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PubMed2001

Induction of transplantation tolerance with a short course of tacrolimus (FK506): I. Rapid and stable tolerance to two-haplotype fully mhc-mismatched kidney allografts in miniature swine.

BACKGROUND: Inbred miniature swine provide a large animal model in which the effects of selective major histocompatibility complex (MHC) matching can be reproducibly studied. We have previously demonstrated that although a 12-day course of cyclosporine uniformly induces tolerance to class I-mismatched renal allografts, it does not induce tolerance across full MHC barriers. In this study, we assessed whether and at what dose tacrolimus might permit allografts to induce tolerance across different MHC barriers. METHODS: Recipients of MHC disparate renal allografts were treated with a 12-day course of tacrolimus by continuous intravenous infusion. Groups were divided as follows: (1) class I-mismatched kidneys with 0.3 mg/kg/day tacrolimus (n=3); (2) fully MHC-mismatched kidneys with 0.3 mg/kg/day tacrolimus (n=2); and (3) fully MHC-mismatched kidneys with 0.12-0.16 mg/kg/day tacrolimus (n=4). RESULTS: In groups 1 and 2, recipients with tacrolimus levels of 45-80 ng/ml accepted renal allografts long-term with stable renal function. Donor-specific hyporesponsiveness was demonstrated by cell-mediated lymphocytotoxicity and mixed lymphocyte response, and subsequent donor-matched grafts were also accepted, without further immunosuppression (n=4), confirming systemic tolerance. In group 3, recipients that achieved tacrolimus levels of 35 ng/ml (n=2) accepted their grafts without chronic changes, whereas recipients with levels of 20-26 ng/ml (n=2) developed chronic allograft glomerulopathy, suggesting 35 ng/ml as the threshold blood level for tolerance induction. In vitro assays demonstrated that peripheral blood lymphocytes from tolerant animals produced inhibitory cytokines, suggesting the involvement of regulatory mechanisms. CONCLUSIONS: To our knowledge, this study represents the first demonstration of the induction of transplant tolerance across a two-haplotype full MHC barrier with a short course of immunosuppression in a large animal model. These studies may also have clinical applicability, because the time course required to induce tolerance was sufficiently short that the high drug levels required might be expected to be tolerated clinically with only transient toxicity.

Animals↗

PubMed2002

Rapid breakdown of microvascular barriers and subsequent hemorrhagic transformation after delayed recombinant tissue plasminogen activator treatment in a rat embolic stroke model.

BACKGROUND AND PURPOSE: Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) after stroke increases risk of hemorrhagic transformation, particularly in areas with blood-brain barrier leakage. Our aim was to characterize acute effects of rtPA administration on the integrity of microvascular barriers. METHODS: Stroke was induced in spontaneously hypertensive rats by unilateral embolic middle cerebral artery occlusion. Six hours after stroke, rtPA was intravenously administered (n=10). Controls received saline (n=4). Extravasation of the large-diameter contrast agent monocrystalline iron oxide nanocolloid (MION) was assessed with susceptibility contrast-enhanced MRI during rtPA injection. In addition, we performed perfusion MRI and diffusion-weighted MRI. After MRI, 2 hours after rtPA treatment, intracerebral hemorrhage was quantified with a spectrophotometric hemoglobin assay. RESULTS: Late rtPA treatment resulted in increased hemorrhage volume (8.4+/-1.7 versus 2.9+/-0.9 micro L in controls; P<0.05). In MION-injected animals, during rtPA administration, transverse relaxation rate change (DeltaR2*) increased from 12.4+/-6.0 to 31.6+/-19.2 s(-1) (P<0.05) in areas with subsequent hemorrhage. Significant DeltaR2* changes were absent in nonhemorrhagic areas, in animals without injected MION, and in saline-treated animals. Thrombolytic therapy did not improve perfusion in regions with hemorrhagic transformation (cerebral blood flow index was 22.8+/-19.7% [of contralateral] at 0.5 hours before and 22.4+/-18.0% at 1 hour after rtPA administration). CONCLUSIONS: The DeltaR2* changes during rtPA delivery in MION-injected animals indicate extravasation of MION, which reflects increased permeability of the blood-brain barrier. This implies that late rtPA treatment rapidly aggravates early ischemia-induced damage to microvascular barriers, thereby enhancing hemorrhagic transformation.

