Family history and APOE4 risk for Alzheimer's disease impact the neural correlates of episodic memory by early midlife.

Episodic memory impairment is a consistent, pronounced deficit in pre-clinical stages of late-onset Alzheimer's disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current event-related fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40-58 yrs) with a family history of late onset AD (MA+ FH), or a combined + FH and apolipoprotein E ε4 allele risk factors for AD (MA+ FH + APOE4), will exhibit differences in encoding and retrieval-related brain activity, compared to - FH - APOE4 MA controls. We also hypothesized that the two at-risk MA groups will exhibit distinct patterns of correlation between brain activity and memory performance, compared to controls. To test these hypotheses we conducted multivariate task, and behavior, partial least squares analysis of fMRI data obtained during successful context encoding and retrieval. Our results indicate that even though there were no significant group differences in context memory performance, there were significant differences in brain activity and brain-behavior correlations involving the hippocampus, inferior parietal cortex, cingulate, and precuneus cortex in MA with AD risk factors, compared to controls. In addition, we observed that brain activity and brain-behavior correlations in anterior-medial PFC and in ventral visual cortex differentiated the two MA risk groups from each other, and from MAcontrols. Our results indicate that functional differences in episodic memory-related regions are present by early midlife in adults with + FH and + APOE-4 risk factors for late onset AD, compared to middle-aged controls.

Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain?

The unique pharmacology of remifentanil makes it a popular intra-operative analgesic. Short-acting opioids like remifentanil have been associated with acute opioid tolerance and/or opioid-induced hyperalgesia, two phenomena which have different mechanisms and are pharmacologically distinct. Clinical studies show heterogeneity of remifentanil infusion regimens, durations of infusion, maintenance of anaesthesia, cumulative dose of remifentanil and pain measures, which makes it difficult to draw conclusions about the incidence of acute tolerance or hyperalgesia. However, it appears that intra-operative remifentanil infusion rates of above 0.25 µg.kg-1 .min-1 are associated with higher postoperative opioid consumption, suggesting tolerance. Infusion rates greater than 0.2 µg.kg-1 .min-1 are characterised by lower mechanical/pressure/cold/pain thresholds, which suggests hyperalgesia. The use of concurrent multimodal analgesia, especially N-methyl-D-aspartate receptor antagonists, may be an effective preventive strategy. The clinical significance and long-term consequences of these entities is still uncertain.

Oral carcinoma with perineural invasion has higher nerve growth factor expression and worse prognosis.

BACKGROUND: This study elucidated the association between histopathological factors and the prognosis of oral carcinoma. As the histopathological factors were determined from the surgical specimen and this can only be used for the choices of postoperative regimens, this study also investigated the linkage between prognostic factors and the expression of key molecules to examine the feasibility of markers as predictors. METHODS: Clinicopathological factors of 101 oral carcinomas were cross-analyzed with disease-free survival. The expression of nerve growth factor (NGF) and its receptor, tyrosine kinase A receptor, was assayed with immunohistochemistry. RESULTS: Nodal metastasis was the most crucial clinical predictor for disease-free survival. Perineural invasion (PNI) was an independent histopathological predictor for both nodal metastasis (P = 0.004) and disease-free survival (P = 0.019). Patients with advanced tumor and PNI exhibited the high hazard for tumor progression and poor disease-free survival. NGF immunoreactivity in tumors was correlated with PNI (P = 0.005) and neck lymph node metastasis (P = 0.036). CONCLUSION: Perineural invasion is the indicator of worst prognosis. As NGF immunoreactivity was found to be associated with PNI and nodal metastasis, the NGF immunoreactivity of oral carcinoma revealed by diagnostic biopsy suggests that alternative therapeutic approaches might be appropriate.

Histopathological factors affecting nodal metastasis in tongue cancer: analysis of 94 patients in Taiwan.

The overall prognosis for tongue cancer patients in Taiwan is unpredictable, even when patients are treated following the guidelines according to TNM stages. In order to determine the optimal treatment modality for tongue cancer in Taiwan the authors aimed to correlate histopathological parameters with neck nodal metastasis. A retrospective analysis of 94 patients with different stages of tongue cancer treated in the Taipei Veterans General Hospital was performed. All 94 patients were clinically diagnosed with stage I-IV tongue cancer before surgery and received primary tumor-wide excision and neck dissection. There were 42 (45%) patients with nodal metastasis. Univariate analysis revealed that cases of tongue cancer with moderate or poor differentiation, an invasion depth more than 3mm and positive perineural invasion or lymphovascular permeation at the time of presentation may be subject to a higher incidence of neck nodal metastasis. An elective neck dissection or neck treatment should be considered if these histopathological risk factors are present. Cases of tongue cancer with these risk factors also warrant close follow-up after surgery.

Metformin increases insulin sensitivity and plasma beta-endorphin in human subjects.

