Mechanisms Linking Interparental Aggression to Child Dental Caries.

Research has garnered support for a systemic view of factors affecting child dental caries that accounts for the influence of social factors such as the family environment. Our previous work has demonstrated the association between mother-to-father emotional aggression and child caries. The present study builds on these results by evaluating pathways that might explain this relation. Families (n = 135) completed a multimethod assessment of mother-to-father emotional aggression, child caries, and several hypothesized mediators (i.e., child cariogenic snack and drink intake, child internalizing behaviors, child salivary cortisol and α-amylase reactivity, parental laxness, child oral hygiene maintenance, and parental socialization of child oral hygiene maintenance). Mediation analyses partially supported the role of the child's diet as a mechanism linking mother-to-father emotional aggression and child caries. However, children's neglect of oral hygiene, parental laxness, and child emotional and biological disturbances failed to stand as conduits for this association. Future investigations should expand upon these results to better establish the causal links that could only be suggested by the present cross-sectional findings.

The effect of ongoing blood loss on human serum concentrations of perfluorinated acids.

Perfluorinated alkyl acids (PFAAs) have been detected in serum at low concentrations in background populations. Higher concentrations haven been observed in adult males compared to females, with a possible explanation that menstruation offers females an additional elimination route. In this study, we examined the significance of blood loss as an elimination route of PFAAs. Pooled serum samples were collected from individuals undergoing a medical procedure involving ongoing blood withdrawal called venesection. Concentrations from male venesection patients were approximately 40% lower than males in the general population for perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). A simple pharmacokinetic model was used to test the hypothesis that blood loss could explain why adult males have higher concentrations of PFAAs than females, and why males undergoing venesections had lower concentrations compared to males in the general population. The model application generally supported these hypotheses showing that venesection might reduce blood serum concentrations by 37% (PFOA) and 53% (PFOS) compared to the observed difference of 44% and 37%. Menstruation was modeled to show a 22% reduction in PFOA serum concentrations compared to a 24% difference in concentrations between males and females in the background population. Uncertainties in the modeling and the data are identified and discussed.

The contribution of diet to total bisphenol A body burden in humans: results of a 48 hour fasting study.

Human biomonitoring studies measuring bisphenol A (BPA) in urine have shown widespread exposure in the general population. Diet is thought to be a major route of exposure. We studied urinary BPA patterns in five individuals over a 48-h period of fasting (bottled water only). Personal activity patterns were recorded with a diary to investigate non-dietary routes of exposure. All urine void events during the fast were collected, as well as events before and after the fast. The pattern of BPA concentrations was similar for all participants: they rose near the beginning of the fast (after the pre-fast meal), declined over the next 24h, fluctuated at lower levels during the second day, and then rose after the post-fast meal. Concentrations (~2 µg/g creatine) and calculated BPA intakes (~0.03 µg/kg-day) in these individuals during the first 24h were consistent with general population exposures. For the second 24h, concentrations and intakes declined by about two-thirds. One of the individuals had an extraordinary pre-fast exposure event with concentrations rising as high as 98 µg/g creatine but declining to <5 µg/g creatine by day 2. Given patterns found in day 1 and the subsequent decline to lower levels in day 2, we hypothesize that BPA exposures in these individuals were diet-driven. No events in the diary (use of personal care products, e.g.) appear associated with exposures. On day 2, non-dietary sources may still be present, such as from dust. Another hypothesis is that small reservoirs of BPA from past exposures are released from storage (lipid reservoirs, e.g.) and excreted.

Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses.

An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 µg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 h post-dose. For both DnBP and DiBP, the majority of the dose was excreted in the first 24 h (92.2 % of DnBP, 90.3 % of DiBP), while only <1 % of the dose was excreted in urine on day 2. In each case, the simple monoesters were the major metabolites (MnBP, 84 %; MiBP, 71 %). For DnBP, ~8 % was excreted as various side chain oxidized metabolites. For DiBP, approximately 20 % was excreted mainly as the oxidized side chain metabolite 2OH-MiBP, indicating that the extent of oxidative modification is around 2.5 times higher for DiBP than for DnBP. All DnBP and DiBP metabolites reached peak concentrations between 2 and 4 h post-exposure, followed by a monotonic decline. For DnBP metabolites, the elimination halftime of MnBP was 2.6 h; longer elimination halftimes were estimated for the oxidized metabolites (2.9-6.9 h). For DiBP metabolites, MiBP had the shortest halftime (3.9 h), and the oxidized metabolites had somewhat longer halftimes (4.1 and 4.2 h). Together with the simple monoesters, secondary oxidized metabolites are additional and valuable biomarkers of phthalate exposure. This study provides basic human metabolism and toxicokinetic data for two phthalates that have to be considered human reproductive toxicants and that have been shown to be omnipresent in humans.

