Phenylacetic acid in human body fluids: high correlation between plasma and cerebrospinal fluid concentration values.

In a group of six Parkinsonian patients and 13 "controls" with non-Parkinsonian neurological disease, there was a high correlation between both free and conjugated phenylacetic acid concentrations in plasma and cerebrospinal fluid taken at about the same time. This compound is the major metabolite of phenylethylamine, the production of which may be disturbed in a number of neuropsychiatric illnesses. Thus plasma measurements might be employed clinically to provide an estimate of central changes in phenylethylamine economy. A small but significantly higher proportion of conjugated phenylacetic acid was present in the plasma (but not cerebrospinal fluid) of Parkinsonians compared with controls.     

Short time delays change pattern induced flicker colors (PIFCs)

Subjects decided on whether the colors of the rings on a modified Benham's top were the same or different. The cause of color differences was a variable time delay. Δt, of the black and white stimulus pattern on the disc. Time delays of Δt = 50 μsec and less caused detectable changes in color and brightness.     

Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies

OBJECTIVE: To examine the association between patent foramen ovale (PFO) and atrial septal aneurysm (ASA) and stroke. METHOD: Data from case-control studies that examined the relative frequency of PFO, ASA, or both, in all patients with ischemic stroke, cryptogenic stroke, and known stroke cause as well as control subjects were included. Trials were categorized by age, clinical comparison, and abnormality. Combined OR were calculated using fixed effect (FE) and random effect (RE) methods. RESULTS: Comparing patients with ischemic stroke with control subjects using RE, OR for all ages was 1.83 (95% CI, 1.25 to 2.66) for PFO (15 studies), 2.35 (95% CI, 1.46 to 3.77) for ASA (nine studies), and 4.96 (95% CI, 2.37 to 10.39) for PFO plus ASA (four studies). Homogeneous results were found within the group younger than age 55: using FE, OR was 3.10 (95% CI, 2.29 to 4.21) for PFO, 6.14 (95% CI, 2.47 to 15.22) for ASA, and 15.59 (95% CI, 2.83 to 85.87) for PFO plus ASA. For patients older than age 55, using FE, OR was 1.27 (95% CI, 0.80 to 2.01) for PFO, 3.43 (95% CI, 1.89 to 6.22) for ASA, and 5.09 (95% CI, 1.25 to 20.74) for PFO plus ASA. Comparing cryptogenic stroke with known stroke cause, heterogeneous results were derived from total group examination using RE: OR was 3.16 (95% CI, 2.30 to 4.35) for PFO (22 studies), 3.65 (95% CI, 1.34 to 9.97) for ASA (five studies), and 23.26 (95% CI, 5.24 to 103.20) for PFO plus ASA (two studies). In patients younger than age 55, using FE the OR was 6.00 (95% CI, 3.72 to 9.68) for PFO; only one study examined ASA or PFO plus ASA. In patients aged 55 years or older, three studies produced heterogeneous results for PFO: using RE, OR was 2.26 (95% CI, 0.96 to 5.31); no data were available on ASA prevalence. CONCLUSIONS: PFO and ASA are significantly associated with ischemic stroke in patients younger than 55 years. Further studies are needed to establish whether an association exists between PFO and ischemic stroke in those older than 55.     

