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PubMed2002

Persistent rejection of peritubular capillaries and tubules is associated with progressive interstitial fibrosis.

BACKGROUND: We have reported that a 12-day course of high dose cyclosporine A treatment in thymectomized miniature swine with major histocompatibility complex (MHC) class I-mismatched renal allografts results in transient acute rejection followed by either in chronic rejection (progression group) or graft acceptance (recovery group). Here, we examined the differential features between both groups in the peritubular capillaries (PTCs) and tubules to clarify the pathogenesis of the progressive interstitial fibrosis in chronic rejection. METHODS: Morphometric and immunohistochemical studies were performed on serial renal biopsies (days 0 to 100) obtained from both groups, focusing on the cellular infiltrate, rejection of PTCs and tubules, myofibroblast accumulation, and progressive interstitial fibrosis. RESULTS: In the progression group, acute rejection occurred by day 8 and progressed to chronic rejection by day 100, with the development of interstitial fibrosis. PTC endothelial cell and tubular epithelial cell death associated with CD3+ cell infiltration was evident, confirmed by nick end-labeling (TUNEL), commencing by day 8 and continuing thereafter. In acute rejection, destruction of PTCs and tubules accompanied by disruption of basement membrane (BM) occurred with capillaritis or tubulitis in areas with a severe cellular infiltrate. During the development of chronic rejection, capillaritis of PTCs and tubulitis continued by day 100, accompanied by persistent T cell infiltration, and the remaining PTCs and tubules exhibited progressive atrophy with thickening and/or lamination of BM. On day 100, identifiable PTCs and tubules were lost in areas of interstitial fibrosis. Proliferating (PCNA+) alpha-actin+ myofibroblasts accumulated around PTCs, tubules and in interstitium, and widespread interstitial fibrosis developed by day 100. In contrast, in the recovery group, injured PTCs and tubules recovered by day 100 based on the resolution of acute rejection, and minimal loss of PTCs and tubules was evident by day 100 with minimal interstitial fibrosis. CONCLUSIONS: Persistent rejection directed at PTCs and tubules, and proliferation of myofibroblasts are prominent features in the progressive interstitial fibrosis in chronic rejection, and are probably key events in its pathogenesis.

Animals↗
PubMed1994

Human papillomavirus DNA and genotypes: prognostic factors for progression of cervical intraepithelial neoplasia.

A retrospective study of 227 patients presenting with abnormal cervical cytology was conducted to investigate the relationship between human papillomavirus (HPV) and progression of untreated cervical intraepithelial neoplasia (CIN) lesions. All patients had colposcopically directed biopsies for histologic diagnosis. The patients were followed cytologically and colposcopically for a mean of 19 months (range 6-42 months). Progression of a cervical lesion was defined as progression to a higher CIN grade confirmed histologically by directed biopsy. HPV DNA detection was done on material remaining from the cervical swabs by the general primer polymerase chain reaction (PCR) and type-specific PCR method, which made the detection of HPV types 6, 11, 16, 18, 31, 33 and not yet sequenced DNA types (X) possible. The presence of HPV DNA increased with the severity of the lesion (P < 0.001). In CIN III, a 100% HPV DNA prevalence was found, with HPV type 16 being the most prevalent type in 75%. Progression was significantly related to the presence of HPV DNA, in particular HPV type 16. The percentage of progressive disease was 21% in the case of HPV DNA positive lesions (n = 130) and 29% in the presence of HPV type 16, whereas HPV DNA negative lesions (n = 97) showed no progression. The detection of HPV DNA and HPV genotype can be used to identify patients with high-risk cervical lesions, since the presence of HPV DNA and genotype 16 in particular are closely related to CIN progression.

Journal Article↗
PubMedDate not supplied

Static progressive splinting.

Static progressive splinting is the use of inelastic components to apply torque to a joint in order to statically position it as close to end range as possible. It maximizes total end-range time, thus increasing passive range of motion. As tissue lengthens in response to this carefully applied stress, the clinician or wearer adjusts the joint position to progress tissue at the new maximum tolerable length. Static progressive splinting combines precision in joint position and torque application with patient-controlled stress to create an approach powerful enough to succeed when no other treatment approach does. This article discusses static progressive splinting indications, contraindications, and advantages as well as guidelines for a splinting regimen. It offers many examples of static progressive splinting and makes clear that this approach can be used with any mobilizing splint design. The unique mechanics of this splinting approach are described, and the various methods of achieving static progressive splinting are compared. Offering high levels of patient satisfaction and compliance, static progressive splinting has come to the forefront of clinical practice.

