Biomedical subjects
S Goode
Publications and source records attributed to S Goode.
Marimastat in patients with advanced pancreatic cancer: a dose-finding study.
Patients with solid tumors, including carcinoma of the pancreas, express high levels of matrix metalloproteinases (MMP), and these enzymes are believed to be important for the growth, spread, and dissemination of most solid malignant tumors. Marimastat is the first orally available MMP inhibitor (MMPI) to be tested in humans and has been shown to inhibit the spread and growth of pancreatic cancer in animal models. The purpose of the present study was to define the toxicities, safety, and tolerance of various doses of marimastat and also to get an early indication of potential biologic activity in patients with advanced pancreatic cancer. The authors prospectively studied 64 patients with advanced carcinoma of the pancreas in whom standard treatments had failed. Eligible patients had a progressive rise in CA 19/9 levels of >25% over the 4-week period preceding their entry into the study. Patients were studied in groups of 8 to 10, with each group receiving escalating dosages ranging from 5 mg twice daily to 75 mg twice daily and 10 to 25 mg daily. Patients were considered for long-term (beyond 4 weeks) continuation treatment if clinical benefit, in the view of the investigator, was derived. Study endpoints were safety, tolerance, and changes in the rate of rise of CA 19/9, which were used as surrogate markers for disease progression. Marimastat was well tolerated. Musculoskeletal pain, stiffness, and tenderness emerged as dose-limiting toxicity. No other dose-related toxicities were observed. A reduced rate of rise of CA 19/9 was observed at dose levels of 5, 10, and 25 mg twice daily. The overall median survival was 160 days, with a 1-year survival of 21%. Marimastat was associated with an acceptable toxicity profile, and these preliminary data suggest that long-term oral administration is feasible and safe. Doses of 5, 10, and 25 mg twice daily were identified as the optimal doses to be tested in larger randomized studies.
Inhibition of patterned cell shape change and cell invasion by Discs large during Drosophila oogenesis.
Drosophila Discs large (Dlg) is a tumor suppressor gene whose loss in epithelial tissues causes disrupted cell polarity and increased cell proliferation. A human Dlg homolog, hDlg, has been implicated in tumorigenic processes via its association with the product of the Adenomatous Polyposis Coli (APC) gene. We show for the first time that Drosophila Dlg is required to block cell invasion. Loss of dlg activity during oogenesis causes follicle cells to change shape and invade in a pattern similar to border cells, a small population of cells that break from the post-mitotic follicular epithelium during wild-type oogenesis, yet dlg mutant cells have not adopted a border cell fate. Both functional and morphological evidence indicates that cooperation between germ cell and follicle cell Dlg, probably mediated by Dlg PDZ domains, is crucial for regulating cell mixing, suggesting a novel developmental mechanism and mode of action for the Dlg family of molecules. These findings suggest that Dlg does not simply inhibit individual cell behaviors during oogenesis, but rather acts in a developmental pathway essential for blocking cell proliferation and migration in a spatio-temporally defined manner. A model for Dlg action in blocking cell invasion is presented.
Elective mutism and chromosome 18 abnormality.
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Brainiac and fringe are similar pioneer proteins that impart specificity to notch signaling during Drosophila development.
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Brainiac encodes a novel, putative secreted protein that cooperates with Grk TGF alpha in the genesis of the follicular epithelium.
brainiac (brn) is involved in a number of developmental events. In addition to being required zygotically for segregation of neuroblasts from epidermoblasts, it is essential for a series of critical steps during oogenesis which also depend upon gurken (grk), a TGF alpha homolog. Animals harboring strong mutations of either grk or EGF receptor tyrosine kinase (Egfr) or doubly mutant for brn and weak grk or Egfr mutations produce ovarian follicles with multiple sets of nurse cell-oocyte complexes. These follicles frequently have discontinuities in the follicular epithelium that uncover nurse cells but not the oocyte. Gaps first appear in the germarium, suggesting that some nurse cells lack affinity for invading prefollicular cells. This is the first evidence that grk, in addition to its involvement in the genesis of anterior-posterior and dorsal-ventral polarity, is also required for Egfr-dependent development of the follicular epithelium that surrounds each nurse cell/oocyte cluster to form an egg chamber. We have used restriction fragment length polymorphisms to localize brn to a 10-kb region within a 300-kb stretch of DNA on the X-chromosome, and we have identified the brn gene by means of RNA rescue. brn codes for a putative secreted protein. brn is expressed in germ cells at the time follicle cells first surround the nurse cell-oocyte complex. Our genetic data suggest that brn acts in a parallel, but partially overlapping pathway to the Grk-Egfr signaling pathway. The brn pathway may help to provide specificity to TGF alpha -Egfr function during oogenesis.
