Biomedical subjects
Publications and source records attributed to B Morgan.
We describe the construction of a nostril splint made from heavy body silicone-based dental impression material. This bio-compatible material supported a large chondrocutaneous auricular graft during early healing. The splint immobilized and maintained the shape of the alar rim and was further used nightly during the expected period of wound contraction.
Stargardt disease (STGD) is the most common hereditary macular dystrophy and is characterized by decreased central vision, atrophy of the macula and underlying retinal-pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. STGD is most commonly inherited as an autosomal recessive trait, but many families have been described in which features of the disease are transmitted in an autosomal dominant manner. A recessive locus has been identified on chromosome 1p (STGD1), and dominant loci have been mapped to both chromosome 13q (STGD2) and chromosome 6q (STGD3). In this study, we describe a kindred with an autosomal dominant Stargardt-like phenotype. A genomewide search demonstrated linkage to a locus on chromosome 4p, with a maximum LOD score of 5.12 at a recombination fraction of.00, for marker D4S403. Analysis of extended haplotypes localized the disease gene to an approximately 12-cM interval between loci D4S1582 and D4S2397. Therefore, this kindred establishes a new dominant Stargardt-like locus, STGD4.
The search for synthetic analogues of somatostatin (SRIF) which exhibit selective affinities for the five known receptor subtypes (sst1-5) has generated a large number of potent agonist analogues. Many of these agonists display good subtype selectivities and affinities for the subtypes 2, 3, and 5, with very few selective for sst1 or sst4. Until the recent report by Bass and co-workers (Mol. Pharmacol. 1996, 50, 709-715; erratum, Mol. Pharmacol. 1997, 51, 170), no true antagonists had been discovered, let alone any displaying differential receptor subtype selectivity. In this present study, we explore the effect of this putative L5,D6 antagonist motif on various series of somatostatin agonist analogues, both linear and cyclic. It was found that many D5,L6 agonists could be converted into competitive antagonists by applying this motif, the most potent of which was H-Nal-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 (32). This antagonist was selective for hsst2 with an affinity of 75 nM and an IC50 of 15.1 nM against SRIF-14 in a rat in vitro antagonist bioassay. Receptor-selective somatostatin antagonists should provide valuable tools for characterizing the many important physiological functions of this neuropeptide.
The brain is an immunoprivileged organ isolated from the peripheral immune system. However, it has been shown that resident cells, notably astrocytes and microglia, can express numerous innate immune molecules, providing the capacity to generate a local antipathogen system. Perforin is a cytolytic protein present in the granules of cytotoxic T lymphocytes and natural killer cells. Expression in cells other than those of the hemopoetic lineage has not been described. We report here that fetal astrocytes in culture (passages 2 to 15), astrocytoma, and adult astrocytes expressed perforin. Reverse transcriptase polymerase chain reaction followed by Southern blot was carried out using multiple specific primers and all cDNAs were cloned and sequenced. Human fetal astrocyte perforin cDNA sequence was approximately 100% identical to the reported perforin cDNA cloned from T cells. Western blot analysis using monoclonal and polyclonal antiperforin peptide antibodies revealed a protein of 65 kD in both human fetal astrocyte and rat natural killer cell lysates (n = 4). Immunostaining followed by FACS(R) and confocal and electron microscopy analysis revealed that perforin was expressed by 40-50% of glial fibrillary acidic protein positive cells present in the fetal brain culture (n = 11). Perforin was not localized to granules in astrocytes but was present throughout the cytoplasm, probably in association with the endoplasmic reticulum. Perforin was not detected in normal adult brain tissue but was present in and around areas of inflammation (white and grey matter) in multiple sclerosis and neurodegenerative brains. Perforin-positive cells were identified as reactive astrocytes. These findings demonstrate that perforin expression is not unique to lymphoid cells and suggest that perforin produced by a subpopulation of astrocytes plays a role in inflammation in the brain.