Humans↗
PubMed1999

Recent progress in the diagnosis and treatment of multiple sclerosis.

Magnetic resonance imaging (MRI) now provides valuable diagnostic and prognostic information for the management of multiple sclerosis (MS) but the diagnosis still largely rests on the clinical features of central nervous system (CNS) lesions disseminated in time and place. Recent histological and MRI studies indicate that extensive axonal damage can occur in MS, even early in the disease course, and is likely to be an important cause of accumulating disability. Several immunomodulating agents have now been shown to have beneficial effects in MS. High dose intravenous or high dose oral methylprednisolone therapy accelerates recovery from attacks of relapsing-remitting MS, but at present there is no convincing evidence that standard dose (intermediate dose) oral corticosteroid therapy is beneficial for such attacks. Interferon beta, copolymer 1 (glatiramer acetate) and i.v. immunoglobulin therapy each significantly reduce the frequency of attacks of relapsing-remitting MS. Interferon beta also inhibits the progression of disability in relapsing-remitting MS and secondary progressive MS, but its effect on primary progressive MS is unknown. Oral low dose methotrexate therapy slows the progression of disability in secondary progressive MS and possibly in primary progressive MS, but it is likely that the currently used dosage (7.5 mg weekly) is suboptimal. Further research is needed to determine the optimal doses and combinations of the above therapies in MS and to develop better therapies, particularly for primary progressive MS. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMed2002

Analysis of predictive factors for progression of type B aortic intramural hematoma with computed tomography.

PURPOSE: For patients with Stanford type B aortic intramural hematoma (IMH), medical treatment is usually selected. However, the outcomes of patients with type B IMH are not completely understood, and some cases can have fatal complications develop or surgical treatment necessitated. The purpose of this study was to investigate predictors of progression of the affected aorta in patients with type B IMH with initial computed tomography (CT) images. METHODS: Thirty-five patients with type B IMH were studied with serial CT images. Initially, medical therapy was selected for all patients. CT findings of the affected aorta were evaluated on admission and at follow-up. We divided the patients into two groups (progression group or regression group) on the basis of CT findings and investigated predictors of progression of the affected aorta with initial CT images. RESULTS: We defined 15 patients who showed increased maximum aortic diameter (n = 14), increased maximum aortic wall thickness (n = 3), progression to overt dissection (n = 4), or rupture of the aortic wall (n = 2) during the follow-up period as the progression group. The other 20 patients, who all showed decreased maximum aortic wall and aortic wall thickness, were defined as the regression group. In the maximum aortic diameter, an optimal cutoff value of 40 mm resulted in positive predictive and negative predictive values of 86.7% and 90.0%, respectively. Both a maximum aortic diameter of 40 mm or more (P =.0011) and a maximum aortic wall thickness of 10 mm or more (P =.0009) were shown to be significantly predictive of the progression with Cox regression analysis. CONCLUSION: Maximum aortic diameter and maximum aortic wall thickness on initial CT images are predictive for progression of the affected aorta in patients with type B IMH. For type B IMH with a maximum aortic diameter of 40 mm or more or a maximum aortic wall thickness of 10 mm or more, careful follow-up studies must be required.

Aged↗
PubMed2005

Trends of caesarean sections for failure to progress: Indian rural experience.

