The high jugular bulb: report of five cases and a review of the literature

The jugular bulb varies widely in position and dimensions. A high jugular bulb is not an uncommon finding in temporal bones. Besides our five cases with different clinical manifestations, we review 52 cases diagnosed clinically and published previously in the English literature. The high jugular bulb occurs more often on the right temporal bone. Certain pathologic conditions, such as an abnormal bone formation, an aberrant sinusojugular system, or decreased pneumatization of the mastoid bone, may predispose an individual to its occurrence. Most people with this anatomical variation remain asymptomatic. However, various otologic problems and symptoms may be attributed to this condition. A high resolution computed tomography scan is the most convenient diagnostic tool at present. Law projection plain mastoid radiography may reveal a high jugular bulb in certain cases, providing a preoperative warning to an otologic surgeon. An exploratory tympanotomy is not suggested for those with a high jugular bulb with a conductive hearing loss, while jugular vein ligation has been reported to have good results in alleviating intractable pulsatile tinnitus. For most asymptomatic patients, regular long-term follow-up is recommended.     

Synaptically evoked glutamate transport currents may be used to detect the expression of long-term potentiation in cerebellar culture

Cerebellar long-term potentiation (LTP) is a use-dependent increase in the strength of the granule cell-Purkinje neuron synapse that occurs after brief stimulation of granule cell axons at 2-8 Hz. Previous work has shown that cerebellar LTP also may be seen when synaptic currents are evoked in granule cell-glial cell pairs in culture. This finding suggests a model in which cerebellar LTP is expressed presynaptically and therefore may be detected by either neuronal or glial postsynaptic cells. However, synaptic currents evoked in both granule cell-glial cell pairs and granule cell-Purkinje neuron pairs in culture are mediated primarily by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors, raising the possibility that cerebellar LTP might be expressed postsynaptically in both glial cells and Purkinje neurons in a similar manner. To address this question, glutamate transport currents were recorded in granule cell-glial cell pairs in culture by pharmacological isolation. These currents were increased by substitution of internal Cl with NO3 and were blocked by -pyrrolidine-2,4-dicarboxylate, both characteristics of the major cloned Bergmann glial cell glutamate transporter, EAAT1. After acquisition of baseline responses, LTP of isolated transport current was evoked by stimulation at 4 Hz (100 pulses) and could be blocked by removal of external Ca during this stimulation. The expression of LTP was associated with a decrease in the rate of synaptic failures and a decrease in the degree of paired-pulse facilitation. These findings, when taken together with the previous observation that both Purkinje neuron and glial AMPA/kainate responses can be used to detect cerebellar LTP, strongly suggest that the expression of cerebellar LTP is, at least in part, presynaptic. This strategy should also be useful in illuminating the locus of expression of other model systems of information storage such as hippocampal LTP/long-term depression.     

Structure of nitric oxide synthase oxygenase dimer with pterin and substrate

Crystal structures of the murine cytokine-inducible nitric oxide synthase oxygenase dimer with active-center water molecules, the substrate L-arginine (L-Arg), or product analog thiocitrulline reveal how dimerization, cofactor tetrahydrobiopterin, and L-Arg binding complete the catalytic center for synthesis of the essential biological signal and cytotoxin nitric oxide. Pterin binding refolds the central interface region, recruits new structural elements, creates a 30 angstrom deep active-center channel, and causes a 35 degrees helical tilt to expose a heme edge and the adjacent residue tryptophan-366 for likely reductase domain interactions and caveolin inhibition. Heme propionate interactions with pterin and L-Arg suggest that pterin has electronic influences on heme-bound oxygen. L-Arginine binds to glutamic acid-371 and stacks with heme in an otherwise hydrophobic pocket to aid activation of heme-bound oxygen by direct proton donation and thereby differentiate the two chemical steps of nitric oxide synthesis.     

HLA-B27-restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading

Tapasin is a resident ER protein believed to be critical for antigen presentation by HLA class I molecules. We demonstrate that allelic variation in MHC class I molecules influences their dependence on tapasin for peptide loading and antigen presentation. HLA-B*2705 molecules achieve high levels of surface expression and present specific viral peptides in the absence of tapasin. In contrast, HLA-B*4402 molecules are highly dependent upon human tapasin for these functions, while HLA-B8 molecules are intermediate in this regard. Significantly, HLA-B*2705 like HLA-B*4402, requires tapasin to associate efficiently with TAP (transporters associated with antigen processing). The unusual ability of HLA-B*2705 to form peptide complexes without associating with TAP or tapasin confers flexibility in the repertoire of peptides presented by this molecule. We speculate that these properties might contribute to the role of HLA-B27 in conferring susceptibility to inflammatory spondyloarthropathies.     

