Defining daptomycin resistance prevention exposures in vancomycin-resistant Enterococcus faecium and E. faecalis.

Daptomycin is used off-label for enterococcal infections; however, dosing targets for resistance prevention remain undefined. Doses of 4 to 6 mg/kg of body weight/day approved for staphylococci are likely inadequate against enterococci due to reduced susceptibility. We modeled daptomycin regimens in vitro to determine the minimum exposure to prevent daptomycin resistance (Dapr) in enterococci. Daptomycin simulations of 4 to 12 mg/kg/day (maximum concentration of drug in serum [Cmax] of 57.8, 93.9, 123.3, 141.1, and 183.7 mg/liter; half-life [t1/2] of 8 h) were tested against one Enterococcus faecium strain (S447) and one Enterococcus faecalis strain (S613) in a simulated endocardial vegetation pharmacokinetic/pharmacodynamic model over 14 days. Samples were plated on media containing 3× the MIC of daptomycin to detect Dapr. Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in Dapr derivatives. Dapr derivatives were assessed for changes in susceptibility, surface charge, membrane depolarization, cell wall thickness (CWT), and growth rate. Strains S447 and S613 developed Dapr after simulations of 4 to 8 mg/kg/day but not 10 to 12 mg/kg/day. MICs for Dapr strains ranged from 8 to 256 mg/liter. Some S613 derivatives developed mutations in liaF or cls. S447 derivatives lacked mutations in these genes. Dapr derivatives from both strains exhibited lowered growth rates, up to a 72% reduction in daptomycin-induced depolarization and up to 6-nm increases in CWT (P<0.01). Peak/MIC and AUC0-24/MIC ratios (AUC0-24 is the area under the concentration-time curve from 0 to 24 h) associated with Dapr prevention were 72.1 and 780 for S447 and 144 and 1561 for S613, respectively. Daptomycin doses of 10 mg/kg/day may be required to prevent Dapr in serious enterococcal infections.

Successful treatment of a left ventricular assist device infection with daptomycin non-susceptible methicillin-resistant Staphylococcus aureus: case report and review of the literature.

Recipients of left ventricular assist devices (LVADs) are highly susceptible to the development of infections with multidrug-resistant (MDR) organisms. We describe the case of a patient with an LVAD who developed a device-related, daptomycin non-susceptible, methicillin-resistant Staphylococcus aureus infection, highlighting this patient population as highly vulnerable to the development of such antimicrobial resistance. This report includes a thorough review of the literature on the mechanisms of development of daptomycin non-susceptibility and suggests ways to prevent its emergence. We also provide and underscore the appropriate guidelines to abide by when attempting to control infections with such resistant isolates. This case also demonstrates the importance of definitive treatment with LVAD removal and transplantation as a component of appropriate management of invasive LVAD infections. In addition, we suggest that even infections with MDR organisms may not adversely affect post-transplant outcomes.

Growth hormone pretranslationally regulates the sexually dimorphic expression of the prolactin receptor gene in rat liver.

The female-specific expression of the rat liver PRL receptor (PRL-R) gene was investigated by Northern analysis of hypophysectomized rats after two alternative human GH treatments that were to mimic either 1) the continuous female-specific or 2) the discontinuous male-specific serum GH patterns. The former (female-specific) pattern was shown to result in a dramatic increase in PRL-R mRNA in both males and females, while the latter (male-specific) pattern failed to evoke this response. A similar inductive effect in hypophysectomized females was shown after continuous administration of bovine GH and was found to constitute an approximately 60-fold increase in PRL-R mRNA levels. This effect by bovine GH, which, unlike the human isoform, is devoid of lactogenic properties, thus indicates the somatogenic origin of the signal resulting in this inductive response. These observations in conjunction with previous data obtained for other GH-regulated nonreceptor genes are interpreted to support the proposal of GH serum patterns being an early signal in a more general mechanism for pretranslational regulation of sex-specific gene expression. In contrast to GH, only a slight elevation of PRL-R mRNA was evoked by the ligand ovine PRL, while coadministration of ovine PRL with bovine GH failed to enhance the mRNA level found with bovine GH alone. The detection of previously unreported PRL-R mRNAs in liver of approximately 3.0, 3.8, and 5 kilobases in addition to the major 2.2-kilobase form was also evident after continuous GH administration.

A pilot study of neoadjuvant paclitaxel and radiation with correlative molecular studies in stage II/III breast cancer.