Psychosocial issues in geriatric urology: problems in treatment and treatment seeking.
Psychological and social issues are important in geriatric urology because they affect not only the patient's ability and willingness to seek out therapy, but also their ability to benefit from it. Many older adults with problems of bladder control, such as frequency, urgency, nocturia, and incontinence are deterred from seeking treatment by factors such as social disapproval and belief that bladder symptoms are normal or untreatable. Many older adults who present for treatment experience limitations of mental status or functional ability that merit attention because they can interfere with learning, motivation, and cooperation needed for successful treatment. Strategies are described that help to address these psychosocial issues and needs in older patients.
A broader phenotype of autism: the clinical spectrum in twins.
The diagnostic boundaries of the behavioural phenotype for autism were examined in 28 MZ pairs and 20 DZ same-sex twin pairs, where one or both twins had autism. In the non-autistic cotwin (i.e. in twin pairs discordant for autism) it was common to find language impairments in childhood and social deficits persisting into adulthood. Concordance for this broader phenotype was much greater in MZ pairs than DZ pairs, indicating a strong genetic component. Behavioural and cognitive manifestations of autism were compared both within and between MZ twin pairs. The variation was as great within MZ twin pairs as between pairs, suggesting that it does not index genetic heterogeneity (although aetiological heterogeneity probably exists). Current diagnostic practices need re-evaluation.
The neurogenic genes egghead and brainiac define a novel signaling pathway essential for epithelial morphogenesis during Drosophila oogenesis.
Notch (N) and other neurogenic genes have been implicated in two fundamental processes, lateral specification of cell fates, and epithelial development. Previous studies have suggested that the neurogenic gene brainiac (brn) is specifically required for epithelial development (Goode, S., Morgan, M., Liang, Y-P. and Mahowald, A. P. (1996). Dev. Biol. 178, 35-50). In this report we show that egghead (egh), a gene with phenotypes identical to brn, encodes for a novel, putative secreted or transmembrane protein. We describe the role of egh and brn germline function in the morphogenesis of the follicular epithelium from the time it is born through the time that it migrates towards the oocyte late in oogenesis. By comparing the function of germline egh and brn to N during oogenesis, we have obtained direct evidence for the involvement of Notch in maintenance of the follicle cell epithelium, and the specificity of brn and egh in epithelial development during oogenesis. The most striking phenotype observed for all three genes is a loss of apical-basal polarity and accumulation of follicular epithelial cells in multiple layers around the oocyte. The spatiotemporal onset of this adenoma-like phenotype correlates with the differential accumulation of egh transcripts in the oocyte at stage 4 of oogenesis. In contrast to N, we find that brn and egh are essential for the organization, but not specification, of stalk and polar cells. The expression patterns and functional requirements of brn, egh, and N lead us to propose that these genes mediate follicular morphogenesis by regulating germline-follicle cell adhesion. This proposal offers explanations for (1) the involvement of egh and brn in N-mediated epithelial development, but not lateral specification, (2) why brn and egh embryonic neurogenic phenotypes are not as severe as N phenotypes, and (3) how egh and brn influence Egfr-mediated processes. The correlation between the differential expression of egh in the oocyte and the differential requirement for brn, egh, and N in maintaining the follicular epithelium around the oocyte, suggests that Egghead is a critical component of a differential oocyte-follicle cell adhesive system.
Impact of Bariatric Surgery on Body Image Perception and Sexuality in Morbidly Obese Patients and their Partners.
BACKGROUND: This study was undertaken to determine whether surgery for morbid obesity affects sexual attitudes and performance in patients and their partners. METHODS: Questionnaires concerning sexuality were sent to 94 patients who underwent gastric restriction procedures and their partners. Twenty-eight patients at least 1 year postoperatively (range of 1-11 years, mean 4.2 years +/- 3.24 SD) and 16 of their partners responded. The blinded questionnaires addressed the enjoyment and frequency of sexual intercourse, orgasms, body image, number of partners, abuse, sexual problems and masturbation. Comparisons were made before and after surgery. Patient answers were compared with their partners. RESULTS: Preoperatively, 64% of patients stated that they enjoyed sexual intercourse. Postoperatively, 50% of patients and 78% of partners stated that they enjoyed sex more. Improved orgasms were noted by 44% of patients and 40% partners after surgery. Improvement in body image was also achieved. Only 27% of patients felt they were attractive before surgery, while 80% felt they were more attractive after surgery; 94% of their partners agreed. While 48% of patients undressed in darkness in front of their partners before surgery, only 27% did so after surgery. CONCLUSIONS: Weigh loss attained though bariatric surgery improves body image and sexuality. Sexual intercourse and orgasms are improved postoperatively both for patient and partner.
