Alloresponses to HLA-DP Detected in the Primary MLR: Correlation with a Single Amino Acid Difference

The one-way mixed lymphocyte reaction (MLR-1) response was measured in both directions in 50 HLA-A, B, DR and DQ identical pairs and the role of DP studied in MLR stimulation. DR, DQ and DP typing was performed at the allele level by the polymerase chain reaction-sequence specific oligotyping (PCR-SSO) technique. The group consisted of 19 potential bone marrow transplant recipients and 34 matched unrelated donors. When more than one matched donor was available for a patient, donor/donor MLR-1 was also studied. DP identity was observed in 3 out of 50 pairs (6%), however due to homozygosity no incompatibility was present in the stimulating cells in 21 out of 100 cases (21%). There was a significant difference in the range of relative responses (RR) between zero DPB1 mismatches and one (p = 0.002) and two (p = 0.02) DPB1 mismatches: 52.4% of cases in the zero DPB1 mismatch group had RR < 1.0% compared with 31.6% and 27.3% in the one and two DPB1 mismatches. Stimulation by DPB1*0201 and 0301 gave the highest RR (12.9 ± 22.5 and 17.5 ± 17.0, respectively) while stimulation with DPB1*0401 and 0402 resulted in low levels of T cell response (1.3 ± 8.2 and 0.6 ± 11.5, respectively). When the responses were restricted to DPB1*0401 homozygotes to standardise for responder type similar results were obtained (DPB1*0201 v DPB1*0402 p = 0.008). The protein products of the DPB1*0201 and 0402 alleles differ by a single amino acid at position 69 (DPB1*0402—Lysine, DPB1*0201—glutamic acid). A further analysis was performed therefore scoring responders and stimulators as glutamic acid positive (E+) or negative (E−). There was a highly significant increase in the response to E+ stimulators compared with E− stimulators (p = 0.004). There was also a significant difference in the distribution of relative responses between the E+ stimulator group and the subgroups of E− responders/E− stimulators (p = 0.012) and E+ responders/E− stimulators (p = 0.009). However the amino acid difference at position 69 does not explain all responses due to DP in the MLR-1 as evidenced by the strong responses observed in cases where DPB1*0301 (lysine pos.) was the only difference on the stimulator cells. The results indicate that not all DP incompatibilities elicit a measurable T cell MLR response, but where a response does occur residue 69 in the first domain of DP appears to be pivotal. These results may have implications with respect to GVHD in bone marrow transplantation.     

Allele sharing for schizophrenia and schizo‐affective disorder within a region of Homo sapiens specific XY homology

A case (based upon an association with cerebral asymmetry) has been presented for a gene for psychosis within the Xq21.3/Yp region of homology that is specific to Homo sapiens. We tested this hypothesis using the pentanucleotide marker DXYS 156 that is located within this region. In 84 families affected by schizophrenia or schizo‐affective disorder no tendency toward increased allele sharing amongst siblings was observed (χ² = 0.002). We conclude either that this region does not include a gene predisposing to psychosis or that if it does, the relevant variation is epigenetic rather than sequence‐based. With respect to the latter possibility we draw attention to the recent evolutionary history of the Xq21.3/Yp region. Genes within the region are in transition to protection from X inactivation and therefore may be epigenetically labile. © 2002 Wiley‐Liss, Inc.     

An evaluation of signs in ocular myasthenia gravis and correlation with acetylcholine receptor antibodies

Fifteen patients with ocular myasthenia gravis were examined in detail for 21 different signs, and tested for acetylcholine receptor antibodies. The major signs of ocular myasthenia gravis included ptosis, disorders of ocular rotations, weakness of eyelid closure, "pseudosupranuclear" signs and the lid twitch sign. Acetylcholine receptor antibodies were found in eight of the 15 patients. One hundred and four normal, non-myasthenic patients were also examined for the lid twitch response, and the relationship between the lid twitch of ocular myasthenia gravis and that found in normal subjects is discussed.     

Magnetic resonance imaging for detecting lesions of multiple sclerosis: comparison with computed tomography and clinical assessment.

Eighty-two patients with known or suspected multiple sclerosis (MS) were examined by means of magnetic resonance imaging (MRI) with a 0.15-T resistive scanner. The diagnosis could be made by MRI in 34 (97%) of the 35 patients with chronic, well-documented, stable MS and by high-volume delayed x-ray computed tomography (HVD CT) in only 6 (54%) of 11 patients in this group. The stage of the disease as judged from the MRI scans correlated poorly with the clinical status of the patient and with the known duration of the disease. MRI identified 28 (88%) of the 32 patients in whom MS was subsequently diagnosed by a neurologist, whereas regular contrast or HVD CT identified only 11 (52%) of 21 such patients. MRI is the most sensitive imaging modality for MS but is of little value in assessing the severity of the disease: many of the lesions seen on MRI scans are clinically "silent", and MRI does not usually detect small lesions in the brainstem, cerebellum or spinal cord that may be clinically significant.     

