Biomedical subjects
Publications and source records attributed to T W Lee.
[structure: see text]. The new silyllithium reagent 1 and the corresponding cyanocuprate 3 are readily generated under optimal conditions and are useful for the formation of C-Si bonds. Tamao-Fleming oxidation of such C-Si bonds can be effected under very mild conditions.
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G protein-coupled receptors represent the largest class of drug discovery targets. Drugs that activate G protein-coupled receptors are classified as either agonists or partial agonists. To study the mechanism whereby these different classes of activating ligands modulate receptor function, we directly monitored ligand-induced conformational changes in the G protein-coupling domain of the beta(2) adrenergic receptor. Fluorescence lifetime analysis of a reporter fluorophore covalently attached to this domain revealed that, in the absence of ligands, this domain oscillates around a single detectable conformation. Binding to an antagonist does not change this conformation but does reduce the flexibility of the domain. However, when the beta(2) adrenergic receptor is bound to a full agonist, the G protein coupling domain exists in two distinct conformations. Moreover, the conformations induced by a full agonist can be distinguished from those induced by partial agonists. These results provide new insight into the structural consequence of antagonist binding and the basis of agonism and partial agonism.
An enantioselective, stereocontrolled total synthesis of eunicenone A (1) is described starting from geranylgeranylacetylene (9) in 14 steps via intermediates 10-20. The most critical construction in the synthesis is the highly effective Diels-Alder combination of the achiral components 2-bromoacrolein and diene 13 in the presence of the chiral Lewis acid catalyst 14 to form 15 (85% yield, 97% ee, >98:2 endo-exo ratio). The synthesis utilizes a novel reagent (12) for introduction of silicon, which serves to activate and direct the diene 13 for Diels-Alder reaction and to provide for eventual oxygen functionality of homoallylic alcohol 17 under mild conditions. Other noteworthy steps include the position selective and diastereoselective epoxidation 17 --> 18, the methoxycarbonylation with allylic transposition 19 --> 20, and the alpha,beta-enone unmasking 20 --> 1.
The advent of video-endoscopy revolutionizes the practice of surgery. Within a short span of time, video-assisted thoracic surgery (VATS) has become an acceptable approach to a wide range of thoracic procedures. The use of VATS as a diagnostic modality is now well established. For therapeutic procedures, VATS has also been generally accepted for the treatment of such conditions as primary spontaneous pneumothorax, loculated effusions, thoracodorsal sympathectomy, and resection of simple mediastinal cysts. Its roles in more complex procedures such as thymectomy and anatemic lung resections, however, remain poorly defined at present, even though the existing intermediate-term results are encouraging. VATS is still in evolution. Miniaturization of instruments promises to reduce access-induced trauma even further. On the other hand, attention to cost-containment is essential if VATS is to be applicable to patients in developing countries. Technology will continue to change. Carefully conducted clinical trials should precede the general acceptance of any new technology, no matter how attractive it may appear initially.
Phosphorus burns are a rarely encountered chemical burn, typically occurring in battle, industrial accidents, or from fireworks. Death may result even with minimal burn areas. Early recognition of affected areas and adequate resuscitation is crucial. Amongst our 2765 admissions between 1984 and 1998, 326 patients had chemical burns. Seven admissions were the result of phosphorus burns. Our treatment protocol comprises 1% copper sulfate solution for neutralization and identification of phosphorus particles, copious normal saline irrigation, keeping wounds moist with saline-soaked thick pads even during transportation, prompt debridement of affected areas, porcine skin coverage or skin grafts for acute wound management, as well as intensive monitoring of electrolytes and cardiac function in our burns center. Intravenous calcium gluconate is mandatory for correction of hypocalcemia. Of the seven, one patient died from inhalation injury and the others were scheduled for sequential surgical procedures for functional and cosmetic recovery. Cooling affected areas with tap water or normal saline, prompt removal of phosphorus particles with mechanical debridement, intensive monitoring, and maintenance of electrolyte balance are critical steps in initial management. Fluid resuscitation can be adjusted according to urine output. Early excision and skin autografts summarize our phosphorus burn treatment protocol.
The aim of this study is to gain an understanding of the penetration pathways for a drug to enter the posterior segment of the eye after subconjunctival injection. 14C-mannitol was injected subconjunctivally, and 14C-mannitol and 14C-inulin were injected intracamerally. The aqueous and vitreous levels were determined at selected time points. The results of subconjunctival injection and intracameral injection were compared. The vitreous level of the dosed eye is much higher than that of the corresponding contralateral eye after subconjunctival injection so that the recirculation pathway is not a dominant penetration pathway. In addition, the results also showed that it is unlikely for significant amounts of drug to move from the aqueous to the vitreous chamber after subconjunctival injection. Therefore, direct penetration is the dominant pathway for a subconjunctivally injected compound to enter the vitreous chamber.
