Hepatic elimination of diazepam: interactions with albumin, desflurane and sevoflurane

We have studied the effect of sevoflurane and desflurane on the hepatic elimination of diazepam, by incubating slices of rat livers in a closed system. Protein free and protein containing (albumin 10 g litre-1) buffers were used to examine the effect of the anaesthetics on enzyme activity and diazepam binding to albumin. Both anaesthetics (in concentrations of 0.5, 1.5 and 3.0 mmol litre-1) reduced the elimination of diazepam slightly in the absence of albumin, while the presence of the protein increased elimination to a maximum of 30% at the greatest concentration of the anaesthetics. These data support previous observations that volatile anaesthetics may interact pharmacokinetically with both liver enzyme activity and drug binding to albumin.     

Sudden cardiac death: a retrospective and prospective study

Since the inception of mobile coronary care units (MCCU), patients with sudden cardiac death (SCD) saved by advanced emergency medical technicians (EMT-A) can be studied retrospectively and prospectively. Forty-eight cases of SCD found in ventricular fibrillation (VF) were successfully resuscitated. Only 32% had a myocardial infarction. Most survivors were New York Heart Association (NYHA) class I or II. All class IV survivors with severe congestive heart failure died within 45 days. All class II survivors had angina as the limiting factor. Of all patients with VF, 23% survived. Eighty percent of survivors were class I or II and have resumed previous lifestyles. No clear cut symptom complex was identified. Rescue response time was generally less than five minutes. Intracardiac medications were administered without complications. Empirical administration of sodium bicarbonate correlated poorly with arterial blood gas determinations.     

The BsmI vitamin D receptor restriction fragment length polymorphism (bb) influences the effect of calcium intake on bone mineral density

Previous studies of the vitamin D receptor (VDR) polymorphisms and bone mineral density (BMD) have suggested that there may be differences in calcium absorption among groups of women with different VDR genotypes, and that the association may be stronger in younger women. To investigate the association between the VDR polymorphisms and BMD, this study was undertaken in the Framingham Study Cohort and a group of younger volunteers. Subjects from the Framingham Study (ages 69-90 years) included those who underwent BMD testing and who had genotyping for the VDR alleles (n = 328) using polymerase chain reaction methods and restriction fragment length polymorphisms with BsmI (B absence, b presence of cut site). A group of younger volunteer subjects (ages 18-68) also underwent BMD testing and VDR genotyping (n = 94). In Framingham Cohort subjects with the bb genotype, but not the Bb or BB genotypes, there were significant associations between calcium intake and BMD at five of six skeletal sites, such that BMD was 7-12% higher in those with dietary calcium intakes greater than 800 mg/day compared with those with intakes < 500 mg/day. The data also suggested that BMD was higher in persons with the bb genotype only in the group with calcium intakes above 800 mg/day. No significant differences were found in the Framingham Cohort for age-, sex-, and weight-adjusted BMD at any skeletal site between those with the BB genotype and those with the bb genotype regardless of 25-hydroxyvitamin D levels or country of origin. In the younger volunteers, BMD of the femoral neck was 5.4% higher (p < 0.05) in the bb genotype group compared with the BB group and 11% higher (p < 0.05) in males with the bb genotype compared with the BB group. There were no significant differences at the lumbar spine. In this study, the association between calcium intake and BMD appeared to be dependent upon VDR genotype. The findings of an association between dietary calcium intake and BMD only in the bb genotype group suggests that the VDR genotype may play a role in the absorption of dietary calcium. Studies that do not consider calcium intake may not detect associations between VDR genotype and BMD. In addition, the association between VDR alleles and BMD may become less evident in older subjects.     

Unilateral total lobectomy: is it sufficient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma?

BACKGROUND: Controversy continues regarding the optimal extent of primary thyroid resection in most patients with papillary thyroid carcinoma (PTC), who are at minimal risk of cause-specific mortality (CSM). This study was designed to compare CSM and recurrence rates after either unilateral lobectomy (UL) or bilateral lobar resection (BLR) in patients with PTC considered low risk by AMES criteria. METHODS: Outcome was studied in 1685 patients initially treated during 1940 through 1991 and followed for up to 54 postoperative years (mean, 18 years). One thousand six hundred fifty-six patients (98%) had complete primary tumor resection; 634 (38%) had involvement of regional nodes. One hundred ninety-five patients (12%) had UL; BLR accounted for 1468 (near-total 60%; total thyroidectomy 18%). RESULTS: Thirty-year rates for CSM and distant metastasis were 2% and 3%, respectively. Twenty-year rates for local recurrence and nodal metastasis were 4% and 8%, respectively. There were no significant differences in CSM or distant metastasis rates between UL and BLR (P > .2). After UL, 20-year rates for local recurrence and nodal metastasis were 14% and 19%, significantly higher (P = .0001) than the 2% and 6% rates seen after BLR. CONCLUSIONS: UL was not associated with higher CSM rates, but it was associated with a significantly higher risk of locoregional recurrence. Thus BLR probably represents a preferable initial surgical approach to patients with low-risk PTC.     

