Lesions In Target Organs Research Articles

Evaluation of Neospora caninum and Toxoplasma gondii infections in alpaca ( Vicugna pacos) and llama ( Lama glama) aborted foetuses from Peru

The aim of this study was to investigate the participation of Neospora caninum and Toxoplasma gondii in abortion cases of Peruvian llamas and alpacas. Fifteen aborted foetuses were recovered from two main rearing areas of camelids in Peru (Central or South Andean region). Foetal histopathology was used to detect the presence of protozoal-associated lesions in target organs. N. caninum and T. gondii infections were confirmed by immunohistochemistry (IHC) combined with PCR and by PCR alone, respectively. The influence of the species (llama and alpaca), foetal age (first, second and third gestational periods) and geographical location (Central or South Andean region) of the foetuses was also studied. Thirteen of the samples (26%, 13/50) showed lesions suggestive of protozoal infection. N. caninum infection was detected by either IHC or specific PCR in 14 out of 50 foetuses (28%), of which 8 also showed protozoal-associated lesions. T. gondii DNA was not detected in any of the foetuses analysed. Protozoal infection was more frequent in the foetuses from the second gestational period ( P < 0.05, Fisher F-test). No significant association was observed between protozoal infection and species or geographical location ( P > 0.05, χ 2 test). The results of the present study indicate that neosporosis should be included during the differential diagnosis of abortion in llamas and alpacas.

Neutrophil Function in Severe Sepsis

Sepsis and septic shock continue to be a major cause of morbidity and mortality in critically ill patients. During the onset of sepsis, several inflammatory mediators, including cytokines, chemokines and nitric oxide are released systemically and mediate most of the pathophysiological events present in sepsis and septic shock, such as cardiovascular dysfunction and target-organ lesions. Polymorphonuclear leukocytes are critical effector cells during the inflammatory process and their migration to the infection focus is extremely important for the local control of bacterial growth and consequently for the prevention of bacterial dissemination. In experimental models and in human sepsis a profound failure of neutrophil migration to the infection focus is observed. It seems that the failure of neutrophil migration is dependent on toll-like receptor 4 (TLR4) and mediated by cytokines and chemokines, which induce the production of nitric oxide that inhibits neutrophil adhesion to venular endothelium and also the neutrophil chemotactic ability.

Diferencias en variables representativas de enfermedad o repercusión cardiovascular entre sujetos de alto riesgo cardiovascular con y sin antecedentes familiares de eventos cardiovasculares precoces

INTRODUCTION, BASES AND AIMS: Study the possible associations between any family history of early heart disease and variables expressive of heart disease, lesion or repercussion in subjects of high cardiovascular risk. Nationwide cross-sectional study with 2264 consecutive patients in the Outpatient Clinic of Internal Medicine 18 years of age or older and with high or extremely high cardiovascular risk taken from the CIFARC (Integral Control of High Risk Cardiovascular Factors) study run by the SEMI (Spanish Internal Medicine Association) cardiovascular Risk Group. We have studied the relationship between the presence or lack of same in family histories of early heart disease (AFP-Family History of early heart disease, hereafter FH) and different variables in the factors concerning cardiovascular risk and target organ lesion. The statistical treatment (Chi-2, ANOVA and Pearson s linear regression) was performed using the STATISTIX programme. We observed a significative increase (p<0.05) in the group with FH with a percentage of the following variables: Total cholesterol>250 mg/dl, HDL<40 mg/dl, LDL>130 mg/dl, LVH (left ventricular hypertrophy), creatinine 1.2-2mg/dl, retinopathy I-II, serious retinopathy, smoking, proteinuria>300 mg/dl, kidney insufficiency and peripheral vascular disease. This significative increase in the variables under study appeared in males of over 55 years of age and in females of over 65 years of age; nevertheless, this increase in the incidence rate is becoming more common as of age 50 in males, with a maximum in both sexes after the age of 70. No significative differences were noted with regard to sex, BMI (Body Mass Index), atheromatosis, ischemic cardiopathy and cerebrovascular disease. On the whole, subjects of both sexes of the FH group have come to the clinic 3 years earlier than those of the group without FH. Patients with FH show a greater incidence of certain factors concerning heart risk and target organ lesion.

