current delivery of health services.

Posttraumatic stress disorder in Israeli combat veterans. Effect of phenelzine treatment.

Twenty-five Israeli combat veterans fulfilling DSM-III criteria for posttraumatic stress disorder (PTSD) participated in an open, prospective trial of phenelzine sulfate administration (median daily dose, 60 mg; range, 30 to 90 mg); three patients withdrew early due to side effects. Treatment was continued for at least four weeks in 22 cases and thereafter for as long as it was felt to be of benefit. Therapeutic efficacy was rated using a new PTSD scale, the Hamilton Depression Scale, and the Hamilton Anxiety Scale administered at four weekly intervals. Six patients completed four to eight weeks of phenelzine treatment; seven patients, nine to 13 weeks; and nine patients, 14 to 18 weeks. Comparison of mean prediscontinuation scores with pretreatment ratings showed, at best, only small (23% to 38%) differences (on the PTSD and Hamilton Anxiety scales) in the group treated for nine to 13 weeks. Two patients with a concurrent diagnosis of panic disorder and two with a concurrent diagnosis of dysthymic disorder were the most improved symptomatically but fell short of clinically significant remission. Although statistically significant improvement was observed on seven of the 12 items of the PTSD scale, sleep disturbance was the only symptom showing a clinically impressive change. These results only partially support previous positive reports of phenelzine treatment of PTSD.

A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma.

Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

Biochemistry of factor X.

Factor X circulates as a serine protease which is converted to the active form at the point of convergence of the intrinsic and extrinsic coagulation pathways. Subsequently, the enzymatic species, factor Xa, is involved in macromolecular complex formation with its cofactor factor Va, a phospholipid surface and calcium to convert prothrombin into thrombin. The gene encoding factor X shares a number of structural and organisational features in common with the other vitamin K-dependent coagulation proteins, suggesting that they have evolved from a common ancestral gene. Each of the exons encoding these proteins can be considered as a module coding for a homologous domain in each protein. These structural domains in factor X are responsible for specific functional properties including gamma-carboxylase recognition, calcium binding, phospholipid surface interaction, as well as cofactor and substrate binding. Studies of recombinant proteins and proteolytic fragments continue to provide significant insight into structure-function relationships of the protein modules within factor X.

A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder.

BACKGROUND: The anticonvulsant, lamotrigine, may be useful for symptom management in PTSD. METHODS: Subjects enrolled in a 12-week double-blind evaluation of lamotrigine and placebo. Patients were randomized 2:1 to either lamotrigine or placebo. Lamotrigine was initiated at 25 mg/day and slowly titrated every 1 to 2 weeks over 8 weeks to a maximum dosage of 500 mg/day if tolerated. RESULTS: Fifteen subjects entered treatment, fourteen of whom returned for subsequent visits. Of 10 patients who received lamotrigine, 5 (50%) responded according to the DGRP, compared to 1 of 4 (25%) who received placebo. Lamotrigine patients showed improvement on reexperiencing and avoidance/numbing symptoms compared to placebo patients. Treatments were generally well tolerated. CONCLUSIONS: Lamotrigine may be effective as a primary psychopharmacologic treatment in both combat and civilian PTSD and could also be considered as an adjunct to antidepressant therapy used in the treatment of PTSD. These promising results warrant further large sample double-blind, placebo-controlled trials.

Health status, somatization, and severity of posttraumatic stress disorder in Vietnam combat veterans with posttraumatic stress disorder.