Recent studies have shown that narrower excision margins may be safe, but the optimal or minimum margin for melanoma is unknown. Wide margins of excision are possible on the trunk and limbs, but functional and cosmetic constraints often limit the extent of excision on the face. A collaborative study from two continents (Cape Town, South Africa and Northwood, England) investigated the outcome of different excision margins of 106 patients with stage I melanoma of the face. The margin of excision was measured from the records of the pathological specimen. Thirty patients had margins of less than 1 cm, 64 had margins of between 1 and 2 cm, and 12 had margins greater than 2 cm. Primary apposition or flap closure was possible in 85 patients. Seven patients developed local recurrences and these were not influenced by the excision margin. This study supports the contention that the primary treatment of cutaneous melanoma on the face should be histologically confirmed complete excision, and that this can be achieved with margins of excision less than 1 cm. Local recurrence is not related to the margin of excision or to tumour thickness.
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Development of the lymphoid system is dependent on the activity of zinc finger transcription factors encoded by the Ikaros gene. Differences between the phenotypes resulting from a dominant-negative and a null mutation in this gene suggest that Ikaros proteins act in concert with another factor with which they form heterodimers. Here we report the cloning of Aiolos, a gene which encodes an Ikaros homologue that heterodimerizes with Ikaros proteins. In contrast to Ikaros--which is expressed from the pluripotent stem cell to the mature lymphocyte--Aiolos is first detected in more committed progenitors with a lymphoid potential and is strongly up-regulated as these differentiate into pre-T and pre-B cell precursors. The expression patterns of Aiolos and Ikaros, the relative transcriptional activity of their homo- and heteromeric complexes, and the dominant interfering effect of mutant Ikaros isoforms on Aiolos activity all strongly suggest that Aiolos acts in concert with Ikaros during lymphocyte development. We therefore propose that increasing levels of Ikaros and Aiolos homo- and heteromeric complexes in differentiating lymphocytes are essential for normal progression to a mature and immunocompetent state.
Somatostatin (SRIF), a hypothalamic inhibitor of pituitary growth hormone (GH) and thyroid-stimulating hormone (TSH) secretion, binds to five distinct receptor (SSTR) subtypes. We therefore tested SSTR subtype-specific SRIF analogs in primary human fetal pituitary cultures (23-25-wk gestation) to elucidate their role in regulating human pituitary function. Using reverse transcription-PCR, mRNA expression of SSTR2 and SSTR5 were detected in fetal pituitary by 25 wk. SRIF analog affinities were determined by membrane radioligand binding in cells stably expressing the human SSTR forms. GH secretion was suppressed equally (40-60%, P < 0.005) by analogs preferential for either SSTR2 (IC50 for receptor binding affinity, 0.19-0.42 nM) or SSTR5 (IC50, 0.37 nM), and compounds with enhanced affinity for SSTR2 were more potent (EC50 for GH suppression, 0.05-0.09 nM) than Lanreotide (EC50, 2.30 nM) and SRIF (EC50, 0.19 nM). Similarly, analogs with high affinity for SSTR2 or SSTR5 decreased TSH secretion (30-40%, P < 0.005). However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05). Luteinizing hormone was modestly decreased (15-20%) by SSTR2- or SSTR5-specific analogs. An SSTR5-specific analog also exclusively inhibited GH in acromegalic tumor cells. Thus, SRIF regulation of GH and TSH in primary human fetal pituitary cells is mediated by both SSTR2 and SSTR5, both of which are abundantly expressed by 25 wk. In contrast, suppression of prolactin is mediated mainly by SSTR2. These results indicate that SSTR5 is critical for physiologic regulation of GH and TSH. SRIF analogs with selective affinity for this receptor may therefore be more effective in the treatment of hormone-secreting pituitary adenomas.
The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.
A patient developing acute pancreatitis with pseudocyst formation after an uncomplicated bone marrow harvest is reported. The diagnosis was confirmed by elevated serum amylase and lipase, and by CT scan. We suggest that the pancreatitis may have been precipitated by spasm of the sphincter of Oddi secondary to opiates administered as premedication and for pain relief.
