Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to α-Hexabromocyclododecane.

Assessing the role of α-hexabromocyclododecane α-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of α-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to α-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to α-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of α-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. α-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate α-HBCDD co-exposure.

Release of monomers from composite dust.

OBJECTIVES: Dental personnel are more at risk to develop asthmatic disease, but the exact reason is so far unknown. During abrasive procedures, dental personnel are exposed to nano-sized dust particles released from dental composite. The aim of this study was to investigate whether respirable composite dust may also release monomers. METHODS: Respirable (<5µm) composite dust was collected and the release of methacrylate monomers and Bisphenol A (BPA) in water and ethanol was evaluated by liquid chromatography/mass spectroscopy (LC-MS/MS). The dust was ultra-morphologically and chemically analyzed by transmission electron microscopy and energy-dispersive X-ray spectroscopy (TEM-EDS). RESULTS: LC-MS/MS analysis revealed that, irrespective of the type of composite, the respirable fraction of composite dust may release relatively high concentrations of unpolymerized methacrylate monomers, both in water and ethanol. Higher release was observed in ethanol. The endocrine disruptor BPA also emanated from the composite dust particles. TEM showed that most particles were nano-sized, although particle size ranged between 6nm and 5µm with a mode value between 12 and 39nm. Most particles consisted of several filler particles in resin matrix, although single nano-filler particles could also be observed. Elemental analysis by TEM-EDS proved that the particles collected on the filters originated from the dental composites. CONCLUSION: Theoretically, composite dust may function as a vehicle to transport monomers deeply into the respiratory system. The results of this study may shed another light on the increasing incidence of respiratory disease among dental personnel, and more care should be taken to prevent inhalation of composite dust. CLINICAL SIGNIFICANCE: Special care should be taken to prevent inhalation of composite dust, as the dust particles may release methacrylate monomers.

The effect of paternal methyl-group donor intake on offspring DNA methylation and birth weight.

Most nutritional studies on the development of children focus on mother-infant interactions. Maternal nutrition is critically involved in the growth and development of the fetus, but what about the father? The aim is to investigate the effects of paternal methyl-group donor intake (methionine, folate, betaine, choline) on paternal and offspring global DNA (hydroxy)methylation, offspring IGF2 DMR DNA methylation, and birth weight. Questionnaires, 7-day estimated dietary records, whole blood samples, and anthropometric measurements from 74 fathers were obtained. A total of 51 cord blood samples were collected and birth weight was obtained. DNA methylation status was measured using liquid chromatography-tandem mass spectrometry (global DNA (hydroxy)methylation) and pyrosequencing (IGF2 DMR methylation). Paternal betaine intake was positively associated with paternal global DNA hydroxymethylation (0.028% per 100 mg betaine increase, 95% CI: 0.003, 0.053, P=0.03) and cord blood global DNA methylation (0.679% per 100 mg betaine increase, 95% CI: 0.057, 1.302, P=0.03). Paternal methionine intake was positively associated with CpG1 (0.336% per 100 mg methionine increase, 95% CI: 0.103, 0.569, P=0.006), and mean CpG (0.201% per 100 mg methionine increase, 95% CI: 0.001, 0.402, P=0.049) methylation of the IGF2 DMR in cord blood. Further, a negative association between birth weight/birth weight-for-gestational age z-score and paternal betaine/methionine intake was found. In addition, a positive association between choline and birth weight/birth weight-for-gestational age z-score was also observed. Our data indicate a potential impact of paternal methyl-group donor intake on paternal global DNA hydroxymethylation, offspring global and IGF2 DMR DNA methylation, and prenatal growth.

Microscopic mechanisms of self-compensation in Si delta-doped GaAs.

We combined systematic cross-sectional scanning tunneling microscopy and spectroscopy investigations with Hall measurements on single Si delta-doped layers, as well as Si delta-doped superlattices in GaAs. We found that Si self-compensation involves nucleation and growth of electrically neutral Si precipitates at the expense of the conventional donor Si phase.

