Phenytoin kinetics during pregnancy and the puerperium

During pregnancy changes in maternal physiology and plasma composition may alter drug binding and dose requirements. We have measured plasma unbound and total phenytoin, and saliva concentrations at intervals in 11 pregnant epileptics. Plasma albumin concentrations were also measured in pregnant and non-pregnant women. Saliva phenytoin correlated closely with the plasma unbound concentrations (r = 0.98). The saliva:plasma (S:P) ratio, reflecting the free fraction, was variable during pregnancy but tended to increase to maximal values at delivery and return to non-pregnant values within 2-8 weeks thereafter. Plasma albumin concentrations correlated poorly with phenytoin binding. Binding in umbilical cord plasma appeared higher than that in maternal plasma and total fetal concentrations correlated closely with maternal plasma concentrations at delivery. No ill effects of phenytoin were detected in the newborn infant. During the third trimester phenytoin dose increments were necessary to maintain therapeutic concentrations. After delivery maternal saliva phenytoin concentrations rose, and dose reductions were necessary to avoid clinical symptoms of toxicity. It is therefore appropriate to monitor saliva phenytoin concentrations regularly both during pregnancy and the puerperium.     

Factors associated with refusal to provide a buccal cell sample in the Agricultural Health Study.

Epidemiological studies are increasingly collecting buccal cells and other sources of DNA for genetic analysis. However, high refusal rates raise concerns about possible selection bias. This study examines the subject characteristics associated with refusal or failure to provide a buccal cell sample. Subjects were male farmers in the Agricultural Health Study, which is being conducted in Iowa and North Carolina. As part of a 5-year follow-up, cohort members were contacted by telephone and asked to participate in a telephone interview and to consent to providing a buccal cell sample using a kit that was mailed to them. Demographic, lifestyle, disease, and occupational characteristics were compared between consenters who returned a sample ("compliers"), nonconsenters ("refusers"), and consenters who failed to return a sample ("noncompliers"). Compliers (n = 8794), refusers (n = 3178), and noncompliers (n = 3008) were quite similar, although compliers tended to be slightly older. Although some significant differences between these groups were observed, the magnitude of these differences was generally small, usually no more than a few percentage points. In conclusion, this study found little difference between male farmers who agreed to provide buccal cell samples versus those who either refused to provide a sample or who agreed but failed to return the sample. Observed differences were typically small and would be unlikely to compromise etiologic associations identified in such a prospective study. In short, there appears to be little selection bias in the Agricultural Health Study buccal cell collection process, further supporting the use of such mailed collection kits in epidemiological research.     

Regulatory aspects of noninvasive glucose measurements

The Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Act (the Act) established three regulatory classes for medical devices. Section 513 of the Act specifies three classes based upon the degree of control and Food and Drug Administration (FDA) oversight that is necessary to assure that the various types of devices are safe and effective. High-risk devices are placed into the most regulated device class, Class III. Under Section 515 of the Act, all devices placed in Class III are subject to premarket approval (PMA) requirements. PMA by FDA is the required process of scientific review to ensure the safety and effectiveness of Class III devices. Advisory panel review is required of virtually all original submissions. Manufacturing facilities of devices requiring PMA approval are also subject to preapproval inspection to assure data integrity and compliance with good manufacturing practices. An approved PMA is granted for marketing a particular medical device for a particular intended use. FDA considers noninvasive and minimally invasive glucose devices that are intended to measure, monitor, or predict blood glucose levels in diabetics to be high-risk medical devices. These devices will have a significant potential impact on the medical care of people with diabetes. The technology offers potential improvements in the quality of life, enhanced blood glucose control through increased frequency of testing, or access to testing, in a broader range of patients. However, the technology is not yet well understood, and the information obtained from these devices is often different from the information that has been the traditional base for the management of diabetes. As a result, FDA requires both analytical and clinical studies to support the intended claims for these new devices.     

Two distinct tumor cell growth-inhibiting factors from a human rhabdomyosarcoma cell line

Tumor cell growth-inhibiting factors (TIFs) have been shown to inhibit the growth of tumor cell lines in culture. TIF-1, the first TIF to be described, is a low-molecular-weight, acid- and heat-stable polypeptide with no antiviral activity. A second class of TIFs (TIF-2) has now been isolated from the conditioned media of a human rhabdomyosarcoma cell line and partially purified by polyacrylamide gel filtration, cation exchange, and reverse-phase high-pressure liquid chromatography. Partially purified preparations of TIF-2 inhibit the growth of a variety of human tumor cells in soft agar and monolayer cultures and are mitogenic for normal human and mouse cells. TIF-2 has no antiviral activity. The growth-inhibitory effects of TIF-2 are reversible when the affected cells are no longer exposed to the factor. Although both TIF-1 and TIF-2 are obtained from the same source, they can be distinguished by their molecular weight, heat lability, elution pattern from reverse-phase high-pressure liquid chromatography, and their effect on the growth of mink lung epithelial cells. The growth of a human tumor cell variant, selected for resistance to growth inhibition by TIF-1, is inhibited by TIF-2. TIFs may therefore be a family of related polypeptides which selectively inhibit the growth of tumor cells.     