Is 44-Hour Better than 24-Hour Ambulatory Blood Pressure Monitoring in Hemodialysis?

The aim of this study is to evaluate if hemodialysis (HD) patients with similar blood pressure (BP) in the whole inter-HD period could have different target organ lesions and survival if the behavior of BP differs from the first to the second day of the inter-HD period. The present study compares 44-hour ambulatory BP monitoring (ABPM) patterns in 45 HD patients. Three BP patterns emerged: group A (n = 15) had similar BPs throughout (138 ± 11/88 ± 12 in the first 22 h vs. 140 ± 11/87 ± 12 mm Hg in the second 22-hour period); group B (n = 15) had a significant systolic BP rise from the first to the second period (132 ± 15/80 ± 12 vs. 147 ± 12/86 ± 13 mm Hg, p < 0.05); group C (n = 15) had significantly higher BPs (p < 0.05) than the other 2 groups throughout the whole inter-HD period, with no significant change between the 2 halves (172 ± 14/108 ± 12 vs. 173 ± 18/109 ± 14 mm Hg). Ventricular mass and survival during the 30-month follow-up period were statistically significantly better in group A, intermediate in group B and worse in group C. The data suggest that a 44-hour ABPM is more accurate than a 24-hour one in evaluating organ lesion and prognosis in HD patients.

Influence of target organ lesion detection (assessment of microalbuminuria and echocardiogram) in cardiovascular risk stratification and treatment of untreated hypertensive patients

European guidelines indicate the importance of the evaluation of global cardiovascular risk (CVR) to determine the management of the hypertensive patients (EH). However, in primary care, the diagnostic work-up (PCD) only includes the metabolic risk factors. The aim of this study was to assess the importance of microalbuminuria (MA) and echocardiogram (ECHO) in the process of risk stratification, and the number of patients to be treated with drugs at diagnosis. In total, 155 nontreated EH were included in the study. Blood pressure, a lipid profile and plasma glucose (LG) were determined after an overnight fast. MA was evaluated with dipstick MICRALTEST, and in those patients with two positive results, it was measured again in two 24-h urine samples and was considered positive (MA+) if the average was >30 mg/24 h. Left ventricular mass index was calculated and values>125 g/m2 were considered as LV hypertrophy (LVH+). When the patients were stratified according to PCD, 22 had to be treated with drugs. When MA, ECHO and both tests used together were added to the risk evaluation, the number of patients to be treated were 42, 51 and 64, respectively (P<0.001 vs PCD). It is mainly in patients who have moderate cardiovascular risk that risk changes, whereas risk hardly changes in those having low and very high risk. In conclusion, in EH with moderate risk, measurement of MA, due to its easy availability and low cost, seems to be a cost effective screening test to avoid the underestimation of the CVR.

Utilidad de indapamida retard en el tratamiento de la hipertensión arterial en población anciana de riesgo. Estudio RETARD

Introduction It is estimated that more than 65% of the elderly population in Spain is hypertensive. This study aimed to evaluate the safety and efficacy of extended release indapamide in hypertensive patients over 60 years of age, having high cardiovascular risk and the factors that influence this effect. Material and methods Prospective study made in 944 patients with essential HBP and age > 60 years (55.9% women) in whom treatment with extended release indapamide in single drug therapy or in combination was indicated, whether as a new drug or due to lack of efficacy of the previous therapy. The action scope was hospital out-patient clinics of Internal Medicine and follow-up time of the patients was 6 months. Results Extended release indapamide causes a significant decrease (p < 0.05) of systolic blood pressure (SBP) (21.3 mmHg) and diastolic blood pressure (DBP) (10.8 mmHg). No significant differences were found between the results in monotherapy or combined therapy. A total of 52.7% of the patients included had 3 or more cardiovascular risk factors (RF) or had target organ lesion (TOL) and 41.1% had an associated cardiovascular disease (CVD). Those patients with greater baseline SBP and DBP were those having a greater decrease in BP. On the other hand, patients with 1 or 2 RF showed a greater decrease of the SBP in comparison with patients with 3 or more RF, TOL or associated CVD. The adverse reactions rate was 2.8%. Conclusions Extended release indapamide is an effective drug in the elderly population having high cardiovascular risk and is well tolerated.