OBJECTIVE: A two-part study was conducted to examine the health status of Vietnam veterans with posttraumatic stress disorder (PTSD). In part 1, veterans with and without PTSD were compared on health behaviors and on self-reported and physician-rated health problems. Consistency of self-report with physician rating for health problems across the two groups was compared. In part 2, the association between health status and PTSD symptom severity, depression, somatization, and health behaviors in PTSD patients was evaluated. METHOD: In part 1, 276 combat veterans (225 with PTSD and 51 without PTSD) provided health status information, and medical records were reviewed. In part 2, 225 PTSD patients completed standardized PTSD severity, somatization, and depression measures. RESULTS: When analyses controlled for age, socioeconomic status, minority status, combat exposure, alcohol use, and pack-year history, veterans with PTSD reported and were rated as having a greater number of health problems than veterans without PTSD. Agreement between self-report and physician ratings for both groups ranged from low to moderate. Level of agreement between patient and physician was similar across groups. In the analysis of veterans with PTSD, somatization and PTSD symptom severity were significantly related to self-report of health problems, whereas only PTSD symptom severity was related to physician-rated health. Pack-year history was significantly related to self-reported health status in both groups. CONCLUSIONS: The presence and severity of PTSD in veterans were associated with greater physical health problems and conditions. Psychological variables (e.g., PTSD status, PTSD severity, somatization) and a behavioral variable (pack-year history) were related to health status.

Discrimination of von Willebrands disease (VWD) subtypes: direct comparison of von Willebrand factor:collagen binding assay (VWF:CBA) with monoclonal antibody (MAB) based VWF-capture systems.

Discrimination of von Willebrand's Disease (VWD) subtypes is important since it influences management. Qualitative [ie Type 2A, 2B, 2M] defects exhibit von Willebrand factor (VWF) discordance and give high VWF:Ag to VWF:'activity' ratios. Classically, VWF:'activity' is assessed using the VWF:RCof assay. The VWF:CBA is an ELISA-based VWF-functional adhesive assay which has consistently proved to be superior to VWF:RCof. A commercially available monoclonal antibody (MAB) based ELISA assay system claimed to mimic a VWF:RCof-like activity has also been recently described ('SE'), as has the production and characterisation of a large number [n = 10] of locally generated anti-VWF MAB. In the current study, we have adapted these MAB to in-house ELISA assays to assess their utility for VWD diagnosis and subtype discrimination, and to compare them with other assay systems. Thus, the VWF:CBA, VWF:RCof by agglutination, the SE assay, and in-house MAB based assays have been directly compared for their ability to discriminate Type 1 [n = 9] from Type 2 VWD samples [phenotypes 2A and 2B; n = 11]. In summary, MAB-based systems can be used to measure VWF and confirm a diagnosis of VWD, as well as exhibiting some VWD-subtype-discriminatory capabilities. However, better evidence of VWF-discordance was usually achieved using the VWF:RCof (agglutination) assay, while the greatest degree of VWF-discordance was consistently observed using the VWF:CBA assay. In conclusion, the VWF:CBA assay proved to offer the best diagnostic predictive tool for a Type 2 VWD defect, while MAB-based systems appear to be less effective in this regard.

Laboratory testing for von Willebrand's disease: an assessment of current diagnostic practice and efficacy by means of a multi-laboratory survey. RCPA Quality Assurance Program (QAP) in Haematology Haemostasis Scientific Advisory Panel.

