Investigation of the potential of buffalo and couch grasses to grow on AFIs and for removal of nutrients from paper mill wastewater.

The potential growth of buffalo grass (Stenotaphrum secundatum) and couch grass (Cynodon dactylon) on artificial floating islands (AFIs) and their ability to remove total nitrogen (TN) and total phosphorus (TP) from a simulated paper mill wastewater was studied. This was done to assess the potential of AFIs for removal of nutrients from aerated stabilization basins (ASBs) that had occasional growth of blue-green algae (BGA) to bloom levels. Small scale AFIs were prepared using polyethylene foam and planted with the grasses in 30 L of tested water. Trials were conducted in a plastic covered greenhouse over a three-month period where temperatures ranged from 15 to 44 °C. The results showed that both buffalo and couch grasses can adapt to planting in AFIs showing increases of 125% and 148% in wet weight, respectively. Nutrient uptake by buffalo grass and couch grass were found to be similar. Percentage uptakes of TP and TN from the synthetic water by the buffalo grass were 82% and 47%, whereas by couch grass, uptakes were 83% and 45%, respectively.

[The dysregulated brain - Consequences of spatial and temporal brain complexity for bipolar disorder pathophysiology and diagnosis]. / Het ontregelde brein; consequenties van ruimtelijke en temporele complexiteit van het brein voor pathofysiologie en diagnostiek van de bipolaire stoornis.

BACKGROUND: Despite the existence of several pathophysiological theories about bipolar disorder, it has so far been difficult to find diagnostic biomarkers and to develop new pharmacologic treatments based on the more novel theories. AIM: To reflect on the causes and consequences of problems that beset pathophysiological research into psychiatric disorders in general and bipolar disorder in particular. METHOD: In this essay we address the problems facing professionals engaged in research into bipolar disorder and we interpret these problem in the light of brain complexity. RESULTS: The complexity of the brain can be divided into two types: spatial complexity, which reflects the various physiological levels of the central nervous system (genetic, molecular, cellular, neuronal circuits and phenomenological levels), and temporal complexity, i.e. neurodevelopment. We discuss the consequences of these two types of complexity and make suggestions relating to clinical practice and pathophysiological psychiatric research. CONCLUSION: To achieve further progress in the field of brain research, we need to acquire a deeper understanding of the spatial and temporal complexity of the brain and consider the possible consequences of such knowledge for the pathophysiology and treatment of psychiatric illnesses such as bipolar disorder.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age.

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean = 35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 µg, transdermal estradiol 100 µg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 µg than 100 µg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 µg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.

Evaluation of a smartphone human activity recognition application with able-bodied and stroke participants.

BACKGROUND: Mobile health monitoring using wearable sensors is a growing area of interest. As the world's population ages and locomotor capabilities decrease, the ability to report on a person's mobility activities outside a hospital setting becomes a valuable tool for clinical decision-making and evaluating healthcare interventions. Smartphones are omnipresent in society and offer convenient and suitable sensors for mobility monitoring applications. To enhance our understanding of human activity recognition (HAR) system performance for able-bodied and populations with gait deviations, this research evaluated a custom smartphone-based HAR classifier on fifteen able-bodied participants and fifteen participants who suffered a stroke. METHODS: Participants performed a consecutive series of mobility tasks and daily living activities while wearing a BlackBerry Z10 smartphone on their waist to collect accelerometer and gyroscope data. Five features were derived from the sensor data and used to classify participant activities (decision tree). Sensitivity, specificity and F-scores were calculated to evaluate HAR classifier performance. RESULTS: The classifier performed well for both populations when differentiating mobile from immobile states (F-score > 94 %). As activity recognition complexity increased, HAR system sensitivity and specificity decreased for the stroke population, particularly when using information derived from participant posture to make classification decisions. CONCLUSIONS: Human activity recognition using a smartphone based system can be accomplished for both able-bodied and stroke populations; however, an increase in activity classification complexity leads to a decrease in HAR performance with a stroke population. The study results can be used to guide smartphone HAR system development for populations with differing movement characteristics.