The Role of p53 and Fas in a Model of Acute Murine Graft-versus-Host Disease

Graft-vs-host disease (GVHD) is a devastating, frequently fatal, pathological condition associated with lesions in specific target organs, including the intestine, liver, lung, and skin, as well as pancytopenia and alopecia. Bone marrow (BM) atrophy is observed in acutely diseased animals, but the underlying mechanisms of hemopoietic stem cell depletion remained to be established. We used an experimental mouse model of acute GVHD in which parental cells were injected into F(1) hosts preconditioned by sublethal irradiation. The resulting graft-vs-host response was kinetically consistent, resulting in lethality within 3 wk. We observed disease pathology in the liver and small intestine, and consistent with previous observations, we found BM atrophy to be a factor in the onset of acute disease. The product of the protooncogene, p53, is known to be a key player in many physiological examples of apoptosis. We investigated the role of p53 in the apoptosis of BM cells (BMC) during the development of acute disease and found that at least one copy of the p53 gene is necessary for depletion of BM and subsequent lethality in host animals. BM depletion was preceded by induction of the death receptor, Fas, on the surface of host stem cells, and induction of Fas was coincidental with the sensitization of BMC to Fas-mediated apoptosis. Our data indicate that BM depletion in acute GVHD is mediated by p53-dependent up-regulation of Fas on BMC, which leads to Fas-dependent depletion and subsequent disease.

Complicações da hipertensão arterial em homens e mulheres atendidos em um ambulatório de referência

To assess the association between sex and left ventricular hypertrophy, stroke, and renal failure in hypertensive patients in a referral outpatient care unit. This study assessed 622 hypertensive patients diagnosed with left ventricular hypertrophy based on electrocardiography, renal failure based on serum creatinine level > or = 1.4 mg/dL, and stroke based on a previous history and physical examination. Logistic regression was used to estimate the odds ratio of the association between sex and target-organ lesions in hypertension adjusted for race, age, and duration of the disease. The mean age of the patients was 48.4 +/- 13.8 years; 74.1% were women, and 84.9% were mulattos or blacks. Almost half of the men and more than 40% of the women had had at least 1 definite event involving a target-organ lesion. The incidence of renal failure was greater among men [adjusted OR (ORa) = 2.73, P= 0.002]. In white patients, the incidence of stroke was significantly (P= 0.017) greater among men (4/33) than among women (0/56), and, in the age group > or = 49 years, the prevalence of left ventricular hypertrophy was significantly greater among men (ORa = 1.99, P= 0.024). The data obtained suggest a greater prevalence of renal failure in men than in women, of stroke in white men than in white women, and of left ventricular hypertrophy in men than in women aged 49 years and above.

Hypertensive crisis profile. Prevalence and clinical presentation.

To assess the prevalence of hypertensive crisis, related clinical findings, and the organic lesions involved. This retrospective study comprised the analysis of the medical records of symptomatic patients with an elevation in diastolic blood pressure levels > or = 120 mmHg, who sought the emergency unit of a university-affiliated hospital over 12 months. Hypertensive urgency was characterized as the symptomatic elevation of blood pressure levels with no evidence of target-organ lesions, and hypertensive emergency was characterized as the symptomatic elevation of blood pressure levels with evidence of acute or ongoing target-organ lesion. This study comprised 452 patients with hypertensive crisis, accounting for 0.5% of all clinicosurgical emergencies, of which, 273 (60.4%) were hypertensive urgencies and 179 (39.6%) were hypertensive emergencies. Eighteen percent of the patients ignored their hypertensive condition. Smoking and diabetes were risk factors associated with the development of a hypertensive crisis in 1/4 and 1/5 of the patients, respectively. The patients with a hypertensive emergency were older (59.6+/-14.8 versus 49.9+/-18.6 years, p < 0.001) and had greater diastolic blood pressure (129.1+/-12 versus 126.6+/-14.4 mmHg, p < 0.05) than those with hypertensive urgencies. Ischemic stroke and acute pulmonary edema were the most common hypertensive emergencies, being in accordance with the most frequently found clinical manifestations of neurologic deficit and dyspnea. Hypertensive crises accounted for 0.5% of all emergency cases studied and for 1.7% of all clinical emergencies, hypertensive urgency being more common than hypertensive emergency. Ischemic stroke and acute pulmonary edema were the most frequent target-organ lesions in hypertensive emergencies.