Partial portal decompression alleviates thrombocytopenia of portal hypertension.
Thrombocytopenia due to splenic sequestration of platelets occurs commonly in patients with portal hypertension. Partial portal decompression for bleeding esophagogastric varices, via the small diameter H-graft portacaval shunt (HGPS), is intended to partially decompress the portal system below bleeding threshold but also to maintain a degree of portal hypertension sufficient to maintain prograde portal perfusion. This study was undertaken to determine whether the reduction of portal pressures seen in patients undergoing HGPS is sufficient to relieve the thrombocytopenia seen in patients with portal hypertension. A total of 74 patients underwent small diameter HGPS for bleeding esophagogastric varices not amenable to medical management. Thirty-four (46%) patients had thrombocytopenia (platelet count < 80,000/mL) before shunting. Platelet counts were obtained preshunt, at discharge, and from 1 to 3 years after shunting. Portal pressures decreased significantly from 30mm Hg +/- 5.6 (SD) pre shunt to 19mm Hg +/- 5.8 (SD) after shunting (P < 0.001). Platelet counts increased from a pre-shunt value of 61,000/mL +/- 2,700 (SEM) to a platelet count of 139,000/mL +/- 21,800 (SEM) at discharge (P < 0.006) and to 102,000/mL +/- 17,500 (SEM) 1 to 3 years after shunting (P < 0.001). Patients undergoing portasystemic shunting for bleeding esophagogastric varices are frequently thrombocytopenic. Partial portal decompression using the 8 mm HGPS is sufficient to alleviate thrombocytopenia associated with portal hypertension immediately following HGPS and for years to follow. The presence of thrombocytopenia does not preclude the use of partial portal decompression in patients with bleeding varices requiring operative intervention.
A case-control family history study of autism.
Family history data on 99 autistic and 36 Down's syndrome probands are reported. They confirmed a raised familial loading for both autism and more broadly defined pervasive developmental disorders in siblings (2.9% and 2.9%, respectively, vs 0% in the Down's group) and also evidence for the familial aggregation of a lesser variant of autism, comprising more subtle communication/social impairments or stereotypic behaviours, but not mental retardation alone. Between 12.4 and 20.4% of the autism siblings and 1.6% and 3.2% of the Down's siblings exhibited this lesser variant, depending on the stringency of its definition. Amongst autistic probands with speech, various features of their disorder (increased number of autistic symptoms; reduced verbal and performance ability) as well as a history of obstetric complications, indexed an elevation in familial loading. No such association was seen in the probands without speech, even though familial loading for the lesser variant in this subgroup, was significantly higher than in the Down's controls. The findings suggest that the autism phenotype extends beyond autism as traditionally diagnosed; that aetiology involves several genes; that autism is genetically heterogeneous; and that obstetric abnormalities in autistic subjects may derive from abnormality in the foetus.
The neurogenic locus brainiac cooperates with the Drosophila EGF receptor to establish the ovarian follicle and to determine its dorsal-ventral polarity.
We have characterized the function of a new neurogenic locus, brainiac (brn), during oogenesis. Homozygous brn females lay eggs with fused dorsal appendages, a phenotype associated with torpedo (top) alleles of the Drosophila EGF receptor (DER) locus. By constructing double mutant females for both brn and top, we have found that brn is required for determining the dorsal-ventral polarity of the ovarian follicle. However, embryos from mature brn eggs develop a neurogenic phenotype which can be zygotically rescued if a wild-type sperm fertilizes the egg. This is the first instance of a Drosophila gene required for determination of dorsal-ventral follicle cell fates that is not required for determination of embryonic dorsal-ventral cell fates. The temperature-sensitive period for brn dorsal-ventral patterning begins at the inception of vitellogenesis. The interaction between brn and DER is also required for at least two earlier follicle cell activities which are necessary to establish the ovarian follicle. Prefollicular cells fail to migrate between each oocyte/nurse cell complex, resulting in follicles with multiple sets of oocytes and nurse cells. brn and DER function is also required for establishing and/or maintaining a continuous follicular epithelium around each oocyte/nurse cell complex. These brn functions as well as the brn requirement for determination of dorsal-ventral polarity appear to be genetically separable functions of the brn locus. Genetic mosaic experiments show that brn is required in the germline during these processes whereas the DER is required in the follicle cells. We propose that brn may be part of a germline signaling pathway differentially regulating successive DER-dependent follicle cell activities of migration, division and/or adhesion and determination during oogenesis. These experiments indicate that brn is required in both tyrosine kinase and neurogenic intercellular signaling pathways. Moreover, the functions of brn in oogenesis are distinct from those of Notch and Delta, two other neurogenic loci that are known to be required for follicular development.