To investigate current concerns that potent opioid drugs, such as fentanyl, used for labour regional analgesia may affect neonatal status, maternal and umbilical plasma concentrations of fentanyl and bupivacaine at delivery were measured in 40 nulliparous patients receiving low-dose combined spinal epidural analgesia. Neonatal assessments included Apgar scores, umbilical blood gases and neurobehavioural tests. All maternal and umbilical venous plasma concentrations were low. Maternal and umbilical vein total fentanyl concentrations increased with increasing doses of epidural fentanyl (r = 0.46 and 0.30, respectively, p < 0.01). There were no significant differences between maternal and umbilical venous plasma total or free concentrations of fentanyl. Mean umbilical vein/maternal fentanyl ratios were 1.12 for total drug and 1.20 for free drug and values were unrelated to the last epidural bolus to delivery interval (r = 0.12, p = 0.49). There were no correlations between Apgar scores, umbilical blood gases or neurobehavioural scores and umbilical venous concentrations of either fentanyl or bupivacaine. The dose of fentanyl used for ambulatory combined spinal epidural analgesia would appear to have a negligible effect on neonatal condition.
OBJECTIVE: To determine the effect of patient-controlled combined spinal epidural analgesia (PCEA) on maternal pulse and blood pressure, and fetal heart rate in primigravid women, when adapting different positions in labour. DESIGN: A prospective study. SETTING: Queen Charlotte's and Chelsea hospital, London. PARTICIPANTS: Fifty-five primigravid women in labour at > or = 37 weeks of gestation; 40 women had supervised standing top-ups given by an anaesthetist. A further 15 women had PCEA top-ups given in each of standing, sitting and lying positions. MAIN OUTCOME MEASURES: Maternal pulse rate, blood pressure and fetal heart rate changes following epidural top-ups. RESULTS: In the first 40 women there was no clinically significant fall in their blood pressure (< 5 mmHg). The subsequent 15 women who had PCEA top-ups had no fall in blood pressure in the standing and sitting positions, though the average blood pressure fell significantly when a top-up was given in the lying position. Maternal heart rate increased significantly at 12 min post top-up when the women were in the standing position (P = 0.0018). In the 15 women who had PCEA top-ups, the CTG showed improvement in decelerations when women were in the standing position but deterioration when in the lying position (P < 0.01). CONCLUSION: Patient-controlled epidural analgesia top-ups with maternal mobility may be beneficial to the fetus possibly by reducing the hypotension normally associated with top-ups in the lying position.
The Royal College of Radiologists (RCR) has published guidelines concerning indications for imaging investigations. These include plain radiography of the knee, the indications for which are locking or signs of restricted movement. This audit consisted of 1153 knee radiographs in a 9 month period, results of a questionnaire sent to general practitioners (GPs), analysis of radiological reports and returned questionnaires (55% of cases), and subsequent comments from the GPs on receiving these results. Only 50% of cases fall within RCR guidelines, 90% of radiographs were normal or showed degenerative change. In 42% of cases, knee radiographs were requested to confirm previously expected degenerative change, and in 30% patient pressure was a significant factor. Most knee radiographs (87%) result in no significant change in management apart from continuation of symptomatic measures. Application of current guidelines, however, would miss some important diagnoses manifest clinically by persistent pain or effusion, for example loose body or Brodie's abscess. In cases of locking, where a radiograph may miss significant soft tissue abnormality, there was concern that reassurance was often gained by a normal examination. This audit shows that many knee radiographs are unnecessary. The guidelines appear appropriate with the proviso that persistent pain and effusion should be included as indications for investigation. Many GPs report medico-legal considerations as important reasons for unnecessary referrals, although the application of guidelines should be protection against this. The referral rate for knee radiographs before and after the communication of these results has not altered.
HIV-specific cytotoxic T lymphocytes (CTLs) play an important role in the immune response to HIV infection. Long-term nonprogressors (LTNPs) or slow progressors (SPs) in HIV infection may make qualitatively different CTL responses compared to those generated by seropositive individuals who progress to disease at a faster rate. The class I molecule HLA-B*57 has been identified as one restriction element overrepresented in SP groups studied, and, together with the closely related molecule HLA-B*58, occurs commonly in ethnic groups where HIV is most prevalent. In this study, we have identified five new HLA-B*57-restricted CTL epitopes recognized by SP donors, one of which is also HLA-B*5801 restricted. These HLA-B*57-restricted responses represent the dominant HIV-specific CTL response in each of the SP donors tested. These and other such epitopes may be an important component in future vaccine design.
