EVALUATION OF INDOCYANINE GREEN RETENTION AND AMINOPYRINE BREATH TESTS IN PATIENTS WITH MALIGNANT BILIARY OBSTRUCTION

Impaired hepatic function is a major contributory factor to the high incidence of postoperative morbidity and mortality in patients with malignant biliary obstruction. Dynamic hepatic function tests such as indocyanine green (ICG) retention and aminopyrine breath tests were evaluated in such patients to define whether they were clinically useful for prediction of postoperative morbidity and mortality. Forty-four patients with malignant biliary obstruction undergoing surgery for relief of obstructive jaundice were recruited into the study. Indocyanine green retention and aminopyrine breath tests were carried out in all patients pre-operatively and repeated in 36 patients postoperatively. The ICG retention was abnormal in all patients before surgery and there was significant improvement 2 weeks after surgery (32.8 ± 2.5%vs 18.3 ± 2.8%, P= 0.001). The change in ICG retention levels correlated with the serum bilirubin levels but the pre-operative ICG retention value could not predict postoperative morbidity and mortality. The aminopyrine breath test was abnormal in all but one patient. It correlated with pre-operative prothrombin time of the patients before surgery but it did not improve significantly after surgery and was not predictive of postoperative outcome. It is concluded that both ICG retention and aminopyrine breath tests have limited clinical value in the pre-operative evaluation of patients with malignant biliary obstruction.     

KCNJ2 mutations in arrhythmia patients referred for LQT testing: A mutation T305A with novel effect on rectification properties

BACKGROUND: Loss-of-function mutations in the KCNJ2 cause approximately 50% of Andersen-Tawil Syndrome (ATS) characterized by a classic triad of periodic paralysis, ventricular arrhythmia, and dysmorphic features. Do KCNJ2 mutations occur in patients lacking this triad and lacking a family history of ATS? OBJECTIVES: The purpose of this study was to identify and characterize mutations in the KCNJ2-encoded inward rectifier potassium channel Kir2.1 from patients referred for genetic arrhythmia testing. METHODS: Mutational analysis of KCNJ2 was performed for 541 unrelated patients. The mutations were made in wild type (WT) and expressed in COS-1 cells and voltage clamped for ion currents. RESULTS: Three novel missense mutations (R67Q, R85W, and T305A) and one known mutation (T75M) were identified in 4/249 (1.6%) patients genotype-negative for other known arrhythmia genes with overall incidence 4/541 (0.74%). They had prominent U-waves, marked ventricular ectopy, and polymorphic ventricular tachycardia but no facial/skeletal abnormalities. Periodic paralysis was present in only one case. Outward current was decreased to less than 5% of WT for all mutants expressed alone. Co-expression with WT (simulating heterozygosity) caused a marked dominant negative effect for T75M and R82W, no dominant negative effect for R67Q, and a novel selective enhancement of inward rectification for T305A. CONCLUSIONS: KCNJ2 loss of function mutations were found in approximately 1% of patients referred for genetic arrhythmia testing that lacked criteria for ATS. Characterization of three new mutations identified a novel dominant negative effect selectively reducing outward current for T305A. These results extend the range of clinical phenotype and molecular phenotype associated with KCNJ2 mutations.     

Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage.

We tested the hypothesis that astrocytic matrix metalloproteinase-9 (MMP-9) mediates hemorrhagic brain edema. In a clinical case of hemorrhagic stroke, MMP-9 co-localized with astrocytes and neurons in peri-hematoma areas. In a mouse model where blood was injected into striatum, MMP-9 was colocalized with astrocytes surrounding the hemorrhagic lesion. Because MMP-9 is present in blood as well as brain, we compared four groups of wild type (WT) and MMP-9 knockout (KO) mice: WT blood injected into WT brain, KO blood into KO brain, WT blood into KO brain, and KO blood into WT brain. Gel zymography showed that MMP-9 was elevated in WT hemorrhagic brain tissue but absent from KO hemorrhagic brain tissue. Edematous water content was elevated when WT blood was injected into WT brain. However, edema was ameliorated when MMP-9 was absent in either blood or brain or both. To further assess the mechanisms involved in astrocytic induction of MMP-9, we next examined primary mouse astrocyte cultures. Exposure to hemoglobin rapidly upregulated MMP-9 in conditioned media within 1 to 24 h. Hemoglobin-induced MMP-9 was reduced by the free radical scavenger U83836E. Taken together, these data suggest that although there are large amounts of MMP-9 in blood, hemoglobin-induced oxidative stress can trigger MMP-9 in astrocytes and these parenchymal sources of matrix degradation may also be an important factor in the pathogenesis of hemorrhagic brain edema.     

