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PubMed2005

Serological markers of persistent C. trachomatis infections in women with tubal factor subfertility.

BACKGROUND: Persistent C. trachomatis infections are assumed to increase the risk of tubal pathology. We studied whether serological markers, assumed to be associated with persistent C. trachomatis infections, could identify subfertile women at risk of tubal pathology. METHODS: Sera of 313 subfertile women, who all underwent a laparoscopy with tubal testing to assess the grade of tubal pathology, were tested for the presence of immunoglobulin (Ig) G and IgA antibodies to C. trachomatis, IgG antibodies to chlamydia heat shock protein 60 (cHSP60) and C-reactive protein (CRP). RESULTS: C. trachomatis IgA, cHSP60 IgG and CRP, all serological markers of persistent infections, were significantly more prevalent in women with tubal pathology as compared to those without tubal pathology. The predictive value of the currently used screening test for tubal pathology (IgG to C. trachomatis) could be significantly improved by adding the CRP test. CONCLUSIONS: In subfertile women with tubal pathology, serological markers of persistent C. trachomatis infections are significantly more common as compared to women without tubal pathology. C. trachomatis IgG-positive subfertile women with slightly elevated (< 10 mg/l) CRP levels are at highest risk of persistent C. trachomatis infections and tubal pathology.

Adult↗
PubMed2000

Time to pregnancy as a correlate of fecundity: differential persistence in trying to become pregnant as a source of bias.

BACKGROUND: Subfecundity is a frequent and often serious problem and it is important to identify its preventable determinants and to monitor fecundity over time. Since follow-up studies are difficult and expensive to conduct, time to pregnancy (TTP) in pregnant women is often used as a surrogate measure of fecundity. TTP data can be retrieved at low costs and they need no valid population registry as a source for sampling. While TTP may serve as a valid surrogate measure in many situations, its validity rests upon a number of assumptions. We have analysed one of these overlooked assumptions, the importance of persistence in trying to become pregnant. METHODS: By means of computer simulations we estimated bias caused by differences in persistence in pregnancy attempts. We investigated whether the assumptions made in the simulation were realistic by using empirical data from a European study. RESULTS: The mean waiting time to pregnancy and other estimates of subfecundity (or infertility) strongly depend upon the persistence of couples in pursuing a pregnancy. We show that even moderate changes in the planning behaviour considerably modify the waiting time distribution. Empirical data confirm that persistence in trying to become pregnant is age-related. CONCLUSIONS: Persistence in pregnancy attempts affects outcome measures of subfecundity in studies based upon TTP in pregnant women. It is likely that the length of time during which couples keep trying to become pregnant is influenced by a number of factors which would probably change over time or be different between populations to be compared.

Adult↗
PubMed1992

Enteropathogens associated with acute and persistent diarrhea in Bangladeshi children less than 5 years of age.

A longitudinal study of diarrhea was carried out from May 1988 to April 1989 by household surveillance of 705 children less than 5 years old in rural Bangladesh. Stool samples were examined for enteric pathogens at the beginning of each diarrheal episode. For persistent episodes, stool examination was repeated on days 15-17 of the illness. For each case of persistent diarrhea, stool samples from age-matched acute diarrheal and healthy controls were examined. Compared with healthy controls, cases of diarrhea were associated with Shigella species (P = .07) and rotavirus (P less than .05). Diffusely adherent Escherichia coli (P less than .05) and cryptosporidia (P = .07) were the only enteropathogens associated with persistent diarrhea in comparison with acute diarrhea. No more than 15% of children had the same class of pathogen identified from stool on both days 1-3 and days 15-17, indicating that persistent infection was uncommon. However, a different enteropathogen was frequently found on days 15-17, suggesting that sequential infection may be a cause of persistent diarrhea.

Bangladesh↗
PubMed1994

Persistent cytomegalovirus infection of semen increases risk of AIDS.