Anxiety and depression during pregnancy in Central America: a cross-sectional study among pregnant women in the developing country Nicaragua.

BACKGROUND: Around the world, maternal psychopathology during pregnancy is associated with a range of negative consequences for mother and child. Nevertheless, in Central America the magnitude of this public health problem is still unknown. The objective of this first explorative study was to investigate the prevalence and severity of anxiety and depression during pregnancy in the Central American developing country Nicaragua, as well as the availability of mental health care and to compare with a developed country. METHODS: A population-based cohort of pregnant women in Nicaragua (N = 98) was compared with a parallel cohort in the Netherlands (N = 4725) on symptoms of anxiety (Spielberger State Trait Anxiety Inventory) and depression (Edinburgh Postnatal Depression Scale). Associations with the women's knowledge how to reach professional psychological support were assessed using multivariable linear regression analyses. RESULTS: Of the Nicaraguan women, 41 % had symptoms of anxiety and 57 % symptoms of depression, versus 15 % and 6 % of the Dutch women. Symptom scores of both anxiety and depression were significantly higher in Nicaragua (p < 0.001). However, only 9.6 % of the women indicated that professional psychological help was available for the Nicaraguan pregnant women, which was associated with an increased anxiety score. CONCLUSIONS: In Nicaragua, both prevalence and severity of symptoms of antenatal anxiety and depression are substantially higher than in developed countries. However, availability of psychological help is very limited for pregnant Nicaraguan women. These findings indicate that there is need for further research and support for these women, to prevent negative consequences for both mother and child.

A Commentary on a recent update of the ovarian cancer risk attributable to menopausal hormone therapy.

The incidence of ovarian cancer is tenfold lower than that of breast cancer. The goal of the recently published meta-analysis by Beral and colleagues, using 'individual participant datasets from 52 epidemiological studies', was to provide an updated assessment of the effect of menopausal hormone therapy (MHT) on ovarian cancer risk. The relative risk generated from the cited prospective studies was significantly increased but the relative risk from the retrospective studies was not. This is quite unusual since retrospective studies usually display higher levels of relative risk. No further increase was observed with increasing duration. Moreover, a number of the studies could not be adjusted for important ovarian cancer risk factors. From the meta-analysis, it can be calculated that the absolute excess risk of 5 years of MHT for a 50-year-old UK woman is 1 in 10 000 per year, indicating a very low risk. We conclude that this meta-analysis mostly reflects the previously published data from the Million Women Study, from which the majority of this new publication is derived.

Predictive accuracy of Edinburgh postnatal depression scale assessment during pregnancy for the risk of developing postpartum depressive symptoms: a prospective cohort study.

OBJECTIVE: To investigate whether the 10-item Edinburgh Postnatal Depression Scale (EPDS) administered antenatally is accurate in predicting postpartum depressive symptoms, and whether a two-item EPDS has similar predictive accuracy. DESIGN: Prospective cohort study. SETTING: Obstetric care in the Netherlands. POPULATION: One thousand six hundred and twenty women from the general population. METHODS: Mean values, area under the receiver operating characteristics curve (AUC), sensitivity, specificity and predictive values of antenatal EPDS for the likelihood of developing postpartum depressive symptoms were calculated. Analyses were repeated for each trimester, several cut-off values and a two-item EPDS (low mood and anhedonia). MAIN OUTCOME MEASURES: Postpartum depressive symptoms, defined as EPDS score≥10. RESULTS: Mean EPDS scores were significantly higher during each trimester in women with postpartum depressive symptoms than in those without the symptoms (P<0.001). Using the prevailing cut-off (≥13), the AUC was reasonable (0.74), sensitivity was 16.8% (95% CI 11.0-24.1), positive predictive value was 41.8% (95% CI 28.7-55.9), specificity was 97.8% (95% CI 97.0-98.5) and negative predictive value was 92.7% (95% CI 91.3-94.0). Using a lower cut-off value (≥5), sensitivity was 70.8% (95% CI 62.4-78.3) and specificity was 65.4% 4 (95% CI 62.9-67.8), but positive predictive value was low (15.9%, 95% CI 13.1-19.0). Negative predictive value was exceedingly high at 96.0% (95% CI 94.6-97.2). Results were similar during the second and third trimester. The predictive accuracy of the two-item EPDS appeared inferior. CONCLUSIONS: The EPDS was not sufficiently accurate in predicting risk of postpartum depressive symptoms. Nevertheless, when using the ≥5 cut-off value, it may be adequate for initial screening, followed by further assessments and possibly antenatal intervention when positive. Furthermore, when negative, women may be reassured that postpartum depressive symptoms are unlikely. A two-item version showed poor predictive accuracy.

