Characterization of the pharmacology and regional distribution of (S)-[3H]-5-fluorowillardiine binding in rat brain.

1. This study examined the binding of the new radioligand (S)-[3H]-5-fluorowillardiine to rat brain synaptic membranes. Specific binding represented greater than 80% of the total binding and was increased by 10% in the presence of 100mM potassium thiocyanate (KSCN). 2. In the absence of KSCN, (S)-[3H]-5-fluorowillardiine identified two binding sites with KD1=22.5 nM, Bmax1=1.4 pmol mg(-1) protein and KD2=1.5 microM, Bmax2=10.8 pmol mg(-1) protein. In the presence of 100 mM KSCN the affinities of both the binding sites were increased, yielding values of KD1=6.9 nM and KD2=0.4 microM KSCN was without effect on the Bmax values. 3. (S)-[3H]-5-fluorowillardiine binding was displaced by non-NMDA receptor ligands with the rank order of potency: 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX) > domoate > (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionice acid (AMPA) = L-glutamate > 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) > kainate >> (R)-5-fluorowellardiine. In contrast, both N-methyl-D-aspartate (NMDA) and the metabotropic glutamate receptor agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were inactive. 4. By use of quantitative autoradiography the regional distribution of (S)-[3H]-5-fluorowillardiine binding in rat brain was assessed. The highest levels of binding were in the dentate gyrus and the CA1 region of the hippocampus. Lower levels of binding were detected in the cerebral cortex, olfactory system, lateral septum, caudate putamen and nucleus accumbens. 5. We conclude that the pharmacological profile and regional distribution of (S)-[3H]-5-fluorowillardiine binding is consistent with its specific interaction with AMPA receptors.     

Quality systems and total process control in blood banking

Blood banking has dramatically changed in the past few years. Is the old business hierarchy and medical model for management still workable? How do we want to organize our work today for success in the future? Implementation of quality systems may seem overwhelmingly complex at this time to many blood banking establishments. However, by methodically adhering to the requirements of organization development described in this review, blood centers can achieve goals of quality improvement and TPC. The FDA and the pharmaceuticals and medical device industries have set the direction and provided guidance to blood establishments. The AABB, American Society for Quality Control, the American Society for Training and Development, and numerous other professional organizations can contribute information and materials. The FDA's document on quality assurance and the CFR are the basic texts guiding the approach presented in this paper. The organization's structure and processes may need to be reengineered to meet the requirements of a culture based on quality and process control.     

Cerebral white matter and cognition in hydrocephalic children.

Although children with hydrocephalus frequently show poor development of nonverbal cognitive skills relative to verbal skills, little is known about the neuropathologic correlates of these discrepancies. In this study, cerebral white-matter structures and lateral ventricles were measured from the magnetic resonance images of age-matched children with meningomyelocele, meningocele, and aqueductal stenosis and normal subjects. The volume of each lateral ventricle and the cross-sectional area of the corpus callosum and internal capsules were correlated with concurrent measures of verbal and nonverbal cognitive skills. The corpus callosum in the meningomyelocele and aqueductal stenosis groups was smaller. The lateral ventricles were larger, and the internal capsules were smaller, in all patient groups than in normal subjects. There were no differences in the size of the centra semiovale. Although verbal and nonverbal measures correlated positively with the size of the corpus callosum, the correlation was higher for nonverbal measures. Nonverbal measures correlated with the right, but not the left, lateral ventricle and with the area of the right and left internal capsules. Verbal measures correlated with the left, but not right, lateral ventricle and with the left, but not right, internal capsule. These results show a relationship between the corpus callosum and cognitive skills that is also influenced by hydrocephalus-related changes in the lateral ventricles and other cerebral white-matter tracts.     