To evaluate if persistent cytomegalovirus (CMV) infection of semen in human immunodeficiency virus type 1 (HIV-1) antibody-positive men increases AIDS risk, serial cultures for CMV every 3-6 months were attempted four or more times from 164 men followed 3 years. CMV was never isolated from 58 men, in 1 or 2 samples from 54 (intermittently positive), and in > or = 3 samples from 52 (persistently positive). The Cox model was used to estimate relative hazards while controlling for CD4 cell number. The relative hazard was 2.9 for those intermittently and 4.0 for those persistently positive (P < .001). No Kaposi's sarcoma occurred in culture-negative men, 3 cases (5.6%) in intermittently positive men, and 4 cases (7.7%) in persistently positive men (P < .04). Persistent CMV in semen increases the hazard of AIDS in HIV-1 antibody-positive men, possibly by activating CD4 cells to produce HIV-1. Thus, control of CMV in HIV-1-infected persons may slow progression to AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

V region dependent selection of persistent resting peripheral B cells in normal mice.

In this study, we compare the VH gene family repertoire of persistent long-lived splenic B cells with that of the whole splenic B cell compartment. Persistent long-lived B cells were obtained by two independent strategies. Firstly, we studied cells that persist in the peripheral pools with or without cell division. We have transferred mature lipopolysaccharide (LPS)-reactive splenic B cells into LPS non-responder recipients and studied the donor population that could be recovered in host mice at differing time intervals after cell transfer. Secondly, we studied non-cycling resting long-lived B cells. These cells were obtained in normal mice after cytostatic treatment with hydroxyurea and in mice transgenic for the HSV-1 thymidine kinase gene after treatment with the anti-herpetic ganciclovir. Studying the VH gene family usage at the single level by in situ hybridization, we found that persistent B cells show an increased expression of the VHJ558 family and a diminished representation of the VH7183 family. These results demonstrate that in a normal non-immunized mouse, B cell survival and persistence in the resting state results from V region dependent selection.

Animals↗
PubMed2006

Human papillomavirus type 16 and 18 variants: race-related distribution and persistence.

BACKGROUND: Analogous to the geographic distribution of variants of human papillomavirus (HPV) types, the distribution and persistence of these variants among infected individuals may be related to the racial composition of a population living in one geographic region. METHODS: We studied 1114 women in the United States participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study who were positive for HPV16 and/or HPV18 at enrollment. Race was self-reported. HPV samples were characterized by sequencing the E6 gene and part of the long control region and classified as variants according to established lineages. Subjects were examined for HPV every 6 months for 2 years. All statistical tests were two-sided. RESULTS: HPV18 African variants were predominant in the 97 HPV18-infected African American women (i.e., 62 women or 63.9%, 95% confidence interval [CI] = 53.5% to 73.4%), and European variants were common in the 168 HPV18-infected white women (i.e., 91 women or 54.2%, 95% CI = 46.3% to 61.9%). HPV16 African variants accounted for 43 (26.5%, 95% CI = 19.9% to 34.0%) of the infections in the 162 HPV16-infected African American women but for only 25 (4.3%, 95% CI = 2.8% to 6.3%) in the 584 HPV16-infected white women. The likelihood of remaining HPV18 positive was statistically significantly higher in white women infected with European than in white women infected with African variants (P = .04); the reverse was observed in African American women (P = .03). A similar pattern was observed for persistence of HPV16 variants, with the likelihood of remaining positive being higher for white women, but lower for African American women, infected with an European variant than with an African variant (P = .03 and P = .16, respectively). CONCLUSIONS: Variants of HPV16 and HPV18 appear to persist longer in a host whose race indicates an ancestral geographic distribution that was once shared with that of the variant-i.e., European variants persist longer in white women, and African variants persist longer in African American women.

Adult↗
PubMed1990

A prospective study of persistent diarrhea among children in an urban Brazilian slum. Patterns of occurrence and etiologic agents.

