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Biomedical subjects

T R Morgan

Publications and source records attributed to T R Morgan.

At least 19 recordsLinked to original sources
PubMed2006

Black patients with chronic hepatitis C have a lower sustained viral response rate than non-Blacks with genotype 1, but the same with genotypes 2/3, and this is not explained by more frequent dose reductions of interferon and ribavirin*.

In previous hepatitis C virus (HCV) treatment studies, Black patients not only had a lower sustained viral response (SVR) rate to interferon and ribavirin (RBV) than non-Black patients but also a higher frequency of HCV genotype 1 (GT-1) infection. The aim of this community-based study was to determine whether Black patients have a lower SVR rate independent of genotype. We prospectively enrolled 785 patients (24.8% Black, 71.5% White, 3.7% others) who received interferon alpha-2b 3 MU three times weekly + RBV 1000-1200 mg/day for 24 weeks (GT-2/3) or 48 weeks (GT-1). Black patients were more commonly infected with GT-1 (86.8%vs 64.8%, P < 0.001) and less frequently had an SVR compared with non-Black patients (8.4%vs 21.6%, P < 0.001). Within GT-1, Black patients had a lower SVR rate than non-Black patients (6.1%vs 14.1%, P = 0.004) but not within GT-2/3 (50.0%vs 36.5%, P = 0.47). Black patients had lower baseline haemoglobin levels (14.8 vs 15.3 g/dL, P < 0.001) and neutrophil counts (2900 vs 4100/mm(3), P < 0.001) and required more frequent dose reductions of RBV (29.8%vs 18.5%, P < 0.001) and interferon (4.7%vs 1.6%, P = 0.012). However, dose reductions were not associated with lower SVR rates while early treatment discontinuations were (2.9%vs 25.7%, P < 0.001). Independent predictors of SVR were GT-1 [odds ratio (OR) 0.33; 95% confidence interval (CI) 0.20-0.55; P < 0.001], Black race (OR 0.45; 95% CI 0.22-0.93; P = 0.030), and advanced fibrosis, stages 3 + 4 (OR 0.53; 95% CI 0.31-0.92; P = 0.023). In conclusion, Black patients infected with HCV GT-1 (but not GT-2/3) have a lower SVR rate than non-Black patients. This is not explained by their lower baseline haemoglobin levels and neutrophil counts that lead to higher rates of ribavirin and interferon dose reductions.

Alanine Transaminase↗
PubMed2001

Non-immunogenic murine hepatocellular carcinoma Hepa1-6 cells expressing the membrane form of macrophage colony stimulating factor are rejected in vivo and lead to CD8+ T-cell immunity against the parental tumor.

Hepatocellular carcinoma is a lethal disease and methods that develop effective cellular-based immunotherapy are needed. We retrovirally transduced non-immunogenic mouse Hepa1-6 hepatoma cells with the gene encoding the membrane form of macrophage colony stimulating factor (mM-CSF). Excess recombinant M-CSF and phagocytosis-inhibiting chemicals blocked macrophage-mediated killing of cloned mM-CSF transfected Hepa1-6 hepatoma cells. Macrophages derived from Hck(-/-)Fgr(-/-) and Lyn(-/-) triple knockout mice, which are incapable of performing phagocytosis, failed to kill the mM-CSF transduced cells. The mM-CSF transfected tumor clones failed to grow when injected into C57BL/6 or C57L/J mice. Splenocytes from these vaccinated mice displayed cytotoxicity against parental Hepa1-6 cells, but not against B16 and CT-26 tumor cells in vitro. Mice that rejected the mM-CSF transfected Hepa1-6 tumor subsequently rejected parental Hepa1-6 cells but not the B16 melanoma cells when rechallenged. Elimination of the CD8+ effector cells by an anti-CD8 antibody and complement treatment prevented the adoptive transfer of anti-Hepa1-6-specific immunity into naive animals. Thus, mM-CSF provides a method of generating effective anti-tumor immune responses by macrophages and cytotoxic T cells against the parental Hepa1-6 cells. Our work suggests that mM-CSF transduced hepatoma cells could be used as a tumor vaccine to stimulate immune responses against hepatocellular carcinoma.