Animals↗

PubMed1993

Lactobacillus casei strain GG reverses increased intestinal permeability induced by cow milk in suckling rats.

BACKGROUND: Lactobacilli constitute a major part of the microflora throughout the gastrointestinal tract. This study aimed to investigate the effect of lactobacilli on the gut mucosal barrier. METHODS: Rat pups were divided into three experimental feeding groups at the age of 14 days. In addition to normal maternal milk, group "milk" received a daily gavage of cow milk, group "milk-GG" received Lactobacillus casei strain GG with cow milk, and controls were gavaged with the same volume of water. At 21 days, the absorption of horseradish peroxidase across patch-free jejunal segments and segments containing Peyer's patches was studied in Ussing chambers. RESULTS: The mean absorption of intact horseradish peroxidase expressed in ng.h-1.cm-2, was significantly different in the study groups in both patch-free segments (controls, 9 [95% confidence interval, 7-12]; milk, 72 [60-87]; and milk-GG, 15 [4-52]) and in segments containing Peyer's patches (controls, 3 [1-17]; milk, 80 [43-151]; and milk-GG, 15 [4-56]). There was a significant increase in the frequency of cells secreting antibodies to beta-lactoglobulin (enzyme-linked immunospot assay) in the milk-GG group. CONCLUSIONS: Prolonged cow milk challenge in suckling rats increases gut permeability to intact proteins, whereas Lactobacillus GG counteracts this permeability disorder. The results suggest a link between the intensity of the antigen-specific immune response and stabilization of the mucosal barrier.

Animals↗

PubMedDate not supplied

Contraception guidance in women with pre-existing disturbances in carbohydrate metabolism.

OBJECTIVES: To review our studies on the clinical and metabolic impact of contraceptive methods in women with insulin dependent diabetes mellitus (IDDM) and women with previous gestational diabetes mellitus (GDM) in order to provide suggestions for the contraceptive counselling of these women. METHODS: The clinical events following first insertions of copper IUDs were studied in 103 women with IDDM and in 119 non-diabetic women. Moreover we studied the effects on glycometabolic control and lipid metabolism in women with well-controlled IDDM using low-dose oral contraceptives (OCs) containing ethinylestradiol combined with norethisterone (n = 10), levonorgestrel (n = 9) or gestodene (n = 11). Hemostatic and endothelial function was also studied in the women using the gestodene-containing preparation. Finally, we studied the impact of oral contraceptives on the insulin sensitivity in women with previous GDM. RESULTS: The continuation rates and indications for medical removal of the IUDs were similar in the diabetic and the non-diabetic women. There was no increased pregnancy rate or increased frequency of pelvic inflammatory disease in the diabetic women. The glycemic control was not changed by the OCs and none of the treatment regimens were associated with changes in plasma lipids linked to increased risk of atherosclerosis. Indications of increased fibrin formation, which seemed to be compensated by increased fibrinolytic activity, were noted with the gestodene-containing preparation. None of the women developed microalbuminuria during the study. Compared to normal women, we found reduced insulin sensitivity in the women with previous GDM using the pill. CONCLUSION: Intrauterine devices and barrier methods can be used by diabetic women with the same reservations as in the general population. Low-dose OCs do not influence the glycemic control and have no adverse impact on plasma lipids. The balance between fibrin formation and resolution was maintained during intake of the gestodene-containing pill. Our findings suggest that combined oral contraceptives can be used in women with uncomplicated IDDM and in women with previous GDM if clinical and metabolic monitoring can be ensured.

Case-Control Studies↗

PubMed1995

Emergency contraception--why women don't use it.

