Long, intrinsic horizontal axons radiating through and beyond rat barrel cortex have spatial distributions similar to horizontal spreads of activity evoked by whisker stimulation.

Stimulation of a single whisker evokes a peak of activity that is centered over the associated barrel in rat primary somatosensory cortex, and yet the evoked local field potential and the intrinsic signal optical imaging response spread symmetrically away from this barrel for over 3.5 mm to cross cytoarchitectonic borders into other "unimodal" sensory cortical areas. To determine whether long horizontal axons have the spatial distribution necessary to underlie this activity spread, we injected adeno-associated viral vectors into barrel cortex and characterized labeled axons extending from the injection site in transverse sections of flattened cortex. Combined qualitative and quantitative analyses revealed labeled axons radiating diffusely in all directions for over 3.5 mm from supragranular injection sites, with density declining over distance. The projection pattern was similar at four different cortical depths, including infragranular laminae. Infragranular vector injections produced patterns similar to the supragranular injections. Long horizontal axons were detected both using a vector with a permissive cytomegalovirus promoter to label all neuronal subtypes and using a calcium/calmodulin-dependent protein kinase II α vector to restrict labeling to excitatory cortical pyramidal neurons. Individual axons were successfully reconstructed from series of supragranular sections, indicating that they traversed gray matter only. Reconstructed axons extended from the injection site, left the barrel field, branched, and sometimes crossed into other sensory cortices identified by cytochrome oxidase staining. Thus, radiations of long horizontal axons indeed have the spatial characteristics necessary to explain horizontal activity spreads. These axons may contribute to multimodal cortical responses and various forms of cortical neural plasticity.

Variability in the preoperative management of infants with hypoplastic left heart syndrome.

Infants with hypoplastic left heart syndrome (HLHS) commonly undergo initial surgical palliation during the first week of life. Few data exist on optimal preoperative management strategies; therefore, the management of these infants prior to surgery is anecdotal and variable. To more fully define this variability in preoperative care of infants with HLHS, a survey was designed to describe current preoperative management practices in the infant with HLHS. The questionnaire explored management styles as well as preoperative monitoring techniques and characteristics of the respondent's health care institution. The responses were compiled and are reported. A striking lack of consistency in preoperative management techniques for infants with HLHS is apparent. The impact of these preoperative strategies is unknown. Despite challenges in anatomic and hemodynamic variability at presentation, a prospective randomized controlled trial comparing ventilatory management techniques, enteral feeding strategies, and the utility of various monitoring tools on short- and long-term outcome is needed.

Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

Diagnostic properties of transbronchial biopsy in lung transplant recipients who require mechanical ventilation.

INTRODUCTION: Bronchoscopy with transbronchial biopsy (TBBx) and bronchoalveolar lavage is useful and safe for diagnosing acute rejection and infection in lung transplant recipients. However, its role is less well defined in determining the etiology of allograft dysfunction in the setting of respiratory failure necessitating mechanical ventilation. METHODS: We retrospectively identified 41 mechanically ventilated patients with respiratory failure in whom 42 TBBx were followed within a 10 day period by surgical lung biopsy (SLBx) to determine the sensitivity, specificity, and positive and negative predictive values of TBBx compared with SLBx. RESULTS: The sensitivity, specificity, and positive and negative predictive values of TBBx for all episodes of acute rejection and for significant episodes of acute cellular rejection were 53.3% and 36.0%; 91.7% and 94.1%; 94.1% and 90.0%; 44.0% and 50.0%, respectively. A significantly higher histologic grade was noted on SLBx compared with TBBx specimens obtained within a 10-day period (2.39 +/- 1.02 vs 0.97 +/- 0.11, p

A fatigue clinic in a comprehensive cancer center: design and experiences.

Cancer-related fatigue is now the most prevalent symptom of cancer, occurring in 60-90% of patients. Fatigue has been identified by cancer patients as a factor influencing functionality and quality of life. Our objectives in developing a fatigue specialty clinic at The University of Texas M. D. Anderson Cancer Center were to improve our patients' quality of life by decreasing fatigue; educate health care providers, patients, and patients' families about cancer-related fatigue; develop an appropriate clinical and diagnostic evaluation for this symptom; correlate objective measures of fatigue with its clinical evaluation; and develop innovative treatment plans for cancer-related fatigue. This article describes the general clinic design and operations and the preliminary analysis of the first 40 patients evaluated in the fatigue clinic.