Metformin has been widely used in clinical type 2 diabetes treatment and prevention. The present study was designed to explore the effect on people with a sedentary lifestyle at therapeutic doses. Twenty-two physically-inactive volunteers with normal glucose tolerance were studied. Escalating doses of metformin in low-dose (250 mg), intermediate-dose (500 mg), and high-dose (750 mg) treatment three times per day were administrated into each subject for a three-week treatment period. Fasting plasma glucose, A1C, HOMA-IR for insulin resistance, lipid profile, and plasma beta-endorphin-like immunoreactivity (BER) were measured before treatment and weekly at the end of each dosing period. Metformin significantly reduced fasting plasma glucose and HOMA-IR in healthy humans after receiving this treatment at therapeutic doses including low-dose (5 %, 17 %), intermediate-dose (6 %, 25 %) and high-dose treatment (6 %, 21 %). Plasma BER was also increased from 135.46 +/- 61.73 pg/ml to 137.52 +/- 66.11 pg/ml by low-dosing (p = 0.39), to 139.17 +/- 64.08 pg/ml by intermediate-dosing (p = 0.32), and to 149.59 +/- 63.32 pg/ml by high-dosing (p < 0.05). Also, serum cholesterol decreased significantly using metformin at therapeutic doses including low-dose (4 %), intermediate-dose (8 %) and high-dose treatment (7 %). However, metformin failed to modify levels of serum HDL-cholesterol and C-reactive protein (CRP) in healthy subjects. Also, the reduction of serum cholesterol by metformin did not correlate to the increase in insulin sensitivity. In conclusion, metformin causes a significant parallel increase in insulin sensitivity and plasma beta-endorphin level in human subjects.

Cytochrome c release and caspase-3 activation in retinal ganglion cells following different distance of axotomy of the optic nerve in adult hamsters.

This study examined the relationship between the distance of axotomy and the death of injured retinal ganglion cells (RGCs) in adult hamsters and the relationship of cytochrome c and caspase-3 on the death pathway of RGCs. The left optic nerve (ON) of adult hamsters was transected either at 1 or 3 mm away from the optic disc, and retrogradely labeled with Flurogold on the ON stump. After a predetermined period of postoperative time, the surviving RGCs were counted by retina flat-mount, and the activation of cytochrome c and caspase-3 were investigated by immunohistochemistry. Cell loss was found to be much faster (P < 0.01), more cells with cytochrome c were observed (P < 0.05) and the activation of caspase-3 was earlier when ON was transected 1 mm away from the optic disc than when was transected 3 mm away from the optic disc. Distance of axotomy affects the axotomized cell death rate where more RGCs died when the ON transection was applied closer to the eye. The timing of activation of caspase-3 in the RGCs may be linked to the distance of axotomy.

Contrast-enhanced quantitation of left ventricular ejection fraction: what is the best method?

The need to enhance the echocardiographic determination of left ventricular ejection fraction (LVEF) is greatest in patients with suboptimal images. We have previously demonstrated that in difficult-to-image patients, contrast-enhanced power harmonic imaging resulted in accurate calculation of LVEF by using Simpson's method. However, the incremental accuracy of contrast enhancement with other methods of determining LVEF has not been examined. This study prospectively assessed the comparative accuracy of LVEF determination by using the Quinones' method with fundamental imaging (FU), tissue harmonic imaging (TH), contrast-enhanced harmonic imaging [TH(CON)], as well as Quinones' method with contrast-enhanced power harmonic imaging [POW(QUIN)] in 62 patients with suboptimal images. LVEF was also calculated by using contrast-enhanced power harmonic imaging and Simpson's method [POW(SIMP)] in these patients. We demonstrated that LVEF calculated from the POW(QUIN) mode had the best agreement with radionuclide angiography (standard of comparison) compared with FU, TH, and TH(CON). However, POW(SIMP) was even more accurate. In conclusion, when the Quinones' method was used to calculate LVEF in difficult-to-image patients, POW(QUIN) mode was the most accurate. However, POW(SIMP) was even more accurate and should be the method of choice when a high degree of quantitative accuracy is required.

A Rho-dependent signaling pathway operating through myosin localizes beta-actin mRNA in fibroblasts.

BACKGROUND: The sorting of mRNA is a determinant of cell asymmetry. The cellular signals that direct specific RNA sequences to a particular cellular compartment are unknown. In fibroblasts, beta-actin mRNA has been shown to be localized toward the leading edge, where it plays a role in cell motility and asymmetry. RESULTS: We demonstrate that a signaling pathway initiated by extracellular receptors acting through Rho GTPase and Rho-kinase regulates this spatial aspect of gene expression in fibroblasts by localizing beta-actin mRNA via actomyosin interactions. Consistent with the role of Rho as an activator of myosin, we found that inhibition of myosin ATPase, myosin light chain kinase (MLCK), and the knockout of myosin II-B in mouse embryonic fibroblasts all inhibited beta-actin mRNA from localizing in response to growth factors. CONCLUSIONS: We therefore conclude that the sorting of beta-actin mRNA in fibroblasts requires a Rho mediated pathway operating through a myosin II-B-dependent step and postulate that polarized actin bundles direct the mRNA to the leading edge of the cell.

Mitral regurgitation in hypertrophic obstructive cardiomyopathy: relationship to obstruction and relief with myectomy.