Animals↗
PubMed2001

Predicting response to initial therapy with interferon plus ribavirin in chronic hepatitis C using serum HCV RNA results during therapy.

In patients with chronic hepatitis C, 48 weeks of therapy with interferon (IFN) plus ribavirin results in a sustained virologic response of 40%. Preliminary analysis suggests that measuring HCV RNA at week 24, rather than week 12, might provide the best prediction of treatment response. To assess the clinical utility of serum HCV RNA determinations at different times during therapy as a predictor of a sustained virologic response we evaluated 912 treatment-naïve patients. Patients were randomized to receive IFN-alpha2b, 3 million units (MU) three times weekly (tiw), for 24 or 48 weeks with either ribavirin or placebo, and then followed for 24 weeks. Serum HCV RNA was measured at weeks 4 and 12 in patients treated for 24 weeks; at 4, 12, and 24 weeks during therapy in those treated for 48 weeks, and week 24 post-therapy in all patients. Sustained response was defined as loss of serum HCV RNA at week 24 follow-up. Other patients were considered virologic nonresponders. For patients receiving 48 weeks of combination therapy, detectable serum HCV RNA at week 24 predicted nonresponse (positive predictive value) in 99% of patients compared to 89% at week 12. In patients treated for 24 weeks, testing at week 12 was more predictive of nonresponse than testing at week 4 in the combination-therapy group but not in the monotherapy group. Hence, for combination therapy, testing for serum HCV RNA as a predictor of nonresponse is most accurate at week 24 of therapy; a positive test correctly identified 99% of nonresponders.

Alanine Transaminase↗
PubMed2001

Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study.

Persons with non-A, non-B hepatitis (cases) identified in 5 transfusion studies in the early 1970s have been followed ever since and compared for outcome with matched, transfused, non-hepatitis controls from the same studies. Previously, we reported no difference in all-cause mortality but slightly increased liver-related mortality between these cohorts after 18 years follow-up. We now present mortality and morbidity data after approximately 25 years of follow-up, restricted to the 3 studies with archived original sera. All-cause mortality was 67% among 222 hepatitis C-related cases and 65% among 377 controls (P = NS). Liver-related mortality was 4.1% and 1.3%, respectively (P =.05). Of 129 living persons with previously diagnosed transfusion-associated hepatitis (TAH), 90 (70%) had proven TAH-C, and 39 (30%), non-A-G hepatitis. Follow-up of the 90 TAH-C cases revealed viremia with chronic hepatitis in 38%, viremia without chronic hepatitis in 39%, anti-HCV without viremia in 17%, and no residual HCV markers in 7%. Thirty-five percent of 20 TAH-C patients biopsied for biochemically defined chronic hepatitis displayed cirrhosis, representing 17% of all those originally HCV-infected. Clinically evident liver disease was observed in 86% with cirrhosis but in only 23% with chronic hepatitis alone. Thirty percent of non-A, non-B hepatitis cases were unrelated to hepatitis viruses A,B,C, and G, suggesting another unidentified agent. In conclusion, all-cause mortality approximately 25 years after acute TAH-C is high but is no different between cases and controls. Liver-related mortality attributable to chronic hepatitis C, though low (<3%), is significantly higher among the cases. Among living patients originally HCV-infected, 23% have spontaneously lost HCV RNA.

Aged↗
PubMed2000

Pressurized sleeves and gloves for protection against acceleration-induced arm pain.

BACKGROUND: Acceleration (or G) induced arm pain may develop in centrifuge runs and in flight with low arm position and assisted pressure breathing during G (PBG) in combination with an extended coverage anti-G suit. To decrease this arm pain, pressurized sleeves and gloves were developed. METHODS: Eight subjects who earlier exhibited G-induced arm pain were tested on the centrifuge. The G-exposures consisted of a gradual onset run up to a maximum of +9 G2, rapid onset runs to +3, +4, +5, +6, +7, +8, and +9 Gz and a simulated aerial combat maneuver (SACM) with peaks up to +9 Gz. On separate days, the subjects were tested without the sleeves and gloves, and with the sleeves and gloves pressurized to a maximum of 40, 60, or 80 mmHg at +9 Gz. The subjects reported their left and right arm pain on a subjective rating scale. RESULTS: G-induced arm pain, usually starting above +6 Gz, was often the reason for termination of the G-exposure without the pressurized sleeves and gloves. The pressurized sleeves and gloves significantly (p < 0.001) decreased arm pain, put no significant difference was found among the different pressures used. Heart rate was not different with and without the pressurized sleeves and gloves. CONCLUSIONS: The pressurized sleeves and gloves are an effective method to alleviate and sometimes eliminate G-induced arm pain.

