Depression among adults with neurofibromatosis type 1: prevalence and impact on quality of life.

Neurofibromatosis type 1 (NF1) carries a significant psychosocial burden for affected individuals. The objective of this study was to measure the prevalence of depressive symptoms among a large sample of adults with NF1 and to quantify the impact of depressive symptoms on quality of life (QoL). This cross-sectional study used an Internet-based questionnaire to collect data from 498 adults who self-reported as having NF1. Using the Center for Epidemiologic Studies Depression (CESD) scale, 55% of all participants (61% of females and 43% of males) scored above 16, indicating a high likelihood of clinical depression. In a multivariate regression model controlling for demographics and potential confounders, depressive symptoms accounted for 32% of the variance in QoL as measured by the Quality of Life Index. This study is the largest to date and found the highest prevalence of depression compared to prior studies. Our data provide more compelling evidence that individuals with NF1 are at increased risk for psychiatric morbidity and suggest that this population should be routinely screened for depression. Because depression was found to be strongly associated with QoL and accounted for nearly one-third of the variance in QoL, it is likely that effectively treating depression may significantly enhance QoL for individuals with NF1.

Interventional magnetic resonance imaging for guiding gene and cell transfer in the heart.

BACKGROUND: Interventional magnetic resonance imaging (iMRI) has the potential for guiding interventional cardiac procedures in real time. OBJECTIVES: To test the feasibility of iMRI guided gene and cell transfer to the heart and to monitor myocardial remodelling after myocardial infarction in a rat model. METHODS: The MRI contrast agent GdDTPA, together with either Evans blue dye, or a recombinant adenovirus encoding the LacZ gene, or primary fibroblasts tagged by BrdU, were injected into the myocardium of rats under iMRI guidance. Rats were killed seven days after the injection and the hearts sectioned to identify the blue dye, LacZ expression, or fibroblast presence, respectively. In a parallel study, left ventricular area was measured before and after myocardial infarction and in sham operated rats by T1 weighted MRI and by echocardiography. RESULTS: Location of GdDTPA enhancement observed with iMRI at the time of injection was correlated with Evans blue stain, beta-gal expression, and the primary fibroblast location in histological studies. iMRI and echocardiography measured a comparable increase in left ventricular area at seven and 30 days after myocardial infarction. A good correlation was found between the iMRI and echocardiographic assessment of left ventricular area (r = 0.70; p < 0.0001) and change in left ventricular area with time (r = 0.75; p < 0.0001). CONCLUSIONS: The results show the feasibility and efficiency of iMRI guided intramyocardial injections, and the ability to monitor heart remodelling using iMRI. Genes, proteins, or cells for tissue engineering could be injected accurately into the myocardial scar under iMRI guidance.

Prosthetic iris implantation for congenital, traumatic, or functional iris deficiencies.

PURPOSE: To determine the efficacy and safety of surgical implantation of prosthetic iris devices in patients with anatomic or functional iris deficiencies. SETTING: Cincinnati Eye Institute, Cincinnati, Ohio, USA. METHODS: Twenty-five patients were enrolled in an interventional prospective noncomparative case series. Twenty-eight eyes had prosthetic iris diaphragm implantation for traumatic iris defects, congenital aniridia or iris coloboma, herpetic iris atrophy, surgical iris loss, or ocular albinism. Prosthetic iris implantation was performed with phacoemulsification and intraocular lens (IOL) implantation in 20 eyes, secondary IOL implantation in 6 eyes, and IOL exchange in 1 eye. A single pseudophakic eye with disabling glare secondary to traumatic aniridia had secondary prosthetic iris implantation alone. The surgical ease of insertion, intraoperative and postoperative complications, postoperative anatomic results, visual acuity, and subjective glare reduction were evaluated. RESULTS: Patients were followed postoperatively for a mean of 10.2 months (range 1.4 to 25.7 months). All eyes achieved the desired anatomic result. Visual acuity was improved in 22 of 28 eyes (79%), unchanged in 5 eyes, and worsened by a single line in 1 eye. Patients were surveyed postoperatively to determine the change in glare disability. The severity of glare disability was subjectively improved in 23 of 24 patients (96%) who responded to the survey. Intraoperative complications included 3 fractured implants as well as an incomplete or torn capsulorhexis in 3 eyes. Postoperative complications included transient hypotony in 2 eyes, mild persistent inflammation in 1 eye, and macular edema followed by a retinal detachment in 1 eye with recent severe trauma. CONCLUSIONS: Implantation of prosthetic iris devices improved postoperative outcomes by reducing glare disability and, in selected cases, by correcting aphakia. Although operating on traumatized, congenitally aniridic, or uveitic eyes presents special challenges, implantation of prosthetic iris devices appears to be a safe and effective method for reducing the ubiquitous glare in patients with iris deficiency.

