Flow-independent angiography for peripheral vascular disease: Initial in-vivo results

Flow-independent angiography (FIA), an approach that isolates arterial blood using MR relaxation characteristics rather than flow effects, was evaluated for application in peripheral vascular disease (PVD). First, pilot studies were conducted in which FIA coronal projection images were obtained from controls and symptomatic patients with PVD to assess clinical utility. All control images corresponded to the expected leg arterial anatomy with little interference from deep veins (one of five) and muscle (zero of five). Superficial venous signal was less well suppressed in comparison to deep veins (four of five). Images of symptomatic patients were less consistent with difficulty suppressing muscle and deep venous signal in some cases and edema when present. We then compared T2 values for muscle (T2_m, tibialis anterior), arterial blood (femoral and popliteal arteries), and venous blood (femoral, popliteal, and saphenous veins) in controls (n = 8) and symptomatic patients with intermittent claudication (n = 5) or ischemic rest pain (n = 7). Changes in T2 measurements of various tissues accounted for poorer contrast in symptomatic patients. Patients with ischemic rest pain had significantly higher T2_m compared with controls (T2_m = 39.3 ± 2.1 (1 standard error of the mean [SEM]) versus 30.9 ± .4, P < .01). For all measurements, other than saphenous vein, variances were greater in symptomatic patients. To realize the inherent advantages of FIA for this clinical application, additional work on suppression of signals from muscle, veins, and edema is required. One promising approach involves shifting from projection images to three-dimensional acquisitions for improved tissue suppression.     

The thermal effect on the blood flow response to electrical stimulation.

BACKGROUND: Wounds, especially in the elderly, can be life threatening. One modality which allegedly increases blood flow (BF) as an aid to heal chronic wounds is electrical stimulation. This technique applies electrical current (ES) across wounds. However, while many studies show positive findings, others do not. The purpose of this investigation was to investigate some of this inconsistency in results by determining the effect of environmental temperature on the circulation of the skin which may negate the effects of electrical stimulation in a clinical setting. MATERIAL/METHODS: Ten people with no wounds, controls (C), and 12 people with wounds (W) were examined in a thermally neutral or cool room (20 degrees C) and a warm room (34 degrees C) to observe the effect of reducing sympathetic vasoconstrictor activity on the response to 5 and 15 mA sine wave biphasic ES delivered by 2x2 cm surface electrodes. RESULTS: C and W subjects showed a greater BF in the skin in a warm room. In group C, after 30 minutes of stimulation at a current of 15 milliamps, BF increased significantly (p<0.05) but by an average of only 4 flux in the cool room. In the warm environment, BF increased significantly (p<0.01) by 19.3+/-7 flux and increased further during the 60 minute recovery phase. In the W group, BF during ES increased much more during stimulation in a warm room compared to a cool room. CONCLUSIONS: The results show that local vasoconstriction due to exposure to a warm global temperature greatly increases the response of the skin the ES.     

Bone marrow transplantation in miniature swine. III. Graft-versus-host disease and the effect of T cell depletion of marrow

Graft-versus-host disease (GVHD) has been evaluated in partially inbred miniature swine in order to study this complication of allogeneic bone marrow transplantation (BMT) in a major histocompatibility complex (MHC) genetically defined large animal model. Bone marrow from MHC homozygous ("parental") swine was injected into irradiated (900 rads total-body irradiation) MHC heterozygous ("F1") swine that shared one haplotype with the donor. All 18 animals successfully engrafted with donor bone marrow, and 17 of these developed skin rash of varying intensity depending on the extent of T cell depletion of infused marrow. Of 18 animals, 8 received undepleted bone marrow from exsanguinated donors and 2 also received additional peripheral blood lymphocytes (PBL) as a source of mature T cells. All 8 showed a moderate-to-severe rash, and the 2 pigs that received additional donor PBL developed the most severe rash. The cutaneous eruption seen in this model clinically, histologically, and immunologically resembled human GVHD. Two protocols of T cell depletion of donor bone marrow by antiporcine T cell monoclonal antibodies plus complement were tested for their effect on development of GVHD. The combination of two monoclonal antibodies, 74-12-4 (PT4) and 76-2-11 (PT8), had a marginal effect on the subsequent development of cutaneous manifestations of GVHD. However, treatment of the donor marrow by a combination of three monoclonal antibodies--PT4, PT8, and MSA4 (PT11)--effectively decreased the severity of the GVHD skin rash. These results indicate that (1) the GVHD associated with allogeneic bone marrow transplantation in swine is dependent on T cells in the marrow; (2) effective T cell depletion of donor marrow by monoclonal antibodies and complement does not prevent engraftment; and (3) this swine GVHD model, which allows study with F1 and homozygous parental combinations in an MHC genetically defined large animal, is particularly useful for the understanding of GVHD pathogenesis, prevention, and treatment.     

Synergistic antiviral activity of human interferon combinations in the hepatitis C virus replicon system.