Stem cell factor enhances the adhesion of AML cells to fibronectin and augments fibronectin-mediated anti-apoptotic and proliferative signals

Acute myeloid leukaemia (AML) cells express the SCF receptor c-kit (CD117) on their cell surface and demonstrate enhanced adhesion to fibronectin (FN) following exposure to stem cell factor (SCF). Increased adhesion occurs within 5 min, is dose dependent, and persists beyond 2 h. Baseline and enhanced adhesion occur through the surface FN receptor very late antigen-5 (VLA-5, CD49e/CD29) which is expressed by AML cells. Unstimulated AML cells exposed to FN undergo less apoptosis than controls (inhibition 22.5 +/- 7.0%, P = 0.02, n = 8). Exposure to SCF alone without FN also inhibits AML cell apoptosis (by 19.0 +/- 7.7% compared to controls, P = 0.06, n = 8). Simultaneous exposure to SCF and FN increases the inhibition of AML cell apoptosis to 37.8 +/- 7.9% (P = 0.005 compared to control, P = 0.04 compared to FN alone, P = 0.06 compared to SCF alone) demonstrating that SCF not only enhances the propensity of AML cells to adhere to FN, but also results in an additive survival benefit following FN contact. Some but not all the reduction in apoptosis is mediated through VLA-5. The combination of SCF and FN also affects proliferation, resulting in a synergistic enhancement of AML cell proliferation in half the cases studied. When normal CD34+ human haemopoietic progenitors were studied, FN had little effect on their apoptosis and failed to enhance the anti-apoptotic effect of SCF. It did, however, synergise with SCF in promoting CD34+ cell proliferation. Exposure of AML cells to SCF and FN, both of which can be found in high concentration in the bone marrow stroma, inhibits apoptosis. Cytokines and extracellular matrix proteins augment each others' effects since SCF enhances adhesion to fibronectin, which in turn augments the survival signal delivered by the cytokine alone. Cytokine and adhesion receptors can combine to affect cell characteristics including proliferation and survival.     

Gallstones and isoflurane hepatitis

OBJECTIVES: To assess the level of satisfaction of physicians in provincial psychiatric hospitals with Review Boards (RBs) regarding Civil Commitment Certificates (CCCs), Certificates of Incompetence (COIs), and Treatment Orders (TOs). METHOD: A total of 200 survey questionnaires were distributed to physicians in provincial psychiatric hospitals. Ninety surveys (completed by 25 females, 45 males, and 20 unknown gender) were returned, representing a 45% return rate. Because of their assignments (for example, outpatient department), not all physicians were involved with RBs, and the return rate is likely to have been influenced by this factor. RESULTS: Physician satisfaction rates of 58.2% for CCCs, 66.7% for COIs, and 70.0% for TOs were obtained. Stepwise multiple regression analysis showed that the level of physician satisfaction with RBs for CCCs was predicted best (44.7% of variance) by physician level of comfort with certification and years of institutional affiliation. Qualitative physician responses revealed 3 major themes: patient-related issues, physician-related issues, and RB structure- and process-related issues. CONCLUSIONS: Strategies that increase physician comfort level with RBs and changes in the medicolegal structure and process are discussed. A similar survey of patients and RB members is recommended.     

Orthotopic heart transplantation in a transgenic pig-to-primate model

BACKGROUND: Previous studies demonstrated that hearts from transgenic pigs expressing human decay-accelerating factor (hDAF) were not hyperacutely rejected when transplanted heterotopically into the abdomen of cynomolgus monkeys. This study examines orthotopic transplantation of hDAF transgenic pig hearts into baboon recipients. METHODS: Orthotopic xenogeneic heart transplantation was performed using piglets, transgenic for hDAF, as donors. Ten baboons were used as recipients and were immunosuppressed with a combination of cyclophosphamide, cyclosporine, and steroids. RESULTS: Five grafts failed within 18 hr without any histological signs of hyperacute rejection. Pulmonary artery thrombosis induced by a size mismatch was observed in two of these animals. The other three recipients died because of failure to produce even a low cardiac output and/or dysrhythmia. The remaining five animals survived between four and nine days. One animal died of bronchopneumonia on day 4. Three xenografts stopped beating on day 5 due to acute vascular rejection. The longest survivor was killed on day 9 with a beating, histologically normal xenograft, because of pancytopenia. CONCLUSIONS: The results reported here demonstrate that hDAF transgenic pig hearts are not hyperacutely rejected when transplanted into baboon recipients. Orthotopically transplanted transgenic pig hearts are capable of maintaining cardiac output in baboons. An optimum immunosuppressive regimen is the subject of ongoing research.     