Aorto-oesophageal fistula. A rare cause of gastrointestinal haemorrhage.
Primary aorto-oesophageal fistula is a rare cause of massive and usually fatal gastrointestinal hemorrhage. We herein present a case of a 62-year-old chronic alcohol abuser who had a small haematemesis after a week of persistent vomiting. He succumbed to an exsanguinating bleed 36 hours after admission. An aorto-oesophageal fistula was found at autopsy. We emphasize the need for a high index of suspicion and recognition of premonitory signs for accurate diagnosis and management of this condition.
Possible cerebroprotective and in vivo NMDA antagonist activities of sigma agents.
The recent finding that ifenprodil binds with high affinity to sigma sites suggests that other sigma agents may have ifenprodil-like cerebroprotectant and functional N-methyl-D-aspartate (NMDA) antagonist effects. The present study, compared the in vivo effects of ifenprodil and the sigma agents, BMY 14802, caramiphen and haloperidol, in three tests sensitive to NMDA antagonists and purported cerebroprotectant drugs. When administered at or below the rotorod TD50 dose, all four compounds significantly increased survival time in an hypoxic environment (4% O2 in nitrogen). Caramiphen and ifenprodil (ED50 = 52 and 61 mg/kg, respectively) also blocked maximal electroshock-induced seizures, whereas BMY 14802 and haloperidol were ineffective. Finally, caramiphen (ED50 = 95 mg/kg) antagonized seizures and lethality induced by administration of NMDA (250 mg/kg, IP). BMY 14802, haloperidol and ifenprodil only partially antagonized NMDA-induced seizures, but did enhance the anticonvulsant potency of the noncompetitive NMDA antagonist, MK-801. Together, these findings suggest that sigma agents may have cerebroprotective effects.
Transscleral cyclophotocoagulation using a contact laser probe: a histologic and clinical study in rabbits.
Transscleral photocoagulation of the ciliary body was achieved in pigmented rabbits using a sapphire probe delivery system coupled to a commercial surgical continuous-wave Nd:YAG laser. This contact technique was found to be effective in reducing intraocular pressure (IOP); greater treatment energies were associated with a more prolonged reduction in IOP, and also correlated with a greater degree of histologic damage to the ciliary body. Treatment energies of 0.8-1.0 Joules produced substantial disruption of the ciliary body. This technique is easy to learn and offers ease in control and placement of the coagulation spots.
Autism diagnostic observation schedule: a standardized observation of communicative and social behavior.
The Autism Diagnostic Observation Schedule (ADOS), a standardized protocol for observation of social and communicative behavior associated with autism, is described. The instrument consists of a series of structured and semistructured presses for interaction, accompanied by coding of specific target behaviors associated with particular tasks and by general ratings of the quality of behaviors. Interrater reliability for five raters exceeded weighted kappas of .55 for each item and each pair of raters for matched samples of 15 to 40 autistic and nonautistic, mildly mentally handicapped children (M IQ = 59) between the ages of 6 and 18 years. Test-retest reliability was adequate. Further analyses compared these groups to two additional samples of autistic and nonautistic subjects with normal intelligence (M IQ = 95), matched for sex and chronological age. Analyses yielded clear diagnostic differences in general ratings of social behavior, specific aspects of communication, and restricted or stereotypic behaviors and interests. Clinical guidelines for the diagnosis of autism in the draft version of ICD-10 were operationalized in terms of abnormalities on specific ADOS items. An algorithm based on these items was shown to have high reliability and discriminant validity.
Experimental ab interno sclerotomies using a pulsed-dye laser.
We studied the use of a short-pulse, flashlamp-pumped dye laser, emitting at 666 nm, to create ab interno sclerotomies in cynomolgus monkeys using a fiberoptic delivery system. Because of the low optical absorption of the sclera in the visible portion of the spectrum, ablation of sclera by continuous wave lasers emitting in this region requires high energies and produces significant thermal damage to surrounding tissues. To enhance the optical absorption of sclera, methylene blue dye was applied iontophoretically; patent sclerotomies were obtained in all 10 eyes of six cynomolgus monkeys, with energies ranging from 15 to 50 mj/pulse. Thermal damage to the adjacent sclera was confined to 300 microns. Complications included mild intraoperative hyphema at all pulse energies and iridodialysis at higher pulse energies. Filtration blebs routinely failed within 7 days; the use of 5-fluorouracil postoperatively significantly prolonged bleb duration. The small incision technique described allows ab interno sclerotomies to be created with low pulse energies without the need for conjunctival dissection, thereby avoiding the problems associated with conjunctival wounds. An advantage of this technique is that it can be modified to create ab interno sclerotomies noninvasively by delivering pulsed visible radiation through the cornea with a gonioscopic-slitlamp system.