Pure motor hemiparesis and sensorimotor stroke. Accuracy of very early clinical diagnosis of lacunar strokes.

BACKGROUND AND PURPOSE: Clinical differentiation of lacunar from nonlacunar strokes in the very early phase could help to exclude patients with lacunar stroke from pharmacologic trials designed for nonlacunar strokes, namely, those with thrombolytic agents. In a continuous series of acute ischemic stroke patients, we evaluated how accurately a clinical diagnosis of pure motor hemiparesis or sensorimotor stroke formulated in the first hours from onset predicts a lacunar stroke documented by cerebral computed tomography or by autopsy. METHODS: We examined 517 patients (299 men, 218 women; mean +/- SD age, 67 +/- 10 years) within 12 hours (mean +/- SD, 6.1 +/- 3.2 hours) of the event. At hospital admission, we observed 151 (29%) patients with pure motor hemiparesis and 68 (13%) patients with sensorimotor stroke. RESULTS: Computed tomography or autopsy was compatible with a lacunar stroke (ie, detection of a lacune or permanently negative computed tomography) in 170 (33%) patients, of whom 123 (72%) had pure motor hemiparesis and 47 (28%) had sensorimotor stroke. This led to a sensitivity of 72%, a specificity of 72%, a positive predictive value of 56%, and a negative predictive value of 84%. Overall positive predictive value of pure motor hemiparesis was 58% (60% for two areas and 58% for three areas involved), and that of sensorimotor stroke was 51% (87% for two areas and 40% for three areas involved). By separately evaluating the sides of lesions, we found a positive predictive value of 46% for right-side infarcts and of 72% for left-side infarcts. Right-side lesions constituted 51% of lesions in lacunar syndrome patients with lacunar stroke, 76% in those with nonlacunar stroke, 19% in nonlacunar syndrome patients with lacunar stroke, and 31% in those with nonlacunar stroke (P < .0001). During the first days of hospital stay we observed a deterioration of 21% of lacunar syndrome patients with nonlacunar stroke and an improvement of 49% of nonlacunar syndrome patients with lacunar stroke, with appearance and disappearance of symptoms of cortical involvement, respectively. The examination of these patients after the occurrence of these clinical changes would have led to a daily increase of the positive predictive value up to a maximum of 66% at day 7. CONCLUSIONS: Pure motor hemiparesis and sensorimotor stroke diagnosed within 12 hours of the event are poorly predictive of lacunar strokes. Hence, the very early identification of these syndromes cannot be used for patient selection in therapeutic trials.

Posttransplant renal rejection: comparison of quantitative scintigraphy, US, and MR imaging.

Accuracy of ultrasonography (US), quantitative scintigraphy, and magnetic resonance (MR) imaging in diagnosis of acute renal allograft rejection was studied in 46 patients who underwent renal biopsy. Thirty-three patients had acute rejection; six, cyclosporine nephrotoxicity, as shown by biopsy, clinical findings, and follow-up study; two, acute tubular necrosis; and five, normal biopsy findings and renal function. Accuracy in demonstrating rejection was 72% for US and 75% for scintigraphy, indicating no significant difference between the two. MR imaging was significantly more accurate, reaching a level of 98%. However, accuracy of MR in demonstrating acute tubular necrosis in a larger number of patients is not known, and its accuracy in indicating recurrent glomerulopathy or infectious disease has not been addressed. The definitive role of MR in evaluating posttransplant renal failure is currently not established, but because of its high sensitivity in detecting renal abnormality, MR can be used for cases when results of US or scintigraphy are equivocal or contradict clinical impressions or when biopsy cannot be performed for medical reasons.

Twenty years of renal transplantation in children.