Levels of phospholipid metabolites in breast cancer cells treated with antimitotic drugs: a 31P-magnetic resonance spectroscopy study.

Magnetic resonance spectroscopy (MRS) methods have provided valuable information on cancer cell metabolism. In this study, we characterized the 31P-MR spectra of breast cancer cell lines exhibiting differences in hormonal response, estrogen receptors (positive/negative), and metastatic potential. A correlation was made between the cytotoxic effect of antimitotic drugs and changes in cell metabolism pattern. Because most anticancer drugs are more effective on proliferating cells, our study attempted to elucidate the metabolic profile and specific metabolic changes associated with the effect of anticancer drugs on proliferating breast cancer cell lines. Accordingly, for the 31P-MRS experiments, cells were embedded in Matrigel to preserve their proliferation profile and ability to absorb drugs. The MRS studies of untreated cells indicated that the levels of phosphodiesters and uridine diphosphosugar metabolites were significantly higher in estrogen receptor-positive and low metastatic potential cell lines. 31P-MRS observations revealed a correlation between the mode of action of anticancer drugs and the observed changes in cell metabolic profiles. When cells were treated with antimicrotubule drugs (paclitaxel, vincristine, colchicine, nocodazole), but not with methotrexate and doxorubicin, a profound elevation of intracellular glycerophosphorylcholine (GPC) was recorded that was not associated with changes in phospholipid composition of cell membrane. Remarkably, the rate of elevation of intracellular GPC was much faster in cell population synchronized at G2-M compared with the unsynchronized cells. The steady-state level of GPC for paclitaxel-treated cells was reached after approximately 4 h for synchronized cells and after approximately 24 h (approximate duration of one cell cycle) for the unsynchronized ones. These observations may indicate a correlation between microtubule status and cellular phospholipid metabolism. This study demonstrates that 31P-MRS may have diagnostic value for treatment decisions of breast cancer and reveals new aspects of the mechanism of action of antimicrotubule drugs.

Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging.

Convection-enhanced drug delivery (CEDD) is a novel approach to enhance the delivery of drugs directly into brain tumors. We have used diffusion-weighted MRI (DWMRI) to monitor the effects of intratumoral CEDD in three brain tumor patients treated with Taxol. Clear changes in the images and the water diffusion parameters were observed shortly after the initiation of treatment. Initially, a bright area corresponding to decreased diffusion appeared, followed by the appearance of a dark area of increased diffusion within the bright area. The time to appearance of the dark area varied among the patients, suggesting different response rates. In this work, we have demonstrated the feasibility of using DWMRI as a noninvasive tool to achieve unique early tissue characterization not attainable by other conventional imaging methods.

Electrospray ionization mass spectrometry analysis of changes in phospholipids in RBL-2H3 mastocytoma cells during degranulation.