Hemophilia B and free tissue transfer: medical and surgical management

Hemophilia B (Christmas disease) is a rare, X-linked bleeding diathesis, which may present with life-threatening hemorrhage. Management of the coagulopathy in the setting of free tissue transfer may be particularly challenging. The authors present the first case in the English literature of a male with hemophilia B undergoing microvascular free flap reconstruction, as well as a review of the current surgical and medical management of hemophilia B. Based upon this experience, perioperative specific factor replacement is recommended. Given physiologic trough levels of the replaced factor, routine antiplatelet therapy appears appropriate. Management of free tissue transfer in the setting of severe hemophilia is significantly more challenging and should benefit from multidisciplinary coordination.     

ATP elicits inward currents in isolated vasopressinergic neurohypophysial terminals via P2X2 and P2X3 receptors

Effects of extracellular adenosine tri-phosphate (ATP) on ionic currents were investigated using the perforated-patch whole-cell recording technique on isolated terminals of the Hypothalamic Neurohypophysial System (HNS). ATP induced a current response in 70% of these isolated terminals. This inwardly-rectifying, inactivating current had an apparent reversal near 0 mV and was dose-dependent on ATP with an EC₅₀=9.6±1.0 M. In addition, current amplitudes measured at maximal ATP concentrations and optimum holding potentials had a current density of 70.8 pA pF^–1 and were greatly inhibited by suramin and PPADS. Different purinergic receptor agonists were tested, with the following efficacy: ATP 2-methylthioATP > ATP--S > Bz-Bz-ATP > ,-methylene-ATP > ,-methylene-ATP. However, UTP and ADP were ineffective. These data suggest the involvement of a P2X purinergic receptor in the ATP-induced responses. Immunocytochemical labeling in vasopressinergic terminals indicates the existence of P2X_{2,3,4, and 7}, but not P2X₆ receptors. Additionally, P2X_{2 and 3} were not found in terminals which labeled for oxytocin. In summary, the EC₅₀, decay, inactivation, and pharmacology indicate that a functional mixture of P2X_{2 and 3} homomeric receptors mediate the majority of the ATP responses in vasopressinergic HNS terminals. We speculate that the characteristics of these types of receptors reflect the function of co-released ATP in the terminal compartment of these and other CNS neurons.     

Bax deficiency rescues resection-induced enterocyte apoptosis in mice with perturbed EGF receptor function

BACKGROUND: Adaptation after massive smallbowel resection (SBR) is associated with increased cell turnover, increased rates of enterocyte proliferation, and apoptosis. Epidermal growth factor receptor (EGFR) inhibition attenuates adaptation and increases apoptosis. Intestinal levels of bax appear to correlate with EGFR signaling. This study tested the hypothesis that bax is required for the exaggerated postresection apoptosis induced by perturbed EGFR signaling. METHODS: Waved-2 mice with impaired EGFR signaling were crossbred with bax-null mice. Offspring were subjected to either 50% proximal SBR or sham operation (bowel transection and reanastomosis). After 7 days, parameters of adaptation (villus height, wet weight), proliferation (% Ki-67 immunostaining of crypt cells), and apoptosis (# apoptotic bodies per crypt) were recorded in the remnant ileum. RESULTS: Enterocyte apoptosis was increased in waved-2 mice and prevented in bax-null mice after SBR. The accelerated apoptosis in the waved-2 mice was rescued in the context of deficient bax expression. Other parameters of adaptation were restored in the bax-null/waved-2 mice. CONCLUSION: Bax is required for the induction of postresection enterocyte apoptosis. Defective EGFR signaling augments resection-induced enterocyte apoptosis via a mechanism that also requires bax expression. These data implicate a link between EGFR signaling and bax in the genesis of postresection apoptosis and adaptation.     

Reconstruction of a tracheobronchial tree disruption with bovine pericardium

Iatrogenic tracheobronchial disruption is a rare, life-threatening condition. Depending upon the extent of the injury, its location, and the condition of the patient, repair/reconstruction options may be limited. The natural history of bovine pericardium used to repair one such tracheal injury has been documented.