Biomedical subjects
Publications and source records attributed to J Lynch.
This study is the first to examine the genetic risk in a breast cancer-prone family wherein two of three triplet sisters and their mother manifested breast cancer. The unaffected triplet, the proband, was found to be monozygotic with her deceased sister through DNA testing of tumor blocks and dizygotic to her living affected sister. Genetic counseling implications are discussed.
UNLABELLED: The objective of the study was to evaluate the role of autologous blood transfusion in current clinical practice in the Federal Republic of Germany after reunification. METHODS: Questionnaires were sent to the anaesthesia departments of 684 German hospitals in January 1993. The sample consisted of 400 randomly selected hospitals from the former West Germany ("old federal states") and 284 hospitals from the former German Democratic Republic ("new federal states"). Only hospitals with more than 25 surgical beds were included in the study. The questionnaire contained 36 questions related to (1) general information on the hospital, (2) preoperative autologous blood donation (PABD), (3) preoperative plasmapheresis, (4) isovolaemic haemodilution, (5) perioperative blood salvage, and (6) general management of blood transfusion. RESULTS: A total of 502 completed questionnaires (73%) were returned, 305 from hospitals in the "old federal states" and 197 from hospitals in the former German Democratic Republic. Nine per cent of the responding hospitals were running their own transfusion services, and 56% were located in the vicinity of a regional blood bank. The overall proportion of surgical procedures requiring perioperative blood transfusion ranged from 1% to 90% (median 10%). PABD was performed "not at all" in 18%, "rarely" in 20% "occasionally" in 27%, "frequently" in 17%, and "mostly" in 16% of the responding hospitals. The principal use of PABD was in orthopaedic surgery and cardiac surgery (83% and 70% of the departments in question, respectively). In more than 50% of the hospitals reporting, the PABD service was run by the anaesthesia department. Patients not meeting the established criteria for homologous blood donors were accepted for autologous blood donation "frequently" and "mostly" in 20% and 12% of the hospitals, respectively, but at most "occasionally" in 63% of the hospitals. Preoperative plasmapheresis was performed in 12% of the responding hospitals. Autologous fresh frozen plasma predominantly was used for volume replacement, and for prevention of coagulation disorders when major blood loss was anticipated. Isovolaemic haemodilution was performed "not at all" in 28%, "rarely" in 19%, "occasionally" in 28%, "frequently" in 16%, and "mostly" in 8% of the responding hospitals. The reasons most frequently invoked for not performing haemodilution were "too time consuming" and "too little blood-saving effect". Cell separators for perioperative blood salvage were available in 30% of the responding hospitals. Of the other hospitals not equipped with cell-washing devices, 11% performed perioperative blood salvage of unprocessed blood by means of simple collection devices. Some 80% of those hospitals using intraoperative autotransfusion devices also performed blood salvage postoperatively. The principal use of perioperative blood salvage was in cardiac surgery, orthopaedics, and vascular surgery (90%, 54%, and 54% of departments, respectively). Some 48% of the responding anaesthetists "mostly" considered haemoglobin levels of 8-10 g/dl acceptable in patients without cardiopulmonary disease, but only 18% did so in patients with cardiopulmonary disease. CONCLUSIONS: Although available in the majority of hospitals surveyed, the simple techniques of both PABD and isovolaemic haemodilution are unduly neglected in routine clinical practice. The consistent use of both of these techniques, and the careful weighing up of the indication for every single blood transfusion, would not only effectively reduce homologous blood transfusions, but also enable even small hospitals to run successful autologous transfusion programmes without expensive cell-washing and plasmapheresis devices.