Biological membranes contain an extraordinary diversity of lipids. Phospholipids function as major structural elements of cellular membranes, and analysis of changes in the highly heterogeneous mixtures of lipids found in eukaryotic cells is central to understanding the complex functions in which lipids participate. Phospholipase-catalyzed hydrolysis of phospholipids often follows cell surface receptor activation. Recently, we demonstrated that granule fusion is initiated by addition of exogenous, nonmammalian phospholipases to permeabilized mast cells. To pursue this finding, we use positive and negative mode Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS) to measure changes in the glycerophospholipid composition of total lipid extracts of intact and permeabilized RBL-2H3 (mucosal mast cell line) cells. The low energy of the electrospray ionization results in efficient production of molecular ions of phospholipids uncomplicated by further fragmentation, and changes were observed that eluded conventional detection methods. From these analyses we have spectrally resolved more than 130 glycerophospholipids and determined changes initiated by introduction of exogenous phospholipase C, phospholipase D, or phospholipase A2. These exogenous phospholipases have a preference for phosphatidylcholine with long polyunsaturated alkyl chains as substrates and, when added to permeabilized mast cells, produce multiple species of mono- and polyunsaturated diacylglycerols, phosphatidic acids, and lysophosphatidylcholines, respectively. The patterns of changes of these lipids provide an extraordinarily rich source of data for evaluating the effects of specific lipid species generated during cellular processes, such as exocytosis.

Phospholipases stimulate secretion in RBL mast cells.

Roles for glycerophospholipids in exocytosis have been proposed, but remain controversial. Phospholipases are stimulated following the activation of the high-affinity receptor for immunoglobulin E (IgE) in mast cells. To study the biochemical sequelae that lead to degranulation, broken cell systems were employed. We demonstrate that the addition of three distinct types of exogenous phospholipases (i.e., bcPLC, scPLD, and tfPLA(2)), all of which hydrolyze phosphatidylcholine (PC), trigger degranulation in permeabilized RBL-2H3 cells, a mucosal mast cell line. Production of bioactive lipids by these phospholipases promotes release of granule contents through the plasma membrane and acts downstream of PKC, PIP(2), and Rho subfamily GTPases in regulated secretion. These exogenous phospholipase-induced degranulation pathways circumvent specific factors activated following stimulation of the IgE receptor as well as in ATP- and GTP-dependent intracellular pathways. Taken together, these results suggest that regulated secretion may be achieved in vitro in the absence of cytosolic factors via phospholipase activation and that products of PC hydrolysis can promote exocytosis in mast cells.

Trabeculectomy with intraoperative mitomycin C versus 5-fluorouracil. Prospective randomized clinical trial.

OBJECTIVE: To evaluate the relative efficacy and safety of 5-fluorouracil (5-FU) and mitomycin C (MMC) when used as adjuncts with primary trabeculectomy in eyes not at high risk for failure. DESIGN: Prospective multicenter, randomized clinical trial. PARTICIPANTS: One hundred thirteen patients with primary open-angle, pseudoexfoliative, pigmentary, or angle-closure glaucoma undergoing primary trabeculectomy were recruited. METHODS: One eye of each patient was randomized to receive either 5-FU (50 mg/ml for 5 minutes) or MMC (0.4 mg/ml for 2 minutes). MAIN OUTCOME MEASURES: Intraocular pressure (IOP), visual acuity, complications, and interventions were documented at fixed intervals after surgery. The study also examined progression of visual field loss, long-term complications, and bleb appearance 3 years after surgery. RESULTS: Of the 108 patients with complete perioperative information, 54 eyes received 5-FU and 54 received MMC. The proportion of patients reaching different predefined target IOPs after surgery was slightly higher in the MMC group than in the 5-FU group. This difference was less than 25%, which would have been necessary to achieve statistical significance with a power of 0.8 and the sample size used. Likewise, there was no statistically significant difference between the groups with regard to mean preoperative IOP, complications, or interventions. Mean postoperative follow-up was 309 and 330 days in the 5-FU and MMC groups, respectively (P = 0.593). CONCLUSIONS: 5-Fluorouracil and MMC were found to be equally safe and effective adjuncts to primary trabeculectomy in the short- and medium-term postoperative periods.

Noninvasive real-time monitoring of intracellular cancer cell metabolism and response to lonidamine treatment using diffusion weighted proton magnetic resonance spectroscopy.