AIM: The aim of the study was to examine knowledge of and perceived availability of the emergency contraceptive pill as well as reasons for its non use. METHODS: One hundred women each attending Epsom day unit or the Auckland medical aid clinic in Auckland seeking termination of pregnancy, and 100 women seeking contraceptive advice from the Alice Bush centre in Auckland, were asked to take part in the study. RESULTS: At Alice Bush centre 57% of women had previously used the emergency contraceptive pill compared with 43% women at Epsom day unit and 32% women at Auckland medical aid clinic. Only 7% of women attending Epsom day unit or Auckland medical aid clinic had used the emergency contraceptive pill in the month they conceived. When asked why they had not used the emergency contraceptive pill 38% of respondents said they had not heard of it and 41% did not know where to obtain it. Pacific Island women were least likely to have heard of it. Approximately 50% knew the correct time interval for using the emergency contraceptive pill. Sixty two percent attending the abortion clinics would have used the emergency contraceptive pill if they had a supply at home and 57% stated they would have used it if it was available over the counter through pharmacies. CONCLUSIONS: The discrepancy between the numbers of women who knew of the emergency contraceptive pill (72%) and the numbers who used it to try to prevent pregnancy (7%) indicates that there are barriers to obtaining and using the emergency contraceptive pill. This study demonstrated a lack of knowledge of the emergency contraceptive pill in women attending the abortion clinics. The majority of women seeking termination of pregnancy would have used the emergency contraceptive pill if they had it available at home or over the counter through a pharmacy. Doctors prescribing the pill and barrier methods of contraception should consider providing a supply of emergency contraceptive pill at the same time and consideration should be given to over the counter prescribing of the emergency contraceptive pill in New Zealand.

Adult↗

PubMed2000

Causes of re-recurrence after polytetrafluoroethylene patch saphenoplasty for recurrent varicose veins.

BACKGROUND: The aim of this study was to determine whether a polytetrafluoroethylene (PTFE) patch sutured over the religated saphenofemoral junction could reduce the rate of recurrence after operation for recurrent varicose veins. METHODS: Fifty patients who had surgery for recurrent long saphenous incompetence (81 legs had a small PTFE patch sutured over the religated saphenofemoral junction. There were no major complications following surgery. Three patients had a wound infection or delayed healing. All patients were invited for clinical examination and duplex imaging at a median of 19 (range 6-39) months after operation. RESULTS: Some 38 of 43 patients (70 legs) remained satisfied with the results of surgery; 16 (23 per cent) of 70 legs had visible veins on inspection and eight of these (11 per cent) involved symptomatic recurrence. Duplex imaging showed that recurrence was due to saphenofemoral junction incompetence in ten legs; two appeared to have a major groin connection but the other eight appeared to have neovascularization. Other causes were thigh perforator reflux (three legs) and cross-groin collaterals (three). Eleven of the 16 legs with recurrence had varicography but in two the procedure was a technical failure. Two legs had evidence of a significant connection (more than 3 mm) and two a minor connection (less than 3 mm) to the femoral vein at the level of the PTFE patch, but in the remainder recurrence was due to upper thigh perforating veins. There was good concordance between duplex imaging and varicography. CONCLUSION: PTFE patch saphenoplasty appears to be safe. Although these are early results, the technique seems potentially as effective as other barrier methods that have been investigated; in ten legs (12 per cent) recurrence was attributed to failure at the level of the PTFE patch.

Adult↗

PubMed2003

Sex in Australia: safer sex and condom use among a representative sample of adults.

OBJECTIVE: To provide reliable estimates of the frequency of condom use and correlates of condom use among Australian adults. METHODS: Computer-assisted telephone interviews were completed by a representative sample of 10,173 men and 9,134 women aged 16-59 years. The response rate was 73.1% (69.4% men, 77.6% women). RESULTS: Although the majority of respondents had used a condom at some time in their lives, fewer than half of the respondents who were sexually active in the year before being interviewed had used a condom in the past year. Condom use in the past year was associated with youth, greater education, residence in major cities, lower incomes, white-collar occupations, being a former smoker, and having more sexual partners in the past year. In the six months prior to interview, 7.1% of respondents always used condoms with regular cohabiting partners, 22.5% always used condoms with regular non-cohabiting partners, and 41.4% always used condoms with casual partners. Approximately 20% of respondents used a condom the last time they had vaginal intercourse, and one in eight of these condoms were put on after genital contact. Condom use during the most recent sexual encounter was associated with youth, living in a major city, having a lower income, having sex with a casual partner, and not using another form of contraception. CONCLUSION: As in other studies, condom use was strongly associated with partner type and use of other contraception. IMPLICATIONS: People with multiple sexual partners need to be aware that non-barrier methods of contraception (and condoms applied late) do not protect against sexually transmitted infections.

Adolescent↗

PubMed2006

Demonstration of an anterior diffusional pathway for solutes in the normal human eye with high spatial resolution contrast-enhanced dynamic MR imaging.