Persistent diarrhea is a major health problem among children in developing areas of the world. Since few community-based studies have addressed the epidemiology or etiology of this condition, we undertook prospective diarrheal surveillance among a cohort of 175 children less than 5 years of age over a 28-month period in an urban slum in northeastern Brazil. Very high diarrhea illness burdens were found. The children in this cohort had an average of 11 episodes per year and spent 82 days per year with diarrhea. A total of 65% of children had at least one episode of persistent diarrhea (greater than or equal to 14 days duration). These episodes accounted for 50% of all days of diarrhea and 11% of all episodes. The occurrence of at least one episode of persistent diarrhea identified all children who spent at least 15% percent of days with diarrhea. Among children with and without diarrhea, rotavirus was the agent isolated most frequently, followed by Giardia lamblia and enterotoxigenic coliforms. The agents isolated from children with acute and persistent diarrhea were similar, which suggests that other factors must be operative in the development of persistent diarrhea.

Brazil↗
PubMed2002

Persistence and reversibility of the elevation in free sphingoid bases induced by fumonisin inhibition of ceramide synthase.

These studies determined (1) the time course for sphingoid base elevation in the small intestines, liver, and kidney of mice following a single 25 mg/kg body weight (bw) oral dose (high dose) of fumonisin B(1) (FB(1)), (2) the minimum threshold dose of FB(1) that would prolong the elevated sphingoid base concentration in kidney following the single high dose, and (3) the importance of the balance between the rate of sphingoid base biosynthesis and degradation in the persistence of sphingoid base accumulation. Following the high dose of FB(1), there was an increase in sphinganine in intestinal cells and liver that peaked at 4 to 12 h and declined to near the control level by 48 h. In kidney, sphinganine peaked at 6-12 h but remained elevated until 72 h, approaching control levels at 96-120 h. Oral administration of 0.03 mg FB(1)/kg bw (low dose) for 5 days had no effect on the sphingoid bases in kidney. However, following an initial high dose, daily administration of the low dose prolonged the elevation in kidney sphinganine compared to mice receiving a single high dose. Thus, a single exposure to a high dose of FB(1) followed by daily exposure at low levels will prolong the elevation of sphinganine in kidney. In cultured renal cells FB(1) was rapidly eliminated, but elevated sphinganine was persistent. This persistence in renal cells was rapidly reversed in the presence of the serine palmitoyltransferase inhibitor (ISP-1), indicating that the persistence was due to differences in the rates of sphinganine biosynthesis and degradation. The in vivo persistence in kidney may be due to similar differences.

Acyltransferases↗
PubMed2002

Persistent and recurrent hyperparathyroidism after total parathyroidectomy with autotransplantation.

OBJECTIVE: To conduct a retrospective study of 15 patients with persistent (n = 4) and recurrent (n = 11) hyperparathyroidism. SUMMARY BACKGROUND DATA: Secondary hyperparathyroidism may persist or recur because of hyperfunction of the parathyroid remnant or transplanted parathyroid tissue. It is a great challenge to localize the parathyroid tissue either in the neck or at the arm before surgery. METHODS: From June 1994 to June 2000, 15 patients with recurrent and persistent secondary hyperparathyroidism were selected for surgery for the removal of parathyroid tissue. The indications for surgery included bone pain, hypercalcemia, general weakness, and skin itching. Their ages ranged from 23 to 66 years. The average period of persistent hyperparathyroidism after total parathyroidectomy with autotransplantation was 3.8 months; that of recurrent hyperparathyroidism was 53 months. Serum levels of calcium, phosphorus, parathyroid hormone (iPTH), and alkaline phosphatase were measured before surgery and 1 week after surgery. Before surgery, the parathyroid gradient in the blood draining the graft-bearing arm versus the contralateral arm was measured. A 99mTc-sestamibi (MIBI) scan was performed including the neck and the arm area, and a computed tomography (CT) scan of the neck was performed to confirm the localization. The neck and mediastinal exploration was done directly at the side of localization under general anesthesia to remove the parathyroid tissue that had been located with the MIBI scan or CT scan. An arm exploration was done under local anesthesia to remove all parathyroid tissues detected in the MIBI scan or palpable masses during surgery. If all glands were removed, 0.5 x 0.5 x 0.5 cm of tissue (60-100 mg) was maintained in situ or the same amount of tissue was reimplanted. RESULTS: The average ratio of iPTH in the graft-bearing arm to the contralateral arm in the 5 patients with parathyroid tissue in the neck was 1.17 +/- 0.16, and that in the 10 patients with parathyroid at the arm was 14.15 +/- 16.62. A significant difference was found between the two groups. MIBI scans showed parathyroid tissues in the neck in four of five patients and in seven of eight patients at the arm. Computed tomography showed the parathyroid tissues in the neck and mediastinum in five of five patients (100%). Five glands were removed from these five patients, three in the neck, one in the mediastinum, and one in the carotid sheath. In total, 20 glands and 2 half-glands were removed from 10 patients; among these, 14 glands were shown in the MIBI scan. All patients had improvements of symptoms and signs after surgery. Serum levels of calcium, phosphorus, and iPTH decreased rapidly after surgery, but alkaline phosphatase did not. CONCLUSIONS: With the results obtained from the ratio of iPTH of the graft-bearing arm to the contralateral arm, clinical palpation of the arm, MIBI scan, CT scan, careful surgical exploration, and adequate resection, recurrent and persistent secondary hyperparathyroidism can be successfully treated with surgery in the neck or at the arm.