A commonly used approach to the management of locally advanced breast cancer currently involves neoadjuvant chemotherapy, followed by surgery and radiation. Earlier neoadjuvant regimens had utilized doxorubicin, making concurrent treatment with radiation less desirable given dose-limiting normal tissue toxicities. With the development of paclitaxel, we can now reconsider the use of concurrent chemoradiation in the treatment of breast cancer. Although paclitaxel is a known radiation sensitizer, its precise mechanism of action is still unclear. One of its proposed mechanisms is that it binds tubulin and induces an M-phase arrest. As cells in M-phase are very sensitive to radiation, it thereby increases radiation sensitivity. The ability to predict tumor response for individual patients would allow us to tailor subsequent therapy for the individual patient. This study is designed to evaluate if paclitaxel's effects on the cell cycle of an individual patient can predict the responsiveness of that patient's tumor to paclitaxel and radiation. Patients will be treated with 3 cycles of paclitaxel followed by concurrent paclitaxel and radiation prior to definitive surgery.

The role of leucine in hepatic ketogenesis.

Isolated hepatocyte studies demonstrated that leucine can be a precursor of ketone bodies. In this study we examine the relative contribution of leucine to hepatic ketogenesis in vivo. Three groups of conscious dogs with long-term indwelling catheters in the femoral artery, hepatic vein, and portal vein were studied. Group I (n = 3) animals were fasted overnight for 24 hours, and those in groups II and III (n = 4, each) were fasted for 62 to 68 hours (designated 3-day fast). Groups I and III received intravenous saline solution (0.9%) and served as controls. In group II selective acute insulin deficiency (SAID) was induced by a peripheral intravenous somatostatin (SRIF) infusion and intraportal glucagon (0.55 ng/body weight/min). Net hepatic production (NHP) of ketone bodies (kb) and leucine (leu) was measured by the arteriovenous difference technique. Hepatic conversion of leucine to ketone bodies was measured by continuous infusion of L-U-[14C]-leucine and by determination of the appearance of [14C]-ketone bodies across the liver. In the group fasted overnight NHPleu was 0.02 +/- 0.01 mumol/kg/min, a value not different from zero. NHPkb was 3.1 +/- 0.1 mumol/kg/min and hepatic conversion of leucine to ketone bodies accounted for 3.5% of NHPkb. Insulin deficiency after 3 day's fasting resulted in a near 70% increase in NHPleu (from basal values of 0.31 +/- 0.1 mumol/kg/min to 0.52 +/- 0.06 mumol/kg/min during SAID, p less than 0.01). NHPkb increased from 11.0 +/- 1.0 to 15.5 mumol/kg/min (p less than 0.05). The rate of leucine conversion to ketone bodies (L-C) increased from 1.1 +/- 0.25 to 2.4 +/- 0.3 mumol/kg/min (p less than 0.01) with SAID. We conclude that as the dog progresses to fasting, the contribution of leucine carbon to hepatic production of ketone bodies increases from 3.5% to 10% (p less than 0.01), and this value increases to 15% (p less than 0.01 versus groups I and II) after SAID. Furthermore, the amount of leucine carbon taken up by the liver was not sufficient to account for all [14C]-labeled leucine to ketone bodies. The data suggest that the leucine carbon converted to ketone bodies must have been derived from intrahepatic protein sources of possibly from the keto acids of leucine, which are derived by the breakdown of leucine at distant sites, such as skeletal muscle or adipose tissue.

Dementia, quantitative neuroimaging, and apolipoprotein E genotype.

BACKGROUND AND PURPOSE: Quantitative MR imaging differences in an elderly population of subjects with various clinical disorders (including dementia, particularly Alzheimer's disease and vascular dementia) and disorders of mild cognitive impairment were examined. Potential quantitative MR differences were assessed by presence or absence of the apolipoprotein E (APOE) epsilon4 allele and by level of cognitive deficit. METHODS: One hundred eighty subjects with a diagnosis of dementia or other clinical disorders were identified from an eligible population of 5,677 elderly individuals. Age, duration of disease, and head size (where appropriate) were considered as covariates. APOE genotype was determined by polymerase chain reaction using buccal material. Axial and coronal intermediate- and T2-weighted MR images were quantified using a multispectral segmentation algorithm. Cognitive status was assessed by means of a modified Mini-Mental Status Examination. RESULTS: All types of dementing illness showed significant volume reductions in the majority of structures examined, particularly in the total brain, hippocampus, and white and gray matter, and increased CSF and ventricular volumes. Subjects with mild cognitive impairment showed fewer atrophic changes but were still distinguishable from the 24 control subjects. Presence of an epsilon4 allele was associated with smaller hippocampal volume in subjects with Alzheimer's disease and vascular dementia within just 1 year of disease onset. For other analyses, atrophy related to the presence of the epsilon4 allele disappeared after controlling for age and length of disease. CONCLUSION: The effects of the epsilon4 allele on brain morphology may be subtly expressed early in the development of dementia, but do not specifically affect cerebral atrophy thereafter. Cognitive impairment is associated with atrophy irrespective of diagnosis and presence of epsilon4.

Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells.

OBJECT: Coexpression of platelet-derived growth factor (PDGF)-BB and activated PDGF-beta receptor in meningioma cells indicates that this cytokine may act as an autocrine or paracrine stimulant of meningioma growth. The intracellular events transducing signals from PDGF-beta receptor tyrosine kinases are unknown. In this study the authors evaluated whether or not mitogen-activated protein kinases (MAPKs) are expressed in meningiomas, regulate their growth, and transduce mitogenic signals of PDGF-BB. METHODS: Ten human meningioma tumors as well as cells cultured from two normal leptomeninges and 10 additional human meningiomas were evaluated using Western blot analysis to determine the presence of MAPK and phosphorylated (activated) MAPK. The effects of PD098059, a selective inhibitor of MAPK phosphorylation/activation, on proliferation of meningioma cells stimulated with 10% fetal bovine serum was also evaluated. Last, the authors evaluated whether PDGF-BB stimulation of meningioma cells was associated with activation of MAPK. Western blots of lysates from meningiomas and from cultured leptomeningeal and meningioma cells demonstrated MAPK and phosphorylated MAPK. Treatment with PD098059 produced a 52 to 84% (x = 69.8) loss in [3H]thymidine incorporation, which was associated with a partial or complete loss of phosphorylated MAPK after 3 days of treatment. The PDGF-BB produced a significant increase in [3H]thymidine incorporation and phosphorylation of MAPK at 1 and 3 days. Coadministration of PD098059 completely blocked PDGF-BB's stimulation of [3H]thymidine incorporation and cell proliferation concomitant with reduced MAPK phosphorylation. CONCLUSIONS: The findings indicate that MAPK is constitutively expressed in leptomeningeal and meningioma cells and transduces mitogenic signals of PDGF, contributing to the growth of human meningiomas.

What getting sick means.

The concepts of health, disease and death have intrigued man since the beginning of time and are continually evolving. In the nonwestern societies the models which have been proposed for the etiology of disease have a dichotomous view of disease causation which is derived from either natural or supernatural forces. In the Western societies these concepts are well defined. The numerous advances in the fields of genetics and molecular biology have added a new dimension to the understanding of the various factors involved in the pathogenesis of disease processes. These advances have allowed a greater understanding of numerous disease processes including the inborn errors of metabolism, endocrine disorders and human neoplasia. Several recent advances in the areas of molecular biology and physiology allowing this increased understanding of human disease are presented.

Amino acids enhance insulin resistance to exogenous glucose infusion in overnight-fasted humans.

The role that amino acids play in regulating exogenous glucose infusion during hyperinsulinemia was examined in overnight-fasted volunteers. Each study consisted of both a 30-minute basal period and a 4-hour experimental period during which insulin was infused at either 0.6, 1.2, 2.5, 5.0, 10, or 20 mU/kg/min with euglycemia maintained. Two protocols were used. In the first (I), subjects were allowed to develop hypoaminoacidemia, and in the second (II), plasma amino acid levels were maintained near basal by frequently monitoring plasma leucine levels in conjunction with exogenous infusion of an L-amino acid solution. The amount of amino acids infused were 0.85 +/- 0.11, 1.53 +/- 0.17, 1.97 +/- 0.13, 2.18 +/- 0.50, 2.78 +/- 0.61, and 2.83 +/- 0.44 mg/kg/min at escalating insulin doses, respectively. When amino acids were infused, the amount of glucose required to maintain euglycemia was lower at each insulin dose used (4.5 +/- 0.3 vs 3.6 +/- 0.4, 7.6 +/- 0.5 vs 6.9 +/- 0.3, 10.4 +/- 1.0 vs 8.7 +/- 0.5, 13.3 +/- 0.8 vs 10.2 +/- 0.4, 14.7 +/- 0.8 vs 11.7 +/- 0.6, and 14.9 +/- 0.6 vs 11.8 +/- 0.8 mg/kg/min at escalating insulin doses, respectively; p less than 0.05). The calculated maximal infusion rates were 15.8 +/- 0.6 vs 12.6 +/- 0.4 mg/kg/min (protocol I vs II, p less than 0.001), while the concentrations required to achieve half-maximal rates were 153 +/- 22 and 134 +/- 22 microU/ml (p = ns), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Experience with adrenocortical neoplasms in childhood.