Two-hundred three children 1 to 16 years of age received kidney transplants during a 20-year period, 100 from living donors and 103 from cadaver donors. The overall survival rate was 79%. Actuarial patient and kidney survival rates at 15 years were 79% and 52%, respectively, for recipients of living donor kidneys and 57% and 19%, respectively, for recipients of cadaver donor kidneys. One of two children who received transplants in 1964 was alive 20 1/2 years later. Twenty-nine children had kidneys that had functioned more than 10 years; their mean serum creatinine concentration was 1.7 mg/dL and 24 were fully rehabilitated. Eighteen were more than 2 SD below the mean height of normal children, however. Comparison of survival rates during successive 5-year intervals showed significant improvement in patient survival during the 20-year period and smaller improvements in kidney survival after 1979. Patient survival after living donor transplants during the last 10 years was 100%, and kidney survival during the last 5 years was 92%. Improvement was attributed to the effect of experience, as well as to changes in immunosuppressive therapy in 1972 and the introduction of donor-specific transfusions in 1978.

Is a "low" dose of prednisone better than a "high" dose at the time of renal transplantation?

It has been suggested that a low dose of prednisone initially given post-transplant, besides producing lower patient morbidity, is as effective as high dose regimens in providing positive graft and satisfactory patient outcome. In 1981 and 1982, we prospectively and randomly studied 77 cadaveric kidney recipients who received a high dose (2.0 mg/kg body weight) (H) and 66 who received a low dose of prednisone (0.5 mg/kg body weight) (L) at the time of transplant. Mean time to the first rejection episode was 9.7 +/- 13.8 and 13.3 +/- 12.9 days in the L and H groups, respectively; 10.6% and 15.6% of the patients in the L and H groups, respectively, never had a rejection episode. Among subjects younger than 45 years, graft and patient survival was better for those treated with the high dose (N = 60, 63.9% vs 32.2%, P = 0.032, and 100% vs 88.4%, P = 0.027, respectively) than for those treated with the low dose (N = 46). Patient and graft response to H and L was similar for patients older than 45. Morbidity was similar for both the L and H groups.

Dramatic improvement in the success rate for renal transplants in diabetic recipients with donor-specific transfusions.

The chance of achieving successful kidney transplants in diabetic patients was previously limited because few of them had optimally-matched (2-haplotype) related donors. Hence, transplants were usually not carried out until renal failure had already occurred. The application of donor-specific transfusions (DSTs) prior to transplantation to poorly matched donor-recipient pairs (1-haplotype) has been associated with a high success rate for type-I diabetic recipients in our center. The rate of graft survival for 35 consecutive transplants in this category was 88%, 80%, and 73% at 1, 2, and 5 years, respectively. Furthermore, the rate of patient survival was 94%, 90%, and 90% at 1, 2, and 5 years. These patient and graft survival data were without significant difference when compared with the corresponding data for 142 optimally-matched (2-haplotype) related transplants performed without DSTs for nondiabetic recipients, and also when compared with the corresponding data for 130 poorly matched (1 or 0-haplotype) related transplants involving nondiabetic recipients who were prepared for transplantation with DSTs. These good results with DSTs in diabetic recipients emphasize that earlier transplantation utilizing poorly matched related donors should be seriously considered for diabetic patients even before the onset of renal failure, as long as the transplants are carried out in association with DSTs.

Peptic ulcer disease in kidney transplant recipients.

The occurrence of peptic ulcer in kidney transplant recipients treated with corticosteroids for immunosuppression is a problem of considerable magnitude and threatens both patient and graft survival. The fact that peptic ulcer usually occurs in the early months after transplantation, and that there are known risk factors including treatment for rejection, sepsis, and hepatitis, demand a high level of clinical suspicion, early and accurate diagnosis, and prompt treatment. Aggressive medical prophylaxis is important, but if it should fail prompt reduction of the dose of corticosteroids is imperative so that continued patient survival is emphasized rather than the continued survival of the transplant. Surgical intervention, when indicated, should also be prompt, and the more definitive operations such as vagotomy with pyloroplasty or gastric resection are preferred because of a lesser occurrence of reoperation among such patients. Prophylactic operations in patients with an antecedent history of peptic ulcer may provide considerable protection against the development of corticosteroid-related ulcers after transplantation.