Cyclic AMP receptor protein (CRP) plays a key role in the transcription regulation of many prokaryotic genes. Upon the binding of cyclic AMP, CRP is allosterically activated, binds to target DNA sites, and interacts with RNA polymerase. Although the protein-protein interaction between CRP and RNA polymerase is known to be important for the transcription initiation of the target genes, its structural understanding is still lacking, particularly due to the high molecular mass (approximately 120 kDa) of the protein complex. We assigned all of the (13)C-carbonyl resonances of methionine residues in CRP by using the double labeling and the enzyme digestion techniques. The result of (13)C-carbonyl NMR experiment on [(13)C'-Met]-CRP in the presence of both cyclic AMP and RNA polymerase alpha subunit showed that the two proteins interact with each other in solution in the absence of DNA via the region around the residues from Met 157 to Met 163 in CRP. The results also showed the effectiveness of the selective labeling and (13)C-carbonyl NMR spectroscopy in the specific detection of the protein-protein interaction between large molecules.
The management of upper-extremity burn contractures is a major challenge for plastic surgeons. After approval by the Food and Drug Administration, artificial skin (Integra) has been available in Taiwan since 1997. From January of 1997 to July of 1999, the authors applied artificial skin to 13 severely burned patients for the reconstruction of their upper extremities, resulting in an increased range of motion in the upper-extremity joints and improved skin quality. An additional benefit was the rapid reepithelialization of the donor sites. There were no complications of infection throughout the therapeutic course, and the overall results were satisfactory. During the 2-year study, scar condition was monitored between 8 and 24 months, and a good appearance and pliable skin were obtained according to the Vancouver Scar Scale. According to this evaluation of Oriental skin turgor, normal pigmentation was restored about 6 months after the resurfacing procedure. For patients with severe burns in whom there is insufficient available skin for a full-thickness skin graft or another appropriate flap for scar revision, Integra is an alternative. The two major concerns in dealing with artificial skin are (1) a 10- to 14-day waiting period for maturation of the neo-dermis, necessitating a two-stage operation, and (2) prevention of infection with antibiotics and meticulous wound care.
OBJECTIVE: To compare the effectiveness of routine neonatal examination performed by senior house officers (SHOs) and advanced neonatal nurse practitioners (ANNPs). DESIGN: A prospective study of all infants referred to specialist orthopaedic, ophthalmology, and cardiology clinics. A standardised proforma was used to record details of the professional performing the neonatal check, any abnormalities discovered, source of ultimate referral to the specialist clinic, and specialist findings. RESULTS: 527 eligible infants were recruited. For hip abnormalities, ANNPs displayed greater sensitivity than SHOs (96% v 74%; p < 0.05). Similarly for eye abnormalities, ANNPs were more sensitive (100% v 33%; p < 0.05). There were no significant differences between ANNPs and SHOs in terms of positive predictive values or effectiveness of detecting cardiac abnormalities. There was no difference in underlying incidence of abnormalities between the two hospitals. CONCLUSION: ANNPs are significantly more effective in detecting abnormalities during the neonatal check. This has implications both for future workforce planning and current methods of medical training.
The combined use of a lightwand and the intubating laryngeal mask airway (ILMA) was compared with the use of the ILMA alone to determine whether the combination was a more efficient method of endotracheal intubation. One hundred healthy patients were randomly assigned to two groups. After induction of anaesthesia, Group A patients were intubated blindly through the ILMA while in Group B, intubation was guided by a lightwand. A sequence of standard manoeuvres was followed it attempts at intubation failed. The number of manoeuvres used, the time taken for successful intubation and complications associated with intubation were recorded. Intubations were successful in all patients, but the mean endotracheal intubation time was longer in Group A than in Group B (38.3 +/- 10.4 s versus 26.4 +/- 9.1 s, P < 0.001). The number of patients who needed one or more manoeuvres was significantly higher in Group A than in Group B (76% versus 42%, P = 0.001). We conclude that the lightwand is a useful adjunct in endotracheal intubation through an ILMA.
We applied independent component analysis (ICA) to hyperspectral images in order to learn an efficient representation of color in natural scenes. In the spectra of single pixels, the algorithm found basis functions that had broadband spectra and basis functions that were similar to natural reflectance spectra. When applied to small image patches, the algorithm found some basis functions that were achromatic and others with overall chromatic variation along lines in color space, indicating color opponency. The directions of opponency were not strictly orthogonal. Comparison with principal-component analysis on the basis of statistical measures such as average mutual information, kurtosis, and entropy, shows that the ICA transformation results in much sparser coefficients and gives higher coding efficiency. Our findings suggest that nonorthogonal opponent encoding of photoreceptor signals leads to higher coding efficiency and that ICA may be used to reveal the underlying statistical properties of color information in natural scenes.