The present observational study was carried out at a rural referral healthcare, educational institute in India. The objectives were to study the trends of contribution of caesarean section (CS) for failure-to-progress to the overall CS rate and their relationship to variables such as age, parity, stage of labour, augmentation of labour, in order to look at the trends and the scope for reduction in the CS for failure-to-progress and also the reduction in fetomaternal morbidity either by early intervention or reducing CS rates. Over 16 years, a total of 7,309 caesarean operations were performed, (contributing to 22.5% of births) and 533 (7.3%) were for failure-to-progress. The rate of CS for failure-to-progress was reduced in 2002 (5.0%), compared with 1992 (10.5%). The age of these women were similar to overall cases. A majority (346, 64.9%) of Sections for failure-to-progress were performed between 37 and 40 weeks of pregnancy, 125 (23.5%) between 41 and 42 weeks and only 62 (11.6%) were preterm. Rates of CS for failure-to-progress were 16.3% in primigravida and 8.8% in multipara, a decade ago, compared with 7.0% in primigravida and 2.8% in multipara now. Among the primigravida, 66 (18.3%) were performed in latent phase, 217 (60.3%) in the active first stage and 77 (21.4%) in the second stage of labour. Among multigravida, 35 (20.2%) were in the latent phase, 68 (39.3%) in the active first stage and 70 (40.5%) in the second stage. The authors were not always involved in the decisions to proceed to CS but probably because of the discussions before the observational study was undertaken, everyone involved with the decision making became concerned. So it seems critical evaluation of each CS before decision (keeping in mind materno-fetal well-being rather than hours), separating imminent labour from latent phase and higher doses of oxytocin should lead to a reduction in CS for failure-to-progress. Efforts need to be continued and should involve further research and evidence-based management strategies.

Cesarean Section↗
PubMed2002

Obstetric risk factors for failure to progress in the first versus the second stage of labor.

OBJECTIVE: To compare obstetric risk factors for failure of labor to progress in the first versus the second stage. STUDY DESIGN: A comparison was performed of all singleton, vertex and term deliveries with an unscarred uterus, complicated with non-progressive labor during the first and the second stages. Deliveries occurred between the years 1988 and 1999 in a tertiary university medical center. RESULTS: Patients with non-progressive labor in the first stage (n = 1197) were significantly older, of higher birth order, and were more likely to have complications such as gestational diabetes, hypertensive disorders, premature rupture of membranes, meconium-stained amniotic fluid, hydramnios and oligohydramnios (p < 0.001 for all variables) as compared to patients with non-progressive labor in the second stage (n = 1545). In addition, pregnancies complicated with non-progressive labor in the first stage had a significantly higher rate of fetal macrosomia as compared to patients with non-progressive labor in the second stage (11.6% vs. 8.8%; p < 0.001). CONCLUSIONS: Higher rates of fetal macrosomia and high-risk pregnancies were noted among pregnancies complicated with non-progressive labor during the first vs. the second stage. The significant increase in Cesarean deliveries during the first stage of labor among high-risk pregnancies might reflect exaggerated concern of caregivers. This concern may influence an overall conservative attitude leading to the seemingly simpler mode of direct intervention by Cesarean delivery.

Adolescent↗
PubMed1991

Correlation of spontaneous suppressor cell activity with progression of human immunodeficiency virus infection.

The immune system has been extensively evaluated in the acquired immunodeficiency syndrome (AIDS). The central role of the T-helper (CD4) cell in the immunopathogenesis of AIDS and the immunologic markers that can predict human immunodeficiency virus (HIV) disease progression have been described. However, the potential influence of suppressor cells in this disease process has not been clearly addressed. Spontaneous suppressor cell activity (SSCA) was evaluated in 78 patients with documented HIV infection at different clinical stages of disease progression. Higher levels of SSCA were found in patients with clinical AIDS less than 6 months and those dying of AIDS when compared with controls. Significant elevations (p less than 0.05) of SSCA were seen in patients newly diagnosed with AIDS, and those having AIDS greater than 6 months and less than one year. Patients surviving AIDS for greater than one year had depressed levels of SSCA compared to controls. Furthermore, SSCA appears to predict disease progression as patients with AIDS-related complex (ARC) with elevations in SSCA progressed to AIDS while those with blunted SSCA did not progress. The level of SSCA in these patients was able to predict disease progression (p = 0.00016, Pearson correlation coefficient = 0.739). Patients with documented AIDS were also followed prospectively, and the level of SSCA was shown to be predictive of mortality (p = 0.009, Pearson correlation coefficient = 0.746). It is concluded that SSCA is a valid predictor of disease progression, and can serve as a prognostic indicator of disease outcome.

AIDS-Related Complex↗
PubMed2004

A method to monitor replication fork progression in mammalian cells: nucleotide excision repair enhances and homologous recombination delays elongation along damaged DNA.

