Proteins implicated in Alzheimer disease. The role of FE65, a new adapter which binds to beta-amyloid precursor protein.
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Alzheimer Disease↗
Biomedical subjects
A Chang
Publications and source records attributed to A Chang.
Squamous cell carcinoma arising from a nonhealing wound and osteomyelitis treated with Mohs micrographic surgery: a case study.
The treatment of choice for squamous cell carcinoma arising from chronic ulcer at the lower extremity has traditionally been amputation. Recently, Mohs micrographic surgery has been used as a limb-saving option in selected patients. One of these patients, a 69 year-old white male, presented with a two-year history of a progressive non-healing would and osteomyelitis. A four-month history of an enlarging mass within the ulcer suggested squamous cell carcinoma, which was confirmed by biopsies. The patient was treated with Mohs micrographic surgery for local eradication of the tumor, intravenous antibiotics, and skin grafting.
Aged↗
Are surgical residents allowed to make mistakes?
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Adult↗
Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate-dependent RNase L.
2',5'-Oligoadenylate-dependent RNase L functions in the interferon-inducible, RNA decay pathway known as the 2-5A system. To determine the physiological roles of the 2-5A system, mice were generated with a targeted disruption of the RNase L gene. The antiviral effect of interferon alpha was impaired in RNase L-/- mice providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. In addition, remarkably enlarged thymuses in the RNase L-/- mice resulted from a suppression of apoptosis. There was a 2-fold decrease in apoptosis in vivo in the thymuses and spleens of RNase L-/- mice. Furthermore, apoptosis was substantially suppressed in RNase L-/- thymocytes and fibroblasts treated with different apoptotic agents. These results suggest that both interferon action and apoptosis can be controlled at the level of RNA stability by RNase L. Another implication is that the 2-5A system is likely to contribute to the antiviral activity of interferon by inducing apoptosis of infected cells.
Adenine Nucleotides↗
Novel genes involved in endosomal traffic in yeast revealed by suppression of a targeting-defective plasma membrane ATPase mutant.
A novel genetic selection was used to identify genes regulating traffic in the yeast endosomal system. We took advantage of a temperature-sensitive mutant in PMA1, encoding the plasma membrane ATPase, in which newly synthesized Pma1 is mislocalized to the vacuole via the endosome. Diversion of mutant Pma1 from vacuolar delivery and rerouting to the plasma membrane is a major mechanism of suppression of pma1(ts). 16 independent suppressor of pma1 (sop) mutants were isolated. Identification of the corresponding genes reveals eight that are identical with VPS genes required for delivery of newly synthesized vacuolar proteins. A second group of SOP genes participates in vacuolar delivery of mutant Pma1 but is not essential for delivery of the vacuolar protease carboxypeptidase Y. Because the biosynthetic pathway to the vacuole intersects with the endocytic pathway, internalization of a bulk membrane endocytic marker FM 4-64 was assayed in the sop mutants. By this means, defective endosome-to-vacuole trafficking was revealed in a subset of sop mutants. Another subset of sop mutants displays perturbed trafficking between endosome and Golgi: impaired pro-alpha factor processing in these strains was found to be due to defective recycling of the trans-Golgi protease Kex2. One of these strains defective in Kex2 trafficking carries a mutation in SOP2, encoding a homologue of mammalian synaptojanin (implicated in synaptic vesicle endocytosis and recycling). Thus, cell surface delivery of mutant Pma1 can occur as a consequence of disturbances at several different sites in the endosomal system.
Biological Transport↗
3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist.
Recent work has suggested that heroin and morphine-6beta-glucuronide (M6G) both act through a novel mu opioid receptor subtype distinct from those mediating morphine's actions. This very high affinity 3H-M6G site is selectively competed by 3-methoxynaltrexone. In vivo, 3-methoxynaltrexone (2.5 ng, i.c.v.) selectively antagonizes the analgesic actions of heroin and M6G without interfering with mu (morphine and [D-Ala2,MePhe4,Gly(ol)5]enkephalin), delta ([D-Pen2,D-Pen5]enkephalin), kappa1 (U50,488H) or kappa3 (naloxone benzoylhydrazone) analgesia. In dose-response studies, 3-methoxynaltrexone (2.5 ng, i.c.v.) significantly shifted the ED50 values for heroin and its active metabolite, 6-acetylmorphine, without affecting the morphine curve. These results indicate that 3-methoxynaltrexone selectively blocks a novel 3H-M6G binding site which is responsible for the analgesic actions of heroin and M6G. This ability to selectively antagonize heroin actions opens new possibilities in the development of therapeutics for the treatment of opioid abuse.