BACKGROUND: It has not been clear whether immunosuppressive therapy favorably influences renal function and proteinuria in IgA nephropathy (IgAN). Angiotensin converting enzyme inhibitor (ACEi) has an anti-proteinuric effect in IgAN. A retrospective study was done to see whether the addition of immunosuppressive therapy to ACEi produces a more excellent anti-proteinuric effect and preserves better renal function than ACEi alone. METHODS: A total of 49 patients with proteinuria > 1.0 g/day and serum creatinine concentrations < 1.5 mg/dL were followed-up from at least 1 year to 9 years. Among them, 25 patients were treated with the combination of cyclophosphamide, prednisolone and ACEi while the other 24 were treated with ACEi alone. RESULTS: The combination therapy or ACEi alone both reduced proteinuria with significant value (the combination group: from 5.74 +/- 5.08 to 2.29 +/- 2.77 g/day, ACEi group: from 3.85 +/- 2.54 to 1.68 +/- 1.91 g/day), while no significant differences in reduction of proteinuria were noticed between the two groups. There was no significant elevation of serum creatinine in both groups during follow-up (the combination group: from 0.91 +/- 0.20 to 1.03 +/- 0.38 mg/dL, ACEi group: from 0.93 +/- 0.27 to 0.99 +/- 0.37 mg/dL). This study showed no significant differences in the change in slope of 1/serum creatinine levels during the follow-up period between the two groups. CONCLUSION: We conclude that immunosuppressive therapy may not be beneficial in patients with proteinuric IgAN. ACEi may be a valuable therapeutic agent avoiding serious side effects of immunosuppressive agents.
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Mutant mice with abnormalities are potentially useful as models for studying human defects. Here we report a group of mice with abnormal behavioral patterns. A new spontaneous mutant mouse exhibited hyperactive behavior at about seven days of age, followed by tight circling behavior. Breeding studies suggest that this mutation is caused by a single gene defect inherited in an autosomal recessive manner. Consequently, this mutation is referred to as a circling (cir) mouse mutation with the gene symbol cir. Auditory test results identified clearly the hearing loss of the cir, compared with wild-type mice. Pathologic studies confirmed developmental defects in cochlea and spiral ganglions that were correlated to the abnormal behavior observed in the cir mice. Thus, cir mice may be useful as a model for studying inner ear abnormalities and deafness in humans.
Cyclic AMP receptor protein (CRP) plays a key role in the regulation of more than 150 genes. CRP is allosterically activated by cyclic AMP and binds to specific DNA sites. A structural understanding of this allosteric conformational change, which is essential for its function, is still lacking because the structure of apo-CRP has not been solved. Therefore, we performed various NMR experiments to obtain apo-CRP structural data. The secondary structure of apo-CRP was determined by analyses of the NOE connectivities, the amide proton exchange rates, and the (1)H-(15)N steady-state NOE values. A combination of the CSI-method and TALOS prediction was also used to supplement the determination of the secondary structure of apo-CRP. This secondary structure of apo-CRP was compared with the known structure of cyclic AMP-bound CRP. The results suggest that the allosteric conformational change of CRP caused by cyclic AMP binding involves subunit realignment and domain rearrangement, resulting in the exposure of helix F onto the surface of the protein. Additionally, the results of the one-dimensional [(13)C]carbonyl NMR experiments show that the conformational change of CRP caused by the binding of cyclic GMP, an analogue of cyclic AMP, is different from that caused by cyclic AMP binding.
BACKGROUND: Follicular dendritic cell (FDC) sarcoma is an uncommon neoplasm occurring primarily in lymph nodes but also in extranodal sites. A correct diagnosis can be difficult to make, especially in the latter sites. METHODS: Two patients with FDC sarcoma of the cervical soft tissues that metastasized to the lungs are reported. Both were initially misdiagnosed as having CASTLE (carcinoma showing a thymus-like element). Additional immunohistochemical stains were performed. RESULTS: The primary tumors showed jigsaw puzzle-like lobulation resembling thymic epithelial tumor and consisted of spindly cells arranged in fascicles, whorls, and a storiform pattern. The spindly cells had indistinct cell borders, vesicular nuclei, and distinct nucleoli. Perivascular spaces were present. Lymphocytes were sprinkled throughout the tumor in one case but were sparse in the other. The metastatic deposits in the lungs appeared 27 and 2 years, respectively, after the initial presentation and were histologically similar to the original tumors. The FDC nature of the primary and metastatic tumors was confirmed by positive staining with CD21/CD35 cocktail and CD23 and by negative staining for cytokeratin. In one case, in direct continuity with the main tumor, there was a lobulated lesion composed of small lymphocytes punctuated by large cells with vesicular nuclei, histologically reminiscent of thymoma. The large cells were shown by immunohistochemistry to represent FDCs forming complex interconnecting meshworks. It is unclear whether this contiguous mass represents a precursor lesion or an unusual-looking component of the neoplasm. CONCLUSIONS: FDC sarcoma can look deceptively like a thymic epithelial tumor histologically. A correct diagnosis requires a high index of suspicion and immunohistochemical evaluation. The tumor shows a propensity to metastasize to the lungs, which can be delayed until more than 20 years after initial presentation.
Exposure of alpha-diazo thiol esters (1) to the action of catalytic rhodium(II) acetate leads to a remarkably facile "thia-Wolff rearrangement", producing thio-substituted ketenes which combine with a variety of ketenophiles to provide access to alpha-thiocyclobutanones, cyclobutenones, and beta-lactams. Reductive desulfurization of these cycloadducts takes place under mild conditions and in excellent yield, and this sequence thus represents a useful new alternative to the existing dichloroketene-based methodology for the synthesis of four-membered carbocycles and heterocycles.