Adult↗
PubMed1998

Specific requirements for cytochrome c-550 and the manganese-stabilizing protein in photoautotrophic strains of Synechocystis sp. PCC 6803 with mutations in the domain Gly-351 to Thr-436 of the chlorophyll-binding protein CP47.

The requirement of cytochrome c-550 (PSII-V) in photosystem II (PSII) has been assessed in Synechocystis sp. PCC 6803 containing mutations between Gly-351 and Thr-436 of the loop E domain of the chlorophyll a-binding protein CP47. Six photoautotrophic strains were utilized to compare the effect of removal of either the manganese-stabilizing protein (PSII-O) or PSII-V on PSII activity in vivo. These were a wild-type control; two strains with amino acid deletions, Delta(R384-V392) and Delta(G429-T436); and three carrying specific amino acid substitutions, G351L/T365Q, G351L/E364Q/T365Q, and G351L/E353Q/E355Q/T365Q. The removal of PSII-O prevented the assembly of PSII in Delta(G429-T436) but not in Delta(R384-V392). Neither Delta(G429-T436) nor Delta(R384-V392) could support photoautotrophic growth in the absence of PSII-V. In chloride-limiting conditions, the photoautotrophic growth of Delta(R384-V392) was severely impaired and that of Delta(G429-T436) totally inhibited, and no strains lacking PSII-V could grow in chloride-limiting or calcium-limiting media. Substitutions at Gly-351, Glu-353, Glu-355, and Thr-365 produced phenotypes that were similar to those of the control in the presence or absence of PSII-O and PSII-V, but removal of PSII-O from G351L/E364Q/T365Q produced a significant reduction of assembled PSII centers and an enhanced sensitivity to photoinactivation while removal of PSII-V prevented photoautotrophic growth. The additional mutants E364Q:DeltaPSII-V and E364G:DeltaPSII-V demonstrated that this inhibition was a consequence of the mutation at Glu-364. These results also show that the removal of PSII-V, in vivo, produces phenotypes in the CP47 mutants examined that are either similar or more severe than those resulting from the removal of PSII-O.

Amino Acid Sequence↗
PubMed1998

A pilot randomized, controlled trial of the effect of iron depletion on long-term response to alpha-interferon in patients with chronic hepatitis C.

BACKGROUND/AIMS: Some studies have suggested that hepatic iron may influence the response to interferon therapy in chronic hepatitis C patients. We conducted this randomized, controlled trial to evaluate the effect of iron depletion on: (1) aminotransferase activity and hepatitis C RNA levels; and (2) response to interferon therapy in 38 patients with elevated alanine aminotransferase levels and who were HCV RNA positive. METHODS: Seventeen patients underwent a 500-ml phlebotomy every 2 weeks until iron deficiency was achieved. Patients were then started on a 6-month course of alpha-interferon 2b (3 mu tiw). Controls were 21 patients who were monitored for a 6- to 8-week period without phlebotomy prior to interferon therapy. Response to interferon was defined as loss of serum HCV RNA by reverse transcriptase-polymerase chain reaction. Serum HCV RNA was quantitated by bDNA technique. RESULTS: Alanine aminotransferase levels decreased in 15/17 patients after phlebotomy. Mean alanine aminotransferase fell from 156.8 to 89.7 U/l (p=0.008). Changes in iron indices and alanine aminotransferase after phlebotomy were not accompanied by changes in HCV RNA levels. In control patients, neither alanine aminotransferase nor HCV RNA levels changed during the observation period. At the end of 24 weeks of interferon therapy, 7/17 phlebotomized patients had a response, compared to 6/21 control patients (p=ns). After 6 months of follow-up, 5/17 phlebotomized patients remained HCV RNA negative, in contrast to only 1/21 controls (p=0.07). CONCLUSIONS: Iron depletion led to a reduction in aminotransferase levels; this was not accompanied by changes in levels of hepatitis C RNA. There may be an improvement in the sustained response to interferon therapy, but this requires confirmation.