Long-term renal function in kidney donors. Sustained compensatory hyperfiltration with no adverse effects.

Twenty patients who underwent uninephrectomy for kidney donation between 1964 and 1968 participated in a long-term study of the function of the solitary kidney. Mean follow up after uninephrectomy was 15.8 +/- .3 years. One patient with a strong family history of essential hypertension developed de novo mild hypertension. The current creatinine clearance of the donors was 80 +/- 4 ml/min. The 1-week, 3-6 months and 14-18 years postuninephrectomy percentages of predonation creatinine clearance were 72 +/- 3%, 76 +/- 3% and 78 +/- 2%, respectively. The 24-hr urine protein excretion in kidney donors was significantly higher than in controls (141 +/- 20 mg vs. 74 +/- 3 mg, respectively, P less than .0005). Except for one donor who may have developed glomerulonephritis, the donors had normal urinary albumin excretion. The cause of the slightly elevated nonalbumin proteinuria is not known. However, this long-term study of kidney donors shows no adverse effects on the blood pressure and renal function after many years of compensatory hyperfiltration.

Blood transfusions before and on the day of transplantation: effects on cadaver graft survival.

Pre-BTs significantly improve the survival rate for first cadaver transplants, by a mechanism that remains obscure. The maximal influence is seen with smaller numbers of pre-BTs (1-5 units), but is also observed with larger numbers of pre-BTs. The possible beneficial influence of Tx-BTs on graft survival is not proven, and if it exists at all is not nearly as striking as the effect seen with pre-BTs. Tx-BTs neither potentiate nor nullify the benefit of pre-BTs on graft survival. It is therefore recommended that pre-BTs in smaller numbers, such as 1-5 units, be administered to candidates for first cadaver transplants to increase the probability of a successful outcome. Tx-BTs should be utilized when clinically indicated but not with the expectation that they will necessarily improve graft survival.

Update of the University of California at San Francisco experience with donor-specific blood transfusions.

Prospective pretreatment with deliberate DST has afforded MLC reactive related donor-recipient pairs enhanced opportunity for successful transplantation. The sensitization rate in patients receiving DST prior to primary transplantation was 30%, but this sensitization has been generally specific and narrow-those patients developing a positive DSXM do not appear to be jeopardized regarding later cadaver transplantation. Graft survival rates in 86 recipients of kidneys from their blood donors are 95% (1-year) and 93% (2-year). This graft survival rate appears to outweigh the minimal risk of possible unfavorable sensitization. Potentially unsuccessful transplants in immunologically disparate related donor-recipient pairs can be avoided, and the transplants actually performed have enhanced prospects of success.

Prognostic features of early renal transplant rejections.

In an analysis of 632 cadaver transplants, the early renal transplant course gave important prognostic information depending on temporal and/or renofunctional characteristics of rejection episodes. Two transplant rejections occurring within the first 2 mo posttransplant were associated with either 37%, 27%, or 6% 1-yr graft survivals depending on whether these episodes were separate, temporally back-to-back, or were without interrejection renofunctional recovery, respectively. This compares to 1-yr graft survivals of 89% or 73% in those patients who had no rejection or one with recovery early posttransplant. Patient survival in groups with multiple early rejections was also associated with a poor prognosis. Ninety to 93% 1-yr patient survival was noted when there was no or one rejection. There was only a 74%-83% 1-yr patient survival with two early treated rejections. Transplant rejection therapy must be individualized or even withheld in order to ensure optimum graft and patient survival.

An alternative to cadaver kidney transplants for patients with insulin-dependent diabetes mellitus.