The capacity to rescue stalled replication forks (RFs) is important for the maintenance of cell viability and genome integrity. Here, we have developed a novel method for monitoring RF progression and the influence of DNA lesions on this process. The method is based on the principle that each RF is expected to be associated with a pair of single-stranded ends, which can be analyzed by employing strand separation in alkali. This method was applied to examine the rate of RF progression in Chinese hamster cell lines deficient in ERCC1, which is involved in nucleotide excision repair (NER), or in XRCC3, which participates in homologous recombination repair, following irradiation with ultraviolet (UV) light or exposure to benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE). The endpoints observed were cell survival, NER activity, formation of double-strand breaks and the rate of RF progression. Subsequently, we attempted to explain our observation that cells deficient in XRCC3 (irs1SF) exhibit enhanced sensitivity to UV radiation and BPDE. irs1SF cells demonstrated a capacity for NER that was comparable with wild-type AA8 cells, but the rate of RF progression was even higher than that for the wild-type AA8 cells. As expected, cells deficient in ERCC1 (UV4) showed no NER activity and were hypersensitive to both UV radiation and BPDE. The observation that cells deficient in NER displayed a pronounced delay in RF progression indicates that NER plays an important role in maintaining fork progression along damaged DNA. The elevated rate of RF progression in XRCC3-deficient cells indicates that this protein is involved in a time-consuming process which resolves stalled RFs.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1993

Dietary micronutrient intake and risk of progression to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus type 1 (HIV-1)-infected homosexual men.

The authors sought to determine if different levels of dietary intake of micronutrients are associated with the progression of human immunodeficiency virus type 1 (HIV-1) infection to acquired immunodeficiency syndrome (AIDS). A total of 281 HIV-1 seropositive homosexual/bisexual men were seen semiannually since 1984 at the Baltimore/Washington, DC site of the Multicenter AIDS Cohort Study. Participants completed a self-administered semiquantitative food frequency questionnaire at baseline. Levels of daily micronutrient intake at baseline were examined in relation to subsequent progression to AIDS (1987 Centers for Disease Control definition; n = 108) during a median follow-up period of 6.8 years. For each nutrient, the authors used a Cox proportional hazards model to adjust for age, presence of symptoms, CD4+ lymphocyte count, energy intake, use of antiretrovirals, and use of Pneumocystis carinii pneumonia prophylaxis. The highest levels of total intake (from food and supplements) of vitamins C and B1 and niacin were associated with a significantly decreased progression rate to AIDS: vitamin C (relative hazard (RH) = 0.55, 95% confidence interval (CI) 0.34-0.91), vitamin B1 (RH = 0.60, 95% CI 0.36-0.98), and niacin (RH = 0.52, 95% CI 0.31-0.86). The relation between total vitamin A intake and progression to AIDS appeared to be U-shaped; the lowest and highest quartiles of intake did most poorly, while the middle two quartiles were associated with significantly slower progression to AIDS (RH = 0.55, 95% CI 0.35-0.88). Increased intake of zinc was monotonically and significantly associated with an increased risk of progression to AIDS (for highest vs. lowest quartiles, RH = 2.06, 95% CI 1.16-3.64). In a final multinutrient model, vitamin A, niacin, and zinc remained significantly associated with progression to AIDS, while vitamin C was only marginally significant.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Prediction of the progression of cardiac hypertrophy in middle-aged mild hypertensives.

To investigate the predictive value of exercise tests and diastolic function measurements for the progression of left ventricular hypertrophy, symptom-limited treadmill stress testing and echocardiography were performed before and after a follow-up period of 3.5 years in 47 mild hypertensive men aged 42 +/- 2 years. The men were classified into three groups by the progression of the left ventricular mass index (%LVMI) during the observation, i.e. (LVMI after follow-up) - (LVMI before follow-up)/(LVMI before follow-up). The high-progression group (n = 13) had a %LVMI exceeding mean +/- 2/3s.d. of all subjects; the low-progression group (n = 21) had a %LVMI within mean +/- 2/3s.d. and the non-progression group (n = 13) had a %LVMI less than mean -2/3s.d. At the beginning of the observation, age, blood pressure at rest, LVMI, ejection fraction, mean velocity of circumferential fibre shortening, peak shortening rate and systolic time intervals (ET/PEP, ratio of ejection time to pre-ejection period) were similar among the three groups. However, the high-progression group showed a higher systolic pressure at peak exercise, a lower peak filling rate and a longer time to peak filling rate (TPFR) as corrected by the R-R interval of the ECG. These data suggest that systolic pressure at peak exercise and echocardiographically assessed diastolic function are useful in predicting the progression of cardiac involvement in mild hypertension.