Relationship between morning rise blood pressure and arterial distensibility in type ii diabetic and non diabetic hypertensive patients

P-265 Key Words: Morning Surge, Arterial Distensibility, Target Organ Lesion

24-hour blood pressure monitoring in clinical practice: do we overestimate its value?

Ambulatory 24-hour blood pressure (BP) monitoring (24-h BPM) occupies its right place as one of the greatest advances in cardiology. By paying a well-deserved tribute to the evident advantages of this technique, is the question of whether this expensive labor-intensive method that is burdensome for a patient and provides very much information is optimally used in clinical practice and whether we always consider the findings critically rightful? Many cross-sectional and longitudinal studies have demonstrated that ambulatory BP is closer correlated with target organ lesions than clinical BP and it is of greater prognostic value for the development of cardiovascular complications. By interpreting the data of these studies, it should be remembered that while on the subject of clinical BP, we mean the mean value of less than 10 measurements of BP over a short period of time while 24-h BPM provides information on several tens of BP measurements. There is evidence for the fact that only patients with a good reproducibility of 24-h BPM exhibit a closer correlation of the latter with lesion to target organs than that with clinical BP. Most patients with arterial hypertension may be followed up with repeated clinical measurements of BP or its self-control. But 24-h BPM is the method of choice in assessing patients with wide variations in clinical and domestic BP, the symptoms of hypotension, sporadic hypertension, unexplained target organ lesions. 24-h BPM preserves its leading role in evaluating the antihypertensive efficacy of novel drugs under the conditions of clinical studies.

Efecto del tratamiento antihipertensivo con irbesartán sobre el riesgo cardiovascular absoluto

Blockade of the renin-angiotensin system with angiotensin converting enzyme inhibitors or with angiotensin receptor antagonists confers patients with arterial hypertension (AH) and associated risk factors, target organ lesion or cardiovascular disease with greater protection in morbidity and mortality terms. The objective of the present study was to evaluate the effect of irbesartan, an angiotensin II receptor antagonist, on the absolute cardiovascular risk in a cohort of hypertensive patients with moderate, high, or very high cardiovascular risk. This was a multicenter, prospective, observational, cohort study with 1974 patients (63 11 years; 47% males) with newly diagnosed essential AH or AH non-controlled with anti-hypertensive monotherapy, and moderate to very high cardiovascular risk. Irbesartan therapy at a dosage of 150300 mg was instituted as monotherapy or associated with hydrochlorothiazide, 12.5 mg. The clinical follow-up was 6 months. The evaluated parameters included the absolute cardiovascular risk, measured either quantitatively (Framingham algorithm) or qualitatively (low, moderate, high, and very high risk groups following the WHO/International Hypertension Society guidelines). Irbesartan therapy led to a significant (p = 0.0001) decrease in SBP (from 170.9 18.4 to 138.5 16.5 mmHg) and DBP (from 96.6 11 to 82 9 mmHg). The quantitative absolute cardiovascular risk decreased by 29.8% (from 12.14 8 to 8.65 6.2; p < 0.0001). The percentage of patients with very high cardiovascular risk decreased from 1.52% to 0.51% and that for patients with high cardiovascular risk from 92.77% to 88.32%. The latter patients changed to the moderate risk group. As a result, this moderate risk group increased from 5.71% to 11.17%. The adverse reaction rate was very low as only 2.2% of patients had some adverse reaction. In conclusion, irbesartan as monotherapy or associated with hydrochlorothiazide has been shown to be effective in reducing the absolute cardiovascular risk, which is obtained by a substantial decrease in arterial pressure and a good safety profile on the biochemical parameters. Tolerability was excellent, with a very low rate of adverse reactions.