We have used diffusion-weighted proton magnetic resonance spectroscopy (DWMRS) to noninvasively selectively observe only the intracellular metabolites of breast cancer and melanoma cell lines in vitro in real time. Breast cancer cell lines representing different stages in breast cancer progression were chosen for study. Intracellular biochemical profiles of six cell lines perfused in alginate beads were obtained. Spectral differences between groups of cell lines, including choline, lactate, and threonine peaks, were investigated. We also monitored response to the antineoplastic agent, lonidamine (LND), as a function of time and drug concentration in perfused cancer cells. Previous studies reported that this drug induced intracellular acidification and lactate accumulation. Diffusion weighted proton spectra demonstrated a 2- to 9-fold increase in the intracellular lactate signal as a response to LND treatment in several cancer cell lines. These results are consistent with the hypothesis that the principal mechanism of LND in some cancer cells is marked inhibition of lactate transport. Moreover, we have shown that there is a factor of two to three between the response of melanoma cells and that of some types of breast cancer cells. The higher sensitivity of the melanoma cells, as predicted by proton DWMRS, was correlated with changes in water-suppressed magnetic resonance spectra and confirmed by a biological assay. This study demonstrates the feasibility of using DWMRS for monitoring intracellular metabolism and for studying the effects and mechanisms of action of anticancer drugs. We believe that this method can be used for noninvasive clinical applications, such as the differentiation between benign and malignant tissue, real-time monitoring of response to therapy, dose response, and toxicity effects.

Atomic force microscopy examination of conformations of polynucleotides in response to platinum isomers: significance of GC content at broken ends.

Atomic force microscopy is a technique that enables visualization of macromolecular conformations of polynucleotides at nanometer resolution. We investigated the results of interactions of cisplatin, a DNA binding anticancer drug, and its inactive counterpart, transplatin isomer, on the molecular conformation of polynucleotides: poly d(G-C). poly d(G-C) (polyGC) and poly d(A-T). poly d(A-T) (polyAT). We observed that polyAT exhibited an increased number of enlarged ends of molecules, which we attribute to unwound and/or collapsed regions of polyAT. PolyGC molecules did not show such ends unless cisplatin was added to the PolyGC polymers. Transplatin had the apparent effect of causing overlapping or stacking of the polymer molecules. Addition of exonuclease-III to these polymers removed the visible enlarged ends. The effects of cisplatin as compared to transplatin on the polyGC duplex polymers provide support for the presence of intrastrand covalent linkages, consistent with known N7 guanine interaction of the cis isomer on molecular conformation. Furthermore, our results indicate that the mechanism of interactions of DNA with cisplatin may be dependent on the GC content of the molecules. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 68-72, 2000.

Avoiding adverse reactions. Effective lower-dose drug therapies for older patients.

Adverse drug reactions (ADRs) are a leading cause of morbidity and mortality, with the highest incidence occurring in patients age 60 and older. Prescribing the lowest effective doses of medications to older patients can help avoid ADRs, minimize bothersome side effects, and increase rates of compliance. For many drugs, clinical experience and published studies demonstrate the effectiveness of doses substantially lower than those recommended in standard references. This article examines the problem of ADRs in older patients, discusses pharmacokinetic data regarding older versus younger adults, and provides effective lower doses for many common drugs.

Clinical and laboratory improvement in ankylosing spondylitis after treatment with etanercept: a case report.

A patient with ankylosing spondylitis involving the back, feet, ankles, knees, wrists, hands, and elbows exhibited intolerance or inadequate response to multiple prior therapies. Because of the potential role of tumor necrosis factor in the pathogenesis of AS, the tumor necrosis factor antagonist etanercept (Enbrel) 25 mg was given s.c. twice weekly. Beginning 2 weeks after the initiation of etanercept, the patient noted symptomatic improvement in axial and peripheral joints. The patient experienced resolution of morning stiffness and near complete resolution of fatigue. Marked improvement in hemoglobin and erythrocyte sedimentation rate was also seen, although knee joint fluid leukocytes did not change appreciably. This response is encouraging, especially because both axial symptoms and peripheral disease responded to treatment, in contrast to what has been previously reported for sulfasalazine. Further study of etanercept in ankylosing spondylitis is warranted.

In vitro cytotoxic effects of tumor necrosis factor-alpha in human breast cancer cells may be associated with increased glucose consumption.