Adult↗
PubMed1991

Progression of spondylolisthesis in children and adolescents. A long-term follow-up of 272 patients.

The radiologic progression of spondylolisthesis during a long-term follow-up was studied in 272 children and adolescents. There were 134 girls and 138 boys. The mean age at the first visit was 14.3 years (girls, 13.8 years; boys, 14.9 years). The radiologic follow-up time was 14.8 years on average (range, 5-32). The operation was done in 190 patients younger than 20 years of age. Fusion in situ, using a posterior or posterolateral technique, had no statistically significant effect on progression. Surgically treated patients did not differ from conservatively treated patients. Ninety percent of the slip, on average, had already occurred at the first radiologic examination compared with the final amount of slip. More than 10% progression occurred in 62 patients, mainly within the first year postoperatively or after the first examination. Progression of the lumbosacral kyphosis and sinking of the vertebral body was noted in severe slips. Although female gender and dysplasia (spina bifida) at the lumbosacral junction were more frequent in severe slips, they statistically had no value in predicting progression. A wedge form of L5 or sacral rounding also had no prognostic value. These were secondary to the slip and expressed it but did not predict it. The only radiologic variable with predictive value of progression was the percentage amount of the primary slip. In age groups corresponding to the growth spurt in early puberty (girls, 9-12 years; boys, 11-14 years), there was a tendency to progress.

Adolescent↗
PubMed2001

Prediction of progression of spinal deformity in Duchenne muscular dystrophy: a preliminary report.

STUDY DESIGN: Discriminatory power was statistically estimated for multiple combinations of risk indicators for the progression of spinal deformity in Duchenne muscular dystrophy (DMD). OBJECTIVE: To differentiate DMD cases in which spinal deformity will rapidly and severely progress from those with lesser progression of spinal deformity. SUMMARY OF BACKGROUND DATA: Early surgical intervention using instrumentation has recently been advocated for DMD patients to prevent the progression of spinal deformity. However, early determination of cases needing surgical intervention is difficult because of variations in the severity of the clinical courses of DMD patients. METHODS: Charts and spinal radiographs of 12 DMD patients were reviewed retrospectively. Patterns of progression in spinal deformity were classified into three types according to Oda's classification. Discriminant analysis was conducted to categorize the patients into either a severe progression group (type-1 and type-2 patients) or a less severe progression group (type-3 patients and patients without spinal deformity) on the basis of four predictors: 1) vital capacity at the age of 10 years, 2) the age at which ambulation ceased, 3) curve pattern of spinal scoliosis, and 4) Cobb angles of spinal scoliosis at the age of 10 years. RESULTS: Eleven of the twelve DMD patients showed spinal deformity. Three were classified as type 1, six were classified as type 2, and two were classified as type 3. The remaining patient showed no spinal deformity. Multiple discriminant analysis correctly predicted the severity of the clinical course of 91.7% of the DMD patients. Vital capacity at age 10 was found to be the strongest predictor among the variables. CONCLUSIONS: Through multiple discriminant analysis, the clinical course of spinal deformity in DMD patients was correctly predicted in 92% of subjects. This method would be useful to determine early which DMD cases need surgical intervention for treatment of spinal deformity.

Child↗
PubMed1991

The progression of mild acute cardiac rejection evaluated by risk factor analysis. The impact of maintenance steroids and serum creatinine.