Transforming factor-bl and markers of leukocytic activation in hypertensive disease

The study was undertaken to determine the serum concentration of an active form of transforming growth factor-bl (TGF-bl) and the functional status of leukocytes in patients with Stage II hypertensive disease (HD) and to assess the pathogenetic value and capacities of correction of detected changes with the angiotensin-converting enzyme (ACE) inhibitor quinapril. Materials and methods. Thirty patients with Stage II HD and 17 apparently healthy individuals were examined. The data of ultrasound studyofthe heart, radial and carotid arteries, the functional activity of leukocytes and the concentration of (TGF-bl) in the serum were assessed. Of them, 15 patients with HD were reexamined during treatment with quinapril (accupro, Pfizer, USA) in a daily dose of 10-40 mg for 12 weeks. Results. The study established an increase in the elevated serum levels of TGF-bl of hypertensive patients with HD and its association with the mass of the left ventricular myocardium, with the thickness of an intima-media complex of the common carotid arteries, and with endothelial dysfunction. A relationship is shown between the concentration of TGF-bl and the functional activity of leukocytes: elevated peripheral leukocytes, the adhesive capacity of neutrophils, the lymphocytic expression of the antiapoptic protein Bcl-2 and Fas-receptors. With quinapril treatment, a 10-mm Hg or more reduction in 87% of the patients was attended by the lower adhesion of neutrophils to the endothelium, with elevated Bcl-2-negative and Fas-positive lymphocytes. Conclusion. The changes in the serum levels of TGF-bl are associated with lesions of target organs and with the activation of leukocytes in HD. The decrease in leukocytic functional activity during therapy with quinapril did not depend on the antihypertensive effect of the drug.

New DNA-based biomarkers for oxidative stress and cancer chemoprevention studies

Etheno (ε) modified DNA bases (εdA, εdC, εdG) are generated from the carcinogens vinyl chloride and urethane, but also by reactions of DNA with products derived from lipid peroxidation (LPO) and oxidative stress via endogenous pathways. Recently developed ultrasensitive methods allowed the detection of these ε-adducts in vivo and their role to be studied in experimental and human carcinogenesis. Highly variable background levels of ε-adducts were detected in DNA from different organs of unexposed humans and rodents. Several known cancer risk factors increased the level of these DNA lesions in target organs: elevated ε-adducts were found in hepatic DNA from patients with metal storage diseases, after overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in a mouse model, and in colonic polyps of familial adenomatous polyposis patients. A high ω-6-polyunsaturated fatty acid diet increased ε-DNA adducts in white blood cells of female subjects. In conclusion, ε-adducts were found to be elevated in cancer-prone tissues, suggesting that these promutagenic lesions could drive cells to malignancy. Therefore, exocyclic DNA adducts offer new tools in cancer aetiological research and in verifying the efficacy of chemopreventive agents.

Organ-dependent modifying effects of oltipraz on N-nitrosobis(2-oxopropyl)amine (BOP)-initiation of tumorigenesis in hamsters

5-(2-Pyrazinyl)-4-methyl-1,2-dithiole-thione (oltipraz), a substituted 1,2-dithiole-3-thione, is known to inhibit tumorigenesis induced by variety of carcinogens in several animal model systems. In the present experiment, the modifying effects of dietary oltipraz, given during N-nitrosobis(2-oxopropyl)amine (BOP) initiation of carcinogenesis, were investigated in Syrian hamsters. A total of 120 six-week-old females were divided into six groups. Groups 1–3 (30 animals each) were thrice given subcutaneous injections of BOP (10 mg/kg, body weight) at 1 week intervals and fed diets supplemented with 400 or 200 ppm of oltipraz or basal diet alone, starting 1 week prior and finishing 1 week after the carcinogen exposure. Groups 4–6 (10 animals each) were similarly treated without application of BOP. At the end of the 52nd experimental week, all surviving animals were autopsied and examined histopathologically for proliferative lesions of the major target organs for BOP tumorigenicity, including pancreas, liver, kidney, and lung. The incidences and multiplicity of adenocarcinomas of the pancreas were higher in groups 1 and 2 than in group 3 although without statistical significance. The incidence of pancreatic duct dysplasias was significantly ( P<0.05) increased in group 2 (62.0%) but not in group 1 (50.0%) as compared with group 3 (46.6%). While the incidences of alveolar adenomas and carcinomas were significantly ( P<0.05) decreased by the high dose, the multiplicities of hepatocellular adenomas, cholagiocellular carcinomas and gall bladder adenomas were elevated in the BOP/oltipraz groups ( P<0.05). The results of the present study suggest that oltipraz exerts organ-dependent modifying effects on BOP-induced carcinogenesis in hamsters when given in the initiation stage.