Psychological correlates of adherence to self-care, disease activity and functioning in persons with systemic lupus erythematosus.

The aim of the study was to assess the effects of Sense of Coherence (SOC), emotional distress and treatment adherence on disease activity and functioning level of persons with systemic lupus erythematosus (SLE). One hundred persons with SLE, aged 18-60, participated in the study. They responded to the SOC scale, hospital anxiety and depression scale (emotional distress) and to questionnaires about adherence to treatment, level of functioning and disease activity. The results show a moderate level of disease activity and everyday functioning, as well as moderate levels of emotional distress. Income, emotional distress and adherence significantly predicted the levels of functioning (p < 0.001), while income and emotional distress significantly predicted the levels of disease activity only (p < 0.001). SOC was significantly associated with higher level of functioning (p < 0.001) and lower disease activity (p < 0.01), while emotional distress, but not treatment adherence, highly mediated these relationships. The results emphasize the associations of emotional distress and SOC with severity of the symptoms and level of functioning, and the associations between SOC and adherence to treatment. Further confirmation of the results with larger samples and longitudinal designs are warranted.

FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study.

This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation.

Leukocyte function associated antigen-1 (LFA-1) has a multifaceted role in the immune response, including adhesion and trafficking of leukocytes, stabilizing the immune synapse of the MHC-TCR complex and providing costimulation signals. Monoclonal antibodies to the CD11a chain of LFA-1 have been seen to result in effective immunosuppression in experimental models. Efalizumab, a humanized IgG1 anti-CD11a, is approved for use in psoriasis and may provide effective immunosuppression in organ transplantation. Thirty-eight patients undergoing their first living donor or deceased renal transplant were randomized to receive efalizumab 0.5 or 2 mg/kg weekly subcutaneously for 12 weeks. Patients were maintained on full dose cyclosporine, mycophenolate mofetil and steroids or half dose cyclosporine, sirolimus and prednisone. At 6 months following transplant patient survival was 97% and graft survival was 95%. Clinical biopsy-proven acute rejection in the first 6 months after transplantation was confirmed in 4 of 38 patients (11%). Three patients (8%) developed post transplant lymphoproliferative disease, all treated with the higher dose efalizumab and full dose cyclosporine. The two doses of efalizumab resulted in comparable saturation and modulation of CD11a. This phase II trial suggests that efalizumab may warrant further investigation in transplantation.

Exposure-efficacy relationships of a fingolimod-everolimus regimen in kidney transplant patients at risk for delayed graft function.

OBJECTIVE: We explored relationships between blood levels of fingolimod (FTY720) and everolimus versus treated biopsy-proven acute rejection (BPAR) in an open-label trial in de novo kidney transplant recipients. METHODS: Patients (n = 52) who fulfilled predefined criteria placing them at increased risk of delayed graft function received fingolimod 2.5 mg/d, everolimus 2 mg twice daily with trough blood levels (C0) adjusted to 4 to 8 ng/mL, and corticosteroids. Everolimus and fingolimod C0 were collected over 1 year; efficacy readout was at 3 months. RESULTS: Fingolimod C0 accumulated over the first 3 months with a time-averaged level (C0avg) of 5.7 +/- 3.5 ng/mL. At steady state in months 3 to 12, C0 was 7.0 +/- 4.4 ng/mL. Overall, 30 patients (58%) were free from BPAR to month 3. Patients were divided into four groups based on whether their fingolimod C0avg and everolimus C0avg were above or below the population medians. Freedom from BPAR was 53% and 57% for low fingolimod combined with low and high everolimus, whereas the percentages were improved to 83% and 85% for high fingolimod combined with low and high everolimus. CONCLUSIONS: This pilot study with an everolimus-fingolimod regimen demonstrated trends in freedom from rejection that were drug concentration-related and that underscored, in particular, a strong contribution to efficacy from fingolimod.

Close association between valvar heart disease and central nervous system manifestations in the antiphospholipid syndrome.