PURPOSE: The present studies were conducted to determine whether a diffusional pathway for solutes exists from the ciliary body stroma to the anterior chamber of the human eye. The existence of such a pathway has been demonstrated in rabbits and monkeys, but such a pathway in humans would necessitate a shift in the physiological paradigm of the blood-aqueous barrier. METHODS: Seven normal human volunteers (five men, two women; age range, 27 to 59 years) underwent nine dynamic T1-weighted, spin-echo MR imaging studies, using intravenous, gadolinium-based contrast agents. RESULTS: In all cases, signal intensity rose rapidly in the ciliary body. In all subjects, there was a measurable latent rise in signal strength (enhancement) in the anterior chamber. Signal enhancement typically occurred in the angle of the anterior chamber earlier, and to a greater degree, than within the center of the chamber. Increased signal within the posterior chamber was significantly less than in the anterior chamber, with measured increases probably attributable to volume averaging. CONCLUSIONS: These findings are consistent with the existence of an anterior diffusional pathway in the human eye. The model warrants further testing.

Adult↗

PubMed2007

Voluntary childlessness is increased in women with inflammatory bowel disease.

BACKGROUND: The women's health aspect of inflammatory bowel disease (IBD) is a newer area of study; childbearing issues have received little attention despite the fact that IBD affects women predominantly during their childbearing years. The aim of this study was to better understand patients' considerations about pregnancy-related issues and to examine trends in childbearing so that physicians are able to better tailor their advice to IBD-specific concerns. METHODS: Data were gathered from specific questions in 3147 surveys mailed anonymously to all members of the Crohn's and Colitis Foundation of America (CCFA) Illinois Carol Fisher chapter. The subjects were provided a pre-addressed, pre-stamped return envelope and were instructed to return their completed surveys with no identifying information. Subjects were from the Illinois community. Females IBD patients were 15-44 of age and were members of the CCFA Illinois Carol Fisher chapter. RESULTS: In this study, 169 females age 15-44 years with IBD, 110 with Crohn's disease (CD) and 59 with ulcerative colitis (UC), were identified. Most subjects were white. IBD patients had a higher rate of voluntary childlessness (CD 18%, UC 14%) than the 6.2% seen in the general population (P = 0.001 for CD, P = 0.08 for UC). Women with UC had a lower rate of temporary childlessness (CD 28%, UC 13.6%) than the general population (33%) (P = NS and P < 0.0001 for UC). The rates of nonvoluntary childlessness in IBD were similar to the general population. Women with IBD also had fewer children than their state and national counterparts. The state of the patients' IBD, including those who had gone through a previous pregnancy with IBD, did not alter their resolve to have children. The educational level of our subjects was higher than the nationwide and statewide levels; 76% of the subjects used contraception before diagnosis of IBD, and 82% used it after diagnosis. The most common choices were oral contraception, barrier methods, and abstinence. This study was unable to compare the lifetime rates of complications of pregnancy with population-based controls because such data were unavailable. Furthermore, their findings in this study may not be generalized to all ethnic groups because our population was mostly white. CONCLUSIONS: Women with IBD had a higher rate of voluntary childlessness and fewer children than the general population. These observations are likely attributable to a higher educational achievement and to racial background of the patients rather than to IBD-related reasons. Although contraception use in patients with IBD was lower that in the general population, use was higher after the diagnosis of IBD than before the diagnosis. Contraceptive choices and adoption rates were similar to the general population. Women with CD were more affected by miscarriages after diagnosis with IBD than those with UC.

Adolescent↗

PubMed2002

Safety and tolerability of the new contraceptive sponge Protectaid.

OBJECTIVE: This study was undertaken to assess the efficacy, safety and acceptability of two different-dose regimens of the Protectaid contraceptive sponge. METHODS: The toxic effects of two forms of the new vaginal contraceptive sponge, Protectaid, in the cervical and vaginal tissues were studied. Both types were impregnated with F-5 gel containing different doses of nonoxynol-9 (NX9; 0.5% and 0.125%). The sponge was used by 35 women aged 20-35 years (mean 28.7 years) randomly allocated into two groups (Group A: 0.5% NX9, n = 20; Group B: 0.125% NX9, n = 15). RESULTS: During a 12-month period both regimens demonstrated a 91.4% overall contraceptive efficacy. Colposcopic examinations showed no significant cervical or vaginal lesions in either group, except for two cases at the 2-week and 3-month examinations in Group A women. In the former, inflammatory changes of little clinical significance were seen and the colposcopic appearance of the vagina was non-specific. In this case, the focal lesions were accompanied by dilated capillaries (hyperemia). In the second case, degenerative inflammatory changes, with the inflammatory foci varying in shape and distribution, were observed. Cervical cultures taken 6 months after the start of treatment showed the presence of Mycoplasma hominis and Candida albicans in one and two cases, respectively, in Group A. In Group B, cervical cultures taken at 3 months showed Gardnerella vaginalis and beta-hemolytic streptococci group B in one and two cases, respectively. CONCLUSION: The potent spermicidal and protective properties of this new contraceptive sponge may be of benefit to the sexually active female. Since the sponge was very well accepted by both the study participants and their sexual partners, it can be considered as a valuable barrier method.