The natural course of mild acute cardiac allograft rejection (MAR) under cyclosporine-based therapy is generally considered benign, and usually antirejection therapy is not instituted. The present study was undertaken to determine the frequency of and the risk factors for progression of MAR into a clinically significant (moderate or severe) rejection on subsequent endomyocardial biopsy (EMB). Among 167 cardiac recipients, transplanted from 3/1984 to 4/1990, MAR under cyclosporine-based therapy was diagnosed on 220 EMBs. Depending upon the outcome on the subsequent EMB, MAR was categorized as progressive or nonprogressive. This served as the dependent variable for a stepwise logistic regression analysis evaluating 11 covariates as potential risk factors: perioperative antibody prophylaxis (ATG vs. OKT3), maintenance therapy, underlying disease, HLA-mismatches for A- and B + DR-loci, serum creatinine (mg/dl) and cyclosporine HPLC blood level (ng/ml) at diagnosis of MAR and at subsequent biopsy, recipient age, donor age. 40 (18.2%) of 220 MARs became progressive as opposed to 37 (7.3%) of a control cohort of 507 negative EMBs (P less than 0.0001). Stepwise logistic regression yielded the type of maintenance therapy (P = 0.0019) and serum creatinine level at diagnosis of MAR (P = 0.0615) as independent predictors of progression of MAR. After adjustment for influence of maintenance therapy and serum creatinine none of the cyclosporine variables provided any additional information. MARs without maintenance steroids and low serum creatinine levels had the highest risk (37.2% observed incidence) to develop moderate or severe rejection on subsequent EMB. This analysis supports evidence that diagnosis of MAR on EMB is associated with a considerable high progression rate into clinically significant rejection when compared to negative EMBs. Progression particularly occurs in MAR under steroid-free maintenance therapy and suggests early augmentation of immunosuppression. In terms of progression of MAR serum creatinine values, obviously indicating cyclosporine nephrotoxicity, appear to reflect the extent of cyclosporine-mediated immunosuppressive activity more properly than parameters of its bioavailability by measuring cyclosporine HPLC blood levels.

Adrenal Cortex Hormones↗
PubMed2005

Determinants of the effect of estrogen on the progression of subclinical atherosclerosis: Estrogen in the Prevention of Atherosclerosis Trial.

OBJECTIVE: To determine the extent to which the estrogen-induced changes in lipids and markers of carbohydrate metabolism explain the beneficial effect of estrogen therapy on the progression of carotid artery intima-media thickness (IMT) in postmenopausal women. DESIGN: A randomized, double-blind, placebo-controlled, single-center trial enrolling 222 postmenopausal women 45 years and older without cardiovascular disease and with low-density lipoprotein (LDL) cholesterol levels of 3.37 mmol/L or greater (> or = 130 mg/dL). Intervention was unopposed micronized 17beta-estradiol versus placebo. Measurements were made using high-resolution B-mode ultrasonography to measure carotid artery IMT at baseline and every 6 months on-trial. RESULTS: Progression of carotid IMT was inversely related to on-trial high-density lipoprotein (HDL) cholesterol (P = 0.04) and was directly related to on-trial LDL-cholesterol (P = 0.005). Compared with placebo, women randomized to estradiol showed a higher mean on-trial HDL-cholesterol level and a lower mean on-trial LDL-cholesterol level. In contrast, fasting glucose, insulin, and hemoglobin A1C were lowered and insulin sensitivity increased with estradiol therapy, but the changes were not related to carotid IMT progression. On-trial HDL-cholesterol and LDL-cholesterol were significant independent determinants of carotid IMT progression, jointly explaining 30% of the treatment effect of unopposed estrogen on the progression of carotid IMT. CONCLUSION: Unopposed 17beta-estradiol reduced carotid IMT progression in postmenopausal women in part by increasing HDL-cholesterol and decreasing LDL-cholesterol. Although women randomized to estradiol showed improvement in all the markers of carbohydrate metabolism, these factors did not play a significant role in carotid IMT progression.

Arteriosclerosis↗
PubMed2000

The rate of progression to AIDS is independent of virus dose in simian immunodeficiency virus-infected macaques.