Limb buds in the limbless chick begin to form normally but fail to form an AER and ultimately degenerate. Wnt7a and LMX-1, which are restricted to the dorsal half of a normal limb bud, are expressed throughout the ectoderm and mesenchyme of the mutant buds, respectively. Engrailed-1, normally expressed in ventral limb ectoderm, is not expressed in the limbless bud. This defect precedes the normal period of AER formation and no localized expression of genes normally found in the AER is observed in limbless buds. Consistent with the lack of molecular specialization of an AER, Shh and BMP-2 are not expressed in the ZPA of the mutant bud. Despite the lack of Shh, FGF-4, or BMP-2 expression, the hoxd genes are expressed at low levels in the posterior mesenchyme of the bud. Forced expression of Shh fails to rescue the positive feedback loop between the AER and the ZPA and does not lead to distal outgrowth. However, Shh does maintain the part of the bud formed during pre-AER stages. These results support the importance of the dorsal/ventral boundary in the initiation of AER formation and imply that Shh is not required for the initial activation of polarized hoxd gene expression during limb development.
INTRODUCTION: It is well recognized that corrected bile duct diameters, as measured by endoscopic retrograde cholangiography (ERC), are often significantly greater than the corresponding ultrasound measurement. This can be attributed to variation in bile duct distensibility and is particularly noted in post cholecystectomy patients, possibly due to loss of the gall bladder reservoir effect. It has been suggested that increased bile duct distensibility may be related to the post-cholecystectomy syndrome. We have observed a similar discrepancy between ultrasound and per-operative cholangiography (POC). This trial investigates whether the discrepancy between ultrasound and POC measurements has clinical significance. METHOD: Seventy-five patients with normal pre-operative ultrasound and POC undergoing standard open cholecystectomy (with benzodiazepine pre-medication) in 1990 were identified. After allowance for magnification, maximum biliary diameters were obtained for the proximal extra-hepatic bile duct. Follow-up was obtained in 67 patients from clinical case notes and contact with general practitioners. RESULTS: Considerable variation of bile duct distensibility was recorded (range 83% to 410%) with 12 cases having POC biliary diameters outside radiological guidelines (12 mm as recorded on the radiograph). This distension is shown to increase with age. After 4 years, 16 patients had recurrent abdominal pain of which nine had undiagnosed right upper quadrant pain. There were no clinical cases of retained stone post-operatively. There was no correlation between POC measured bile duct diameter or distensibility and post-operative or long term problems. This study suggests that the bile duct has a normal variation of distensibility which increases with age and that radiological guidelines, as regards the upper limit for normal POC biliary diameters can be relaxed.
AIM: To assess the prognostic significance of hypertropic osteoarthropathy (HOA) discovered on routine staging bone scintigraphy in patients with lung cancer. PATIENTS AND METHODS: Between 1989 and 1992 all 99mTc-MDP bone scintigrams performed for the staging of bronchogenic carcinoma were reviewed. HOA was diagnosed by the observation of cortical/periosteal increased uptake in the extremities of the long bones. Follow-up and confirmation of the diagnosis was obtained by hospital computer, histology records, operative records, patient notes and radiological data where available. RESULTS: 164 staging scintigrams for lung cancer were identified. Twenty-eight patients (17%) were observed to have HOA. Patients with and without HOA were well matched for age and sex. There was little difference in the distribution of cell type but the HOA groups has a greater incidence of peripheral tumours. There was no significance in survival between the two groups. Two of three long-term survivors had clinically overt HOA and one presented with arthralgia. CONCLUSION: HOA is often seen on skeletal scintigraphy for staging of lung cancer and has no prognostic significance. The data also support current teaching that a high index of suspicion for HOA, as a cause of arthralgia may lead to early diagnosis of a potentially resectable lung carcinoma.