Adult↗
PubMed1992

The persistence of human peripheral lymphocytes, tumor infiltrating lymphocytes, and colon adenocarcinomas in immunodeficient mice.

The reconstitution of severely immunodeficient mice with human peripheral blood mononuclear cells (PBMCs) may represent a unique model system to evaluate human antitumor responses. To evaluate this possibility, we studied human PBMC reconstitution, human tumor infiltrating lymphocyte (TIL) persistence, and human colon adenocarcinoma propagation in beige/nude/xid (BNX) and in severe combined immunodeficient (SCID) mice. To evaluate human PBMC reconstitution, 75 mice received 1 x 10(7)-1 x 10(9) human PBMCs i.p. or i.v. and were studied at intervals ranging from 1 to 8 weeks by fluorescence-activated cell sorting (FACS) analysis and by measurement of circulating human immunoglobulin levels. By FACS analyses, only one of 75 mice had evidence of human PBMC persistence at 2 weeks in the spleen. Moreover, liver and peritoneum showed evidence of human cells in only 13 of 56 and 16 of 55 mice, respectively. In these mice, human cells comprised 1-77% of total cells recovered. Human immunoglobulin levels in mouse serum ranged from 0 to 34,000 micrograms/ml and correlated only weakly with evidence of human PBMC reconstitution in peripheral organs, but were generally higher in SCID mice than in BNX mice. Human TIL persistence was evaluated in BNX and SCID mice that were given 3 x 10(7) TILs i.v. (in divided doses) or 1 x 10(8) i.p. TILs along with interleukin-2 administration. At 1, 2, 7, and 14 days following TIL delivery, evidence of human TIL persistence in liver, lung, peritoneum, and spleen was evaluated by FACS analysis. Fresh organ suspensions did not contain human TILs. In mice given cyclophosphamide followed by human TILs i.p., the TILs were demonstrated at 7 days in the SCID peritoneum (leu 4 = 4%) and at 2 days in the SCID spleen (leu 4 = 2%). In BNX mice, 12 of 14 fresh human colon adenocarcinomas were propagated successfully at subcutaneous sites with latency periods ranging from 1 to 13 weeks. Enzymatic disaggregation of tumors greater than 1 cm following one passage yielded 6.5-47 x 10(6) cells with viabilities ranging from 13 to 85%. We conclude that limitations and variability exist in the use of BNX and SCID mice for human PBMC reconstitution, TIL persistence, and propagation of human colon adenocarcinomas.

Adenocarcinoma↗
PubMedDate not supplied

Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy.