Administration, Intravaginal↗

PubMed2002

The influence of apoptosis of mucosal epithelial cells on intestinal barrier integrity after scald in rats.

OBJECTIVE: To study the influence of apoptosis of intestinal epithelial cells occurring as a result of reperfusion after burn shock on the intestinal barrier. METHODS: Fifty Wistar rats were subjected to a 30% TBSA full thickness burn, and normal saline (40 ml/kg) was given intraperitoneally immediately after the injury (group A). Ten rats served as a sham control group. The experimental group B consisted of 50 rats with identical injuries, but the normal saline was not given until 6h after the injury. Apoptosis of intestinal epithelial cells was verified by DNA fragmentation, DNA agarose gel electrophoresis, TUNEL and electron microscope (EM), and DNA fragmentation rate was expressed as ap%. The D-lactic acid in portal vein blood and intestinal diamine oxidase (DAO) were determined to evaluate the permeability and integrity of intestinal mucosal epithelium. RESULTS: The ap% of intestinal epithelium group B was higher than in that of group A (P<0.05 or 0.01), and its amplitude peaked at 12h for both groups. Typical DNA ladder pattern was seen in electrophoresis in both groups. Apoptotic cells were discerned on the tips of the ileal villi at 3h postscald by TUNEL and EM in the group B, and they appeared earlier than in the group A. There was a significant positive correlation between the ap% and the level of D-lactic acid (group A: r=0.817, P<0.05; group B: r=0.727, P<0.05). On the other hand, a significant negative correlation was found between the ap% and the DAO values (group A: r=-0.937, P<0.01; group B: r=-0.836, P<0.05). CONCLUSION: Apoptosis occurred in enterocytes after scald injury this pathological change might contribute to a breach of integrity of intestinal epithelium, leading to a compromise in its barrier function. Delayed fluid resuscitation might lead to an earlier and higher degree of apoptosis of the intestinal epithelial cells.

Amine Oxidase (Copper-Containing)↗

PubMed1996

The perimenopause and contraception.

OBJECTIVES: To review the implications of pregnancy in women in their forties and the contraceptive options open to them. METHOD: Medline and popline reviews of the literature. RESULTS: Women in their forties are still potentially fertile, and pregnancy in this age group is attended with increased maternal mortality, spontaneous abortion, fetal anomalies and perinatal mortality. In developing countries, these risks are compounded by high parity and poor medical care. Contraception for women in this age group has special risks and benefits, both should be balanced to choose between the different options available. Recent epidemiological and clinical pharmacology studies have indicated the safety of extending the use of combined oral contraceptives (COCs) beyond the age of 35 years and up to menopause. The improved picture of COCs has largely resulted from the use of low-dose-formulations, and avoidance of their use in women with risk factors for developing cardiovascular diseases. Besides their high reliability, which is desirable at this age, COCs will prevent the occurrence of climacteric symptoms and menstrual irregularities which are frequently complained of in the premenopausal years. Moreover, the use of COCs has a substantial protective effect against ovarian and endometrial cancers. Women who have reasons for avoiding COCs can use progestogen-only contraceptives like pills, depot injectables and implants. Norplant combines high efficacy and the long-term effect. Both copper-releasing and levonorgestrel-releasing IUDs (LNG-IUD) combine the advantages of high efficacy and long term effect. The reduced fecundity above the age of forty can allow extending the use beyond the accepted term, and up to one or two years beyond the menopause without the need for replacement. The levonorgestrel IUD has the advantage of reducing the amount of menstrual bleeding. The extent of use of barrier methods will depend upon the availability of a back-up by abortion service in case of failure. The condom has the added benefit of protection against STDs. Male or female sterilization is an excellent contraceptive option, provided that this approach is culturally acceptable and available at reasonable cost and low risk. CONCLUSION: Increasing the number of contraceptive options available to premenopausal women will improve proper counseling and enhance compliance.

