Blinded placebo crossover study of gabapentin in primary orthostatic tremor.

Primary orthostatic tremor (OT) is a rare but disabling condition characterized by leg tremor and feelings of instability during stance. Previous studies have reported a reduction in OT symptoms with gabapentin treatment. In this study, we report on the benefits of gabapentin treatment in a double-blind placebo-controlled crossover study of 6 OT patients. First, the maximally effective gabapentin dosage (600-2,700 mg/day) for each patient was determined during an initial dose-titration phase. Patients were then studied 7 days after drug withdrawal and again after two 2-week periods of treatment with either gabapentin or placebo, using force platform posturography to quantify postural sway and tremor. Other medications for OT were continued unchanged. Symptomatic response was assessed by a patient-rated severity scale and quality of life (QOL) questionnaire. All patients reported an increase in symptoms during the washout phase and symptom reduction (50%-75%) during gabapentin treatment. Tremor amplitude was reduced to 79% +/- 11% and sway area to 71% +/- 11% of the placebo state. QOL improved in all patients, no adverse drug effects were noted, and symptomatic benefit was maintained at follow-up (mean = 19 months). The findings confirm that gabapentin is an effective treatment for OT, reducing both tremor and postural instability and improving quality of life, and support its use as add-on or first-line therapy for OT.     

Utilizing Nottingham Prognostic Index in microarray gene expression profiling of breast carcinomas.

We report a novel approach to gene expression profiling using the Nottingham Prognostic Index (NPI) to stratify 26 patients with invasive breast carcinoma. As an aggregate index of parameters reflecting metastatic potential, growth rate, and genetic instability the NPI has distinct advantages over other clinicopathologic features used to segregate breast cancer patients. As a continuous variable it offers a responsive and sensitive means of modeling a continuum of clinical aggressiveness. Using RNA extracted from 26 tumors and cDNA microarrays with 23 343 unique genetic elements, 84 genes and expressed sequence tags were identified whose expression patterns correlated with NPI. Differential expression by immunohistochemistry (IHC) was also observed for two of three genes evaluated by this method. Correlation was determined by the Spearman rank correlation method with null distribution analysis. Among the 84 genetic elements were seven previously implicated in neoplastic progression (including the two demonstrating differential expression by IHC), 11 without specific cancer association but localized to chromosomal sites whose loss or gain has been identified in cytogenetic studies of breast carcinoma, and 73 not previously associated with breast carcinoma. Collectively, the expression patterns of these 84 elements have potential to distinguish high and low NPI patient samples. These data add support to the assertion that prognostic groups of breast carcinoma are reflected in distinguishable expression profiles of a limited set of genes.     

ADAMTS8 and ADAMTS15 expression predicts survival in human breast carcinoma

We recently undertook expression profiling of all 19 human ADAMTS metalloproteinases (a disintegrin and metalloproteinase with thrombospondin motifs) in malignant and non-neoplastic breast tissue and showed that 11 of the ADAMTS genes are dysregulated in breast carcinoma. We identified a subgroup of ADAMTSs, based on functional and amino acid sequence similarity (ADAMTS1, 4, 5, 8 and 15), to be the focus of further study in breast carcinoma. Further RNA expression analysis by real-time PCR on a different cohort of 229 patients with breast cancer has identified ADAMTS8 as a predictor of poor overall survival (OS) (hazard ratio (HR) = 2.20, 95% C.I. = 1.29-3.74, p = 0.004) and confirmed ADAMTS15 as a predictor of prolonged relapse-free survival (RFS) (HR = 0.54, 95% C.I. = 0.32-0.89, p = 0.016). We explored the differences in survival of the 4 groups that could be categorized based on the expression levels of ADAMTS8 and ADAMTS15. For both RFS and OS, the group with high ADAMTS8 and low ADAMTS15 expression had a particularly poor prognosis. This group had a 3-fold higher chance of recurrence (HR = 3.03, 95% C.I. = 1.49-6.15, p = 0.001) and a greater than 5-fold higher chance of death (HR = 5.40, 95% C.I. = 2.16-13.5, p < 0.001) than the most favorable prognostic group. This prediction of poor prognosis by ADAMTS8 and ADAMTS15 expression was found to be independent of other classical clinicopathological factors. Results observed in FVB-PyMT mice, a robust transgenic model of highly metastatic breast carcinoma, fitted the expectation that relatively high expression levels of ADAMTS8 together with low expression levels of ADAMTS15 seen in human breast carcinoma are associated with a poor clinical outcome. In summary, ADAMTS8 and ADAMTS15 have emerged as novel predictors of survival in patients with breast carcinoma.     