OBJECTIVES: This study examined: 1) the impact of myectomy on postoperative mitral regurgitation (MR) and 2) the association between the severity of MR and the left ventricular outflow tract (LVOT) gradient. BACKGROUND: For patients with hypertrophic obstructive cardiomyopathy (HOCM) and MR, controversy exists as to whether myectomy alone is sufficient in eliminating MR. Furthermore, the relationship between the degree of MR and the LVOT peak gradient has not been well defined. METHODS: We performed pre- and postoperative transthoracic as well as intraoperative transesophageal studies in 104 consecutive patients with HOCM undergoing septal myectomy. Left ventricular outflow tract gradient and the nature of MR were assessed. RESULTS: In the 93 patients without independent mitral valve disease, a relationship was observed between MR severity and the LVOT gradient. Left ventricular outflow tract gradient (mean +/- standard deviation) for trivial, mild, moderate and severe MR were: 23.2+/-19.1, 43.8+/-25.4, 70.1+/-21.0 and 104+/-21.0 mm Hg (p < 0.001). Early postoperative, MR was absent or trivial in 80%, mild in 19% and moderate in 1%. None of these patients required additional mitral valve surgery. For patients with independent mitral valve disease (n = 11), five required mitral valve surgery as well as myectomy. The remainder had significant reductions in the degree of MR with myectomy alone. CONCLUSIONS: For patients with HOCM and MR not due to independent mitral valve disease, myectomy significantly reduced the degree of MR, without requirement for additional mitral valve surgery. In these patients the severity of MR was directly related to the magnitude of the LVOT gradient.

Feasibility and accuracy of left ventricular volumes and ejection fraction determination by fundamental, tissue harmonic, and intravenous contrast imaging in difficult-to-image patients.

The need to enhance the echocardiographic determination of left ventricular ejection fraction is greatest in patients with suboptimal images. Intravenous contrast (CON) and tissue harmonic imaging (THI) are 2 important methods for enhancing endocardial border definition. However, the comparative feasibility and accuracy of THI and contrast-enhanced power harmonic imaging in difficult-to-image patients have not been examined. We assessed the comparative accuracy of THI and CON in determining EF and ventricular volumes in patients with suboptimal fundamental images. We demonstrated that CON is feasible and exhibits a greater correlation with ejection fraction and ventricular volumes determined by radionuclide angiography (standard of comparison) than THI in this difficult-to-image population, with no reported side effects. For both ejection fraction and ventricular volumes, the observer variability was least for CON, intermediate with THI, and greatest for fundamental imaging.

Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case report and review.

Suppurative thyroiditis is rare, and the major pathogens are Staphylococcus and Streptococcus species. We present a case caused by Acinetobacter baumanii, which has never before been reported. We review another 191 cases from the English-language literature (1980 to April 1997) and make a comparison with a review of 224 cases (1900-1980). As the numbers of immunocompromised patients increase, cases of suppurative thyroiditis are increasing. Pneumocystis carinii has become an important pathogen. Most patients (83.1%) with bacterial infections were euthyroid, whereas those with fungal or mycobacterial infections tended to be hypothyroid (62.5%) and hyperthyroid (50%), respectively.

Ambulatory care training in cardiology: redefining the traditional arena of learning.

Fiscal restraint, consolidation of resources and services, and restructuring have led to changes in the case mix of teaching hospitals, which places limitations on the education of medical trainees in this environment and has sparked growing interest in the teaching of clinical medicine in the ambulatory care setting. Early attempts to emphasize ambulatory care in training programs, and the strengths and weaknesses of this teaching forum are reviewed, and a model of its application to the discipline of cardiology is offered.

Clinical profiles in adult diabetic ketoacidotic patients in a tertiary referral medical center in southern Taiwan.

Diabetic ketoacidosis (DKA) is not rare among adults. We retrospectively analyzed the precipitating factors, diabetic history, clinical features, and outcomes of adult DKA patients treated at a tertiary referral medical center in southern Taiwan between January 1994 and May 1996. Seventy-eight patients, aged from 18 to 80 years (median 47), had 87 episodes of DKA (44 males had 49 episodes; 34 females had 38 episodes). Twenty-two episodes occurred in patients with no history of diabetes mellitus (age 18-77 yr, median 40.5). The most common precipitating factor was infection (53 episodes), especially in patients aged more than 40 years. Fifteen patients died during the 87 episodes, giving a case fatality rate of 17%; DKA was precipitated by cerebrovascular accidents in two of the 15 patients and by infection in 13. Among the 53 episodes precipitated by infection, multiple logistic regression analysis showed that old age, requirement for endotracheal intubation, and low body temperature on arrival were associated with fatality. Of the 63 patients who were discharged, 39 required insulin therapy; plasma glucose was well-controlled by oral hypoglycemic agents or diet in only eight (age 29-75 yr, median 57; hemoglobin A1c 5.1-7.8%, median 6.6). The high rate of previously undiagnosed diabetes in adult DKA patients indicates a deficiency in early recognition of, and timely therapy for, diabetes in southern Taiwan.