BACKGROUND: Heart valves lesions and central nervous system involvement are among the most common manifestations of the antiphospholipid syndrome (APS). OBJECTIVE: To evaluate possible interrelations between these manifestations in a large group of APS patients. METHODS: 284 APS patients were evaluated retrospectively, 159 of whom had primary APS. Cardiac-CNS associations were determined for the entire study population, and for subgroups of patients with primary APS or APS associated with systemic lupus erythematosus (SLE). RESULTS: Significant associations where found between cardiac vegetations and epilepsy (p < 0.02), and between cardiac valve thickening or dysfunction and migraine (p = 0.002). Borderline association was found between valvar vegetations and migraine (p = 0.09). A significant association was also found between all valvar lesions and stroke or transient ischaemic attacks. Subanalyses showed that patients with primary APS had significant associations between cardiac valve pathology and all CNS manifestations, while patients with APS associated with SLE had no such associations. CONCLUSIONS: The study suggests potential differences in biological behaviour between primary APS and APS associated with SLE. The presence of cardiac valve pathology may be a risk factor for several types of CNS involvement in PAPS.

Drug-resistant HIV infection among drug-naive patients in Israel.

BACKGROUND: In Israel, <0.06% of the general population is infected with human immunodeficiency virus (HIV), with a much higher prevalence among specific groups. These groups are distinguished demographically by risk behavior category and by virus subtype. We investigated transmission of drug resistance within groups to assess the impact of these factors. METHODS: Plasma samples from >15% of all patients with new diagnoses of HIV infection were randomly collected between June 1999 and June 2003. Sequences from 176 drug-naive patients included 20 of subtype A, 20 of subtype AE, 2 of subtype AC, 29 of subtype B, 100 of subtype C, and 5 of subtype F. RESULTS: Major drug resistance mutations (protease: L90M; reverse transcriptase: M41L, K103N, V106M, M184V, Y181S, G190A, L210W, T215Y/F, and K219R) were detected in 1 subject with A subtype, 3 with subtype B, and 9 with subtype C. In addition, 1 subject with A subtypes, 2 with subtype B, and 10 with subtype C had secondary mutations (protease: M46I; reverse transcriptase: A98G, K101Q, and V108I). Only 1 patient had mutations associated with >1 class of drugs. Among subjects who contracted HIV infection in Israel, 16 of 56 (1 of 7 with subtypes A or AE, 4 of 17 with subtype B, and 11 of 32 with subtype C; P=.7-1.0) carried resistant virus--a significantly higher proportion (P<.001) than in subjects infected in other countries (10 of 120 infected). CONCLUSIONS: Drug-resistant virus was detected in 14.8% of patients with new diagnoses of HIV infection but in 28.6% of patients known to have been infected in Israel. The implications include a need for pretreatment resistance testing and for better programs aimed at prevention of transmission, directed particularly at patients. We did not find significant differences in transmission of resistant virus between those infected with subtypes B and C, despite the different demographic background. A conclusive analysis and interpretation should await a more extensive study.

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers used for the treatment of hypertension appear to be safe in the early posttransplant period.

Angiotensin II converting enzyme inhibitors (ACE) and angiotensin II receptor blockers (ARB) are frequently avoided as treatment for hypertension in the early posttransplant period (0 to 90 days) for fear of nephrotoxicity. The following retrospective study was designed to explore the safety of these drugs in the early posttransplant period and determine appropriate clinical criteria for starting these medications. The records of all adult renal transplants performed between January 1997 and December 2000 (N = 290) were reviewed. All patients started on ACE or ARB for treatment of hypertension within 90 days of their transplant were included in the analysis (n = 17). Controls (n = 19) were patients who were treated with a calcium channel blocker (CCB) for hypertension. Cases and controls were matched for gender and type of transplant, living or cadaver. Patients were considered to be enrolled whey they met the following criteria: hypertension, serum creatinine < or =3.0 mg/dL, or falling 1 mg/dL/d and serum potassium < or =5.5 mEq/L. Exclusion criteria were coexistent pancreas transplant, anaphylaxis to ACE, and use of ACE or ARB for treatment of posttransplant erythrocytosis. There were no differences between cases and controls in hemoglobin or serum potassium concentrations or calculated glomerular filtration rate at 3, 6, and 9 months. In renal transplant patients with reasonable allograft function, administration of ACE and ARB to treat hypertension in the early posttransplant period appears to be well tolerated and not associated with excess hyperkalemia, anemia, or acute renal dysfunction.