Analgesia↗
Enhanced kappa-opioid receptor-mediated analgesia by antisense targeting the sigma1 receptor.
In the current study, we used an antisense oligodeoxynucleotide targeting the recently cloned sigma1 receptor to assess its functions within the nervous system. Sigma1 antagonists potentiate the analgesic actions of opioids. Similarly, the antisense probe targeting the sigma1 receptor enhanced the analgesic activity of the kappa1-opioid receptor agonist U50,488H (trans-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeacetamidel++ +) and the kappa3-opioid receptor agonist naloxone benzoylhydrazone. A mismatch control was inactive. These results confirm the role of sigma1 receptors in an anti-opioid analgesic system and illustrate the utility of antisense approaches towards the elucidation of sigma receptor functions.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Differential expression of the GABAA receptor alpha 1 subunit in developing chicken brain.
A unique segment of chicken GABAA receptor alpha 1 subunit was expressed in E. coli and used to generate an antiserum 2A specific for the subunit. The DNA fragment encoding the segment of alpha 1 was obtained by selective amplification by polymerase chain reaction (PCR) from a chicken brain cDNA library. The antiserum is characterized by its capacity to immunoprecipitate a [3H]flunitrazepam binding protein of 50 kDa, the chicken GABAA receptor alpha 1 subunit. Subsequent immunoblotting and immunocytochemistry analyses reveal that alpha 1 is expressed in the optic tectum and cerebellum as early as embryonic day 15 (E15), in various areas of telencephalon as early as E20 and distributed heterogeneously among different cell types. The early expression of alpha 1 may imply its functional significance in neurotransmission.
Animals↗
A conserved internal hydrophobic domain mediates the stable membrane integration of the dengue virus capsid protein.
The mature flavivirus capsid protein (virion C) is commonly thought to be free in the cytoplasm of infected cells and to form a nucleocapsid-like complex with genomic RNA in mature virus particles. There is little sequence conservation among flavivirus virion C proteins, but they are similar in size (e.g., 99 amino acids [aa] for the dengue-4 [DEN4] C) and in bearing a net positive charge. In addition, we noted that C contained a conserved internal hydrophobic segment (spanning aa 45-65 in the DEN4 C). Results of in vivo expression and in vitro translation of wt and mutant forms of the DEN4 virion C demonstrated that the conserved internal hydrophobic segment in the DEN C functioned as a membrane anchor domain. Signal peptide function of this segment was also suggested by its requirement for the entry of C into membranes. Virion C was integrated in membranes in a "hairpin" conformation; positively charged segments amino- and carboxy-terminal to the hydrophobic signal-anchor segment were accessible to protease digestion in the "cytoplasm." The net positive charge in the amino-terminal extramembraneous portion of C (aa 1-44) was one determinant of the hairpin membrane orientation; a conserved positively charged residue within the hydrophobic segment (Arg-54 in the DEN4 C) was not.
Amino Acid Sequence↗
Biochemical evidence for orphanin FQ/nociceptin receptor heterogeneity in mouse brain.
A recently identified novel peptide, orphanin FQ/nociceptin (OFQ/N), is an endogenous ligand for a unique member of the cloned opioid receptor family. Saturation studies in mouse brain membranes reveal curvilinear Scatchard plots with both a higher (KD 3.8 pM, Bmax 31.6 fmol/mg protein) and a lower (KD 896 pM, Bmax 233 fmol/mg protein) affinity site in brain tissue, compared to only a single site in transfected CHO cells (KD 36 pM). Competition studies confirm the high affinity of OFQ/N for this site, but shallow Hill slopes suggest heterogeneity. Traditional opioids have poor affinity for this receptor and OFQ/N and its fragments do not label traditional opioid receptors. In brain homogenates, both OFQ/N and OFQ/N(1-11) inhibit forskolin-stimulated camp accumulation with IC50 values of 1 nM or less, an action which is readily reversed by opioid antagonists. OFQ/N(1-7) shows little activity. Together, these studies suggest the presence of heterogeneous, functionally active OFQ/N receptors in mouse brain.