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Ondansetron and droperidol are both effective in the prevention of postoperative nausea and vomiting (PONV). In this randomized, double-blind study, 80 inpatients scheduled for minor gynecologic surgery received either ondansetron 8 mg intravenously (i.v.) or droperidol 2.5 mg i.v. 5 min prior to induction of isoflurane-narcotic anesthesia. PONV was absent in 68% of the patients after ondansetron and in 88% after droperidol (P < 0.05). The respective times of complete arousal from anesthesia were 171 min and 229 min (P < 0.001). After ondansetron and droperidol, the incidence of severe drowsiness, restlessness, anxiety, or dizziness was 5% and 28%, respectively (P < 0.01). Thus after minor gynecologic surgery, droperidol 2.5 mg i.v. was superior to ondansetron 8 mg i.v. in the prevention of PONV. However, relative to ondansetron, droperidol entailed an average 1-h delay in recovery from anesthesia.
Normal functioning of the thyroid gland during surgery is important, but few data are available on the possible interactions between anesthesia and thyroid hormones. In two independent studies we examined the influence of different types of general anesthesia on the plasma levels of the thyroid hormones. They revealed an intraoperative increase of free thyroxine (fT4) and total thyroxine (tT4) in plasma to approximately 150% of preanesthesia levels when enflurane was used. No increase in thyroid-stimulating hormone (TSH) secretion was noted prior to this. The increase was not due to a quantitative change in the binding proteins. The plasma levels of fT4 and tT4 returned to normal postoperatively; however, no accompanying increase in plasma triiodothyronine levels was observed. Hence we assume the increase to be due to hormone release from thyroid and/or extrathyroidal stores--an intercompartmental shifting.
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Nerve growth factor-beta (NGF beta) and a NGF beta-immunoreactive protein derived from human prostatic stromal cell secretory protein (hPS) have been shown to stimulate the growth of prostate epithelial cells. An NGF beta-immunoreactive protein has been localized to the stroma of human prostate tissues, and a low affinity NGF receptor (gp75NGFR) has been localized to the adjacent epithelia, consistent with the paracrine regulation of prostate growth. Interestingly, gp75NGFR is progressively lost during neoplastic progression of the human prostate. In this report we have characterized the expression of the signal-transducing component of the NGF receptor, the Trk tyrosine receptor kinase, in prostate epithelial cells that bind exogenous NGF beta and an endogenous NGF beta-immunoreactive protein in hPS. In this context, a pan-Trk antibody that recognizes all of the members of the Trk receptor family (TrkA, TrkB, and TrkC) specifically localized expression of the Trk receptor to the epithelial component of normal prostate tissue, benign prostatic hyperplasia, and adenocarcinoma tissue. The binding of [125I]NGF beta to the surface of primary cultures of human prostate epithelia and the TSU-pr1 human metastatic prostate tumor cell line was displaced with either excess cold NGF beta or hPS, whereas binding was not displaced by epidermal growth factor or platelet-derived growth factor. Scatchard plot analysis of [125I]NGF beta binding to these cells identified a low affinity binding site (Kd = 1.9 x 10(-9) M) and a high affinity binding site (Kd = 1.8 x 10(-11) M) on the primary prostate epithelia, whereas only a high affinity binding site (Kd = 1.3 x 10(-11) M) was observed on the TSU-pr1 tumor cells. Stimulation of TSU-pr1 cells with either NGF beta or hPS induced tyrosine phosphorylation of Trk proteins, whereas no phosphorylation was evident in untreated cells, cells treated with hPS immunoprecipitated with anti-NGF beta antibody, or brain-derived neurotrophic factor- and neurotrophin-3-treated cells. The Trk protein was also observed in these cells by immunoblot analysis with pan-Trk antibody. These results demonstrate a functional Trk receptor in the epithelia of the human prostate that is responsive to exogenous NGF beta and an endogenous NGF beta-immunoreactive protein in hPS, thereby supporting the concept of the paracrine regulation of growth in the human prostate via a stromal neurotrophin-epithelial Trk receptor interaction.