Low-dose olanzapine for levodopa induced dyskinesias

OBJECTIVE: To assess the usefulness of low-dose olanzapine (2.5 to 7. 5 mg/day) for Levodopa-induced-dyskinesias (LID) in patients with PD. METHODS: Ten patients with PD and LID took part in this randomized, placebo-controlled, double blind, crossover trial. Patients received a 2-week course of olanzapine or placebo in each treatment phase with 1-week washout in between. Dyskinesias were assessed at baseline and after each treatment period with an acute dopaminergic challenge and unified PD rating scale (UPDRS) questionnaires. Patients also kept on/off and dyskinesia diaries for the last 3 days prior to each assessment. RESULTS: There was a 41% difference in dyskinesia reduction on olanzapine compared to placebo, as measured by objective dyskinesia rating scales (mean percentage reduction abnormal involuntary movement score: 30% versus -11.2%, p < 0.02). Similar differences were demonstrated by patient diaries (mean reduction: 46% versus -2%, p < 0.02) and UPDRS items 32 and 33. Compared with placebo, treatment with olanzapine resulted in significant increases in 'off' time as measured by patient diaries (30% versus 2%) and reported adverse events (1.7 versus 0.1) including increased parkinsonism (1.1 versus 0.1) and a nonsignificant reported increase in drowsiness. CONCLUSIONS: Low-dose olanzapine is effective in reducing dyskinesias in PD, but even at very low doses can result in unacceptable increases in parkinsonism and 'off' time.     

Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist

BACKGROUND AND PURPOSE: Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies. METHODS: Two pivotal phase 3 ischemic stroke trials tested the hypothesis, by double-blind, randomized, placebo-controlled parallel design, that a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of stroke onset, would improve functional outcome at 90 days, defined as the proportion of patients achieving a Barthel Index score of >/=60. The trials were performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke and a motor deficit. RESULTS: The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS: Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia.     

An in vitro model for videoimaging of human bladder smooth muscle cell contractions

Knowledge regarding human bladder smooth muscle cell (SMC) physiology is very limited. Only a few specific medical therapies for bladder disorders have therefore been established. The objective of this study was to develop a model for videomicroscopy of bladder SMC contractions. Cells were isolated from human cystoprostatectomy specimens and cultured in a modified EMEM medium. These cells were identified as SMCs by means of immunohistochemistry. For videomicroscopy, the culture flasks were coated with a viscous agent to allow cell contraction. Contractions were visualized by means of a cell culture microscope with a time-lapse videosystem. For cholinergic stimulation of the cells, acetylcholine, in concentrations ranging from 100 μM to 10 mM, was applied. The percentage of contracting cells within the observation field was evaluated for quantitative analysis. In control experiments without contractile stimulant 6% of the cells were observed to contract. Stimulation with acetylcholine induced a significant dose-dependent increase to 47% in contracting cells. These results demonstrated that videomicroscopy is an appropriate tool to investigate the contraction mechanisms of bladder SMCs. This model offers the possibility of studying drug effects on the human detrusor in vitro. Received: 16 September 1999 / Accepted: 1 May 2000     

The functional demands on the intact limb during walking for active trans-femoral and trans-tibial amputees

The aim of this study was to investigate the loading demands placed on the intact limb in terms of joint moments and power for active trans-femoral and trans-tibial amputees in comparison to a group of able-bodied subjects. Four (4) trans-tibial, 4 trans-femoral amputees and 10 able-bodied subjects walked at 1.2m.s(-1) along a walkway whilst kinematic data from both the intact and prosthetic limbs, and kinetic data from the intact limb only were collected. A Panasonic VHS video camera was used to film subjects walking in the sagittal plane with simultaneous force data collected from a Kistler force platform. The amputees were found to compensate for the functional loss of one or more joints by increasing net joint moments and power output on their intact limb compared to able-bodied subjects. At the intact limb ankle, the range of motion, peak dorsiflexor moment and power generation at toe-off increased. At the intact limb knee, power generation during stance and extensor moments and power absorption at toe-off increased. At the intact limb hip, extensor moment and power absorption during stance, and hip flexor moment and power generation at toe-off increased. These findings were partly attributed to the prostheses used but mainly to adaptation mechanisms displayed by trans-femoral and trans-tibial amputees. They have implications for the mobility of amputees and the long term health of their joints. It was recommended that prosthesis design, prosthesis fitting and training in the use of the prosthesis were all factors which could be investigated with a view to minimising intact limb loading.     

Hyperglycemia and retinopathy of prematurity in very low birth weight infants.