Of the viral factors that are proposed to influence the rate of progression to AIDS, the role of infectious dose remains unresolved. Intravenous infection of outbred Macaca mulatta with various doses of simian immunodeficiency virus isolate 8980 (SIV(8980)) revealed an endpoint from which an infectious dose 50 (ID(50)) was defined. In the six infected animals, the time to develop AIDS was variable with a spectrum of rapid, intermediate and slow progressors. High and sustained plasma viraemia with marked loss of CD4(+) T-cells was a distinguishing feature between rapid versus intermediate and slow progressors. Animals that received the highest doses did not develop the highest sustained viral loads, nor did they progress more rapidly to disease. Similarly, animals infected with lower doses did not uniformly develop lower viral loads or progress more slowly to AIDS. Furthermore, compiled data from more than 21 animals infected with different doses of the same virus administered by the same route failed to reveal any correlation of infectious dose with survival. Indeed, host factors of these outbred animals, rather than dose of the initial inoculum, were probably an important factor influencing the rate of disease progression in each individual animal. Comparison of animals infected with SIV(B670), from which SIV(8980) was derived, revealed marked differences in disease progression. Clearly, although dose did not influence viral loads nor disease progression, the virulence of the initial inoculum was a major determinant of the rate of progression to AIDS.

Animals↗
PubMedDate not supplied

Effects of thiols on topoisomerase-II alpha activity and cell cycle progression.

Thiol containing compounds exhibiting antioxidant properties are currently being evaluated for use in cytoprotection and chemoprevention. Many of these have also been found to be effective in inhibiting cell cycle progression and cellular proliferation. N-Acetyl-L-cysteine (L-NAC), along with its nonmetabolically active stereoisomer N-acetyl-D-cysteine (D-NAC), together with captopril and dithiothreitol (DTT) were investigated to assess their effects on cell cycle progression as determined by flow cytometry. Topoisomerase-IIa (topo-II alpha) activity, an enzyme involved in DNA synthesis, was also monitored as a function of drug dose using a kinetoplast DNA (kDNA) decatenation assay. Chinese hamster ovary (CHO) AA8 cells were exposed to each thiol at concentrations ranging from 4 microM to 4 mM for a period of 3 h. Following the removal of the thiols, cell cultures were followed for an additional 5 h to assess changes in cell cycle progression. L-NAC, which also serves as a precursor for glutathione (GSH) synthesis, effectively inhibited topo-IIa activity by at least 50% at all concentrations tested. Associated with this reduction in enzyme activity was a sixfold increase in the relative number of cells accumulating in G2phase. D-NAC, which is unable to participate in GSH synthesis, was only half as effective as L-NAC at each concentration tested in inhibiting topo-IIa activity as well as perturbing cell progression through G2. In comparison, captopril, an inhibitor of angiotensin converting enzyme (ACE), had little effect on the progression of cells into G2 phase. In contrast to the repressive effects of L-NAC and D-NAC, it enhanced topo-IIa activity over control values by approximately 20%. DTT, a well characterized thiol known to be capable of reducing disulphides in proteins, was observed to be relatively ineffective in either perturbing cell cycle progression or affecting topo-IIa activity. This suggests an involvement of a mechanism(s) in addition to thiol mediated affects on reduction/oxidation processes. The inhibitory effects of L-NAC and D-NAC on topo-IIa activity, in contrast to the other two thiols, may be due in part to the presence of amine groups which could allow for their participation in polyamine related processes. The difference in the magnitude of the effect exhibited by L-NAC, as compared to D-NAC, on the repression topo-IIa activity also suggests a role for GSH in this process. Inhibition of cellular progression and proliferation by thiols can therefore be mediated by diverse mechanisms which include both cycle-phase specific (i.e. L-NAC and D-NAC) and non cell cycle specific (i.e. captopril) processes.

Acetylcysteine↗
PubMedDate not supplied

Progression of radiological changes in relapsing and chronic pancreatitis.

Progression of radiological changes was noted in 19 (22.1%) of 86 cases of relapsing or chronic pancreatitis followed by serial pancreatograms. The initial feature of chronic pancreatitis was focal minimal pancreatitis, characterized by an irregular dilatation of several side branches on the pancreatogram. Some patients with focal minimal pancreatitis demonstrated progression of the extent and severity of changes only in side branches while others progressed further to moderate or advanced chronic pancreatitis showing changes in the main pancreatic duct. Most of the progressive cases were alcoholic, and some showed progression to advanced pancreatitis within 4 years. Rapid progression of radiological changes was associated with relapses of acute pancreatitis. No remarkable changes were observed in many non-alcoholic patients, whereas some cases complicated with gallstones showed progression of disease in the side branches during a follow-up period of 3-7 years.

Aged↗