Tumor necrosis factor-alpha inhibited growth of cultured MCF-7 human breast cancer cells in a dose dependent manner. Tumor necrosis factor-alpha also markedly increased glucose consumption, and its cytotoxicity was modified by glucose concentrations in the growth medium; higher glucose levels were associated with increased cell survival. However, when the cells were perfused in physiological conditions, very high levels of tumor necrosis factor-alpha (200 ng/ml) in the perfusion solution had no inhibitory effects. Moreover, tumor necrosis factor-alpha had no effects on 31P nuclear magnetic resonance spectra of the perfused cells. In the traditional growth inhibition assays, cells are incubated for several days with a drug, a situation where their metabolism is altered due to the depletion of nutrients, the accumulation of toxic waste materials and pH changes. Perfusion experiments are more relevant to in vivo conditions, and may be used for studying metabolic processes and the mechanisms of action of therapeutic agents.

The investigation of symptomatic inguinal hernia: a complication of barium enema.

The controversy surrounding the value of performing screening barium enema in patients with inguinal hernia persists. It was Myers & Zollinger who, in 1942, reviewed 200 consecutive cases of inguinal hernia and noted that 18%; of patients complained of gastrointestinal symptoms. Of these, two cases of adenocarcinoma were discovered on further evaluation. Subsequently, many authors have reported a low diagnostic yield of barium enema in patients with inguinal hernia unless specific colonic symptoms were present. We present a case in which this investigation was indicated, but led to irreducibility.

The role of mitomycin treatment duration and previous intraocular surgery on the success of trabeculectomy surgery.

PURPOSE: This study was performed to determine the effect of duration of mitomycin exposure during trabeculectomy surgery on filtration success in eyes that had and had not been subjected to previous surgery. METHODS: On hundred six eyes of 92 patients were retrospectively reviewed. The effect of previous surgery and exposure duration of mitomycin 0.5 mg/ml on outcomes of trabeculectomy surgery were evaluated. RESULTS: The mean duration of mitomycin exposure was 0.7 +/- 0.02 min (mean +/- SEM) in the eyes that had not been subjected to previous surgery and 1.5 +/- 0.11 min in the eyes that had (p < 0.001). The mean follow-up times were 14 months in both groups. The mean decrease in intraocular pressure was 13.6 +/- 1.25 mm Hg in the group that had not been subjected to previous surgery and 13.9 +/- 1.45 mm Hg in the group that had been subjected to previous surgery. Analysis of variance techniques demonstrated no predictive value of demographics, history of previous surgery, or duration of mitomycin exposure with results of trabeculectomy surgery. Hypotony was the most frequent complication in both the no previous surgery and the previous surgery groups. The incidence of complications was numerically greater in the group that had not been subjected to previous surgery. CONCLUSIONS: The duration of mitomycin exposure and the history of previous surgery did not correlate with postoperative intraocular pressure, medications, or incidence of complications. The exposure duration response curve of mitomycin 0.5 mg/ml in these patients appears to be flat through the time evaluated. Lower concentrations of mitomycin and shorter exposure should be used to maintain efficacy with reduced risk of complications.

Primary lymphoepithelioma-like carcinoma of the lung in a child. Report of an Epstein-Barr virus-related neoplasm.

Lymphoepithelioma-like carcinoma (LEC), an undifferentiated carcinoma with pronounced lymphocytic infiltration, often is seen in the nasopharynx as well as in other areas. But such primary pulmonary lung neoplasms in children are rare, and we present the first reported case of primary pulmonary LEC in a child.

A placebo-controlled, double-masked evaluation of mitomycin C in combined glaucoma and cataract procedures.