Incidence, timing and site of infections among pancreas transplant recipients.

The incidence, timing and site of infections among the different categories of pancreas transplant recipients were investigated. Patients were divided into three groups: pancreas transplant alone (PTA), pancreas after kidney transplant (PAK), or simultaneous pancreas and kidney (SPK) transplants. Length of follow-up, time to death, pancreas graft survival, incidence, timing and site of bacterial infections were noted. Our study showed that at least 75% of pancreas transplant recipients experienced at least one infection (range from 77.8% in the PTA group to 86.7% in the PAK group). The SPK group presented the highest rate of infections with 35.1 infections per 1000/patient-days. Symptomatic urinary tract infections were the most common cause of infection in all patients. The incidence of infections was higher during the first month after transplantation, except for the SPK transplant group, where infections occurred over a longer time period.

The evolving experience using everolimus in clinical transplantation.

Everolimus is a derivative of sirolimus, a macrocyclic lactone, originally isolated from Streptomyces hygroscopicus. Both everolimus and sirolimus have a similar mechanism of action, exerting potent inhibition of growth factor-induced proliferation of lymphocytes, as well as other hematopoietic and nonhematopoietic cells of mesenchymal origin. Each agent complexes with the FK506 binding protein 12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G1-S phase cell cycle arrest. Safety and efficacy have been documented in large-scale, blinded, randomized, international clinical renal and cardiac transplant trials. Everolimus is more hydrophilic, exhibits a shorter elimination half-life (approximately 30 hours), and demonstrates greater relative bioavailability compared to sirolimus. However, similar to the calcineurin inhibitors and sirolimus, everolimus is biotransformed by the cytochrome P450, 3A4 isozyme. Also similar to sirolimus, clinical experiences identified biologically relevant side effects including hyperlipidemia and exacerbation of cyclosporine (CsA)-associated nephrotoxicity. However, also similar to sirolimus, accumulating evidence suggests that the hyperlipidemia can be controlled and the CsA-associated renal effects appear reduced with a low incidence of acute rejection when everolimus is administered in combination with reduced CsA doses. The experience using everolimus in cardiac transplantation has also provided potentially important insights into the consequences of antiproliferative effects on vascular smooth muscle cells and fibroblasts where reduction in intimal expansion was identified by intravascular coronary ultrasound examination among those patients receiving everolimus. Therefore, available results suggest that the introduction of everolimus as the newest TOR inhibitor should enhance therapeutic options for immunosuppression after organ transplantation.

Prevalence and clinical correlations of antibodies against six beta2-glycoprotein-I-related peptides in the antiphospholipid syndrome.

Two-hundred ninety five patients with the antiphospholipid syndrome (APS) were studied for the presence of antibodies against six anti-beta2GPI-related peptides Abs. The prevalence of a wide spectrum of clinical and laboratory parameters of APS was evaluated in all patients, and correlated with the presence of each anti-beta2GPI peptide antibody. The rates of the various antipeptides Abs ranged from 18.0 to 63.7%. Altogether, 87.1% of the patients had antibody reactivity against at least one of the six beta2GPI-related peptides. A high degree of simultaneous reactivity against several beta2GPI-peptides was found. Positive and negative correlations were found between several antipeptides Abs and the rates of thrombosis and fetal loss. Our results point to a heterogeneous activity of antiphospholipid Abs in APS patients, directed, often concurrently, against various epitopes of the beta2GPI molecule. Evaluation of APS patients for the presence of specific antipeptides Abs may be of a value in predicting the risk for future thrombotic and obstetrical complication, as well as for specific therapeutic purposes.

Quinacrine added to ongoing therapeutic regimens attenuates anticardiolipin antibody production in SLE.

The benefit of combining quinacrine (Qn) with hydroxychloroquine (HCQ) in the treatment of systemic lupus erythematosus (SLE) was previously re-evaluated by us. In our current study we observed that, in 11 active SLE patients (SLEDAI score 5-12), the addition of Qn (100 mg/day) to their existing ongoing therapeutic regimens resulted in a significant attenuation of their previously persistent anticardiolipin antibody (aCL) response. This was in comparison with a matched non-Qn treated control group composed of 14 randomly chosen aCL-positive SLE patients with a similar SLEDAI score 6-10. Prior to Qn treatment the therapeutic regimens of 12 months' duration, included in all cases HCQ (400 mg/day), in many cases prednisone (P, 10-20 mg/day) and in some additional cases immunosuppressive drugs. SLEDAI scores and aCL levels were monitored during the entire follow-up period which totaled 24 months in the study group and 15-18 months in the controls. Along with the beneficial effect of the added Qn on SLEDAI scores, aCL disappearance was documented in eight of 11 patients and remained negative during 8-12 months of follow-up (P = 0.004), compared with such a change in only three of 14 non-Qn treated aCL-positive patients (P = 0.18). We conclude that the added Qn treatment to former established therapeutic protocols may eliminate aCL response in SLE patients. Whether this agent's effect is permanent needs further elucidation.