Palliative chemotherapy with CMF after the same adjuvant regimen for breast cancer. The Breast Cancer Study Group

BACKGROUND: The results of palliative chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in patients with advanced breast cancer who received adjuvant therapy with the same regimen were investigated. RESULTS: Of 47 patients, 14 (30%) achieved an objective remission (median duration 9.5, range 5-21 months) and 8 (17%) stabilisation of disease (median duration 6, range 3-17 months). Objective remissions were observed in premenopausal as well as in postmenopausal women, in patients with all categories of dominant localisation of disease and regardless of the oestradiol receptor status of the primary tumour or eventual previous endocrine therapy. One of 4 and 13 of 43 patients who started palliative chemotherapy within or later than 12 months after the last adjuvant course obtained an objective remission. The median survival time from start of therapy of all treated patients was 12 (range 1-40) months. Patients with an objective remission or stable disease and patients with progressive disease had a median survival time of 20 (range 6-40) and 6 (range 1-35) months respectively (p < 0.0001). CONCLUSIONS: Palliative treatment with CMF should not be rejected for patients who have relapsed after adjuvant chemotherapy with the same modality.     

Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers

The pharmacokinetics and dose proportionality of fexofenadine, a new non-sedating antihistamine, and its enantiomers were characterized after single and multiple-dose administration of its hydrochloride salt. A total of 24 healthy male volunteers (31 +/- 8 years) received oral doses of 20, 60, 120 and 240 mg fexofenadine HCl in a randomized, complete four-period cross-over design. Subjects received a single oral dose on day 1, and multiple oral doses every 12 h on day 3 through the morning on day 7. Treatments were separated by a 14-day washout period. Serial blood and urine samples were collected for up to 48 h following the first and last doses of fexofenadine HCl. Fexofenadine and its R(+) and S(-) enantiomers were analysed in plasma and urine by validated HPLC methods. Fexofenadine pharmacokinetics were linear across the 20-120 mg dose range, but a small disproportionate increase in area under the plasma concentration-time curve (AUC) (< 25%) was observed following the 240 mg dose. Single-dose pharmacokinetics of fexofenadine were predictive of steady-state pharmacokinetics. Urinary elimination of fexofenadine played a minor role (10%) in the disposition of this drug. A 63:37 steady-state ratio of R(+) and S(-) fexofenadine was observed in plasma. This ratio was essentially constant across time and dose. R(+) and S(-) fexofenadine were eliminated into urine in equal rates and quantities. All doses of fexofenadine HCl were well tolerated after single and multiple-dose administration.     

Metabolism of Zidovudine

1. The anti-HIV drug zidovudine (3'-azido-2',3'-dideoxythymidine; ZDV) has three important pathways of metabolism. ZDV is a prodrug and must be phosphorylated in lymphocytes in order to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall metabolic profile. The predominant pathway of metabolism is glucuronidation to GZDV and the metabolite is renally excreted. A further metabolite, derived by reduction of the azido moiety is 3'-amino-3'-deoxythymidine (AMT). 2. Zidovudine glucuronidation has been characterised in human liver microsomes. A number of drugs (e.g., naproxen, indomethacin and probenecid) have been shown to inhibit the in vitro conjugation of ZDV. Some of these drugs have also been co-administered with ZDV in HIV-positive patients. Significant pharmacokinetic interactions have been demonstrated with probenecid, naproxen and fluconazole. 3. 3'-amino-3'-deoxythymidine formation is probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Peak plasma concentrations of AMT are approximately 10-15% of ZDV in patients. This is a potentially important metabolite because of its alleged cytotoxicity. 4. Measurement of intracellular ZDV phosphates in patients provides the key to our understanding of both the efficacy and toxicity of ZDV. Important recent work has demonstrated that as patients deteriorate (i.e., CD4 counts decrease below 100 x 10(6)/L), there is a corresponding increase in intracellular ZDV-monophosphate. This could have toxicological implications.