Adult↗
PubMed1995

Protein consumption and hepatic encephalopathy in alcoholic hepatitis. VA Cooperative Study Group #275.

OBJECTIVE: Patients with alcoholic hepatitis frequently have moderate or severe malnutrition. Dietary protein intake may be restricted in these patients because of concurrent hepatic encephalopathy. To further evaluate the relationship between dietary protein intake and hepatic encephalopathy in alcoholic hepatitis, we evaluated prospectively gathered data from a study of 136 placebo-treated patients with moderate or severe alcoholic hepatitis conducted at eight Department of Veterans Affairs Medical Centers. METHODS: Physical examination, laboratory tests, and grade of hepatic encephalopathy were recorded at entry and every seventh day for the first 28 days of study. Average daily protein intake was calculated from dietary evaluation obtained by a registered dietitian at entry and again three times a week. RESULTS: Sixty-three percent of patients had hepatic encephalopathy at entry. Hepatic encephalopathy decreased over time. Time dependent regression analysis found low protein intake, along with high blood urea nitrogen (BUN) and high serum creatinine, to be independently associated with worsening hepatic encephalopathy. Similar analysis found low BUN and less malnutrition at entry into the study to be independently associated with improved hepatic encephalopathy. Higher protein intake was associated with improved hepatic encephalopathy in univariate (p = 0.01), but not multivariate, analysis. CONCLUSION: In patients with alcoholic hepatitis who can be treated with standard anti-encephalopathy medications (e.g., lactulose and neomycin), low protein intake is associated with worsening hepatic encephalopathy while a higher protein intake correlates with improvement in hepatic encephalopathy.

Blood Urea Nitrogen↗
PubMed1995

Raising the dose of interferon does not improve the response in chronic hepatitis C.

We report results of dose escalation to 5 or 6 million units (MU) three times weekly (t.i.w.) of interferon-alpha in 17 consecutive patients with chronic active hepatitis C who were not responding to 3 MU t.i.w. after > or = 12 weeks of therapy. The mean pretreatment alanine aminotransferase (ALT) level was 206 +/- 62 U/L and, at the time of dose escalation, 113 +/- 71 U/L. Two patients could not tolerate the dose escalation. The remaining 15 patients were treated for an additional 10 +/- 3.5 weeks. Three patients had a complete response 3-8 weeks after dose escalation. At the end of high-dose therapy, the mean ALT level was 105 +/- 76 U/L (n = 15). During the 6-month posttreatment follow-up time, the mean ALT level was 147 +/- 85 U/L. All three responders had a relapse. Increasing the dose of interferon-alpha to 5-6 MU t.i.w. in chronic hepatitis C patients who are not responding to interferon-alpha, 3 MU t.i.w., at the 12th week of therapy is unlikely to result in sustained normalization of ALT levels.

Adult↗
PubMed1995

Information and decision-making preferences of men with prostate cancer.

PURPOSE/OBJECTIVES: To determine whether a relationship exists between preferences for involvement in decision making and type of information in patients with cancer. DESIGN: Survey, correlational. SETTING: Community urology clinic in Winnipeg, Manitoba, Canada. SAMPLE: Convenience sample of 57 men (mean age of 71 years). METHODS: Subjects completed a card sort to elicit their preferred role in treatment decision making. A two-part questionnaire measured the type and amount of information preferred. FINDINGS: The majority (57.9%) of men preferred a passive decision-making role. Information on disease advancement, likelihood of cure, and types of treatment available were the three preferred categories of information. Men in the collaborative group and those who wanted their physician to make treatment decisions-only after seriously considering their opinions-also wanted significantly more information in these three categories. Married men ranked self-care information as significantly less important than did single men. Information preferences were similar regardless of preferred decision-making role. CONCLUSIONS: Although the majority of men in this sample wanted their physician to make final treatment decisions, they did want to be informed. Information preferences were similar to other groups of patients with cancer. Future clinical studies are required to determine if providing these men with more information will enable them to assume a more active decision-making role. IMPLICATIONS FOR NURSING PRACTICE: Given the small variance in decision-making and information preferences accounted for by sociodemographic and treatment/disease-related factors, individual assessment of these preferences remains the best clinical approach.