Fatigue during preoperative chemoradiation for resectable rectal cancer.

BACKGROUND: The aim of this study was to evaluate the severity and patterns of fatigue during preoperative chemoradiation therapy for locally advanced rectal cancer and determine whether there are predictors for patients who develop severe fatigue. METHODS: Seventy-two patients with resectable rectal cancer received chemoradiation (total radiation dose, 45 gray/25 fractions to the pelvis; continuous infusion of 5-fluorouracil [300 mg/m(2)]). The Brief Fatigue Inventory (BFI), a measure that categorizes fatigue severity on a 0-10 scale, was administered weekly during treatment. Severe fatigue was defined as 7-10 on the "worst level of fatigue" item. Demographics, disease information, toxicities, and blood counts were collected. Descriptive statistics, repeated measure analysis of variance, and multiple regression were used to examine fatigue and its correlates. RESULTS: Fatigue increased in 67% of patients during chemoradiation (CTX/XRT). The mean fatigue score increased from 3.16 before treatment to 4.62 at the end of treatment. A significant linear trend suggested that fatigue progressively got worse during CTX/XRT (F = 16.497, P < 0.001). However, 18% of patients experienced severe fatigue before CTX/XRT; this was predicted by uncontrolled pain (r(2) = 0.321; F = 16.52; P < 0.001). During CTX/XRT, uncontrolled diarrhea was the only predictor for increased fatigue (r(2) = 0.182; F = 7.77; P < 0.01). Approximately one-third of patients had severe fatigue, which impaired their function at the end of CTX/XRT. CONCLUSIONS: Preoperative chemoradiation therapy for patients with rectal cancer was associated with progressive fatigue during therapy. Based on identified predictors for fatigue, more active pain management before CXT/XRT and bowel management during CTX/XRT might reduce cancer-related fatigue in these patients.

Use of the lapidus bunionectomy in first ray insufficiency.

Surgical management of first ray insufficiency in HAV or hallux limitus is crucial to long-term success. Although technically demanding, the Lapidus fusion serves to address the deformity at its apex and restores normal weight bearing to the foot. This arthrodesis offers predictable, durable results in addressing various first ray deformities and occupies an important place in the foot and ankle surgeon's armamentarium. The authors' technique is described herein for the interest of and evaluation by surgeons performing this procedure. As clinicians recognize the importance of addressing proximal components of the HAV deformity, the Lapidus and other procedures will likely see increased use in the surgical management of first ray deformities.

Ductography: how to and what if?

Ductography of the breast is an underused procedure that often helps define the cause of unilateral, single-pore, spontaneous nipple discharge. Since nipple discharge may be caused by benign tumors, such as papillomas, or by carcinoma, such as ductal carcinoma in situ, identification of intraductal abnormalities with ductography is important. Further, diagnostic ductography and preoperative ductography help guide accurate surgical intervention. Without prior ductography, central duct excision may not result in removal of the abnormal ductal tissue or may result in removal of only a portion of the abnormal ductal system, causing the extent of disease to be effectively understaged. Once fundamental ductographic principles are learned, the procedure is easy to perform. If extravasation occurs, ductography is rescheduled for 7-14 days later. Elimination of air bubbles from the cannula, syringe, and extension tubing is vital. When reflux occurs, radiologists must be aware of a possible tumor in the distal-most duct. When ductal ectasia or fibrocystic changes are the cause of the discharge, conservative follow-up may be considered. Diagnostic radiologists who learn the technique of ductography and include it in their evaluation of nipple discharge will improve their interdisciplinary approach to this important sign of breast cancer.

A transient assay for regulatory gene function in haemopoietic progenitor cells.