Cell-mediated cytotoxicity: a predictor of chronic rejection in pediatric HLA haploidentical renal transplants

BACKGROUND: Recipient antidonor cytotoxic T-cell activity has been associated with graft loss and acute rejection in renal allograft recipients. The role of immunologic mechanisms in the development of chronic graft rejection is controversial. We analyzed all living related renal transplants performed at Children's Hospital (Boston, MA) from 1983 to 1995 to assess whether cell-mediated cytotoxicity, determined in vitro and measured before transplantation, was predictive of chronic rejection. METHODS: Eighty-three patients were studied retrospectively. Fifty-seven patients with one haplotype-matched renal transplants from living related donors were studied to determine the association between cell-mediated lympholysis (CML) level, acute rejection, chronic rejection, and graft failure. Acute rejection was defined by the decision to treat. Chronic rejection was defined by histology and/or the absolute serum creatinine value using an increasing serum creatinine level >1.0 mg/dl for children less than 3, a creatinine level >1.5 mg/dl for children between 3 and 10 years of age, and a creatinine level >2.0 mg/dl for children above 10 years of age. Return to dialysis or retransplantation was considered graft failure. RESULTS: Of the 57 haploidentical patients, there were 33 males and 24 females. The mean age at transplant was 11.1 years (SD=6.7). Twelve patients developed chronic rejection, 24 patients developed acute rejection, and 7 patients had graft failure. Pretransplant cytotoxic T lymphocyte activity was associated with chronic rejection (P=0.001) and graft failure (P=0.013) but only marginally with acute rejection (P=0.058). Controlling for age and sex, Cox's proportional hazards model revealed that CML level was predictive of time to chronic rejection (P<0.01) but not acute rejection (P=0.11). It was estimated that every 1-unit increase in CML level raises the monthly risk of chronic rejection by 7%. Ten children received HLA-identical kidneys from their siblings. There were no episodes of chronic rejection after 5 years. Two patients with high CML levels had episodes of acute rejection; both patients responded to treatment. CONCLUSION: Our data demonstrate an association between pretransplant cell-mediated cytotoxicity and the occurrence of chronic rejection in living related one-haploidentical renal transplants in pediatric patients.     

Cerebral blood flow velocity and vasomotor reactivity before and after shunting surgery in patients with normal pressure hydrocephalus

The purpose of this study was to evaluate pre- and post-shunting haemodynamic changes and their correlation with the clinical results in normal pressure hydrocephalus (NPH). Accordingly, eleven demented patients with clinical signs suggestive of NPH received examinations of cerebral blood flow velocity (BFV) and vasomotor reactivity (VMR) by transcranial Doppler sonography with carbogen testing before and after shunt treatment. Computerized tomography (CT), clinical assessment and neuropsychological grading were performed prior to and at 3 months following surgery. A control group consisting of 10 patients was included to establish baseline data. The pre-operative CBF studies in the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) revealed the NPH patients did not have significant decreases of BFVs, but had significant decreases of carbogen VMR (P < 0.05). After shunting, there were no significant changes of the BFVs as compared with the pre-shunting data. The post-shunting VMR of the ACA was significantly higher than the pre-shunting one (p < 0.05), but there was no variation in that of the MCA. Both the values of post-shunting VMR in ACA and the post-shunting increase in VMR in MCA of the 7 shunt-responsive patients who improved mentally and in other symptoms were significantly higher than those of patients without improvement (p < 0.05). In addition, the five patients with gait improvement showed significantly higher values of post-shunting VMR of ACA and the post-shunting increase of VMR for both ACA and MCA when compared with those patients without gait improvement (p < 0.05, respectively). Our study supports the view that patients with NPH had various degrees of impaired VMR in both the ACA and the MCA, but showed insignificant reduction in BFVs, indicating a compensatory mechanism of CBF over time to accommodate the subnormal state of cerebral perfusion pressure. Shunt placement would improve the VMR in responsive patients. Postoperatively, an increase of VMR tends to accompany improvement of the functional state: that in the MCA alone is associated with symptomatic improvement in mental function and that increase in VMR in both the ACA and the MCA with improvement in gait, respectively.     

Molecular cloning of CYP1A from the estuarine fish Fundulus heteroclitus and phylogenetic analysis of CYP1 genes: update with new sequences

Since we published a phylogenetic analysis of the CYP1A subfamily in 1995, several additional full-length sequences have been reported, including three members of an entirely new subfamily, CYP1B. Two avian sequences were recently published, so that CYP1A sequence data are now available from three of the five major vertebrate lineages. The two new branches that have been added to the CYP1 family tree significantly add to our understanding of P450 evolution. The inclusion of the CYP1Bs to the phylogenetic analysis allows us to root inferred trees. Addition of the avian CYP1As indicates that the CYP1A1/CYP1A2 duplication present in the mammalian lineage may have occurred after the divergence of birds and mammals. The number of fish species from which full-length coding regions of CYP1A genes have been sequenced has increased from four (trout, plaice, toadfish, and scup) to nine. These include CYP1A sequences from tomcod, butterflyfish, sea bream, sea bass, and the full-length sequence of CYP1A from the killifish Fundulus heteroclitus that is reported here. Phylogenetic analyses incorporating the new fish CYP1A sequences support our original conclusion that the fish CYP1As are monophyletic and indicate that the genes are evolving at very different rates in different species.