Aged↗
PubMed1994

Phospholipid antibodies in alcoholic liver disease.

Alcoholic liver injury has been reported to be directed preferentially against the proteins of the cell membrane, sparing the phospholipids. However, antiphospholipid antibodies against certain cell membrane phospholipids are known to be associated with a variety of diseases. We undertook this investigation to determine whether antiphospholipid antibodies were present in the serum of patients with alcoholic liver disease. We investigated seventy long-term alcoholic patients (> 80 gm ethanol/day for > 1 yr) and 8 normal nonalcoholic controls by means of enzyme-linked immunosorbent assay to determine whether serum antibodies were generated against the following membrane phospholipids: phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin) and phosphatidic acid. Group 1 comprised alcoholic patients with normal liver function (n = 13), group 2 comprised alcoholic patients with abnormal liver function (n = 16), group 3 comprised patients with alcoholic hepatitis or cirrhosis (n = 41) and group 4 comprised nonalcoholic controls (n = 8). The antibody prevalence was 15% in group 1, 31% in group 2, 81% in group 3 and 0% in group 4. In group 3, 20 of 41 patients had antibodies against several cell membrane phospholipids (i.e., phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, cardiolipin and phosphatidylinositol). The antiphosphatidylethanolamine isotype was IgA or IgM in 25 of 41 of these patients. Both IgA (p < 0.01) and IgM (p < 0.008) antiphosphatidylethanolamine correlated significantly with disease severity. Antiphospholipid antibodies in alcoholic patients seem to reflect disease progression and correlate significantly with disease severity.

Adult↗
PubMed1994

U.S. Air Force positive-pressure breathing anti-G system (PBG): subjective health effects and acceptance by pilots.

Current high-performance fighter aircraft subject pilots to acceleration forces that can adversely effect performance and induce unconsciousness during flight. The main strategies to help the fighter pilot sustain +Gz include a pressurized anti-G garment (G-suit), the anti-G straining maneuver, and centrifuge training to optimize this effective, but very fatiguing, maneuver. To improve anti-G support for aircrew, a positive-pressure breathing anti-G system (PBG) has been developed in the COMBAT EDGE program. In order to determine if any acute adverse health effects are occurring from the use of PBG, a survey of 241 (F-15 and F-16) pilots (49 using PBG and 192 using standard methods) was conducted. Questions were asked regarding acute health effects and the impact of PBG on mission accomplishment. With the exception of dry cough, no significant increases in adverse events were found, and acceptance in the F-16 was much greater than in the F-15.

Adult↗
PubMed1993

A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: results of a Department of Veterans Affairs cooperative study.

A Veterans Affairs cooperative study involving 273 male patients was performed to evaluate efficacy of oxandrolone in combination with an enteral food supplement in severe alcoholic hepatitis. All patients had some degree of protein calorie malnutrition. On an intention-to-treat basis, only minimal changes in mortality were observed. However, in patients with moderate malnutrition mortality on active treatment at 1 mo was 9.4% compared with 20.9% in patients receiving placebo. This beneficial effect was maintained so that after 6 mo on active treatment 79.7% of patients were still alive, compared with 62.7% of placebo-treated patients (p = 0.037). Improvements in both the severity of the liver injury (p = 0.03) and malnutrition (p = 0.05) also occurred. No significant improvement was observed with severe malnutrition. To better determine the effect on therapeutic efficacy, we compared results with those from a nearly identical population (cooperative study 119) treated with oxandrolone but not given the food supplement. Patients were stratified according to their caloric intake (greater than 2,500 kcal/day was considered adequate to supply energy needs and promote anabolism). For patients with moderate malnutrition and adequate caloric intake, oxandrolone treatment reduced 6-mo mortality (4% active treatment vs. 28% placebo [p = 0.002]). For patients with moderate malnutrition and inadequate calorie intake, oxandrolone had no effect on mortality (30% active treatment vs. 33% placebo). In cases of severe malnutrition, oxandrolone had no effect on survival. However, adequate caloric intake was associated with 19% mortality, whereas patients with inadequate intake exhibited 51% mortality (p = 0.0001). These results indicate that nutritional status should be evaluated in patients with alcoholic hepatitis. When malnutrition is present, vigorous nutrition therapy should be provided, and in patients with moderate malnutrition oxandrolone should be added to the regimen.