Pathological features of spontaneous and induced tumors in transgenic mice carrying a human prototype c-Ha-ras gene used for six-month carcinogenicity studies.

To validate the transgenic (Tg) mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for short or medium-term carcinogenicity testing, 6-mo carcinogenicity studies using more than 30 chemicals, including carcinogens and noncarcinogens, have been performed. The results obtained so far indicate that rasH2 mice are generally much more susceptible to both mutagenic and nonmutagenic carcinogens than are non-Tg mice, pointing to advantageous application for detection of carcinogenic potential. In this review, histopathological features and diagnostic criteria for spontaneous and induced-tumors observed in our 6-mo carcinogenicity studies are described. Incidences of spontaneous tumors were generally low in rasH2 mice during the 6-mo studies, although values for lung adenomas and splenic hemangiosarcomas were higher than those in the control non-Tg mice. A few forestomach papillomas and skin papillomas were also observed in the control rasH2 mice. The target organs in rasH2 mice treated with known carcinogens were not always identical to those in the treated B6C3F1 mice in 2-yr carcinogenicity bioassays, with forestomach squamous cell tumors, lung alveolar epithelial tumors and/or hemangiosarcomas in the spleen observed in addition to some but not all of the lesions in target organs observed in non-Tg mice in long-term carcinogenicity bioassays. The results of the present histological study suggest that the lung, spleen and/or forestomach, where tumors are induced in rasH2 mice treated with known carcinogens, should be regarded as informative target organs in addition to the target organs reported in previous long-term carcinogenicity bioassays in rats and mice.

Borrelia burgdorferi activates nuclear factor-kappa B and is a potent inducer of chemokine and adhesion molecule gene expression in endothelial cells and fibroblasts.

Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, is a systemic infection with preponderance for the skin, joints, heart, and nervous system. Inflammatory lesions of target organs are characterized by the presence of spirochetes and inflammatory leukocytes. We have analyzed the potential of B. burgdorferi to induce gene expression of chemokines and adhesion molecules in human endothelial cells, keratinocytes, and fibroblasts. We find induction of the chemokines RANTES (regulated upon activation, normal T cells expressed and secreted), monocyte chemoattractant protein-1, IL-8, gro-alpha, IFN-inducible protein-10, and mig (monokine induced by gamma-IFN), and of the adhesion molecules E-selectin, ICAM-1, and VCAM-1 in endothelial cells and induction of the same chemokines and ICAM-1 in fibroblasts. This is mediated by the lipid moiety of the outer surface lipoprotein A. Induction of chemokine and adhesion molecule genes by B. burgdorferi occurs rapidly and does not require new protein synthesis. Induction is blocked by inhibitors of nuclear factor (NF)-kappa B. We also find that B. burgdorferi induces nuclear translocation of NF-kappa B and a transient increase in the expression of its inhibitor I kappa B-alpha. These findings indicate that B. burgdorferi is a potent inducer of molecules required for leukocyte recruitment to inflammatory foci, and the data suggest that this biologic activity is due to the ability of the spirochetes to activate the pleiotropic transcription factor NF-kappa B.

Role of T cells in the pathogenesis of autoimmune lacrimal gland disease in MRL/Mp-lpr/lpr mice