Animals↗
A rapid and simple procedure to detect the presence of MVM in conditioned cell fluids or culture media.
During the manufacture of biopharmaceuticals, numerous adventitious agents have been detected in Master Cell Banks, end-of-production cells as well as bulk harvest fluid. Recently, a number of large-scale production bioreactors have become infected with Minute Virus of Mice (MVM) during cGMP (current good manufacturing practices) operations, and this has resulted in both the loss of product and the need for major cleaning validation procedures to be put in place. We have developed a simple DNA extraction/PCR assay to detect the presence of MVM in cell culture supernatant (conditioned cell fluids). This highly specific assay can detect 10 or fewer genome equivalents (copies) of MVM following PCR and gel electrophoresis visualization. For routine high-throughput detection, 300-100 copies could be consistently detected. The extraction procedure was shown to reliably detect MVM at a concentration of 1 TCID50/ml. The combination of the extraction/PCR procedure establishes a powerful, sensitive, specific assay that can detect the presence of MVM sequences with a 1-day turnaround time.
Animals↗
Dopamine D2 receptor mediates both inhibitory and stimulatory actions on prolactin release.
Dopamine is considered to be the major physiological tonic inhibitor of prolactin release, yet there is increasing evidence showing that it can also stimulate prolactin release from lactotrophs. In primary cultured lactotrophs, the major dopamine receptors responsible for inhibiting prolactin release are dopamine D2 receptors. A dopamine receptor subtype may be responsible for the stimulatory action, yet one cannot exclude the possibility that a dopamine D2 receptor can play dual roles. This study was therefore undertaken to investigate if dopamine both stimulates and inhibits prolactin secretion through activation of the same dopamine D2 receptor. GH4ZR7 cells, which have only one type of dopamine receptors--D2s, were perifused with different concentrations of dopamine, and the perifusate was assayed for prolactin; 10(-7) mol/L dopamine stimulated prolactin release (p < 0.05; n = 5), whereas 5 x 10(-4) mol/L dopamine inhibited prolactin secretion (p < 0.05; n = 5). In the pertussis toxin-treated cells, 10(-7) mol/L dopamine stimulated prolactin release (p < 0.05; n = 5), and 5 x 10(-4) mol/L dopamine did not significantly change the rate of prolactin release. These results indicate that both the stimulatory and inhibitory actions of dopamine are likely mediated by the same D2 receptor subtype, since GH4ZR7 cells express only D2s receptors. They also confirm that the inhibitory action of dopamine is mediated through a Gi protein; and the stimulatory action of dopamine is mediated through a PTX-insensitive pathway. These findings suggest that D2 receptors are coupled to both Gi and Gs proteins.
Animals↗
Relationships between dopamine-induced changes in cytosolic free calcium concentration ([Ca2+]i) and rate of prolactin secretion. Elevated [Ca2+]i does not indicate prolactin release.
This study was undertaken to investigate the relationship between dopamine (DA) induced changes in the cytosolic calcium concentration ([Ca2+]i) and the rate of prolactin secretion using GH4ZR7, a rat pituitary cell line, which express only one subtype of D2 receptor. GH4ZR7 cells were loaded with Fluo-3, a fluorescent Ca2+ indicator, and then perifused with two different doses of DA (10(-7) mol/L and 5 x 10(-4) mol/L). We monitored changes in [Ca2+]i and rate of prolactin release simultaneously by attaching a spectrofluorometer to a dynamic perifusion system. DA has stimulatory and inhibitory effect on prolactin secretion in GH4ZR7 cells; 10(-7) mol/LDA slightly increased [Ca2+]i and stimulated prolactin release, whereas 5 x 10(-4) mol/LDA decreased [Ca2+]i and inhibited prolactin secretion. When the cells were pretreated with pertussis toxin (PTX), 10(-7) mol/L DA had no significant change in [Ca2+]i while stimulating prolactin release, and 5 x 10(-4) mol/L DA reduced [Ca2+]i without having any significant effect on the rate of prolactin secretion. The results of this study demonstrate that changes in [Ca2+]i do not always correlate with the rate of prolactin release from lactotrophs. The dissociation between [Ca2+]i and prolactin release is somewhat expected considering the diverse role of [Ca2+]i and post-[Ca2+]i events, which can change the rate of prolactin release.