This work aimed to provide a means of assaying directly the effects of transient expression of introduced genes on the survival, proliferation, lineage commitment and differentiation of haemopoietic progenitor cells. For this purpose, we have developed a system that allows isolation of productively transfected, mulitipotent haemopoietic cells within a few hours of the introduction of test genes. We have shown that FDCP-mix cells productively transfected with expression plasmids encoding green fluorescent protein (GFP) differentiate normally and retain colony-forming potential. We constructed an expression vector consisting of a bicistronic cassette in which a GFP marker gene and a test gene are driven from the same promoter. The vector design has been optimized for co-expression and the test gene was shown to be biologically active. The expression profile from a transiently transfected template under different growth conditions reveals that active expression continues for at least 2 d after transfection. The transient transfection of FDCP-mix cells with the vectors described provides a powerful tool for analysis of the immediate early effects of test gene overexpression during haemopoietic differentiation.

Similar but distinct effects of the tristetraprolin/TIS11 immediate-early proteins on cell survival.

The immediate early protein tristetraprolin (TTP) is required to prevent inappropriate production of the cytokine TNF-alpha, and is a member of a zinc finger protein family that is associated with RNA binding. TTP expression is induced by TNF-alpha, and evidence indicates that TTP can bind and destabilize the TNF-alpha mRNA. TTP and the closely related TIS11b and TIS11d proteins are evolutionarily conserved, however, and induced transiently in various cell types by numerous diverse stimuli, suggesting that they have additional functions. Supporting this idea, continuous expression of each TTP/TIS11 protein at physiological levels causes apoptotic cell death. By various criteria, this cell death appears analogous to apoptosis induced by certain oncoproteins. It is also dependent upon the zinc fingers, suggesting that it involves action on appropriate cellular targets. TTP but not TIS11b or TIS11d also sensitizes cells to induction of apoptosis by TNF-alpha. The data suggest that the TTP and TIS11 immediate early proteins have similar but distinct effects on growth or survival pathways, and that TTP might influence TNF-alpha regulation at multiple levels.

Pulmonary arterial smooth muscle cells modulate cytokine- and LPS-induced cytotoxicity in endothelial cells.

Cytokines and lipopolysaccharide (LPS) are known to be injurious to vascular endothelial cells (ECs), but the influence of adjacent vascular smooth muscle cells (SMCs) on this injury is unknown. Exposure of cultured rat (RPMECs) or human (HPMECs) pulmonary microvascular ECs on tissue culture plastic to a mixture of cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) and LPS (cytomix) resulted in a significant increase in (51)Cr release to 35-40%. When unstimulated RPMECs were cocultured with cytomix-pretreated rat pulmonary microvascular SMCs (RPMSMCs) there was an increase in (51)Cr release to 8.4%, which was nitric oxide dependent. However, when RPMECs or HPMECs were stimulated in direct contact with their respective SMCs, rather than a further increase in cytomix-induced injury (e.g., >35-40%), (51)Cr release decreased to <10%. This cytoprotection was fully reproduced with fixed RPMSMCs, and partially reproduced by plating HPMECs on gelatin. These data show that the direct toxicity of a cytokine and endotoxin mixture on cultured ECs can be reduced by contact with vascular smooth muscle.

Lesser metatarsal stress fractures.

Stress fractures continue to be a fact of military life. With appropriate attention to training issues, shoe gear, and physical training activities, however, their effect can be minimized.

Upstream elements bestow T-cell and haemopoietic progenitor-specific activity on the granzyme B promoter.

Cytotoxic T cells and early haemopoietic progenitors share the expression of a number of specific genes. Of these, granzyme B has attracted particular interest because of its role in inducing apoptosis during cytotoxic T cell-mediated target cell killing, and its potential role in the mobilisation and homeostasis of haemopoietic stem cells. Studies of granzyme B regulation should therefore yield valuable information concerning the molecular control of these processes, and also identify elements capable of directing gene expression to two cell types of relevance to gene therapy. Here we show that proximal regulatory elements already known to direct promoter activity in T cells are similarly active in haemopoietic progenitors. However, this activity is not strictly specific, since the promoter regions also direct low levels of reporter gene expression in fibroblasts. More importantly, we also report the presence of two previously unidentified clusters of DNaseI hypersensitive sites upstream from the murine granzyme B gene, and show that these regions impart both increased transcriptional activity and the appropriate cell type specificity on the granzyme B promoter. These upstream regulatory regions are therefore likely to play a key role in the coordination of granzyme B expression in vivo.