Prediction of functional outcomes in stroke inpatients receiving rehabilitation.

BACKGROUND AND PURPOSE: Early identification of predictive factors relevant to functional outcomes for stroke patients is important to the establishment of an effective continuing care program. The objective of this study was to identify the predictive factors related to functional outcome at discharge after stroke rehabilitation therapy. METHODS: 105 first-time stroke patients admitted to the inpatient rehabilitation department of a university-based medical center were recruited for this prospective study. The functional outcomes of the patients were assessed at admission and at discharge using the Functional Independence Measure (FIM). Severity of stroke was determined using the Canadian Neurological Scale (CNS). Age, gender, side of hemiplegia (SIDE), type of stroke (TYPE), onset to admission interval (OAI), and length of rehabilitation stay (LORS) were also included as predictor variables. RESULTS: The mean (+/- SD) FIM score at discharge (76.6 +/- 26.4) correlated strongly (r = 0.78, p < 0.001) with the admission FIM score (56.3 +/- 24.1), moderately (r = 0.46, p < 0.001) with the admission CNS score (6.1 +/- 2.2), negatively (r = -0.38, p < 0.001) with age (63.2 +/- 12.3 years), negatively (r = -0.26, p = 0.009) with OAI (24.2 +/- 16.0 days), and negatively (r = -0.29, p = 0.002) with LORS (34.7 +/- 16.8 days). Stepwise regression analyses indicated that admission FIM score, age, and admission CNS score were the strongest predictors of functional outcome and accounted for 66% of the total variation in discharge FIM total score. The admission FIM score was the best predictor and accounted for 61% of the variation. CONCLUSIONS: The findings of this study imply that the admission FIM scores for inpatients receiving stroke rehabilitation can be used to predict functional outcomes at discharge from hospital.     

Impaired motor imagery in patients with essential tremor: a case control study.

Motor imagery (MI), which refers to the process of mental representation of movements, has not been studied in patients with essential tremor (ET). We investigated the presence of impaired MI in ET patients compared with healthy controls. A group of drug-naive and nondemented ET patients and age-matched controls were studied using transcranial magnetic stimulation, while they were specifically instructed to try and imagine themselves performing two motor tasks. The various clinical and electrophysiological variables were evaluated and compared. Repeated measures ANOVA demonstrated a significant difference between ET patients and controls with respect to mean motor-evoked potential (MEP) amplitudes (F(1,38) = 31.92, P < 0.005) during MI. The process of MI effectively facilitated MEP amplitude in controls but not in ET patients, regardless of side of stimulation or motor tasks. We provide evidence to demonstrate impairment of MI in a group of ET patients compared with healthy controls. The basis for this novel finding is unclear, and further studies are warranted to determine whether it is related to cerebellar or motor cortical dysfunction.     

Is focal task‐specific dystonia limited to the hand and face?

Focal task-specific dystonia (FTSD) of the hand and face have been well described; however, FTSD of the leg is exceedingly rare. We describe and demonstrate by videotape 2 patients with FTSD affecting the leg, in both cases triggered specifically by walking down steps. Walking on a level surface, up steps, and down steps backward, and sideways were normal. An interoceptive sensory trick (imagining walking in a different modality) led to temporary improvement. Our patients appear to demonstrated that task-specificity in focal dystonia may not be limited to skilled, rehearsed actions and that FTSD may occur in an activity that is relatively autonomic.     

Scale-up of Adhesive Transdermal Drug Delivery Systems

Pharmaceutical Research -