Evaluation of bromfenac, aspirin, and ibuprofen in postoperative oral surgery pain

Two hundred forty-one outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double-blind basis, to receive a single oral dose of bromfenac 5, 10, or 25 mg, aspirin 650 mg, ibuprofen 400 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief for 8 hours after medicating. Estimates of summed pain intensity difference, peak pain intensity difference, total relief, peak relief, and hours of 50% relief were derived from these subjective reports. All active treatments were significantly superior to placebo, and the slope of the dose-response curve for bromfenac was significant. Bromfenac 5 mg and aspirin 650 mg were equianalgesic; bromfenac 25 mg was slightly more efficacious than ibuprofen 400 mg. Bromfenac 25 mg and ibuprofen 400 mg were significantly superior to the other active treatments. Adverse effects were transient and consistent with the pharmacologic profiles of the medications evaluated.     

The long-term success of fresh, small fragment osteochondral allografts used for intraarticular post-traumatic defects in the knee joint.

Ninety-two fresh osteochondral allografts were implanted in 91 patients with posttraumatic osteoarticular defects of the knee joint. These patients have been prospectively followed since 1972. An analysis of long-term survival of these grafts has been performed to determine their success rates: 75% at 5 years, 64% at 10 years, and 63% at 14 years. An evaluation was made between unipolar grafts, which involve only one surface of the compartment, and bipolar grafts, which involve both surfaces. The unipolar grafts had a lower failure rate at all time periods compared to bipolar grafts, with 76% survival at 5 years, 69% at 10 years, and 67% at 14 years. While investigating other factors that might affect the survival of the fresh osteochondral allografts, we calculated the influence of the anatomical location of the graft, patient sex, and patient age. There was no meaningful impact on allograft survival by either the location of the allograft or the sex of the patient. However, there was a significant effect on allograft longevity in terms of patient age, with patients under age 60 doing better. The best indication for the use of unipolar fresh osteochondral allografts is for posttraumatic defects in relatively young, active patients. Joint malalignment should be corrected to achieve best results.     

A comparison of the analgesic effect of intramuscular nalbuphine and morphine in patients with postoperative pain.

In a double-study, using patients' subjective reports as indices of analgesia, the relative analgesic potency of intramuscular nalbuphine and morphine was determined in 56 postoperative patients. A total of 28 crossover comparisons (utilizing the twin passover, balanced four-point incomplete block design) were performed in two sequentially related experiments, each assay comparing 4 and 8 mg of morphine with either 3 and 6 or 6 and 12 mg of nalbuphine. When both intensity and duration of analgesia are considered (i.e., total analgesic effect), nalbuphine was 0.8 to 0.9 times as potent as morphine. In terms of peak analgesic effect, nalbuphine was 0.7 to 0.8 times as potent. Both the time-effect curves and the relative potency estimates suggest that nalbuphine has a slightly longer duration of action than morphine at doses that are equianalgesic in terms of peak effect. Side effects of the type usually noted after the administration of potent injectable analgesics to postoperative patients were observed after both morphine and nalbuphine. Although nalbuphine is a potent narcotic antagonist, no psychotomimetic reactions were observed.     

Activated factor X and thrombin formation triggered by tissue factor on endothelial cell matrix in a flow model: effect of the tissue factor pathway inhibitor

The procoagulant subcellular matrix of stimulated endothelial cells that contains tissue factor (TF) was used to investigate the mechanism by which TF pathway inhibitor (TFPI) inhibits thrombin formation initiated by TF/factor VIIa (FVIIa) under flow conditions. Purified coagulation factors VII, X, and V and prothrombin were perfused at a wall shear rate of 100 s-1 through a flow chamber containing a coverslip covered with matrix of cultured human umbilical vein endothelial cells. This resulted in a TF- and FVII-dependent FXa and thrombin generation as measured in the effluent at the outlet of the system. Inhibition of this TF/FVIIa-triggered thrombin formation by TFPI purified from plasma was dependent on the amount of TF present on the endothelial cell matrix. The rate of prothrombinase assembly and steady-state levels of thrombin formation were decreased by TFPI. Because persistent albeit decreased steady-state levels of thrombin formation occurred in the presence of TFPI, we conclude that plasma- TFPI does not inhibit FXa present in the prothrombinase complex. The addition of FIX and FVIII to perfusates containing FVII and FX increased the FXa generation on endothelial matrices, and counteracted the inhibition of thrombin formation on endothelial cell matrices by TFPI. Our data provide further evidence for the hypothesis that the rapid inactivation of TF/FVIIa by TFPI in combination with the absence of either FVIII or FIX causes the bleeding tendency of patients with hemophilia A or B.     

Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma [see comments]

We investigated the efficacy of 2-chlorodeoxyadenosine (2-CdA) therapy in patients with mycosis fungoides (MF) and the Sezary syndrome (SS). Between February 1991 and November 1993, 21 patients with relapsed or refractory MF/SS were treated with 2-CdA. 2-CdA was administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days initially (13 patients), but was subsequently reduced to 5 days (nine patients) due to hematologic toxicity. All patients had failed to respond to at least one prior treatment for MF/SS (median number of total prior therapies, five; median number of systemic prior therapies, three) and had an Eastern Cooperative Oncology Group performance status of two or better. Cycles were administered at 28-day intervals. Assessable patients received at least 5 days of 2-CdA. Fourteen patients received more than one cycle of 2-CdA. An overall response rate of 28% was achieved. Three patients (14%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (14%) had a partial response with a median duration of 2 months (range, 2 to 4). Fifteen patients (72%) had no response. The most significant toxicities encountered were bone marrow suppression (62% of patients) and infectious complications (62% of patients). Thirty-eight percent of patients experienced no toxicity from 2-CdA. 2-CdA has activity as a single agent in patients with previously treated relapsed MF/SS. Studies in less heavily pretreated individuals with 2-CdA alone or in combination will be undertaken.     

A scoping review on the experiences and preferences in accessing diabetes-related healthcare information and services by British Bangladeshis

Diabetes is a chronic condition requiring lifelong self-management. Patients are encouraged to access appropriate services to facilitate optimum management of diabetes. Although equitable access to healthcare in the United Kingdom is a legal right, not all groups and individuals in the community experience equity. Despite various equality laws and numerous efforts to minimise health inequalities related to access, particular community groups are more likely to experience inequitable access than others. The Bangladeshi community are one such community who experience some of the worst diabetes-related health outcomes in the United Kingdom. Little is known about their experiences and preferences in accessing diabetes healthcare information and services. Consequently, we undertook a scoping review of the literature by following the York Scoping Reviews Framework to identify the experiences and preferences of Bangladeshi patients and carers when gaining access to diabetes-related healthcare information and services. We identified eight articles and reported our results in relation to four domains of access: health service availability, health service utilisation, health service outcomes and the notion of equity. The review identified that language and literacy issues were the most common barriers hindering access to information and services. Patient knowledge regarding diabetes and its management was generally low, and friends and family were frequently being used as information sources and as informal interpreters. Additionally, there were feelings of isolation from mainstream information and services possibly resulting in the high prevalence of depression in the Bangladeshi community with women more affected than men. Social networks combined with religious and cultural beliefs as well as wider societal duties played a crucial role in accessing information and services for this population, and the identification of these issues merit further research and are possible avenues towards improved access to healthcare information and services for the Bangladeshi population.     

The regulation of hemopoiesis in long-term bone marrow cultures. II. Stimulation and inhibition of stem cell proliferation

The isolation of a DNA synthesis inhibitor (NBME fraction IV) and stimulator (RBME fraction III) specific for the hemopoietic stem cell (CFU-s) from freshly isolated normal adult and regenerating murine bone marrow, respectively, has been well documented. We have utilized long- term liquid bone marrow cultures in a further analysis of the role of these factors in the regulation of CFU-s proliferation. Our results show that shortly after feeding, at a time when the cultured CFU-s are actively proliferating, high levels of the hemopoietic stem cell proliferation stimulator fraction III can be isolated from the culture medium. In contrast, the presence of essentially noncycling CFU-s found in cultures fed 8-10 days previously correlates with high levels of the hemopoietic stem cell inhibitor fraction IV. These results suggest that a certain balance between these factors determines CFU-s proliferation in the long-term cultures. In support of this, DNA synthesis in actively cycling CFU-s in the long-term cultures is inhibited for at least 3 days by the addition of excess NBME fraction IV (inhibitor). Furthermore, DNA synthesis in noncycling cultured CFU-s is stimulated for at least 5 days by the addition of RBME fraction III (stimulator).