The experience with adrenocortical neoplasms in childhood is reviewed. During three decades, ten children with adrenocortical neoplasms were seen at the authors' institution. The literature was reviewed, and 209 patients 16.5 years or younger were found. All ten patients at Vanderbilt University Hospital (VUH) presented with endocrine manifestations of the tumor. Three patients had Cushing's, two patients had virilization, and five patients had features of both. In the literature, virilization, alone or with Cushing's, was the most common mode of presentation. Feminizing tumors were uncommon and nonfunctional tumors rare. The majority of patients were female. Features associated with malignancy included 17-KS levels greater than 40 mg/24 hr, diameter greater than 6 cm, weight greater than 500 g, and histologic evidence of diffuse growth pattern, vascular invasion, and tumor cell necrosis. Although uncommon, adrenocortical neoplasms should be suspected in children with Cushing's, virilization, feminization, or a combination of these. There has been an increased incidence reported in patients with hemihypertrophy, Beckwith-Wiedemann syndrome, hemangiomas, and nevi. Following endocrinologic evaluation, imaging studies should be performed. CT scan appears to be the most useful diagnostic tool. A posterior operative approach is recommended for suspected adenomas. An anterior thoracoabdominal approach is favored for suspected malignancies with uncompromised en bloc resection. There is no evidence that adjuvant therapy provides any additional benefit.

Occult breast carcinoma presenting as an axillary mass.

Breast carcinoma presents rarely (<5% of cases) as an axillary mass without an obvious primary tumor. The value of mammography in detecting an occult breast carcinoma is low, with a sensitivity of 29 per cent and specificity of 73 per cent. MRI and positron emission tomography (PET) are potentially more sensitive in this setting. We present a case recently seen at the Vanderbilt University Hospital, a 63-year-old woman with a 2-cm painless mass in the right axilla. Mammography was negative, and fine needle aspiration revealed atypical cells suspicious for malignancy. An excisional biopsy of the right axillary lymph node revealed metastatic adenocarcinoma, most likely breast primary. A PET showed increased uptake of 18-fluorodeoxyglucose and 99m Technetium in the right axilla and the right lateral breast. The patient underwent right modified radical mastectomy. The final pathological report revealed a 0.9-cm primary tumor in the upper inner quadrant of the breast and 1 of 41 nodes positive for tumor. This case confirms that mammography has low sensitivity in identifying the primary tumor in occult breast carcinoma and illustrates the usefulness of PET in identifying the primary tumor. We advocate an aggressive approach to evaluation of the breast in women presenting with metastatic adenocarcinoma in the axillary nodes. This evaluation should include clinical examination and mammography in all cases, and PET and MRI in selected cases. PET and MRI may be particularly useful when considering a breast-conserving surgical procedure.

Building a nursing quality management program on preprinted charting forms.

The use of preprinted charting forms saves nursing time and, at the same time, increases completeness and accuracy of documentation. Data for Quality Management (QM) are easily gathered from preprinted charting forms, making the forms an effective tool for building a nursing QM program. The enthusiastic response to the presentation of this program at the American College Health Association's 1998 Annual Meeting in San Diego prompted the authors to share this information with journal readers.

The 'fading' Meckel's diverticulum. An unusual scintigraphic presentation.

The usual scintigraphic presentation of a Meckel's diverticulum is progressive accumulation of Tc-99m pertechnetate within the ectopic gastric mucosa that parallels uptake in the stomach. The authors present a case of an adult with acute gastrointestinal bleeding, negative endoscopic and radiologic evaluation, and atypical scintigraphy. An abnormal focus of uptake appeared at the same time as the stomach but faded away in the 15-minute image before reappearing while the stomach was still progressively accumulating the radioisotope. Meckel's diverticulum was confirmed by surgery. This case emphasizes the importance of scintigraphy in the evaluation of gastrointestinal bleeding, and it further emphasizes that any uptake that cannot be physiologically related is suspicious, even in a young adult.