The authors recently reported that adoptive immunotherapy with autologous tumor-reactive tumor infiltrating lymphocytes (TILs) immediately following a conditioning nonmyeloablative chemotherapy regimen resulted in an enhanced clinical response rate in patients with metastatic melanoma. These observations led to the current studies, which are focused on a detailed analysis of the T-cell antigen reactivity as well as the in vivo persistence of T cells in melanoma patient 2098, who experienced a complete regression of all metastatic lesions in lungs and soft tissues following therapy. Screening of an autologous tumor cell cDNA library using transferred TILs resulted in the identification of novel mutated growth arrest-specific gene 7 (GAS7) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts. Direct sequence analysis of the expressed T-cell receptor beta chain variable regions showed that the transferred TILs contained multiple T-cell clonotypes, at least six of which persisted in peripheral blood for a month or more following transfer. The persistent T cells recognized both the mutated GAS7 and GAPDH. These persistent tumor-reactive T-cell clones were detected in tumor cell samples obtained from the patient following adoptive cell transfer and appeared to be represented at higher levels in the tumor sample obtained 1 month following transfer than in the peripheral blood obtained at the same time. Overall, these results indicate that multiple tumor-reactive T cells can persist in the peripheral blood and at the tumor site for prolonged times following adoptive transfer and thus may be responsible for the complete tumor regression in this patient.

Amino Acid Sequence↗
PubMedDate not supplied

Complementary and alternative approaches to the treatment of persistent musculoskeletal pain.

OBJECTIVE: To review common complementary and alternative treatment modalities for the treatment of persistent musculoskeletal pain in older adults. METHODS: A critical review of the literature on acupuncture and related modalities, herbal therapies, homeopathy, and spinal manipulation was carried out. Review included 678 cases within 21 randomized trials and 2 systematic reviews of herbal therapies: 798 cases within 2 systematic reviews of homeopathy; 1,059 cases within 1 systematic review of spinal manipulation for low back pain, and 419 cases within 4 randomized controlled trials for neck pain. The review of acupuncture and related modalities was based upon a paucity of well-controlled studies combined with our clinical experience. RESULTS: Insufficient experimental evidence exists to recommend the use of traditional Chinese acupuncture over other modalities for older adults with persistent musculoskeletal pain. Promising preliminary evidence exists to support the use of percutaneous electrical nerve stimulation for persistent low back pain. While some herbals appear to have modest analgesic benefits, insufficient evidence exists to definitively recommend their use. Drug-herb interactions must also be considered. Some evidence exists to support the superiority of homeopathic remedies over placebo for treating osteoarthritis and rheumatoid arthritis. The benefits of spinal manipulation for persistent low back and neck pain have not been convincingly shown to outweigh its risks. DISCUSSION: While the use of complementary and alternative modalities for the treatment of persistent musculoskeletal pain continues to increase, rigorous clinical trials examining their efficacy are needed before definitive recommendations regarding the application of these modalities can be made.

Acupuncture↗
PubMed1994

Circulation persistence and biodistribution of lyophilized liposome-encapsulated hemoglobin: an oxygen-carrying resuscitative fluid.