4-chloro-m-cresol triggers malignant hyperthermia in susceptible swine at doses greatly exceeding those found in drug preparations.

BACKGROUND: Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves. METHODS: Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed. RESULTS: Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10). CONCLUSIONS: 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.

Epidurography and therapeutic epidural injections: technical considerations and experience with 5334 cases.

BACKGROUND AND PURPOSE: Even in experienced hands, blind epidural steroid injections result in inaccurate needle placement in up to 30% of cases. The use of fluoroscopy and radiologic contrast material provides confirmation of accurate needle placement within the epidural space. We describe our technique and experience with contrast epidurography and therapeutic epidural steroid injections, and review the frequency of systemic and neurologic complications. METHODS: Epidural steroid injections were performed in 5489 consecutive outpatients over a period of 5 1/2 years by three procedural neuroradiologists. In 155 cases (2.8%), the injections were done without contrast material owing to either confirmed or suspected allergy. The remaining 5334 injections were performed after epidurography through the same needle. Patients and referring clinicians were instructed to contact us first regarding complications or any problem potentially related to the injection. In addition, the referring clinicians' offices were instructed to contact us regarding any conceivable procedure-related complications. RESULTS: Only 10 patients in the entire series required either oral (n = 5) or intravenous (n = 5) sedation. Four complications (0.07%) required either transport to an emergency room (n = 2) or hospitalization (n = 2). None of the complications required surgical intervention, and all were self-limited with regard to symptoms and imaging manifestations. Fluoroscopic needle placement and epidurography provided visual confirmation of accurate needle placement, distribution of the injectate, and depiction of epidural space disease. CONCLUSION: Epidurography in conjunction with epidural steroid injections provides for safe and accurate therapeutic injection and is associated with an exceedingly low frequency of untoward sequelae. It can be performed safely on an outpatient basis and does not require sedation or special monitoring.

Flexible sigmoidoscopy: screening for colorectal cancer.

Flexible sigmoidoscopy is an important screening procedure because of its ability to detect early changes in the distal colon. The 60-cm flexible sigmoidoscope provides excellent visualization with minimal discomfort to patients. Successful sigmoidoscopy requires adequate patient preparation, proper equipment and an experienced examiner who can recognize both normal and abnormal findings. Complications arising from sigmoidoscopy are rare, but patients may experience some cramping, gas or watery stools. Screening and primary preventive measures, including regular exercise and increased dietary fiber intake, can lower the morbidity and mortality associated with colorectal cancer.

The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory.

BACKGROUND: Fatigue is a major disease and treatment burden for cancer patients. Several scales have been created to measure fatigue, but many are long and difficult for very ill patients to complete, or they are not easy to translate for non-English speaking patients. The Brief Fatigue Inventory was developed for the rapid assessment of fatigue severity for use in both clinical screening and clinical trials. METHODS: The study enrolled 305 consecutive, consenting adult inpatients and outpatients with cancer who could understand and complete the self-report measures used in the study. The same instruments also were administered to 290 community-dwelling adults to obtain a comparison sample. Research staff completed a form that indicated the primary site and stage of the cancer, rated the Eastern Cooperative Oncology Group performance status of the patient, described the characteristics of the pain, and described the current pain treatment being provided to the patients. RESULTS: The BFI was shown to be an internally stable (reliable) measure that tapped a single dimension, best interpreted as severity of fatigue. It correlated highly with similar fatigue measures. Greater than 98% of patients were able to complete it. A range of scores defining severe fatigue was identified. CONCLUSIONS: The BFI is a reliable instrument that allows for the rapid assessment of fatigue level in cancer patients and identifies those patients with severe fatigue.

Flexible sigmoidoscopy: screening for colorectal cancer.

Flexible sigmoidoscopy is an important screening procedure because of its ability to detect early changes in the distal colon. The 60-cm flexible sigmoidoscope provides excellent visualization with minimal discomfort to patients. Successful sigmoidoscopy requires adequate patient preparation, proper equipment and an experienced examiner who can recognize both normal and abnormal findings. Complications arising from sigmoidoscopy are rare, but patients may experience some cramping, gas or watery stools. Screening and primary preventive measures, including regular exercise and increased dietary fiber intake, can lower the morbidity and mortality associated with colorectal cancer.