Referral for secondary restorative dental care in rural and urban areas of Scotland: findings from the Highlands Et Islands Teledentistry Project.

OBJECTIVES: To compare the reported level of use of secondary care services for restorative dental care in rural and urban areas of Scotland. DESIGN: Postal questionnaire survey SUBJECTS AND METHODS: Postal questionnaire sent to all dentists in the Highland region, the island regions in Scotland and Dumfries Et Galloway (n = 150) and an equal number were sampled from the remainder of Scotland stratified by health board area. Non-respondents were sent 2 reminders after which 62% of the sample had responded. RESULTS: Most dentists (85%) who practised in what they considered were urban areas of Scotland said they felt that they had good access to a secondary referral service. Whereas most of those who practised in what they considered were rural areas either said they had no access to such a service (26%) or that access was difficult (53%), only 3% of those in urban areas said they had no access to a secondary restorative consultative service compared with 14% of dentists practising in rural areas of mainland Scotland and 54% of those practising on Scottish islands. CONCLUSIONS: The survey suggests the people of the Scottish islands and some of the remoter parts of the Scottish mainland would be among those who might benefit from improvement in access to a restorative dentistry consultant service.

An economic evaluation of the Highlands and Islands teledentistry project.

A 12-month trial of teledentistry was conducted in two general dental practices (one in the Orkney Islands and one in the Scottish Highlands at Kingussie). The dental practices had a PC-based videoconferencing link, connected by ISDN at 128 kbit/s, to a restorative specialist at a hospital in Aberdeen. Twenty-five patients were recruited into the trial. A cost-minimization analysis was undertaken by comparing the costs of teledentistry with two alternatives: outreach visits, where the specialist regularly visited the remote communities, and hospital visits, where patients in remote communities travelled to hospital for consultation. For Orkney patients, dental teleconsultations cost the National Health Service (NHS) an additional 36 per patient compared with outreach visits, but cost-savings of 270 per patient could be achieved compared with hospital visits. For Kingussie patients, teleconsultations cost the NHS an additional 44 and there were cost-savings of 1.54 compared with outreach visits and hospitals visits, respectively. However, patients incurred additional costs for radiographs and photographs, and the general dental practitioner incurred additional preparation time costs. When the value of patient time was included, there were cost-savings of around 900 per Orkney patient compared with hospital visits, but compared with outreach visits teledentistry cost an additional 180 per patient. Based on the trial data, there were no cost-savings from teledentistry for Kingussie patients, even when the value of time was included. These results were relatively robust in a sensitivity analysis. However, we estimated that the cost-effectiveness of teledentistry would improve with greater familiarity and use of equipment. Benefits and cost-savings would be greatest in island or remote communities, where patients have to travel long distances to hospital for specialist consultations.

An audit of antibiotic prescribing in general dental practice.

Clinical audit is widely recognised as the systematic and critical analysis of the quality of clinical care, including treatment regimes, the associated use of resources, and the resulting outcome and quality of life for the patient. The prescribing of antibiotics in general dental practice is an area 'wide open' for audit analysis since the profession must clearly accept its responsibility to use antibiotics sensibly; however, the definition of 'sensibly' is likely to vary from practitioner to practitioner. This audit reviews the need for antibiotic prescribing in general dental practice over two consecutive four-month periods. A consensus was achieved on the rationale for antibiotic prescribing and the number of prescriptions fell by 50% as a result.

Verbal fluency in mania: relationship to number of manic episodes.

OBJECTIVE: The objective of this study was to examine verbal fluency in a group of patients with bipolar disorder (BPD) during an acute episode of mania, and to determine whether performance was related to disease chronicity. We hypothesized that manic patients with BPD would be impaired on verbal fluency, and that this impairment would be greatest in those individuals who had experienced a greater number of manic episodes. METHOD: Forty-five manic inpatients with bipolar disorder, and 30 healthy volunteers completed tests of phonemic and semantic verbal fluency. The patients were dichotomized into those experiencing their first episode of mania (FE) and those who had experienced multiple episodes (ME). RESULTS: On the phonemic fluency task, ME patients produced significantly fewer words than both healthy volunteers and FE patients, and they made a greater number of errors. No significant group differences in overall output were found on the semantic fluency task, although the ME group was more error-prone than were the other groups. CONCLUSIONS: These findings suggest that verbal fluency is more impaired in ME patients than in patients who have experienced only a single manic episode.