Application of high field spectroscopic imaging in the evaluation of temporal lobe epilepsy

Previous spectroscopic imaging studies of temporal lobe epilepsy have used comparisons of metabolite content or ratios to lateralize the seizure focus. Although highly successful, these studies have shown significant variations within each of the groups of healthy subjects and patients. This variation may arise from the natural differences seen in metabolite concentration in gray and white matter, the complex anatomy seen about the hippocampus, and the large voxels typically employed at 1.5 T. Using a 4.1 T whole body system, we have acquired spectroscopic images with 0.5 cc nominal voxels (1 cc after filtering) to evaluate the regional variation in metabolite content of the hippocampus, temporal gray and white matter, midbrain, and cerebellar vermis. Using a threshold value of 0.90 for CR/NAA, a value 90% of all normal hippocampal voxels lay below, we have correctly identified the presence of epileptogenic tissue in patients with unilateral as well as bilateral seizures. By using comparisons to healthy values of the CR/NAA ratio, this method enables the visualization of bilateral disease and provides information on the extent of gray matter involvement.     

Multiwavelength spectrophotometric determination of acid dissociation constants of ionizable drugs

A multiwavelength spectrophotometric approach has been developed to determine acid dissociation constants (pKa values) of sparingly soluble drug compounds. UV absorption spectra of the drug solution are acquired using a versatile device based on a fiber optics dip probe, a light source and a photodiode array (PDA) detector while the PH and the ionic strength of the chemical system is manipulated precisely by means of a commercially available titrator. Target factor analysis (TFA) has been applied to deduce the pKa values from the multiwavelength UV absorption data recorded at different pH values. We have called this multiwavelength approach the WApH technique because the pKa results are determined from changes in Wavelength and Absorbance as a function of pH (WApH). The WApH technique is exemplified by using several pure drugs, namely, niflumic acid, nitrazepam, pyridoxine, quinine and terbutaline. The pKa values obtained agree well with those derived from pH-metric titrations. It has been demonstrated that the WApH technique is able to deduce pKa values with high accuracy even if the absorption spectra of the reacting species are very similar.     

Estradiol induction of retinoic acid receptors in human breast cancer cells

Retinoic acid inhibits proliferation and steroid receptor gene expression in human breast cancer cell lines. Retinoic acid receptors (RAR)alpha, -beta, and -gamma are expressed in these cells and the expression of RAR alpha is significantly greater in estrogen receptor (ER)-positive cells. This study was undertaken to determine whether the same relationship between RAR alpha and ER gene expression was present in human breast cancers and to explore the possibility that the higher level of RAR alpha in ER-positive cells was due to estrogen regulation of RAR alpha gene expression. RAR alpha and ER mRNA expression were determined by Northern blot analysis in 116 primary breast tumors; 94 (81%) tumors were ER-positive and of these 87 (93%) were also RAR alpha-positive. The coexpression of ER and RAR alpha was statistically significant (P = 0.0052 by chi 2 contingency analysis). There was also a positive correlation (by linear regression analysis) between the levels of expression of ER and RAR alpha mRNA (r2 = 0.251, P = 0.0001), which confirmed the relationship previously documented in breast cancer cell lines and suggested that RAR alpha expression may be modulated in breast cancer in vivo by estrogens acting via the ER. The ability of estradiol to regulate RAR alpha gene expression was examined in vitro using T-47D cells which had been rendered sensitive to estrogen by repeated passage in steroid-depleted medium. Estradiol increased RAR alpha gene expression, but not that of RAR beta or RAR gamma, in a concentration-dependent manner, with the effect being maximal at 10(-10) M and less marked at higher concentrations. The effect was rapid, being detectable 1 h after and maximal 6 h after treatment with 10(-10) M estradiol. Co-treatment of cells with estradiol and antiestrogens (tamoxifen or ICI 164384, 4 x 10(-7) M for 6 h) inhibited the estradiol induction of RAR alpha gene expression, demonstrating that the effect was ER mediated. The estradiol sensitivity of the effect was underscored by the demonstration that addition of untreated serum to cells growing under steroid-depleted conditions was sufficient to induce maximal RAR alpha gene expression. This effect was totally abolished by addition of ICI 164384. In summary, the demonstration that estradiol increased RAR alpha mRNA levels in breast cancer cells supports the hypothesis that the correlation between RAR alpha and ER gene expression in breast tumors and breast cancer cell lines is due to estradiol augmentation of RAR alpha gene expression.     

Effects of cytosine arabinoside on human leukemia cells

Cytosine arabinoside (Ara-C) is used to treat leukemias, with complete remission induced by combination chemotherapy in approximately 70% of cases of acute myelogenous leukemia (AML). Ara-CTP acts as a competitive inhibitor of DNA polymerase and may also be incorporated into DNA. Accumulation of deoxyribonucleoside triphosphates (dNTPs) induced by Ara-C may indicate disruption of DNA synthesis in susceptible leukemia cells. A procedure has been developed for the quantification of Ara-CTP and dNTPs from small samples of leukaemia cells from patients (4 x 10(7) cells) activated with concanavalin A (10 micrograms/ml, 48 hr) and grown in the presence of [32P]orthophosphate (1.1 microM, 9 x 10(6) Ci/mol, 16 hr). The susceptibilities to Ara-C of the human leukemia cell lines CCRF-CEM (IC50 = 6.30 nM), CCRF-HSB-2 (IC50 = 10.4 nM) and MOLT-4 (IC50 = 10.0 nM) may be correlated with their abilities to accumulate high concentrations of Ara-CTP (> 1000 amol/cell) with increases of between 1.3- and 3.4-fold in dATP, dGTP and dTTP for the four cell lines, while dCTP decreased between 0.23- and 0.78-fold. By contrast, an Ara-C-resistant derivative of HL-60 cells (IC50 = 400 nM) accumulated only low concentrations of Ara-CTP (71 amol/cell) without significant changes in dNTPs. High concentrations of Ara-CTP in leukemia cells induce accumulations of dATP, dGTP and dTTP due to inhibition of DNA synthesis, and depletion of dCTP. This imbalance in the pools of the four dNTPs could lead to genetic miscoding and cell death.     

Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast

BACKGROUND: Few women with locally advanced breast cancer remain disease-free, even for 2 years. Response to induction chemotherapy may be associated with longer disease-free and overall survival rates. The role of breast conservation in selected patients with response to induction chemotherapy was evaluated. METHODS: Since 1979, patients with Stages IIB and III breast cancer have undergone induction chemotherapy; patients with response continued chemotherapy until a plateau of regression was achieved. Before 1983, all patients having a response to chemotherapy underwent mastectomy; since 1983, selected patients have undergone breast conservation. Outcomes were tallied comparing these two groups of patients. RESULTS: The study group included 189 women, who were followed up for 12-159 months (median, 46 months) after diagnosis. Of the patients, 85% had a response to induction chemotherapy. Patients with no response were excluded from additional consideration in this study. One hundred three (64%) women underwent mastectomy; 55 (36%) were treated with breast conservation. The disease-free 5-year survival rate was 61% for all patients with a response to chemotherapy; 56% for those having mastectomy and 77% for those having breast conservation. The overall 5-year survival rate was 69% for all patients with a response to chemotherapy, 67% for those undergoing mastectomy and 80% for those having breast conservation. CONCLUSIONS: Induction chemotherapy achieves significant tumor regression in most women with locally advanced breast cancer, permitting subsequent breast conservation or mastectomy with a greater expectation of long-term success. Breast conservation is used more frequently with the same expectation of success as mastectomy, presuming careful selection based on response to chemotherapy.     

Costs and charges associated with three alternative techniques of hysterectomy

BACKGROUND: Many hysterectomies are now performed by a laparoscopically assisted vaginal technique. This procedure is controversial, partly because of concern about cost. We studied hospital charges and costs for the procedure as compared with those for total abdominal hysterectomy and total vaginal hysterectomy in clinically similar groups of patients. METHODS: From hospital-discharge data and patients' charts, we identified hysterectomies performed in 1993 and 1994 by 96 surgeons at a community teaching hospital to treat benign conditions. The patients were grouped according to the surgical procedures performed in conjunction with the hysterectomy. Data on hospital charges and cost-to-charge ratios for 64 hospital cost centers were used to assess charges and costs for specific resources, as well as for the hospitalization overall. RESULTS: Of 1049 patients studied, 26 percent underwent laparoscopically assisted vaginal hysterectomy, 54 percent underwent abdominal hysterectomy, and 20 percent underwent vaginal hysterectomy. The average hospital stays were 2.6, 3.9, and 2.9 days, respectively, and the mean total charges (facility charges plus professional fees) for the hospitalizations were $6,116, $5,084, and $4,221 (P<0.001 for the comparison of the laparoscopic technique with both other techniques). The mean facility costs were $4,914, $3,954, and $3,116, respectively (P<0.001 for the same comparison), with similar findings in all subgroups. The higher charges and costs for laparoscopically assisted vaginal hysterectomy were due to higher supply costs, particularly when disposable supplies were used, and to longer operating-room time. CONCLUSIONS: Despite shorter hospital stays, in-hospital charges and costs for laparoscopically assisted vaginal hysterectomy are higher than for either alternative procedure, because of the disposable supplies that are typically used and the longer operating-room time.     

Proton MR spectroscopy and magnetization transfer ratio in multiple sclerosis: correlative findings of active versus irreversible plaque disease

PURPOSE: To characterize plaques of multiple sclerosis (MS) using both proton MR spectroscopy and magnetization transfer (MT) imaging. METHODS: The magnetization transfer ratio (MTR) was calculated from two series of three-dimensional gradient-recalled acquisition in the steady state (GRASS) images obtained with and without an MT saturation pulse. Proton spectra were acquired using the point-resolved spectroscopy (PRESS) sequence with a voxel size of 1.5 x 1.5 x 1.5 cm3. A total of 28 spectra were obtained in 13 patients who had clinically definitive MS. The spectra were analyzed together with the MTR. RESULTS: A positive relationship was found between the N-acetylaspartate (NAA)/creatine (Cr) ratio and the MTR in MS plaques, whereas no significant correlation was found between the metabolite ratios and the signal intensity on fast spin-echo T2-weighted MR images. CONCLUSION: Small changes in the MTR of MS plaques relative to the MTR of normal white matter may reflect inflammatory changes and edema, whereas larger changes in MTR correlate with decreased NAA/Cr ratio and therefore suggest demyelination and irreversible damage from chronic MS plaques.     

Atypical multicentric reticulohistiocytosis with paraproteinemia

Two women had multiple subcutaneous nodules that showed features of multicentric reticulohistiocytosis (MR). Neither had joint symptoms. Both had a raised erythrocyte sedimentation rate, an immunoglobulin G paraproteinemia, and raised levels of nonhepatic serum alkaline phosphatase. The skin lesions have been followed up, using light and electron microscopy, immunoperoxidase, and histochemical methods. The material in the giant cells stained positively for gamma heavy chain determinants: the light chain type in each case was that of the paraprotein. An attempt to reproduce the skin lesions in one patient by intradermal injection of her paraprotein failed.