Risks and benefits of hormone therapy: has medical dogma now been overturned?

BACKGROUND: In an integrated overview of the benefits and risks of menopausal hormone therapy (HT), the Women's Health Initiative (WHI) investigators have claimed that their 'findings … do not support use of this therapy for chronic disease prevention'. In an accompanying editorial, it was claimed that 'the WHI overturned medical dogma regarding menopausal [HT]'. OBJECTIVES: To evaluate those claims. METHODS: Epidemiological criteria of causation were applied to the evidence. RESULTS: A 'global index' purporting to summarize the overall benefit versus the risk of HT was not valid, and it was biased. For coronary heart disease, an increased risk in users of estrogen plus progestogen (E + P), previously reported by the WHI, was not confirmed. The WHI study did not establish that E+ P increases the risk of breast cancer; the findings suggest that unopposed estrogen therapy (ET) does not increase the risk, and may even reduce it. The findings for stroke and pulmonary embolism were compatible with an increased risk, and among E+ P users there were credible reductions in the risk of colorectal and endometrial cancer. For E+ P and ET users, there were credible reductions in the risk of hip fracture. Under 'worst case' and 'best case' assumptions, the changes in the incidence of the outcomes attributable to HT were minor. CONCLUSIONS: Over-interpretation and misrepresentation of the WHI findings have damaged the health and well-being of menopausal women by convincing them and their health professionals that the risks of HT outweigh the benefits.

Vascularized Bone Grafts from the Lateral Femoral Condyle for the Treatment of Avascular Lunate Necrosis (Kienböck's).

Background: Avascular necrosis of the lunate (Kienböck's disease) is rare and one of the main causes of progressive painful arthritis, requiring surgical intervention. Various approaches have shown benefits in treating Kienbock's disease but with limitations. The article aims to analyze the functional outcome using lateral femoral condyle free vascularized bone grafts (VBGs) as the first choice of treatment for Kienböck`s. Materials and methods: This was a retrospective analysis of 31 patients with Kienbock's who had microsurgical revascularization or reconstruction of the lunate between 2016 and 2021 using either corticocancellous or osteochondral VBGs from the lateral femoral condyle. The characteristics of lunate necrosis, choice of VBG and postoperative functional outcome were reviewed. Results: Corticocancellous VBGs were used in 20 patients (64.5%), while osteochondral VBGs in 11 patients (35.4%). The lunate was reconstructed in 11 patients, revascularized in 19 patients, and one patient received augmentation of a luno-capitate arthrodesis with a corticocancellous graft. We noted postoperative irritation of the median nerve (n = 3) and screw loosening requiring removal (n = 1) as minor complications. All patients had complete graft healing at eight-month follow-up and acceptable functional outcomes. Conclusions: Free VBG from the lateral femoral condyle represent a reliable method of lunate revascularisation or reconstruction in advanced Kienböck's. Their main advantages are the constant vascular anatomy, straightforward graft harvesting technique and possibility to harvest several graft types according to the requirements at the donor site. Postoperatively, the patients become pain-free and have an acceptable functional outcome.

Cytokine and angiogenic factors associated with efficacy and toxicity of pazopanib in advanced soft-tissue sarcoma: an EORTC-STBSG study.

BACKGROUND: Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome. METHODS: Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated. RESULTS: At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS(12wks)), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P<0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS(12wks), and OS (both P<0.05). CONCLUSION: Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment.

