Evidence that tolerance to cultured thyroid allografts is an active immunological process. Protection of third-party grafts bearing new antigens when associated with tolerogenic antigens.

We studied the tolerance phenomenon that develops in long-term recipients of cultured thyroid allografts. Allogeneic mouse thyroids were cultured under hyperbaric oxygen or acidic conditions and then transplanted beneath the kidney capsule of C57BL/6 recipients. Donors differed from the recipients in minor antigens alone, major histocompatibility complex antigens alone, or both. At 35-77 weeks after the first cultured graft, recipients received two more cultured grafts under the capsule of the opposite kidney and were immunized with donor spleen cells (SC). At 5 weeks after the second transplantation, we observed that whereas second grafts carrying new antigens alone were rejected, second grafts carrying new antigens in association with antigens in the first graft were significantly protected. In another set of experiments, normal mice became tolerant to cultured allografts after 2 weeks in parabiosis with tolerant individuals. Tolerant mice showed reduced specific in vivo and in vitro cytotoxic T lymphocyte responses. However, the frequency of CTL precursors of tolerant mice was the same as in normal mice. The reduced in vitro CTL responses were restored to normal levels by the addition of a lymphokine rich medium. Also, we observed that the injection of specifically activated immune SC caused the rejection of cultured allografts in normal but not in tolerant recipients. We conclude that the tolerance that develops in recipients of cultured allografts is an active immunological process that affects the activation and effector function of CTL.     

Influence of Hemorrhagic Shock Followed by Crystalloid Resuscitation on Propofol: A Pharmacokinetic and Pharmacodynamic Analysis

Background: Previous work has demonstrated that ongoing hemorrhagic shock dramatically alters the distribution, clearance, and potency of propofol. Whether volume resuscitation after hemorrhagic shock restores drug behavior to baseline pharmacokinetics and pharmacodynamics remains unclear. This is particularly relevant because patients suffering from hemorrhagic shock are typically resuscitated before surgery. To investigate this, the authors studied the influence of an isobaric bleed followed by crystalloid resuscitation on the pharmacokinetics and pharmacodynamics of propofol in a swine model. The hypothesis was that hemorrhagic shock followed by resuscitation would not significantly alter the pharmacokinetics but would influence the pharmacodynamics of propofol.

Methods: After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock-resuscitation groups. Swine randomized to the shock-resuscitation group were bled to a mean arterial blood pressure of 40 mm Hg over a 20-min period and held there by further blood removal until 42 ml/kg of blood had been removed. Subsequently, animals were resuscitated with lactated Ringer's solution to maintain a mean arterial blood pressure of 70 mm Hg for 60 min. After resuscitation, propofol (750 [mu]g[middle dot]kg-1[middle dot]min-1) was infused for 10 min. The control group underwent a sham hemorrhage and resuscitation and received propofol at the same dose and approximate time as the shock-resuscitation group. Arterial samples (20 from each animal) were collected at frequent intervals until 180 min after the infusion began and were analyzed to determine drug concentrations. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. Pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model.

Results: The raw data demonstrated minimal differences in the mean plasma propofol concentrations between groups. The compartment analysis revealed some subtle differences between groups in the central and slow equilibrating volumes, but the differences were not significant. Hemorrhagic shock followed by resuscitation shifted the concentration effect relationship to the left, demonstrating a 1.5-fold decrease in the effect-site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale.     

When Is a Bispectral Index of 60 Too Low?: Rational Processed Electroencephalographic Targets Are Dependent on the Sedative-Opioid Ratio

Background: Opioids are commonly used in conjunction with sedative drugs to provide anesthesia. Previous studies have shown that opioids reduce the clinical requirements of sedatives needed to provide adequate anesthesia. Processed electroencephalographic parameters, such as the Bispectral Index (BIS; Aspect Medical Systems, Newton, MA) and Auditory Evoked Potential Index (AAI; Alaris Medical Systems, San Diego, CA), can be used intraoperatively to assess the depth of sedation. The aim of this study was to characterize how the addition of opioids sufficient to change the clinical level of sedation influenced the BIS and AAI.

Methods: Twenty-four adult volunteers received a target-controlled infusion of remifentanil (0-15 ng/ml) and inhaled sevoflurane (0-6 vol%) at various target concentration pairs. After reaching pseudo-steady state drug levels, the modified Observer's Assessment of Alertness/Sedation score, BIS, and AAI were measured at each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for each pharmacodynamic endpoint.

Results: Response surface models adequately characterized all pharmacodynamic endpoints. Despite the fact that sevoflurane-remifentanil interactions were strongly synergistic for clinical sedation, BIS and AAI were minimally affected by the addition of remifentanil to sevoflurane anesthetics.     

Unusual presentation of common acute lymphoblastic leukemia antigen-positive extramedullary disease in childhood. Two patients with isolated masseter muscle involvement.

Two children with unusual extramedullary common acute lymphoblastic leukemia antigen (CALLA)-positive (CD10) disease are reported. Isolated masseter infiltration with CD10/CD19-positive lymphoblasts was present in both patients with no other evidence of disease. One child had relapse of common acute lymphoblastic leukemia, and the other had primary disease. Disease may have spread from lymph nodes overlying the masseter muscle. Immunophenotyping and immunogenotyping provided a rapid and accurate diagnosis for both children.     

Screening for toxoplasmosis in pregnancy.