OBJECTIVE: To evaluate the circulation persistence and organ biodistribution of a freeze-dried, oxygen carrying resuscitative fluid: liposome-encapsulated hemoglobin. DESIGN: Randomized, animal studies. SETTING: Accredited animal research facilities. SUBJECTS: Normal female Balb/c mice and male New Zealand rabbits. INTERVENTIONS: Two groups of normal female Balb/c mice were injected in the tail vein with either lyophilized liposome-encapsulated hemoglobin (n = 9) that was reconstituted just before administration, or with unlyophilized liposome-encapsulated hemoglobin (n = 9) as a comparison. Two groups of male New Zealand rabbits were injected in the ear vein with either lyophilized 99mTc-liposome-encapsulated hemoglobin (n = 6) or unlyophilized 99mTc-liposome-encapsulated hemoglobin as a comparison (n = 6). After injection, mice were anesthetized by brief inhalation of halothane followed by blood sampling through the retro-orbital sinus. Rabbits were anesthetized 30 mins before liposome-encapsulated hemoglobin administration with an intramuscular injection of a 5:1 mixture of ketamine (50 mg/kg) and xylazine (10 mg/kg). Rabbits were then dynamically imaged for 90 mins, housed, and at 20 hrs, imaging again followed by autopsy and tissue sampling to validate imaged organ biodistributions. MEASUREMENTS: Circulation persistence in the mouse was measured by removing a blood sample at various time points up to 24 hrs after injection. The blood sample was centrifuged in a hematocrit capillary tube and the disappearance of the sedimented liposome-encapsulated hemoglobin fraction was measured. The change in the sedimented fraction of the liposomes with time was used to generate circulation persistence profiles in mice. The circulation persistence and organ biodistribution of 99mTc-liposome-encapsulated hemoglobin was measured by circling regions of interest on computer-generated gamma camera images. These image intensities were then calculated as a function of total injected dose which was measured from a known volume and activity of 99mTc-liposome-encapsulated hemoglobin. Actual tissue uptake was estimated from images by subtracting blood pool contribution which was measured by injecting 99mTc-labeled rabbit red cells. Imaged organ biodistribution was validated at 20 hrs by measuring activity in weighed portions of tissue after autopsy. MAIN RESULTS: The mean circulation half-life of liposome-encapsulated hemoglobin in mice injected at a dose of 1.0 g phospholipid/kg mouse and 1.95 g hemoglobin/kg was approximately 10.4 +/- 0.5 (SD) hrs. The circulation half-life of lyophilized liposome-encapsulated hemoglobin was 10.7 +/- 0.7 hrs. The circulation profiles demonstrate a rapid removal phase over the first 4 hrs after injection, followed by a secondary slow removal measured up to 24 hrs. The rapid removal phase of liposome-encapsulated hemoglobin and lyophilized liposome-encapsulated hemoglobin in the rabbit (injected at the same dose) indicated that lyophilized liposome-encapsulated hemoglobin persists longer than the unlyophilized form in the first 4 hrs after injection. The organ biodistributions of unlyophilized 99mTc-liposome-encapsulated hemoglobin and lyophilized 99mTc-liposome-encapsulated hemoglobin in the rabbit demonstrate that the reticuloendothelial system is the primary site of removal, with significant uptake of lyophilized 99mTc-liposome-encapsulated hemoglobin by the liver (15.6 +/- 1.0%), bone marrow (12.6 +/- 1.6%), and spleen (9.7 +/- 1.1%). The kidneys showed little accumulation of unlyophilized 99mTc-liposome-encapsulated hemoglobin or lyophilized 99mTc-liposome-encapsulated hemoglobin (1.6 +/- 0.2% and 1.8 +/- 0.1%, respectively), an important result for the efficacy and safety of this hemoglobin-based blood substitute. (ABSTRACT TRUNCATED)

Animals↗
PubMed1999

Persistence and desistance of oppositional defiant disorder in a community sample of children with ADHD.

OBJECTIVE: To examine the developmental progression of comorbid oppositional defiant disorder (ODD) in a community sample of children with attention-deficit hyperactivity disorder (ADHD) with particular emphasis on persistence and desistance of ODD and the emergence of new cases of conduct disorder (CD). METHOD: A sample of disruptive children was identified from a multiple-gate epidemiological screen and stratified into diagnostic subgroups on the basis of a structured interview. A comparison sample of nondisruptive children was also identified. Group comparisons were performed on demographic, descriptive, family history, and clinical characteristics. Changes in rates of ODD symptoms and diagnostic subgroup membership were assessed after a 4-year longitudinal interval. Predictors of diagnostic group persistence were tested. RESULTS: Few differences distinguished diagnostic subgroups at baseline. Of the 43 children with baseline diagnoses of ADHD + ODD, only 1 (2.3%) was found to have developed CD at follow-up. Over time there was a 57% rate of ODD persistence and a 43% rate of ODD desistance. Negative parenting practices and mothers' psychiatric disorders predicted persistence of ODD. CONCLUSIONS: There was little evidence to show that ODD acted as a precursor to CD. However, when CD was diagnosed at baseline it was always associated with or preceded by ODD (i.e., prodrome). For a subgroup of children with ADHD, comorbid ODD symptoms are relatively unstable and may represent transient developmental perturbations that have little prognostic significance. For a larger subgroup of children with ADHD, ODD symptoms persist into the adolescent years and are associated with adverse parenting practices.