Evidence-based assessment of the impact of the WHI on women's health.

Following the announcement of the first results of the Women's Health Initiative (WHI) to the media in 2002, prior to their scientific publication, the resulting panic headlines had an immediate and lasting negative effect on use of menopausal hormone replacement therapy (HRT) around the world. Rates of use dropped by 40-80%. Symptomatic women then sought multiple alternative therapies but the majority of these have no greater effect than the effect seen from placebo in well-conducted trials of HRT. Some of these therapies have risks. Although anecdotally most menopause practitioners after 2002 can attest to having to counsel large numbers of women with debilitating menopausal symptoms who were too frightened to consider HRT, it is difficult to document loss of health-related quality of life in large population studies as they were not conducted. Similarly, the positive or negative effects of the marked decline in HRT on long-term morbidities and mortality have yet to be fully assessed. Recent studies have shown an increase in postmenopausal fractures and in some, but not all, populations a small temporary decline in breast cancer. Cardiovascular outcomes may not be apparent for another decade. Short-term, randomized, placebo-controlled trials confirm that HRT is the only therapy that effectively improves health-related quality of life in symptomatic women through a reduction in vasomotor and urogenital symptoms, joint pains and insomnia, while improving sexuality. The results of the re-analyses of the WHI data and new data from other studies do not justify the continuing negative attitude to HRT in symptomatic women who start HRT near menopause.

Endurance and performance of two different concepts for left ventricular stimulation with bipolar epicardial leads in long-term follow-up.

BACKGROUND: Epicardial left ventricular (LV) leads represent an alternative for CRT therapy if transvenous lead implantation fails. Data on endurance, performance, the impact of the surgical approach (lateral minithoracotomy vs. median sternotomy simultaneously with other cardiac surgery), and the optimal technical concept (screw-in vs. suture-on) is limited. METHODS: Over a period of 48 months we evaluated 130 consecutive patients with comparable characteristics. A total of 54 screw-in (MyoDex™ 1084T, SJM) and 76 suture-on (Capture Epi 4968, Medtronic) bipolar epicardial steroid-eluting LV leads were implanted either via a left lateral or a median thoracotomy. Sensing, pacing threshold, impedance and NYHA class were recorded at defined time points. RESULTS: No surgery-related death or major complication was observed. At the time of implantation, the pacing threshold, sensing and NYHA class did not differ significantly between the two groups. The impedances of screw-in leads were significantly lower compared to those of suture-on leads. Suture-on leads showed a moderate initial drop in their pacing threshold but afterwards remained stable. Screw-in leads were characterized by a moderate but significant increase in the pacing threshold in the first year followed by a continuous decrease thereafter. Twenty-four months post-implantation no differences between both lead types could be detected. Sensing and NYHA class improved in both groups. The surgical approach had no significant impact on lead functionality. CONCLUSION: Our study showed that the implantation of epicardial leads was safe with very low complication rates. There was no superior technical epicardial lead concept (screw-in vs. suture-on leads) and all epicardial leads demonstrated an excellent long-term performance and durability. Therefore, it seems that epicardial leads represent a good alternative to transvenous leads and surgeons should be encouraged to implant epicardial leads during concomitant cardiac surgery when the indications for CRT are present.

[Hematogenous osteomyelitis due to clavicular fracture : A rare complication after conservative treatment]. / Hämatogene Osteomyelitis bei Klavikulafraktur : Eine seltene Komplikation nach konservativer Behandlung.

We present a case of a nondislocated clavicular fracture that was conservatively treated for 4 weeks with a sling. The patient was a smoker and suffered from type 2 diabetes mellitus. After 2 months a suppurative infection occurred due to an escalation based on a clavicular osteomyelitis. Through antibiotic treatment and an aggressive surgical approach the infection was cured but ended up with a painful malunion of the clavicle. The bone reconstruction was achieved with a long locking plate with an additional vascularized medial femoral condyle free flap. After 18 months the patient was subjectively very satisfied with the outcome, had no pain and excellent functional results in the Constant Murley and DASH (Disabilities of Arm, Shoulder and Hand) scores. The X­ray assessment showed full bone union.