We report an evaluation of current laboratory practice for the diagnosis of von Willebrand's disease (VWD) by means of a multilaboratory survey. This assessment was undertaken with the RCPA Quality Assurance Program (QAP) in Haematology, which covers a wide geographic area encompassing Australia, New Zealand and Asia. A total of 25 laboratories actively involved in testing for VWD were selected to participate in a sample testing assessment exercise. Samples comprised 10 plasmas: (i) a normal plasma pool (in duplicate), (ii) this pool diluted to 50% (in duplicate), (iii) a normal individual (X1), (iv) severe Type 1 VWD (X1), (v) Type 2B VWD (x2 unrelated donors), (vi) Type 3 VWD (x1), (vii) Type 2A VWD (x1). Laboratories were asked to perform all tests available to them in order to establish a laboratory diagnosis of VWD, and then to comment on the possibility or otherwise of VWD. Overall findings indicated a wide variation in test practice, in the effectiveness of various test procedures in detecting VWD, and in the ability of various composite test panels to identify type 2 VWD subtypes. Firstly, while all laboratories (n = 25) performed tests for FVIII:C activity, von Willebrand factor 'antigen' (VWF:Ag) and a functional VWF assay [using the ristocetin cofactor assay (VWF:RCo; n = 23) and/or the collagen binding assay (VWF:CBA; n = 12)], only three laboratories carried out VWF:Multimer analysis. Secondly, for the three quantitative VWF assays, 10/25 (40%) laboratories performed all three, whereas 15/25 (60%) performed only two [VWF:Ag and VWF:RCo (n = 13); VWF:Ag and VWF:CBA (n = 2)]. Thirdly, a variety of assay methodologies were evident for VWF:Ag [ELISA, electro-immuno diffusion (EID), latex immuno-assay (LIA), and VIDAS assay] and VWF:RCo (platelet agglutination/'aggregometry' and a 'functional VWF:RCo-alternative' ELISA assay). Between method analysis for the quantitative VWF assays showed that the VWF:RCo yielded the greatest degree of inter-laboratory assay variation, and had the poorest overall performance with respect to sensitivity to low levels of VWF. The VWF:CBA also performed better than the VWF:RCo in terms of ability to detect functional VWF 'discordance' (i.e. Type 2 VWD). Within VWF:Ag method analysis showed that the EID assay procedure was associated with the greatest variation in assay results, while the EID and LIA test methods showed poorer sensitivity at low VWF levels compared to the ELISA method. Within the VWF:RCo assay procedure, greatest variation in assay results and poorest sensitivity to low VWF levels was obtained using the agglutination method; however, the agglutination procedure showed better performance than the 'functional VWF:RCo-alternative' ELISA assay in identifying Type 2 VWD plasma samples. Finally, despite identified variations, most laboratories appeared to understand the complexities involved in the VWD-diagnostic process, and made appropriate diagnostic predictions regarding tested samples. From a total possible 246 interpretation events, laboratories in most cases correctly identified normal samples as normal (67/75 events = 89%), and VWD samples as derived from individuals with VWD (117/121 events = 97%). Moreover, when VWD was suggested by laboratory findings, laboratories usually correctly predicted the general subtype of VWD present (96/109 events = 88%). When 'misinterpretations' occurred, these could often be linked to the test panels utilised by laboratories. That is, laboratories using the VWF:Ag and VWF:RCo combination were more likely to incorrectly identify samples derived from Type 2 VWD patients as being Type 1, Type 1 VWD patients as being Type 2, and normal plasma samples as potentially derived from patients with VWD, compared to those using the VWF:Ag and VWF:CBA.

Open trial of nefazodone for combat-related posttraumatic stress disorder.

BACKGROUND: Because of its ability to block 5-HT2 receptors postsynaptically and inhibit 5-HT reuptake presynaptically and/or its enhancement of sleep quality, nefazodone may be useful for symptom management in posttraumatic stress disorder (PTSD) patients. METHOD: Ten patients with combat-related DSM-IV posttraumatic stress disorder (PTSD) entered an open-label 12-week trial of nefazodone with a 4-week follow-up, beginning with 100 mg/day and increasing as necessary to achieve a maximal response or until reaching a maximum dosage of 600 mg/day. RESULTS: Nefazodone was well tolerated, and no significant changes in sexual function were reported. Based on Clinical Global Impressions-Improvement scores, all 10 patients were rated as much improved. All PTSD symptoms (except self-reported PTSD reexperiencing symptoms), sleep, and clinician-rated depression significantly improved at week 12. At follow-up, significant changes were maintained, and self-reported PTSD reexperiencing symptoms had also significantly improved. Effect sizes for all changed symptoms were moderate to large at week 12 and at follow-up. Self-reported and clinician-rated anger significantly improved. Self-reported depression failed to improve. Improvement in social and occupational functioning was minimal. CONCLUSION: These preliminary data suggest that nefazodone may be effective in reducing the 3 primary PTSD symptom clusters and may be particularly helpful in improving sleep and decreasing anger.