Adolescent↗
PubMed2001

Persistent cardiovascular effects of chronic renin-angiotensin system inhibition following withdrawal in adult spontaneously hypertensive rats.

OBJECTIVES: It is generally accepted that short-term (4 weeks) inhibition of the renin-angiotensin system (RAS) of young spontaneously hypertensive rats (SHR) in their prehypertensive phase confers long-lasting protection from fully hypertensive levels in adulthood. However, there is very little data pertaining to the effects of such treatment in adult SHR with established hypertension. Therefore, we determined the relative effects of angiotensin converting enzyme (ACE) inhibition (perindopril), AT1 receptor blockade (candesartan cilexetil) and RAS-independent vasodilatation (hydralazine) and their withdrawal in adult SHR, on blood pressure measured by radiotelemetry, as well as on cardiac and vascular structure. METHODS: Adult male SHR were instrumented with radiotelemetry probes to measure blood pressure and heart rate continuously. SHR were given either vehicle, perindopril (1 mg/kg per day), candesartan cilexetil (2 mg/ kg per day) or hydralazine (30 mg/kg per day) at equieffective depressor doses for 4 weeks (treatment study). Separate groups of animals were also given identical treatments but were then monitored for a further 8 weeks after drug withdrawal (withdrawal study). An indirect in-vivo assessment of whole body vascular hypertrophy (mean arterial pressure during maximum vasoconstriction) was made during and after drug withdrawal, as was the pressor activity evoked by angiotensin I and angiotensin II. The effect of antihypertensive treatment on microalbuminuria was also assessed during and after drug withdrawal. Finally, left ventricular: body weight (Iv: bw) and mesenteric media: lumen ratios were determined either immediately after 4-week treatment (treatment study) or 8 weeks later (withdrawal study). RESULTS: Perindopril persistently lowered blood pressure in adult SHR whereas blood pressure returned to vehicle levels within approximately 4 and 15 days after withdrawal of hydralazine and candesartan cilexetil, respectively. Cardiac hypertrophy was reduced by all three treatments, but to a lesser extent by hydralazine (treatment study), and this regression of cardiac hypertrophy persisted only with both types of RAS inhibition (withdrawal study). Vascular hypertrophy, measured indirectly and directly, was also reduced by all three treatments, with perindopril and candesartan cilexetil causing hypotrophic and eutrophic remodelling, respectively (treatment study), although these changes were generally not maintained after drug withdrawal (withdrawal study). Angiotensin I-induced pressor responses were equally inhibited during treatment with either candesaran cilexetil or perindopril (and were unaffected by hydralazine) but normalized rapidly in both groups (within approximately 2-4 days) after withdrawal of RAS inhibition. In addition, there was a small age-related increase in microalbuminuria over the study period, which was not significantly affected by any treatment. CONCLUSIONS: Following 4-week treatment, candesartan cilexetil, perindopril and hydralazine caused similar antihypertensive effects; however, only perindopril persistently reduced blood pressure following drug withdrawal. Both types of RAS inhibition and hydralazine caused marked cardiac and vascular remodelling during treatment, whereas only the RAS inhibitors persistently regressed cardiac hypertrophy 8 weeks later. Collectively, these results indicate the importance of the RAS for the maintenance of hypertension and cardiovascular hypertrophy in adult SHR, as well as identifying differential effects of ACE inhibition and AT1 receptor blockade on persistent blood pressure reduction.

Angiotensin I↗
PubMed2003

Persistent lowering of arterial pressure after continuous and intermittent therapy.