Aniline Compounds↗
A randomized prospective study of laparoscopy and laparotomy in the management of benign ovarian masses.
OBJECTIVE: Our purpose was to compare the results of laparoscopy with laparotomy in the management of ovarian masses not suspected to be malignant. STUDY DESIGN: In a prospective randomized study 102 patients requiring surgical management of ovarian masses were randomly assigned to laparoscopy (52) or laparotomy (50) in a teaching hospital from July 1994 to September 1995. Inclusion criteria was tumor not suspected to be malignant with a diameter of < or = 10 cm as measured by ultrasonography. All operations were performed by trainees under the supervision of an experienced surgeon. Statistical analysis included t tests and chi2 tests. RESULTS: There were no differences in demographic characteristics between the two groups nor any difference in the size of ovarian masses, adnexal adhesion score, or frequency of bilateral disease. All the ovarian masses were benign. Endometriotic cysts and dermoid cysts were the most common disorder in the two groups. Cystectomy was performed in > 70% of cases in each group. Operating time was not increased with the laparoscopic approach, and the frequency of inadvertent rupture of the ovarian masses was just as high as in laparotomy. The laparoscopic approach was associated with a significant reduction in operative morbidity (odds ratio 0.34, 95% confidence interval 0.13 to 0.88), postoperative pain and analgesic requirement, hospital stay, and recovery period. Patients in general were satisfied with the operation, but significantly more patients were satisfied with the laparoscopy scar. CONCLUSION: Operative laparoscopy should replace laparotomy in the management of benign ovarian masses.
Adult↗
Prevalence and associations of epiretinal membranes. The Blue Mountains Eye Study, Australia.
PURPOSE: The purpose of the study is to determine the prevalence and associations of epiretinal membranes in a defined older Australian population and to assess their influence on visual acuity. METHODS: Three thousand six hundred fifty-four persons 49 years of age or older, representing 88% of permanent residents from an area west of Sydney, underwent a detailed eye examination, including stereo retinal photography. Epiretinal membranes were diagnosed clinically and from photographic grading. RESULTS: Signs of epiretinal membranes were found in 243 participants (7%; 95% confidence interval [CI], 6.1, 7.6), bilateral in 31%. The prevalence was 1.9% in persons younger than 60 years of age, 7.2% in persons 60 to 69 years of age, 11.6% in persons 70 to 79 years of age, and 9.3% in persons 80 years of age and older, with slightly higher rates in women. Two stages were identified: an early form without retinal folds, termed "cellophane macular reflex" present in 4.8%, and a later stage with retinal folds, termed "preretinal macular fibrosis" (PMF), found in 2.2% of the population. Preretinal macular fibrosis, but not cellophane macular reflex, had a small, significant effect on visual acuity. Preretinal macular fibrosis was significantly associated with diabetes, after age-gender adjustment, in subjects without signs of diabetic retinopathy (odds ratio, 3.2; 95% CI, 1.4, 7.2). Preretinal macular fibrosis also was associated with increased fasting plasma glucose (odds ratio, 1.2; 95% CI, 1.1, 1.3). Epiretinal membranes were found in 16.8% of persons who had undergone cataract surgery in one or both eyes (including PMF in 3.7%), in 16.1% of retinal vein occlusion cases (PMF in 12.5%), both significantly higher rates than in subjects without these conditions (P < 0.0001), and in 11% of persons with diabetic retinopathy (PMF in 3.6%), not significantly higher (P = 0.17). CONCLUSIONS: This study has documented the frequency and mild effect on vision of epiretinal membranes in an older population. Diabetes was associated significantly with idiopathic cases, whereas well-known associations with past cataract surgery and retinal disease were confirmed.
Adult↗
Development of an improved product enhanced reverse transcriptase assay.