Adult↗

PubMed2005

[Female condom or male condom: offer a choice!].

OBJECTIVES: As in the entire Ile-de-France, the Val-de-Marne is facing an increase in female contamination by HIV, a clear increase in STI and furthermore the number of legal abortions is still high. Various recent studies have emphasized the decrease in condom use since 1998. Can the possibility of proposing another condom, more specifically controlled by women, boost condom use? PATIENTS AND METHODS: The conseil général (local government authority) thus initiated a study in the general population, from January 1st 2001 to December 31st 2001, in order to study the criteria of acceptability of the female condom (FC). RESULTS: Although the women coming to consultation had no specific requests a quarter finally tested the female condom during sexual intercourse. Among them 4 out of 10 are ready to use it again. Curiosity was the primary motivation of those who accepted to test the female condom (77 %). Women who were more at ease with their sexuality were twice more likely to test the female condom. Three main advantages were put forward by the women who tested the FC: the strength of the FC, the fact that insertion was possible prior to the sexual act and the possibility of postponing removal, the latter being considered a supplementary advantage. The disadvantages most frequently cited before use were its appearance and difficult insertion process. The frequency of utilisation of the FC was multiplied by three when women practised putting the condom in place in a non-sexual context. However, even when they recognized one or several disadvantages women accepted to test it. In addition, whenever a woman finds at least one advantage before use she is twice more likely to test it. This is where counselling by professionals in charge of presenting the FC becomes a deciding factor. DISCUSSION AND CONCLUSIONS: The chance of using at least one sort of condom is increased when a choice of condoms is available. When both male and female condoms are available, the responsibility for prevention is better balanced within the couple: each partner can then be in charge of his or her own health. However the adoption of a barrier method such as the condom, means that the individual is conscious of such a need and finds that there are benefits mainly staying in good health. However the insufficient number of prevention and health promotion campaigns in France does not favour such an awareness. The availability of inexpensive female condoms in pharmacies, supermarkets as well as free distribution by certain institutions remains an unresolved question.

Acquired Immunodeficiency Syndrome↗

PubMed2003

The interaction between St John's wort and an oral contraceptive.

OBJECTIVES: The popular herbal remedy St John's wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives. Therefore we evaluated the effect of St John's wort on the disposition and efficacy of Ortho-Novum 1/35 (Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Twelve healthy premenopausal women who were using oral contraception (>3 months) received a combination oral contraceptive pill (Ortho-Novum 1/35) for 3 consecutive 28-day menstrual cycles. During the second and third cycles, the participants received 300 mg St John's wort 3 times a day. The serum concentrations of ethinyl estradiol (day 7), norethindrone (day 7), follicle-stimulating hormone (days 12-16), luteinizing hormone (days 12-16), progesterone (day 21), and intravenous and oral midazolam (days 22 and 23) were determined in serial blood samples. The incidence of breakthrough bleeding was quantified during the first and third cycles. RESULTS: Concomitant use of St John's wort was associated with a significant (P <.05) increase in the oral clearance of norethindrone (8.2 +/- 2.7 L/h to 9.5 +/- 3.4 L/h, P =.042) and a significant reduction in the half-life of ethinyl estradiol (23.4 +/- 19.5 hours to 12.2 +/- 7.1 hours, P =.023). The oral clearance of midazolam was significantly increased (109.2 +/- 47.9 L/h to 166.7 +/- 81.3 L/h, P =.007) during St John's wort administration, but the systemic clearance of midazolam was unchanged (37.7 +/- 11.3 L/h to 39.0 +/- 10.3 L/h, P =.567). Serum concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone were not significantly affected by St John's wort dosing (P >.05). Breakthrough bleeding occurred in 2 of 12 women in the control phase compared with 7 of 12 women in the St John's wort phase. The oral clearance of midazolam after St John's wort dosing was greater in women who had breakthrough bleeding (215.9 +/- 66.5 L/h) than in those who did not (97.5 +/- 37.2 L/h) (P =.005). CONCLUSION: St John's wort causes an induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity. Women taking oral contraceptive pills should be counseled to expect breakthrough bleeding and should consider adding a barrier method of contraception when consuming St Johns wort.