PCR-mediated recombination: a general method applied to construct chimeric infectious molecular clones of plasma-derived HIV-1 RNA.

A PCR-based approach was developed that provides a powerful tool for engineering recombinant molecules without reliance on restriction sites. DNA sequences were first amplified by high-fidelity PCR using Pfu polymerase; they were then used both as 'megaprimers' and templates in subsequent asymmetric long PCR amplifications to form chimeric clones. To demonstrate the technique, we constructed chimeric full-length HIV-1 clones derived from reverse-transcribed plasma viral RNA and proviral LTRs. Biologic characterization of these clones showed that most were infectious in tissue culture and sequence analysis demonstrated an error rate of only one base change in 20 kb of DNA sequence. For PCR-mediated recombination, it is necessary to know the sequence of the 3' and 5' overlapping regions of the desired PCR products. This method may be extended to include construction of chimeras between any DNA fragments lacking sequence homology. Such chimeras may be constructed by introducing overlapping sequences to one of the fragments. To ensure that unwanted mutations have not been introduced into the clones constructed by this method, each clone should be sequenced. Our results demonstrate that by using a high-fidelity polymerase and highly controlled PCR conditions, the PCR-introduced error rate can be greatly minimized. This new procedure may be used to construct infectious chimeras of HIV or SIV for studies of vaccines and pathogenesis. Moreover, the method is designed to exchange viral genes at precise boundaries to study individual gene products from different HIV genomes. It can also be used to construct expression vectors for production of specific proteins or delivery vectors for gene transfer and gene therapy. Finally, the technique described here provides a versatile tool to transfer genes or gene fragments from different sources for genetic investigation and engineering.

Issues in the assessment of non-inferiority: perspectives drawn from case studies.

Superiority claims for improved efficacy are the backbone of clinical development of new therapies. However, not every new therapy in development allows for such a claim. Some therapies per se do not try to improve efficacy further but concentrate on important aspects in safety or convenience. Such improvements can be equally important to patients, and development strategies should be available for such compounds. A three-arm design with placebo, active control and experimental treatment may be viewed as the golden standard for such compounds; however, it may be difficult if not impossible to add a placebo arm in certain diseases. In such situations, non-inferiority designs are the only development option left. This paper will highlight some of the key issues with such designs in practice and will report experience from two studies from different therapeutic areas intended for regulatory submission.

Increased prevalence of metabolic syndrome in patients with bipolar disorder compared to a selected control group-a Northern Netherlands LifeLines population cohort study.

OBJECTIVES: Metabolic syndrome (MetS) is highly prevalent among patients with bipolar disorder (BD). The aims of this cross-sectional study were to determine the prevalence of MetS in Dutch BD subjects and compare it with a control group, to examine the association of demographic and clinical characteristics with MetS in BD, and to determine the extent to which metabolic dysregulation is treated in those patients. METHODS: 493 Dutch adult patients (≥ 18 years) with BD receiving psychotropic drugs and 493 matched control subjects were compared using data from the biobank Lifelines. We determined MetS according to the National Cholesterol Education Program Adult Treatment Panel III-Adapted (NCEP ATP III-A) criteria. The difference in the prevalence of MetS and the associations with characteristics were analyzed with logistic regression. RESULTS: BD subjects (30.6%) showed a significantly higher prevalence of MetS compared to the control group (14.2%) (p < .001, OR:2.67, 95% CI:1.94-3.66). Univariate analysis showed that smoking, body mass index (BMI) and antidepressant drug use were associated with MetS. Multivariate analysis showed that smoking (OR:2.01) was independently associated with MetS in BD. For hypertension, hyperglycemia and lipid disorder pharmacological treatment was provided to respectively 69.5%, 24% and 18.4% of the BD subjects in our sample. LIMITATIONS: Duration of illness of BD subjects was unknown. CONCLUSIONS: This study demonstrated a higher prevalence of MetS in Dutch BD subjects compared to persons without BD. In addition, a remarkable undertreatment of some of the components of MetS was found.