PURPOSE. MRL/Mp- lpr/lpr mice (MRL/lpr) spontaneously develop an autoimmune disease, including lacrimal gland lesions, which are a model for Sjögren's syndrome. Target organ lesions in MRL/lpr mice are composed largely of CD4+ T cells, and treatment with monoclonal antibodies (mAb) against CD4 improves in the systemic autoimmune disease but not the lacrimal gland inflammation. In anti-CD4 mAb-treated MRL/lpr mice, the lacrimal gland lesions are composed largely of CD8+ T cells. The effects of depletion of: (1) all T cells; (2) both CD4+ and CD8+ T cells, and (3) only CD8+ T cells on the lacrimal gland disease were investigated. METHODS. MRL/lpr mice underwent neonatal thymectomy and were treated with weekly injections of 6 mg of anti-Thy 1 mAb from age one week until sacrifice at age five months. Control nonthymectomized mice underwent similar treatment with either saline or normal rat immunoglobulin (rIg) injections. In a second experiment, MRL/lpr mice were treated with weekly injections of either: (1) 2 mg anti-CD4 mAb and 5 mg anti-CD8; or (2) 5 mg anti-CD8 alone. Control mice underwent similar treatment with either saline or rIg injections. RESULTS. Combined treatment with neonatal thymectomy and anti-Thy 1 mAb was effective in reducing the lacrimal gland disease in both frequency (50% = grade 3 vs. 100% in controls, P < 0.002) and extent (median 0% of lacrimal gland area involved by inflammation vs. 14.8% in controls; P = 0.01). Combined anti-CD4 and anti-CD8 therapy also was effective in reducing the lacrimal gland disease in terms of frequency (25% grade 3 vs. 93% in controls; P = 0.002) and extent (median 0% of lacrimal gland involved by inflammation vs. 12.9% in controls; P = 0.0005). Treatment with anti-CD8 mAb therapy alone was ineffective. The systemic autoimmune disease was also improved by T cell depletion and by combined anti-CD4 and anti-CD8 mAb therapy but not by anti-CD8 mAb therapy alone. CONCLUSIONS. Suppression of both CD4+ and CD8+ T cells is required to suppress lacrimal gland inflammation in MRL/lpr mice.

Left ventricular hypertrophy and arterial hypertrophy.

In the most recent WHO recommendations of 1996 it was reiterated that the classification of HT still remains based on the actual BP figures but also on the importance of target organ lesions. Thus the study of cardiac and vascular function and in particular the presence of hypertrophy or remodeling is of importance. A limited number of studies have examined the prevalence, the association and the correlation between modifications and remodeling in the heart and in the vasculature. It is important to distinguish compliance vessels such as the carotid from resistance vessels such as the radial. For compliance vessels the prevalence of cardiac and vascular hypertrophy are nearly identical being around 5% for normotensive subjects and around 12% for hypertensive subjects. This prevalence of thickening in the intima-media is more evident in subjects with left ventricular hypertrophy (LVH). The left ventricular geometric pattern is also an element to take into account. The presence of concentric remodeling of the left ventricle without LVH has already been associated with an increase in intima-media thickness (IMT). When there is an LVH this IMT is similar in severity to the LVH and in particular concentric. For resistance vessels such as the radial artery the number of studies is limited but a significant correlation between left ventricular mean wall thickness and common carotid artery distensibility and compliance has been found. There is also a significant correlation between the radial median lumen ratio and the relative wall thickness but this correlation disappears when age and systolic BP are taken into account. Thus for this type of vessel it is too early to conclude the elements contributing to structural changes. The determinant factors for these structural changes in the heart and the carotid arteries associated with hypertension are certainly multiple be they haemodynamic, hormonal or genetic. The observation establishing an association between anomalies at cardiac and vascular level may have undoubted diagnostic, prognostic and therapeutic implications which are all intimately related and which require refinement and confirmation.

The relevance of clinical pathology to toxicology studies

Standardised lists of haematology, clinical biochemistry and urinalysis parameters are monitored during the course of toxicity studies to assess the potential target organ toxicity of pharmaceuticals, medical and surgical devices, agrochemicals, direct and indirect food additives and industrial chemicals. The biological significance and toxicological importance of any changes which are found between the control and test groups have then to be considered in perspective. Although the temporal relationships between clinical pathology findings and histological lesions in target organs or tissues may not be simple the correlations which can be established with clinical pathology findings and post mortem and histopathology observations are crucial if data are to be correctly evaluated. It is also important to understand how factors other than the experimental treatment can modulate the routinely measured parameters. Clinical pathology data are sometimes useful in elucidating the mechanism of toxic responses observed in animals and their extrapolation to humans. Greater thought with respect to the selection of tests, the timing of investigations and the elimination of sources of biological and experimental variation could lead to improvements in the predictive value of animal toxicology studies.