Administration, Oral↗

PubMed2003

Reduced folate transport to the CNS in female Rett patients.

BACKGROUND: Previous CSF studies in Rett syndrome suggest reduced turnover of the biogenic monoamines serotonin and dopamine. Because diminished turnover may result from CNS folate depletion, the authors studied transport of folate across the blood-brain barrier. METHODS: In four patients with Rett syndrome, the authors measured CSF values of 5-methyltetrahydrofolate (5MTHF), biogenic monoamine end-metabolites, and pterins together with serum and red blood cell folate. In CSF, the overall folate binding capacity by the two soluble folate-binding proteins FBP1 and FBP2 (sFBP) was measured using a radioligand binding method for H3-labeled folate. A specific immunoreactive test (ELISA) detected sFBP1, which normally contributes to 30 to 35% of the total folate binding capacity. Genetic analysis included DNA sequencing of the MECP2, FBP1, and FBP2 genes. Empirical treatment with oral folinic acid was evaluated. RESULTS: Two patients without and two with mutations of the MECP2 gene had normal values for red blood cell folate, serum folate, homocysteine, and methionine. In CSF, all patients had low values for 5MTHF, neopterin, and the serotonin end-metabolite 5-hydroxyindoleacetic acid (5-HIAA). Genetic analysis of FBP1 and FBP2 genes had normal results. Compared to controls, patients with Rett syndrome had normal immunoreactive sFBP1 in CSF, whereas the total folate binding capacity was disproportionately lowered. Empirical treatment with oral folinic acid normalized 5-MHTF and 5-HIAA levels in CSF, and led to partial clinical improvement. CONCLUSION: Irrespective of the MECP2 genotype, 5MTHF transfer to the CNS is reduced in Rett syndrome. Folinic acid supplementation restores 5MTHF levels and serotoninergic turnover. The lowered folate binding capacity of FBP is not explained by a defect of the FBP1 or FBP2 gene, but most likely occurs as a secondary phenomenon in Rett syndrome.

Biogenic Monoamines↗

PubMed1998

HIV-1 gp120 increases the permeability of rat brain endothelium cultures by a mechanism involving substance P.

OBJECTIVE: To analyse whether an HIV-1 envelope protein might play a role in damaging the blood-brain barrier as a fundamental step in the early invasion of the central nervous system by HIV-1. DESIGN: Analysis of permeability of rat brain endothelium cultures to albumin, to assess the functional integrity of the vascular component of the blood-brain barrier. METHODS: Rat brain endothelium cultures prepared by cerebral microvessels were exposed to recombinant gp120IIIB on microporous membranes and passage of biotin-labelled albumin was analysed. Scanning electron microscopy was used to analyse cell culture morphology. Some cultures were preincubated with N-nitro-L-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide synthase, or with spantide, a selective substance P antagonist. RESULTS: HIV-1 gp120 increased the permeability of rat brain endothelial cells to albumin in a dose-dependent manner. Scanning electron microscopy revealed profound gp120-induced alterations in cell morphology accounting for the increased permeability to macromolecules. These alterations were neutralized by anti-gp120 monoclonal antibody but not by isotype control antibody or L-NAME. By contrast, spantide and anti-substance P polyclonal antibody completely blocked the gp120-induced increase in albumin permeability. Control cultures exposed to measles virus nucleoprotein showed an increase in permeability that was not blocked by spantide. Brain endothelial cells, exposed to gp120, displayed cell surface immunoreactivity for substance P, suggesting that substance P is secreted by brain endothelium in response to gp120 stimulation and binds to brain endothelial cells through a receptor-mediated mechanism. CONCLUSIONS: These findings suggest a role for substance P in the gp120-induced increase in permeability of brain endothelium.

Animals↗

PubMedDate not supplied

Sexual partnership patterns as a behavioral risk factor for sexually transmitted diseases.