A collaborative and evolving response to the needs of frontline workers, patients and families during the COVID-19 pandemic at Tygerberg Hospital, Western Cape Province, South Africa.

The global devastation caused by the COVID-19 pandemic and its mental health impact is undeniable. The physical and psychological consequences are wide-ranging - affecting patients fighting the disease, frontline workers in the trenches with them, healthcare staff deployed in high-care settings, and families disconnected from their loved ones in their darkest hours. Within 6 weeks of the COVID-19 outbreak in South Africa, the Department of Psychiatry at Stellenbosch University established the TBH/SU COVID Resiliency Clinic to provide psychological support to frontline workers at Tygerberg Hospital. Identified barriers in healthcare workers accessing mental healthcare resulted in moving towards an on-site visibility to try to remove some of these barriers. This greater on-site presence enabled networking and building of relationships with frontline staff that over time highlighted other frontline needs, such as providing psychosocial and spiritual support to patients and their families. We share challenges, lessons learned and recommendations from two initiatives: the TBH/SU COVID-19 Resiliency Clinic, and an embedded COVID Care Team (CCT). We describe the establishment, roll-out and progress of the Clinic and the subsequent CCT.

Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours.

BACKGROUND: JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327. METHODS: Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood. RESULTS: JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27(kip1), phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%). CONCLUSION: JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.

Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma.

BACKGROUND: Ocrelizumab is a humanized anti-CD20 antibody with increased antibody-dependent cellular cytotoxicity compared with rituximab. This phase I/II study evaluated its safety and efficacy in patients with relapsed/refractory follicular lymphoma (FL) after prior rituximab therapy. DESIGN AND METHODS: Forty-seven patients were treated in three dose cohorts and received eight infusions every 3 weeks: cohort A, 200 mg/m(2) (n = 15); cohort B, 375 mg/m(2) (n = 16); cohort C, first dose 375 mg/m(2), seven subsequent doses of 750 mg/m(2) (n = 16). Patients were assessed for safety, efficacy, pharmacodynamics and pharmacokinetics. RESULTS: The median patient age was 58 years, the majority had Ann Arbor stage III/IV disease and had received a median of 2 (range 1-6) prior regimens. Ocrelizumab was well tolerated with grade 3/4 toxicity occurring in 9% of patients. The most common toxicity was infusion-related reactions (74% patients), all grade 1/2 except one grade 3 event. The objective response rate was 38% and was similar in patients with low-affinity and high-affinity variants of the Fcgamma receptor IIIa (FcgammaRIIIa). With follow-up of approximately 28 months, the median progression-free survival was 11.4 months. CONCLUSION: Ocrelizumab demonstrated activity in patients with relapsed/refractory FL following prior rituximab treatment, with safety similar to rituximab although adverse events appeared milder.

Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

OBJECTIVE: It remains unclear whether unipolar psychotic depression should be treated with an antidepressant and an antipsychotic or with an antidepressant alone. METHOD: In a multi-center RCT, 122 patients (18-65 years) with DSM-IV-TR psychotic major depression and HAM-D-17 > or = 18 were randomized to 7 weeks imipramine (plasma-levels 200-300 microg/l), venlafaxine (375 mg/day) or venlafaxine-quetiapine (375 mg/day, 600 mg/day). Primary outcome was response on HAM-D-17. Secondary outcomes were response on CGI and remission (HAM-D-17). RESULTS: Venlafaxine-quetiapine was more effective than venlafaxine with no significant differences between venlafaxine-quetiapine and imipramine, or between imipramine and venlafaxine. Secondary outcomes followed the same pattern. CONCLUSION: That unipolar psychotic depression should be treated with a combination of an antidepressant and an antipsychotic and not with an antidepressant alone, can be considered evidence based with regard to venlafaxine-quetiapine vs. venlafaxine monotherapy. Whether this is also the case for imipramine monotherapy is likely, but cannot be concluded from the data.