A specific enhanced recovery protocol decreases opioid use after thyroid and parathyroid surgery

BackgroundEnhanced recovery protocols have not been investigated previously for cervical endocrine surgery. The study aim was to determine whether systematic implementation of an enhanced recovery protocol specific for thyroid/parathyroid surgery can improve postoperative outcomes.MethodsA customized enhanced recovery protocol for thyroid/parathyroid surgery was designed and utilized systematically for all patients who underwent parathyroidectomy, thyroid lobectomy, or total thyroidectomy. Outcomes were assessed 12 months before enhanced recovery protocol implementation (n = 464 patients) and after enhanced recovery protocol implementation (n = 654 patients).ResultsEnhanced recovery protocol implementation was associated with a 72% decrease in mean oral morphine equivalents utilized in-house (before 82 ± 64 versus after 23 ± 28; P < .0001) and many enhanced recovery protocol patients were entirely opioid-free (0.2% vs 21%, P < .0001). When used, the enhanced recovery protocol was associated with a lesser mean amount of ondansetron to treat postoperative nausea and vomiting (5.5 mg ± 3 vs 4.5 ± 2: P < .0001). Duration of stay was short before implementation of the enhanced recovery protocol and did not change substantially after implementation (1.1 days ± 0.7 vs 1.1 ± 0.7; P = .26).ConclusionThe systematic use of a simple, cervical, endocrine surgery-specific enhanced recovery protocol decreased perioperative opioid use by ~70%, with significantly less postoperative nausea and vomiting. Implementation of a multidisciplinary enhanced recovery protocol may be an important initial step toward limiting opioid overuse during common operative procedures.     

Failure of Delta(9)-tetrahydrocannabinol and CP 55,940 to maintain intravenous self-administration under a fixed-interval schedule in rhesus monkeys

The lack of procedures which can unequivocally demonstrate cannabinoid self-administration in animals has been an obstacle to the study of the neural basis for the reinforcing effects of this drug class. Because delta(9)-tetrahydrocannabinol (delta(9)-THC) produce a relatively slow-onset, long-lasting behavioral effect, a self-administration procedure with widely spaced drug deliveries was evaluated as an alternative to fixed-ratio schedules which typically require frequent, closely spaced injections to demonstrate reinforcing effects. Three adult male rhesus monkeys were surgically implanted with intravenous catheters and trained to self-administer phencyclidine (PCP) under a 10min fixed-interval schedule of reinforcement. Three injections were available each day, separated by 2h periods during which responding had no programmed consequences. In an attempt to link the effect of the drug with the response which produced it, each 20s injection was paired with a red light which remained illuminated for 10min. PCP (100μg/kg/injection) maintained steady rates of responding during each availability period, ranging from approximately 0.2 to 0.7 responses/s. During 7 day substitution periods, Delta(9)-THC (17-100μg/kg/injection) maintained low rates of responding which occasionally surpassed those during vehicle substitutions, but fell far below rates maintained by PCP. Substitution tests with the potent Delta(9)-THC analog CP 55,940 also resulted in low rates of responding. These results demonstrate that Delta(9)-THC is a poor reinforcer in animals, even under conditions where some of its unfavourable biodispositional properties are taken into consideration.     

Proteolysis and invasiveness of brain tumors: Role of urokinase-type plasminogen activator receptor

Summary The cellular receptor for urokinase-type plasminogen activator (uPAR) in glioblastoma cell lines has been identified and found to be similar to the uPAR expressed by other tumor cell lines. Increased levels of uPAR have been found in primary malignant brain tumor tissues, especially highly malignant glioblastoma, and, to a lesser degree, in malignant astrocytomas, suggesting that this receptor might be involved in efficient activation of pro-uPA and confinement of uPA activity on the cell surface of invading brain tumors. The cell surface uPARs in gliomas could constitute an optimum environment for the generation and activity of plasmin, which is known to play a crucial role in the dissolution of the extracellular matrix during tumor cell invasion.In situ hybridization studies have shown that uPAR mRNA is expressed abundantly in tumor cells and is consistently present at the invasive edges of malignant gliomas. These results imply that uPAR is involved in plasmincatalyzed proteolysis during glioma invasion and that interference with the uPAuPAR interactions could constitute a novel approach for developing therapeutic strategies to counteract invasion of brain tumors.     

Interleukin-1β-converting enzyme and related proteases as potential targets in inflammation and apoptosis

Summary Interleukin-1-converting enzyme (ICE, EC 3.4.22.36) is the cysteine protease responsible for the production of interleukin-1 in monocytes. Since its discovery in 1989, this enzyme has been the subject of enthusiastic investigation because of the suspected role of this cytokine in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. These studies have culminated in the purification and cloning of the enzyme, development of potent inhibitors, determination of its structure by X-ray crystallography and the development of knockout mice, which have confirmed an important role for this protease in inflammation. Late in 1993, the protease became the subject of further interest because of its homology to CED-3, the product of a gene required for programmed cell death in the nematodeC. elegans. It is now clear that ICE is the first identified member of a new cysteine protease family that includes CED-3 and at least four other human homologues. Although the extent to which ICE itself plays a role in mammalian apoptosis remains controversial, it is clear that at least one of these homologues, CPP32, is an important player. The recognition that members of this family play key biological roles in both inflammation and apoptosis, two extremely attractive targets for therapeutic intervention, has led to intense interest in these proteases.