Antiprothrombin antibodies are associated with pregnancy loss in patients with the antiphospholipid syndrome.

OBJECTIVE: To document the clinical association between the history of pregnancy loss in patients with the diagnosis of primary or secondary antiphospholipid syndrome (APS) and the presence of different antiprothrombin antibody subtypes [immunoglobulin G (IgG), IgM and IgA] in a cohort of patients with APS. METHODS: Records of 170 female patients with primary APS, or APS secondary to systemic lupus erythematosus (SLE) or secondary to other autoimmune diseases were studied. RESULTS: In female APS patients with IgG antiprothrombin antibodies (n = 105) significant associations to pregnancy loss (p < 0.0001), early pregnancy loss (p < 0.0001) and a negative association to thrombocytopenia (p < 0.01) could be identified. In the group of patients with IgG antiprothrombin antibodies and at least one pregnancy (n = 84) a significant association with pregnancy loss (p < 0.005) and especially with early pregnancy loss (p < 0.0001) was demonstrated. No association with other immunoglobulin subtypes of antiprothrombin antibodies could be documented. In the subgroup of patients with primary APS and at least one pregnancy in the history, pregnancy loss (p < 0.005) and early pregnancy loss (p < 0.0001) were found to be highly associated with the presence of IgG antiprothrombin antibodies. IgG antiprothrombin antibodies represent the highest independent risk factor for pregnancy loss with an odds ratio of 4.5. There was no statistically significant association with venous or arterial thrombosis in all IgG antiprothrombin antibody positive patients. CONCLUSION: The results of this study document the association of IgG antiprothrombin antibodies with pregnancy loss and in particular early pregnancy loss in a large and well-characterized cohort of patients. We would recommend routine testing for antiprothrombin antibodies in young female patients with APS.

Sirolimus-based immunosuppression with reduce dose cyclosporine or tacrolimus after renal transplantation.

Sirolimus (SRL), a fermentation product of Streptomyces hygroscopicus, complexes with the FKBP12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G(1)-S phase cell cycle arrest. Safety and efficacy have been documented in clinical renal transplantation, but concerns were raised due to important biologically relevant side effects. Hyperlipidemia was identified, beginning with early clinical experiences, and the unexpected findings that SRL may exacerbate CsA associated nephrotoxicity was observed during the pivotal phase III studies. This report details results of our experience using SRL (target trough concentration, 10-15 ng/mL) with low dose CsA (target trough concentration, 50-100 ng/mL), seeking to determine whether this approach might provide effective immunosuppression while reducing associated nephrotoxicity. Among 121 renal transplant recipients, 62 received the SRL based regimen and 59 received MMF with all patients receiving CsA and prednisone. Similar to earlier clinical experiences, hematopoeitic abnormalities and hyperlipidemia were observed among patients who received SRL, and those abnormalities were readily controlled. However, unlike observations from the phase III SRL studies, renal function was not adversely affected. These findings support the growing body of evidence indicating that SRL based immunosuppression in combination low dose calcineurin inhibitors and corticosteroids is safe, efficacious, and without associated renal toxicity.

Aspergillus vertebral osteomyelitis after simultaneous kidney-pancreas transplantation.

Aspergillus osteomyelitis is a rare complication of invasive aspergillosis after organ transplantation. This is the report of a 46-year-old man who underwent a simultaneous pancreas and kidney transplantation, complicated by an Aspergillus osteomyelitis and diskitis of the lumbar spine. Prompt diagnosis with needle biopsy, followed by antifungal therapy using caspofungin, a new antifungal agent recommended for the treatment of refractory aspergillosis, in combination with amphotericin B and an early surgical intervention led to clinical resolution of the infection. Reported cases of spinal aspergillosis after transplantation are reviewed in terms of clinical presentation, risk factors, therapeutic options, and outcome.