OBJECTIVE: Retinopathy of prematurity (ROP) remains a leading cause of morbidity in the very low-birth-weight (VLBW) infant. This study investigates a possible association between serum/blood glucose and the development of ROP. METHODS: A retrospective case-control study of all infants born between 1992 and 1997 at the Johns Hopkins Hospital with birth weights less than 1000 g who developed Stage 3 or 4 ROP was conducted. Controls either had Stage 1 ROP or no eye disease and were matched 2:1 with ROP patients for gestational age, birth weight and year of birth. Odds ratios (ORs) of ROP were calculated for multiple exposures over the first month after birth, including oxygen concentration (FiO(2)), blood glucose levels, vitamin E, mean airway pressure and mean blood pressure. RESULTS: In a simple logistic regression analysis, we found an increased ROP risk for: (1) each 10 mg/dl increase of mean glucose (OR 1.96; 95% CI 1.13 to 3.42), (2) each 1% increase of mean FiO(2) (OR 1.06; 95% CI 1.004 to 1.13), (3) history of dopamine infusion (OR 5.4; 95% CI 1.16 to 25.2) and (4) intraventricular hemorrhage Grade 3 or 4 (OR 7.3; 95% CI 1.53 to 34.7). Using a multiple regression model, we found an increased ROP risk for each 10 mg/dl increase of mean glucose (OR 2.7; 95% CI 1.003 to 7.27). Each IU/kg/day of vitamin E supplementation reduced ROP risk (OR 0.37; 95% CI 0.16-0.86). CONCLUSION: In this study, we could demonstrate that glucose levels in the first month of life are associated with the development of ROP. Further studies have to determine if this association is causal or if hyperglycemia is just an expression of severity of illness.     

Prognostic impact of ANX7-GTPase in metastatic and HER2-negative breast cancer patients.

PURPOSE: ANX7-GTPase located on chromosome 10q21 is significantly altered and associated with hormone-refractory metastatic prostate cancers. Therefore, we investigated whether levels of ANX7 correlate with breast cancer progression and survival EXPERIMENTAL DESIGN: A diagnostic tumor tissue microarray containing 525 human breast tissue specimens at different stages of the disease was assayed for ANX7 using immunocytochemical methods with ANX7 monoclonal antibody. A separate prognostic tumor tissue microarray containing 553 human breast tissue specimens annotated with clinicopathological parameters was assayed for ANX7, HER2, estrogen receptor, progesterone receptor, and p53 protein. RESULTS: We report here for the first time that the expression of ANX7-GTPase is significantly enhanced and associated with the presence of metastatic disease (P < 0.0001) in the 525 human breast tissue specimens analyzed. Furthermore, using a separate 553 case retrospective prognostic tumor tissue microarray, we found that increased ANX7 expression is also significantly associated with poor overall patient survival (P < 0.014). This is particularly true when restricted to patients in whom the BRE clinical grade is 2 (P < 0.001) or for whom there is a lack of HER2 expression (P < 0.002). Finally, Cox regression analysis shows that as the expression of ANX7 rises, the probability of survival decreases by more than 10-fold for those patients with HER2-negative tumors. These latter patients represented 66% of the population affected with breast cancer in this study. CONCLUSIONS: High levels of ANX7 in tumor correlate strongly with poor survival of HER2-negative patients and the most aggressive forms of breast cancer. This is the first study to demonstrate that ANX7 antibody has the potential for development into an in vivo diagnostic and therapeutic tool. This simple and reliable immunohistochemical assay may therefore become an important biomarker for metastatic breast cancer diagnosis and management of HER2-negative breast tumor patients.     

Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission.

PURPOSE: The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. PATIENTS AND METHODS: The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor. RESULTS: Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P =.052), and Philadelphia chromosome-positive patients had no poorer outcome than Philadelphia chromosome-negative patients. Total-body irradiation-based conditioning improved DFS in comparison with busulfan (P =.041). CONCLUSION: Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.