The use of type I interferon (IFN), in combination with ribvirin, to treat chronic hepatitis C virus (HCV) infection has many drawbacks that prevent widespread application, ultimately leading to a significant unmet clinical need. Potential improvements in IFN therapy through targeted delivery, molecular alteration, and combination with other agents are ongoing in an attempt to decrease adverse effects and increase efficacy. In this report, the HCV replicon cell culture system was used to assess potential synergistic antiviral effects of multiple IFN species when administered in combination. Quantitative analysis of HCV replicon RNA by TaqMan (PE Applied Biosystems, Foster City, CA) and qualitative analysis of HCV protein expression were used to measure the antiviral efficacy of individual and combination IFN treatments, and synergistic responses of IFN combinations were determined through statistical analysis of the TaqMan results. We found that when administered simultaneously, type I/II IFN combinations (IFN-alpha2b + IFN-gamma or IFN-beta + IFN-gamma) resulted in dramatic antiviral synergy, whereas a type I/I combination (IFN-alpha2b + IFN-beta) demonstrated a slightly antagonistic profile. The synergistic effect is likely due to differential cell surface receptors and signaling pathways employed by types I and II IFNs. Conversely, all type I IFN species bind the same receptor and signal through similar pathways, possibly accounting for the nearly additive response observed. In support of this hypothesis, IFN treatment resulted in differential induction of Stat1 phosphorylation at Tyr 701. In conclusion, simultaneous type I/II IFN combination treatment may allow an overall decreased effective IFN dose, which may reduce the side effect profiles that hinder current therapy.     

Decreased cortical response to verbal working memory following sleep deprivation

STUDY OBJECTIVE: To investigate the cerebral hemodynamic response to verbal working memory following sleep deprivation. DESIGN: Subjects were scheduled for 3 functional magnetic resonance imaging scanning visits: an initial screening day (screening state), after a normal night of sleep (rested state), and after 30 hours of sleep deprivation (sleep-deprivation state). Subjects performed the Sternberg working memory task alternated with a control task during an approximate 13-minute functional magnetic resonance imaging scan. SETTING: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. PATIENTS OR PARTICIPANTS: Results from 33 men (mean age, 28.6 +/- 6.6 years) were included in the final analyses. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Subjects performed the same Sternberg working memory task at the 3 states within the magnetic resonance imaging scanner. Neuroimaging data revealed that, in the screening and rested states, the brain regions activated by the Sternberg working memory task were found in the left dorsolateral prefrontal cortex, Broca's area, supplementary motor area, right ventrolateral prefrontal cortex, and the bilateral posterior parietal cortexes. After 30 hours of sleep deprivation, the activations in these brain regions significantly decreased, especially in the bilateral posterior parietal cortices. Task performance also decreased. A repeated-measures analysis of variance revealed that subjects at the screening and rested states had similar activation patterns, with each having significantly more activation than during the sleep-deprivation state. CONCLUSIONS: These results suggest that human sleep-deprivation deficits are not caused solely or even predominantly by prefrontal cortex dysfunction and that the paretal cortex, in particular, and other brain regions involved in verbal working memory exhibit significant sleep-deprivation vulnerability.     

Laparoscopic versus open appendectomy: a prospective randomized trial of 81 patients

Objective

To compare the efficacy of laparoscopic appendectomy (LA) and open appendectomy (OA) in the treatment of acute appendicitis.

Design

A prospective randomized trial.

Setting

A university teaching hospital.

Patients

Eighty-one patients with a diagnosis of acute appendicitis were prospectively randomized to undergo either LA or OA. The two groups were matched for age and sex.

Interventions

LA or OA.

Main Outcome Measures

Number of days in hospital and time to full recovery.

Results

The mean hospital stay for LA was 3.23 days compared with 3.03 days for OA (p < 0.001). The mean number of narcotic injections required for patients in the LA group was 4.05 compared with 5.58 for patients in the OA group (p < 0.001). The mean time to complete recovery for patients in the LA group was 9.0 days compared with 16.2 days for patients in the OA group (p < 0.001). The mean operative time for LA was 73.8 minutes compared with 45.0 minutes for OA (p < 0.001). Three patients in the LA group had intra-abdominal abscesses (p > 0.25). No significant difference in wound infection rates was demonstrated (p > 0.05). Similarly, pain scores at 7 and 28 days showed no significant difference (p > 0.05).

Conclusions

With LA significantly fewer narcotic injections are required and there is a more rapid return to normal activities. LA takes longer to perform and was associated with three intra-abdominal abscesses. In cases of simple acute appendicitis the hospital stay for LA is significantly shorter.     

Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days.

PURPOSE: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.     

Specialized DNA arrays for the differentiation of pancreatic tumors.

PURPOSE: Malignant tumors of the pancreas are frequently indistinguishable from inflammatory tumors arising in the context of a chronic pancreatitis with the use of conventional imaging techniques. Thus, cytologic analysis of cells obtained by abdominal ultrasound, computed tomography, or endoscopic ultrasound-guided fine needle aspiration biopsy is required for diagnosis. However, the reliability of cytologic analyses of pancreatic fine needle aspirates remains unsatisfactory, with a diagnostic accuracy of < or =80%. The purpose of the current study was therefore to develop a novel diagnostic approach based on expression profiling of biopsy material using a specialized diagnostic cDNA array. EXPERIMENTAL DESIGN: Previous gene expression profiling studies were reevaluated to design a 558-feature diagnostic array. Minimal amounts of residual material from pancreatic cytology samples as well as surgically resected tumor and control tissue specimens were analyzed using the diagnostic array and a newly developed statistical classification system. RESULTS AND CONCLUSIONS: Our diagnostic approach resulted in 95% accurate differentiation between ductal adenocarcinomas and nonmalignant tumors of the pancreas. The diagnostic array, in conjunction with conventional diagnostic procedures, is thus suitable to significantly improve the reliability of pancreatic cancer diagnostics and can be expected to become a valuable new tool in the routine workup of suspect masses in the pancreas.