Hereditary nonpolyposis colorectal cancer (HNPCC), also termed Lynch syndrome, may account for as much as 10-15 percent of the total colorectal burden. Lynch syndrome I is characterized by site-specific colorectal cancer (CRC) with early (congruent to age 45) onset, predilection to the proximal colon (congruent to 70%), and a marked susceptibility to metachronous CRC (45% following hemicolectomy or segmental resection). Lynch syndrome II shows the same colonic features but includes an excess of extra-colonic CRCs, namely carcinoma of the endometrium, ovary, small bowel, stomach, pancreas and transitional cell carcinoma of the ureter and renal pelvis. These findings form the basis for our surveillance recommendations: full colonoscopy initiated at age 25 and repeated every other year, and, in Lynch syndrome II variant, biannual endometrial aspiration biopsy. Screening for the remaining cancer types is dependent upon the availability of screening modalities and the pattern of cancer expression within specific families. The excess of metachronous CRC mandates that subtotal colectomy be performed for any CRC. The lack of premonitory physical stigmata has forced clinicians to diagnose HNPCC based on the family history in concert with the natural history features of the cancer phenotype within the pedigree. Problems with this approach include variable gene penetrance, the fact that cancer affected may or may not be gene carriers, death of gene carriers prior to developing cancer, and difficulty with pathology verification of tumor site and type. Partial resolution of these problems is possible now that HNPCC has been linked to chromosomes 2p and 3p and the susceptibility gene at chromosome 2p has been cloned.(ABSTRACT TRUNCATED AT 250 WORDS)
Primary genetic factors play a major etiologic role in approximately 5% to 10% of the total cancer burden. Since the bulk of hereditary forms of cancer lack premonitory physical stigmata of cancer risk, a well-orchestrated family history is mandatory for establishing a hereditary cancer syndrome diagnosis. Knowledge of the natural history of the particular hereditary form of cancer will aid the physician in the development and implementation of highly targeted surveillance strategies. Indeed, specific natural history features of cancer, particularly early age onset and multiple primary cancer excess, characterize the more than 200 mendelian inherited cancer syndromes. The veritable explosive developments in molecular biology now enable the identification of germline mutations so that, in certain hereditary cancers, a simple blood test will enable the physician to determine the cancer destiny of patients carrying the particular germline mutation.
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BACKGROUND: There is a paucity of knowledge pertaining to the attitudes, feelings, and emotions of women who are at increased familial risk for breast cancer and how these concerns will affect their surveillance behavior. A review of the literature shows an unevenness in the conclusions about these matters, with some reports indicating that anxiety aroused in the familial cancer setting may abet surveillance behavior, whereas other data indicates a negative effect. METHODS: The authors reported anecdotal accounts of such behavior in women from hereditary breast and hereditary breast-ovarian cancer prone families. RESULTS: Although these responses of fear, anxiety, and apprehension about cancer risk are not unique to this hereditary cohort, they nevertheless must have been tempered by often life-long exposure of cancer occurrences that may have decimated their families. CONCLUSIONS: All accounts agree with the need to devote more research to the special needs--psychological, social, insurance, and general public health measures--of these high risk women.
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We are reporting on a 47-year-old man who presented with a prolongation of the activated partial thromboplastin time (APTT) prior to orthopedic surgery. An evaluation suggested an inhibitor when his plasma prolonged a normal control APTT upon 50:50 solution of patients with normal plasma. The platelet-neutralizing procedure (PNP), anticardiolipin antibody, and antinuclear antibody (ANA) were positive. Further studies revealed decreased von Willebrand factor ristocetin cofactor (vWF:RCoF), von Willebrand factor antigen (vWF:Ag), an inhibitor to vWF, and absent high-molecular-weight vWF multimeters. Assays of FVIII:C, FIX, and FXI were nonparallel to the standard curve. Intravenous immunoglobulin (IVIG) corrected the APTT, multimeric pattern, and FVIII:C by the 7th day postinfusion. This case demonstrates the efficacy of IVIG for acquired von Willebrand's syndrome (vWS) and also represents a unique combination of a lupus-like anticoagulant and acquired vWS in a patient without the full serological requirement for systemic lupus erythematosus (SLE). Whether patients with acquired vWS and lupus inhibitors are more or less susceptible to either a thrombotic complication or hemorrhage is not established. Prospective studies for the incidence of lupus inhibitor/antiphospholipid syndromes and vWF deficiencies are needed to assess this question.