CONTEXT: Women's and men's number of sexual partners and protective practices such as condom use can have a direct effect on their risk of contracting sexually transmitted diseases (STDs), including HIV. METHODS: The 1988 and 1995 cycles of the National Survey of Family Growth and five rounds of the General Social Survey conducted from 1988 to 1996 are used to examine women's and men's numbers of recent sexual partners. Levels of direct risk for STDs (two or more partners in the past year) and the social and demographic correlates of multiple partnership are analyzed among women and men. In addition, women's indirect risk for STDs (their partners' involvement with other partners in the past year) is used to estimate their overall risk of STDs through multiple partnerships. RESULTS: At least three-quarters of sexually active U.S. women and men in the late 1980s and mid-1990s had had only one sexual partner in the preceding 12 months. Moreover, there is no indication that the proportion with more than one partner in the past year changed substantially over that period. Nevertheless, combining women's and men's partnership reports suggests that about 17 million women aged 15-44--34% of those sexually active in the past year--were at risk for STDs because of direct exposure to multiple partners (5.4 million), indirect exposure (6.3 million) or both direct and indirect exposure (5.5 million). In all, 21% of women were at direct risk and 23% were at indirect risk. In comparison, among men aged 18-44, 24% were at direct risk for STDs and an unknown proportion were at indirect risk. Multivariate analyses indicated that unmarried individuals, women younger than 40 and men aged 20-29, blacks and women in the South were all at elevated risk for STDs because of multiple partnership. Overall, in 1995, 19% of sexually active women aged 15-44 had used condoms to protect against STDs over the preceding year, and 19% of those sexually active in the three months before the survey were current condom users. Condom use specifically for STD prevention was more common among women reporting both direct and indirect risk for STDs (58%) and among those at direct risk (46%) than among other women; women whose partners put them at indirect risk only were less likely to be current or recent condom users than women who were not at risk or were only at direct risk. CONCLUSIONS: There is a continuing need to educate people regarding their risk for STDs, to increase the use of existing barrier methods and to develop new methods that protect against STD infection. In addition, if we are to develop a better understanding of the extent of STD risk through multiple partnership, the collection of information on number of partners and relationships between partners must be expanded and improved.

Adolescent↗

PubMed2002

Experimental research photodynamic effects in perifocal, oedematous brain tissue.

BACKGROUND: Photodynamic therapy (PDT) has been under discussion as additional treatment option for malignant gliomas. However, damage not only to tumour tissue but also to normal brain has been demonstrated. The mechanisms of this unwanted side effect have not yet been clearly identified. Spreading of photosensitiser with oedema after disruption of the blood-brain-barrier and potential sensitisation of normal tissue has been found previously. The present study investigates the time- and dose-dependency of normal tissue damage to photodynamic therapy using Photofrin II after disruption of the blood-brain-barrier. METHODS: Male wistar rats anaesthetised with chloral hydrate were subjected to focal, cerebral cold lesions. Simultaneously, Photofrin II (PFII) was injected (2,5 or 5 mg/kg b.w.). Laser irradiation (630 nm) was performed after 4 h, 12 h and 24 h with varying light doses. Control groups were subjected to focal cold lesion alone, cold lesion with laser irradiation, PFII followed by laser irradiation, or laser irradiation alone (n=6 all groups). 24 h later, brains were removed for assessment of necrosis in coronal sections. FINDINGS: Light dose had a significant impact on the extent of necrosis. Compared to control animals (lesion only: 0.84 +/- 0.2 mm2; lesion and irradiation alone: 0.7 +/- 0.3 mm2), the area of necrosis was increased to 2.8 +/- 0.5 (50 J/cm2), 3.5 +/- 1,1 (100 J/cm2) and 4.3 +/- 0.7 mm2 (200 J/cm2, 5 mg/kg b.w.; p<0.01). This effect was time-dependent. Maximal necrosis (6.3 +/- 1,6 mm2) was observed when brains were irradiated 12 h after PFII injection, with less necrosis occurring at 24 h (2.8 +/- 0.4 mm2, p<0.01). Reducing sensitiser dose to 2.5 mg/kg b.w. resulted in a reduction of necrosis (2.09 +/- 0.2 mm2, p<0.05). INTERPRETATIONS: Damage to oedematous tissue after photodynamic therapy using i.v. PFII and laser light at 630 nm depends on laser dose, sensitiser dose and the time point of laser irradiation. The time point of PDT should be considered to prevent unwanted tissue reactions. In the clinical setting however, defined damage to peritumoural tissue may be advantageous. This should be achievable by optimised timing and dosage of photodynamic therapy.

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