Retrocecal appendix location and perforation at presentation

Retrocecal appendicitis has been theorized to follow a more insidious course than other anatomic variants. To determine the influence of retrocecal anatomy on clinical course of appendicitis, 200 adult patients treated at a major university medical center with the diagnosis of appendicitis from 2001 to 2004 were retrospectively studied. Computed tomography (CT) scans of adult patients with an ultimate diagnosis of appendicitis were analyzed to determine an association between retrocecal appendix and perforation of the appendix at presentation. A higher perforation rate in the retrocecal group would imply patient delay in presentation from more tolerable symptoms. CT scans were examined for retrocecal location and perforation. No significant association was found between retrocecal anatomy and perforation rates at presentation (chi-square = 2.1, P = 0.15, odds ratio = 1.6, 95% confidence interval [0.8-3.0]). However, the risk of perforation was 60 per cent higher in the retrocecal group. By regression analysis, age and the presence of a fecalith on CT scan were predictors of appendix perforation. Appendix location was not. In this study, we found no significant association between retrocecal appendix anatomy and perforation at presentation.     

CD4+ T cell-mediated antigen-specific immunotherapy in a mouse model of cervical cancer

A major agenda for tumor immunology is the generation of specific immune responses leading to the destruction of incipient and frank neoplasia. In this report, we show that a novel HPV16 E7 fusion protein can produce objective therapeutic responses against incipient cervical cancer in genetically engineered mice that express in the cervix the HPV16 early region genes implicated as causative agents in human cervical cancer. Although nonresponsive toward the HPV16 E7 oncoprotein in the CD8+ T-cell compartment by virtue of MHC haplotype, the mice were capable of mounting an induced CD4+ T-cell response against E7, and in addition developed spontaneous anti-E7 antibodies. HPV16/CD4-/- mice showed increased tumor burden indicative of CD4-mediated immune surveillance. Seeking to enhance the CD4 response, we immunized mice bearing incipient cervical cancer with a recombinant protein fusing E7 with a mycobacterial heat shock protein. The incidences of cervical carcinoma and of high-grade dysplasia (CIN 3) were consequently reduced by comparison to control mice. Thus, an HPV16 E7 immunogen holds promise for noninvasive treatment and prevention of human cervical cancer.     

Gaze direction modulates visual aftereffects in depth and color

Prior physiological studies indicate that gaze direction modulates the gain of neural responses to visual stimuli. Here, we test gaze modulation in the perceptual domain using color and depth aftereffects. After confirming retinotopy of the effects, we employed a balanced alternating adaptation paradigm (adaptation alternates between opponent stimuli) to demonstrate that opposite color and depth aftereffects can co-develop at the same retinal location for different gaze directions. The results provide strong evidence for (a) gaze modulation of aftereffects, (b) generality of gaze modulation across two visual attributes, and (c) perceptual correlates of the modulation of neural activity by gaze direction.     

Physical activity and exercise in the regulation of human adipose tissue physiology

Physical activity and exercise are key components of energy expenditure and therefore of energy balance. Changes in energy balance alter fat mass. It is therefore reasonable to ask: What are the links between physical activity and adipose tissue function? There are many complexities. Physical activity is a multifaceted behavior of which exercise is just one component. Physical activity influences adipose tissue both acutely and in the longer term. A single bout of exercise stimulates adipose tissue blood flow and fat mobilization, resulting in delivery of fatty acids to skeletal muscles at a rate well-matched to metabolic requirements, except perhaps in vigorous intensity exercise. The stimuli include adrenergic and other circulating factors. There is a period following an exercise bout when fatty acids are directed away from adipose tissue to other tissues such as skeletal muscle, reducing dietary fat storage in adipose. With chronic exercise (training), there are changes in adipose tissue physiology, particularly an enhanced fat mobilization during acute exercise. It is difficult, however, to distinguish chronic "structural" changes from those associated with the last exercise bout. In addition, it is difficult to distinguish between the effects of training per se and negative energy balance. Epidemiological observations support the idea that physically active people have relatively low fat mass, and intervention studies tend to show that exercise training reduces fat mass. A much-discussed effect of exercise versus calorie restriction in preferentially reducing visceral fat is not borne out by meta-analyses. We conclude that, in addition to the regulation of fat mass, physical activity may contribute to metabolic health through beneficial dynamic changes within adipose tissue in response to each activity bout.     

Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest

Anxiety is linked to compromised interactions between the amygdala and the dorsal and ventral medial prefrontal cortex (mPFC). While numerous task-based neuroimaging studies show that anxiety levels predict amygdala-mPFC connectivity and response magnitude, here we tested the hypothesis that anxiety would predict functional connectivity between these brain regions even during rest. Resting-state functional magnetic resonance imaging scans and self-reported measures of anxiety were acquired from healthy subjects. At rest, individuals with high anxiety were characterized by negatively correlated amygdala-ventral mPFC functional connectivity, while low anxious subjects showed positively correlated activity. Further, high anxious subjects showed amygdala-dorsal mPFC activity that was uncorrelated, while low anxious subjects showed negatively correlated activity. These data show that amygdala-mPFC connectivity at rest indexes normal individual differences in anxiety.