In two experiments, multilingual Papua New Guinean subjects were tested using a divided visual field technique designed to determine hemispheric laterality for English and for Tok Pisin. Various factors including age of acquisition, proficiency, mode of instruction, and number of years that the language had been used were considered in relation to language laterality. Only age of acquisition proved to be a significant contributor to the laterality effects obtained; older acquirers of both English and Tok Pisin showed greater right hemisphere involvement than early acquirers. Although proficiency did not seem to be related to language laterality, it too was systematically affected by acquisition age. Older acquirers of English performed significantly poorer than younger acquirers on all four of the language-usage tests given. The strong influence of acquisition age on cerebral laterality for language and proficiency is interpreted as supporting a critical period for language learning.
PURPOSE: The aim of this study was to describe the natural history and management of surgically unresectable intra-abdominal desmoid tumors in two patients with Gardner's syndrome from two unrelated families, where each had failed on conventional therapy. METHODS: Two patients with Gardner's syndrome were placed on a chemotherapy regimen which included doxorubicin (90 mg/m2) and dacarbazine (900 mg/m2) in divided doses over four days of continuous infusion. Their progress on chemotherapy was assessed by abdominal computerized tomography and laparoscopy. RESULTS: The computerized abdominal tomography scans proved difficult to interpret because of adhesions and matted small bowel resulting from the patients original colectomies. These findings made it difficult to differentiate postoperative changes from residual desmoid tumor. Second-look laparotomy in such patients was contraindicated as this may predispose to further desmoid production. Laparoscopy disclosed a complete response to this chemotherapy. Nevertheless, we had an iatrogenic small bowel perforation in one of these patients. Each patient showed a complete response to chemotherapy. CONCLUSION: Surgical resection remains the first-line treatment of intraabdominal desmoid tumors. However, doxorubicin/dacarbazine chemotherapy on a clinical trial basis may be indicated in patients whose intra-abdominal desmoid is unresectable, or who have failed to respond to treatment with hormones (tamoxifen, Toremifene), steroids (prednisone), and nonsteroidal anti-inflammatory agents (Clinoril; Merck & Co., Inc., West Point, PA).
Intestinal absorption of many hydrophilic drugs cannot be explained solely in terms of pH-partition and solvent-drag effects have been described in a number of cases. However, quantitative estimates of sieving coefficient (phi) for drug molecules have tended to be variable. In the present work an in situ perfused intestinal loop preparation in the rat has been used to measure the disappearance of five hydrophilic drugs from the intestinal lumen and a mathematical model of drug absorption in the presence of net and unidirectional fluid fluxes has been developed. The model allows separate estimation of the convective (solvent drag) and nonconvective (partition) components of drug absorption from the experimental data. The five drugs studied were found to have phi values ranging from 0.1-0.9; this was highly dependent on molecular size. Analysis of the data shows that three of the drugs are absorbed almost exclusively by the convective process (caffeine, cimetidine, hydrochlorthiazide) while the other two are absorbed by both convective and nonconvective processes (salicylate, oxprenolol). We conclude that the methodology is a useful and reliable means of deriving separate estimates of these two components of drug absorption.
OBJECTIVE: Our purpose was to describe histologically verified endometrial carcinoma and other cancer types manifested through three generations in a pedigree, where these findings do not fit any classic hereditary cancer syndrome. STUDY DESIGN: Our family study protocol used detailed patient interviews whenever possible and questionnaires with permission forms that, when signed, enabled retrieval of pertinent medical-genetic and pathologic study documents. RESULTS: Endometrial carcinoma was histologically verified in five women through three consecutive generations. The triad of obesity, hypertension, and diabetes mellitus was not observed. Primary carcinomas of both the endometrium and ovary and endometrium and lymphoma were documented in two relatives in the direct genetic lineage of the pedigree. CONCLUSION: An aggregation of endometrial carcinoma in families, even when classic hereditary cancer syndrome identification is lacking, nevertheless merits surveillance and management strategies targeted to putative high-risk family members.