A PCR based reverse transcriptase (RT) assay was developed that has 10(4)-fold higher sensitivity than conventional nucleotide incorporation assays and allows discrimination between false positive results generated by cellular polymerases and positives resulting from authentic RT activity. Recently, several reverse transcriptase (RT) assays have been developed where a reverse transcriptase reaction is performed on an RNA template/DNA primer combination. A specific region of the cDNA product is then amplified by the polymerase chain reaction to increase the sensitivity of cDNA detection. These reverse transcriptase assays up to 10(6)-fold more sensitive at detecting retroviruses than conventional methods. The drawback to these assays with increased sensitivity is the increased incidence of false positive results generated by cellular polymerases that can reverse transcribe. The MS2 bacteriophage RNA template and primers from one of the recently developed assays were used as the basis to develop the assay. A simple high resolution agarose gel was used as the endpoint for the assay without compromising sensitivity. In addition, the pH of the RT reaction was lowered to pH 5.5, the RT incubation was 1 h, and protease inhibitors were added to the RT reaction components. These modifications yield an assay that can discriminate between authentic RT activity and contaminating cellular polymerases.
3T3 Cells↗
Skeletal and dental movements after anterior maxillary advancement using implant-supported distraction osteogenesis in dogs.
PURPOSE: This study evaluated skeletal and dental relapse in the dog after anterior maxillary advancement using an implant-anchored distraction osteogenesis device. MATERIALS AND METHODS: After the placement of implants into the palate, four dogs had a skeletally anchored distraction device fabricated and an anterior maxillary osteotomy performed. The distraction device was activated 0.5 mm two times each day to advance the anterior segment 10 mm in 10 days. The dental and skeletal changes were measured and compared for 26 weeks after distraction was completed. RESULTS: Tooth and radiographic measurements indicated that on the 10th day of distraction the average tooth advancement was 6.83 mm +/- 1.75 mm SD, and the average skeletal advancement, based on radiographs, was 8.67 mm +/- 1.25 mm SD. After 10 weeks, the average tooth advancement was 4.0 +/- 1.73 mm, and the average skeletal advancement was 8.67 +/- 3.59 mm. After 26 weeks, the average tooth advancement was 3.65 +/- 1.69 mm, and the average skeletal advancement was 8.0 +/- 1.98 mm. Bone healing occurred in all animals. The skeletal advancement 26 weeks after distraction was 85% of the initial advancement. The teeth adjacent to the distraction site initially moved 68% of the advancement, but the distance between the teeth subsequently decreased, with a resultant 36% advancement compared with the initial advancement. CONCLUSION: This study showed that skeletal fixation will result in bone movement greater than dental movement, indicating the need for skeletal anchorage to advance the maxilla.
Animals↗
Presentation and management of venous aneurysms.
PURPOSE: Venous aneurysms have been reported to occur in most major veins. These aneurysms may be misdiagnosed as soft tissue masses or as inguinal or femoral hernias. Venous aneurysms of the deep system have been associated with deep venous thrombosis (DVT) and pulmonary embolism (PE). To more precisely characterize these lesions, we reviewed our experience with the disease. METHODS: A retrospective analysis of our experience over 22 years was performed. The presentation and management of these lesions were reviewed and compared with the literature. RESULTS: Thirty-nine venous aneurysms were reported in 30 patients. There were 14 men and 16 women. The patients' ages ranged from 3 to 75 years. Thirty aneurysms were located in the lower extremities, four in the upper extremity, and five in the internal jugular vein. Fifty-seven percent of lower extremity aneurysms occurred in the deep system. Patients' symptoms were a mass (75%) associated with pain (67%) and swelling (42%). Thromboembolism occurred in six patients, DVT in three, and PE in three. Eight of nine patients (89%) who had aneurysms of the superficial venous system had their condition misdiagnosed. Diagnosis was made by phlebography (60%), color flow duplex scanning (27%), continuous-wave Doppler scanning (10%), or magnetic resonance imaging (10%). The aneurysm size ranged from 1.7 to 6.0 cm. Management consisted of tangential excision in five (17%), total excision in 23 (77%), and observation in seven (6%). CONCLUSIONS: Venous aneurysms are unusual vascular malformations that occur equally between the sexes and are seen at any age. Most patients have a painful mass of the extremity, and diagnosis is achieved by radiologic examination. Superficial venous aneurysms of the inguinal region are often misdiagnosed. Thromboembolism is more common in aneurysms involving the deep venous system. Because of their potential morbidity, management should be surgical in the majority of cases.
Adolescent↗