OBJECTIVE: The present study investigates the impact of antihypertensive treatment on persistent reduction of arterial pressure after cessation of drug treatment. DESIGN AND METHODS: Specifically, adult spontaneously hypertensive rats (SHR) were treated for 6 weeks with inhibitors of the renin-angiotensin system (RAS), or combination therapy (hydralazine, nifedipine, hydrochlorothiazide) and following a 14-week 'drug holiday', were re-treated for 4 weeks. Mean arterial pressure (MAP) was continuously monitored via radiotelemetry. RESULTS: Comparison in the first off-treatment period revealed that RAS inhibitor drugs produced a 16-18% persistent lowering of arterial pressure, whereas the triple therapy induced a 10% lowering of MAP relative to untreated SHR. The drug re-challenge induced a further 9% reduction in the 'off'-treatment level of MAP such that in all treatment groups MAP was reduced by more than 30 mmHg compared with controls. CONCLUSIONS: This study provides new evidence that combination therapy, not directly targeting the RAS, can be efficacious in persistently reducing MAP off-treatment. Furthermore, we demonstrated that the 6-week treatment with RAS inhibitors induced equivalent persistent changes as a 10-week treatment. That is, the additional 4 weeks of continuous therapy was ineffective in further altering the off-treatment MAP. In contrast, with the intermittent treatment protocol (the 14-week 'drug holiday') a further effect on persistent lowering of MAP was regained. These findings suggest continuous long-term treatment with antihypertensive drugs may not be the most effective means of reversing underlying circulatory abnormalities and that the introduction of a drug holiday may be beneficial.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Effect of feeding yogurt versus milk in children with persistent diarrhea.

Although the pathophysiology of persistent diarrhea in children remains unclear, it has been suggested that it may be related to the composition of the food ingested. Since lactase deficiency and cow's milk protein intolerance are often identified in children with persistent diarrhea, replacement of milk with yogurt should be beneficial. We, therefore, compared the clinical outcome of children (aged 3-36 months) with persistent diarrhea randomly assigned to receive either milk or yogurt for 5 days. Preliminary results on 45 of the 100 children indicated clinical failure, which was determined after a 5% loss of body weight per day or the persistence of diarrhea after 5 days, in only 14% of the children fed yogurt compared to 42% of those fed milk (p less than 0.05). These preliminary results strongly suggest a clinical advantage of feeding yogurt rather than milk in children with persistent diarrhea.

Child, Preschool↗
PubMed2000

Immune response of Bangladeshi children with acute diarrhea who subsequently have persistent diarrhea.

BACKGROUND: Because altered immune responses may be a risk factor for persistent diarrhea, various aspects of the immune response were examined to elucidate the underlying immune mechanisms that may be involved in the development of persistent diarrhea. METHODS: Children (7-12 months of age) with watery diarrhea for 6 to 8 days from the Dhaka Hospital of the International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B), were enrolled. Children were classified as having acute diarrhea (AD) or persistent diarrhea (PD) if diarrhea resolved within 14 days or persisted for more than 14 days, respectively. Uninfected control children (n = 13), from the Nutrition Follow-Up Unit of ICDDR,B were also enrolled. Of the 123 children with diarrhea who were enrolled, 85 had AD and 38 had PD. Comparisons were performed for clinical features, nutritional status (weight for age, plasma transferrin, and serum albumin levels), and immune responses: neutrophil function; peripheral blood mononuclear cell function, delayed-type hypersensitivity (DTH) responses, plasma levels of immunoglobulins, tumor necrosis factor-alpha, and interferon-gamma. Univariate analyses were conducted to assess differences among the three groups of children and between children with AD and PD. Logistic regression was performed to determine risk factors for PD. RESULTS: There were no differences in clinical features and nutritional status among the groups of children studied. More children in whom PD developed had a negative DTH response to tuberculin than those with AD (P = 0.021). Also, a negative DTH response to tuberculin was a significant risk factor for PD (odds ratio [OR] = 3.8, 95% confidence interval [CI] = 1.5-9.9). CONCLUSIONS: Children with acute diarrhea with a negative DTH response to tuberculin are more likely to have development of persistent diarrhea.

Acute Disease↗