The benefits of successful kidney transplants for patients with end stage renal disease associated with insulin-dependent diabetes mellitus are well known, and the potential advantages of earlier transplantation have been emphasized in other reports. Cadaver transplants, which are not always available for these patients, have not provided a high degree of success in many centers. This has discouraged the use of transplants unless well matched related donors are available. Most patients do not have well matched family members who are able to donate. We have attempted to increase the availability of related transplants for diabetic patients by using a new protocol in which related donors who are poorly matched by mixed lymphocyte culture (MLC) testing (stimulation index (SI) greater than or equal to 7) can often serve as the source of the transplant. This protocol of pretransplant donor-specific transfusions (DSTs) has been applied to 20 diabetic patients. Sixteen transplants have been performed after serial immunological studies following the DSTs detected no specific evidence of recipient sensitization to the respective transfusion donors. Only one of the transplants has been rejected, and this occurred in a patient who intentionally terminated immunosuppressive therapy. Graft survival for the group of 16 patients is 93 and 84% at 1 and 3 years, respectively. The quality of renal function for most of the patients is very good, with a mean serum creatinine of 1.9 and 1.5 ml/dl for those transplants at risk for 12 and 24 months. This new method has given encouraging results for poorly matched related transplants in diabetic patients and makes earlier transplantation possible by providing an alternative to cadaver transplants.

1,500 renal transplants at one center: evolution of a strategy for optimal success.

From analysis of results of more than 1,500 renal transplants has evolved a plan for donor selection and immunosuppressive management whereby patients with end-stage renal disease can obtain maximum graft and patient survival. With superior results in both patient and graft survival with living-related transplantation, this modality should be considered initially. Pretreatment with third party blood transfusions appears effective in all donor categories. Donor-specific blood transfusions have afforded 1-haplotype mixed lymphocyte culture-incompatible recipients enhanced opportunity for successful transplantation. Current results with living-related transplantation suggest realistic expectations of 1 and 2 year graft survival rates of greater than 90 percent. Curtailment of steroid therapy has resulted in improved patient survival at 1 and 2 years: 98 and 97 percent for recipients of living-related grafts, and 91 and 88 percent for recipients of cadaver grafts. These results, in combination with proper donor selection and appropriate recipient pretreatment with blood transfusions, have made renal transplantation a very effective therapeutic method in patients with end-stage renal disease.

Pretreatment with donor-specific blood transfusions in related recipients with high MLC.

Pretreatment with deliberate DST has not resulted in hyperacute or irreversible rejection in patients receiving kidneys after negative donor-specific crossmatches, but has afforded immunologically disparate related recipients enhanced opportunity at successful transplantation. Additionally, with a post-transplant course paralleling that of HLA-identical siblings, high-dose immunosuppressive therapy for rejection has been spared in many recipients. Transplantation, however, proved unsuccessful in a patient receiving a kidney from his positive B-warm crossmatch blood donor in a protocol departure. This case experience and subsequent antibody studies have reconfirmed our initially established criterion of not proceeding with transplantation against a persistently positive B-warm donor-specific crossmatch. By pursuing the initially established DST protocol, it appears that a potentially unsuccessful living related transplant can be avoided, while the transplants actually performed have enhanced prospects of success. The nature of the various immunologic responses in this patient population remain to be more clearly defined.

Decreased secondary hyperparathyroidism in diabetic patients receiving hemodialysis.

Biochemical and bone scintigraphic studies were performed in nondiabetic and diabetic patients receiving hemodialysis at the time of kidney transplantation to assess the degree of secondary hyperparathyroidism. Despite lower serum calcium concentrations, diabetic patients had significantly lower parathyroid hormone (PTH) levels than nondiabetic patients. In addition, diabetic patients had lower graded total-skeletal scintigraphic scores than nondiabetic patients. The PTH levels showed positive correlations with bone scan scores and with alkaline phosphatase in nondiabetic patients but not in diabetic patients. Avascular necrosis occurred in 17% of nondiabetic patients and in only 2% of diabetic patients. Patients with avascular necrosis had significantly higher PTH levels than patients without avascular necrosis. Diabetes mellitus seems to confer a protective effect from the skeletal manifestations of secondary hyperparathyroidism, including avascular necrosis.