PURPOSE: This study was performed to determine if adjunctive use of mitomycin C (MMC) would increase the success of combined phacoemulsification, intraocular lens implantation, and trabeculectomy surgery with releasable sutures. METHODS: Seventy-two eyes with cataract and glaucoma, requiring surgery for decreased vision, uncontrolled intraocular pressure, or to obtain a better view of the optic nerve, were randomized to receive a 2.5-minute subconjunctival exposure to either MMC (0.5 mg/ml) or placebo balanced salt solution. Postoperative evaluations at 3, 6, and 12 months were performed by a masked observer who recorded visual acuity, intraocular pressure, glaucoma medications, presence of filtering blebs, and complications. Endothelial cell counts were measured before and 3 months after surgery. RESULTS: The MMC group had significantly greater reduction in mean intraocular pressure through the first 12 months of follow-up (7.05-7.65 mmHg versus 2.62-3.84 mmHg; P = 0.001-0.028). In addition, through the first 6 months of follow-up, the MMC group required significantly fewer medications (0.4-0.5 versus 1.1-1.2; P = 0.002-0.004). Requirements for additional glaucoma surgery were less in the MMC group (4/ 36) than in the placebo group (7/35) (P = 0.301). Filtering blebs were significantly larger at 6 and 12 months (P = 0.002 and P = 0.001, respectively), and would leaks were more common (P = 0.101) in the MMC group. The mean decrease in endothelial cell count at month 3 was slightly, although not significantly, greater in the MMC treatment group (206.9 versus 91.3 cells/mm2* P = 0.377). CONCLUSION: The increased success of the glaucoma procedure in the MMC group together with relatively minor toxicity, suggests its use is beneficial in combined glaucoma-cataract surgery.

Treatment of perianal infection following bone marrow transplantation.

PURPOSE: Bone marrow transplantation (BMT) is often associated with profound neutropenia. Allogeneic transplant recipients also have defects in both humoral and cellular immunity and thus are subject to increased risk of serious, often life-threatening, infection even beyond the period of granulocyte recovery. The current study was undertaken to evaluate patients who required operative intervention for perianal sepsis following BMT. METHODS: The bone marrow transplant database at a single institution was used to identify all patients diagnosed with perianal infections after autologous or allogeneic BMT. Charts were reviewed in a retrospective manner. RESULTS: Over a ten-year period ending in November 1993, 963 BMT were performed at the City of Hope National Medical Center. Twenty-four patients were diagnosed with perianal infections following their transplants. Fifteen patients did not have purulent collections requiring drainage and were treated with antibiotics and supportive measures alone. Nine patients (37.5 percent) required surgical intervention between 10 and 380 days following transplantation. At the time of surgical intervention, seven patients had purulent collections and two patients had acute and chronic inflammation, tissue necrosis, and fibrosis. Of the two patients with an absolute neutrophil count less than 1,000, a purulent collection was found in one of the patients. Cultures taken from perianal abscesses were almost all polymicrobial, and the most common organisms were Escherichia coli, Bacteroides, Enterococcus, and Klebsiella. For those patients undergoing surgical intervention, mean time to complete wound closure by secondary intention was 37.6 days; five patients healed in less than 15 days, two patients healed at 93 and 114 days, and two patients had persistent, open wounds at time of death, which was unrelated to their perianal disease. Five patients were receiving systemic steroids at time of surgical intervention; this did not appear to affect time to wound healing. CONCLUSIONS: Perianal infections are a rare complication of BMT. Majority of these infections are polymicrobial, and organisms isolated are similar to those seen in the perianal infections of nonimmunosuppressed patients. Despite steroid use, granulocytopenia does not exclude the possible presence of purulent collections, and clinical examination should guide the decision for surgical drainage. In general, perianal wound healing is not prolonged in BMT patients.

A second locus for Rieger syndrome maps to chromosome 13q14.

Rieger syndrome is a genetically and phenotypically heterogeneous disorder typically characterized by malformations of the eyes, teeth, and umbilicus. The syndrome is inherited as an autosomal dominant trait and exhibits significant variable expressivity. One locus associated with this disorder has been mapped to 4q25. Using a large four-generation pedigree, we have identified a second locus for Rieger syndrome located on chromosome 13q14.

Re-forming the flat anterior chamber with Healon.

A shallow or flat anterior chamber may occur after complicated cataract surgery, a filtering procedure for glaucoma, or combined surgery. We describe a technique for injecting sodium hyaluronate (Healon) into the anterior chamber through the previous paracentesis tract in the operating room or at the slitlamp microscope. Re-forming the anterior chamber with Healon may pre-empt the anatomical sequelae of prolonged anterior chamber shallowing and prevent the need for more invasive surgery.