The prevalence of antibody against Toxoplasma gondi in a population of 715 pregnant women has been evaluated by two methods: indirect haemagglutination antibody (IHA) and indirect fluorescent antibody (IFA) test and all positive sera were checked by the dye test. Five hundred of the study population were questioned on diet and on animal contact to elucidate a possible relation to the prevalence of antibody. Results are expressed in international units (IU) of antibody against T gondi. Of the 715 sera, 171 were positive by IHA and 173 by IFA. One hundred and sixty-seven sera were positive by both tests, ninety-eight (58%) correlating exactly, as to the concentration of antibody. The ten sera which were not positive by both tests all had detectable antibody at the minimum concentration only (12 IU). The dye test confirmed all sera positive by both tests with the exception of three. It also confirmed one of four sera positive by IHA antibody alone and two of six positive by IFA alone. All sera that proved dye test-negative had low antibody concentrations (12 IU) by IHA or IFA. The IHA test, which is commercially available in kit form, would be suitable for use as a screening test during pregnancy. The estimated annual rate of antibody acquisition over the age range 16-40 years is 1.2% per annum with the highest rate in the 36-40 age group (2.5% per annum) and the lowest in the 26-30 age group (0.4% per annum). The clinical history was not significantly different between those with and those without antibody against T gondi but significantly more women in the 36-40 age group had a history of animal contact than those in the 26-30 age group. No conclusive evidence of recent or current infection was found.     

The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis

Diabetes insipidus is a well-recognized complication of Langerhans-cell histiocytosis (histiocytosis X), but its frequency and natural history are not well defined. Of 52 children with histiocytosis whom we studied, 12 (23 percent) had diabetes insipidus. Only two children had diabetes insipidus at presentation with histiocytosis, but the cumulative risk that it would develop during the first four years after the presentation and diagnosis of histiocytosis was found to be 42 percent. Diabetes insipidus occurred most often among children with multisystem disease and those with proptosis. To determine the natural history of diabetes insipidus in children with histiocytosis, we measured the response of urinary arginine vasopressin to water deprivation every six months in 21 children who did not have diabetes insipidus and who had had histiocytosis for less than four years. Five of the 21 children (24 percent) had subnormal responses during the initial test. One subsequently had spontaneous improvement in the functioning of the posterior pituitary, and diabetes insipidus subsequently developed in two, as it did in one of the children who initially had normal function of the posterior pituitary. Two of the children received irradiation to the pituitary within two to four weeks after diabetes insipidus developed, but they had no improvement in pituitary function. However, diabetes insipidus improved transiently during prednisolone therapy in one of these children and improved permanently after etoposide therapy in another child. We conclude that prospective study with the use of a simple water-deprivation test will allow partial defects of posterior-pituitary function to be detected in patients with histiocytosis and will permit a more appropriate evaluation of the effects of therapeutic intervention.     

Localization of cellular retinoid-binding proteins in human cervical intraepithelial neoplasia and invasive carcinoma.

Cellular retinoic acid-binding protein (CRABP) and cellular retinol-binding protein (CRBP) were localized in biopsies of normal squamous epithelium, cervical intraepithelial neoplasia (CIN), and invasive squamous cell cancer of the cervix uteri by immunohistochemistry. In both the normal stratified squamous epithelium of the exocervix and low-grade CIN, CRABP I was present predominantly in the basal layer of the epithelium. The more superficial, differentiated cell layers lacked immunoreactive protein. In high-grade CIN (CIN2-3), the distribution of CRABP I was altered. Immunoreactive CRABP I was detected in all layers of high-grade CIN. In squamous cell carcinoma of the cervix, CRABP I was detected in cells throughout the tumor but was minimal in cells demonstrating squamous differentiation. In contrast to CRABP I, CRBP was diffusely present throughout the cervical epithelium irrespective of the state of differentiation or the presence of disease.     

Second molar replacement applied to dentofacial orthopedics and orthodontics much more than a technique

There is seldom a consensus on any dental subject. The literature contains conflicting points of view and results of studies vary considerably. I have endeavored to present my paradigm of second molar replacement in dentofacial orthopedics and orthodontics. I have presented a summation of information known to date regarding this subject. I based this article on my extensive clinical experience and observations over many years. I participate in continuing education, and know many of the traditional and functional post-doctoral educators. I read the literature. For your benefit, I have presented this information and shared a paradigm that has positively changed my life, and perhaps will change the way you practice. Second molar replacement technique has revolutionized orthodontic treatment. The technique offers distinct benefits considering the patient's face, the jaw joints, and the teeth. The reader is strongly encouraged to read bibliography references for a mature understanding of second molar replacement in modern orthodontics and TMD therapy. When extraction of teeth is needed for orthodontic purposes Broadbent considers second molar replacement, second bicuspid removal, first bicuspid removal, lower incisor removal, and then other extraction possibilities to resolve the malocclusion. When extraction guidelines are followed and treatment mechanics are properly designed the extraction of second molars have predicable good results in a high percentage of cases. However, second molar removal may be contraindicated for numerous reasons. Diagnosis and case selection is paramount! The doctor must diagnosis and determine if and when second molar replacement would be in each patient's best interest. The bottom line for each individual patient is the best possible facial esthetics, functional occlusion, and health of jaw joints.     

A rejoinder to Professor Bruening

Point and Counterpoint

A rejoinder to Professor Bruening