Alcohol Drinking↗
PubMed1993

Cell-mediated hepatic injury in alcoholic liver disease. Veterans Affairs Cooperative Study Group 275.

BACKGROUND: The mechanism responsible for the initiation and perpetuation of alcoholic liver disease (ALD) remains poorly understood. This investigation attempted to elucidate the role of cell-mediated immune phenomena in the pathogenesis of ethanol-induced liver injury. METHODS: Frozen liver biopsy specimens from 144 patients with moderate to severe ALD were examined by the avidin-biotin immunoperoxidase technique for the expression of antigenic markers of T and B lymphocytes, natural killer cells, and class I and II MHC molecules in the tissue. RESULTS: Expression of CD3 by lymphocytes correlated significantly with regenerating nodules, intralobular inflammation, central sclerosis, and abnormalities of Kupffer cells. B cells were rarely present, and natural killer cells were absent. CD3+ lymphocytes expressed either CD4 or CD8 surface molecules. Enhanced class I MHC expression correlated significantly with portal inflammation, limiting plate erosion, vascular abnormalities, and hemosiderosis. Expression of class II MHC molecules correlated significantly with necrosis, bile stasis, and Mallory bodies. CONCLUSIONS: The distribution and persistence of CD4+ and CD8+ cells in actively advancing ALD, the enhanced MHC expression on hepatocytes, and their relationship to alcoholic hyalin and necrosis lend support to the hypothesis that a cytotoxic T lymphocyte-hepatocyte interaction plays a role, perhaps via lymphokine production, in the genesis or perpetuation of ALD.

CD3 Complex↗
PubMed1993

Expression of the beta 1 chain (CD29) of integrins and CD45 in alcoholic liver disease. The VA Cooperative Study Group No. 275.

OBJECTIVES: In the active stages of alcoholic liver disease (ALD), we have shown previously an enhanced expression of either CD4 or CD8 molecules on CD3+T cells. Class I and II MHC molecules expression were enhanced on lymphocytes, and on the cell membrane of hepatocytes, thus suggesting that an intrahepatic antigen-dependent lymphocyte-hepatocyte interaction occurs. Here we report the pattern of expression of several additional molecules known to participate in nonspecific cell-cell adhesion preceding alloantigen recognition i.e., the beta 1 chain of integrins (CD29) and the isoforms of the leukocyte common antigen CD45RA and CD45RO. METHODS: Frozen liver samples from 38 patients with advanced ALD were examined immunohistochemically by the avidin-biotin-peroxidase complex method using monoclonal antibodies. Nine patients with alcoholic fatty liver and six patients with only hepatitis C infection were included as controls and studied in a similar manner. RESULTS: CD29 was strongly expressed on the cell membrane of hepatocytes in 18/20 patients with cirrhosis, in 17/18 with alcoholic hepatitis without cirrhosis, in 5/9 of fatty liver and in all six with hepatitis C. CD45RA was present in 5/18 cases of alcoholic hepatitis and in 3/20 cases of cirrhosis on the hepatocytes plasma membrane, in none of the controls, and rarely on lymphocytes. CD45RO was expressed on the surface of lymphocytes in 14/18 cases of alcoholic hepatitis, 13/20 patients with cirrhosis, in 5/9 of fatty liver and in one with hepatitis C. The CD45RO lymphocytes were predominantly CD8 positive. CONCLUSIONS: Our results indicate that in ALD the hepatocytes exhibit on their plasma membrane an enhanced expression of the beta 1 chain of the integrins and less commonly CD45RA. Furthermore, the expression of only CD45RO on the surface of lymphocytes favors the postulate that the intrahepatic lymphocytes in ALD are most likely of the "memory" type. The results of this study lend further support to the contention that a cell-cell contact precedes a cell-mediated mechanism in the pathogenesis of ALD.

Antigens, CD↗