Helicobacter pylori infection: not associated with recurrent abdominal pain in children.
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Abdominal Pain↗
Biomedical subjects
P Lynch
Publications and source records attributed to P Lynch.
SMAD genes in juvenile polyposis.
Juvenile polyposis (JP) is a dominantly inherited condition characterized by the development of multiple hamartomatous tumors, juvenile polyps, in the gastrointestinal tract. The aim of this study was to clarify the role of SMAD4 in JP. DNA from four unrelated JP kindreds and three sporadic JP cases was available for mutation screening. Two truncating defects (one in a familial and one in a sporadic case) and one missense change (in a familial case) that was absent in 55 control samples were detected. To study the possibility that germline mutations in other genes encoding different components of the TGF-beta signaling pathway may be present in these JP patients, mutation analyses of the SMAD2, SMAD3, and SMAD7 genes were also performed. No mutations of these genes were detected in any of the patients. Our results confirm that SMAD4 is a gene predisposing to JP and suggest the existence of further JP loci other than the SMAD2, SMAD3, or SMAD7 genes. Genes Chromosomes Cancer 26:54-61, 1999.
Adenomatous Polyposis Coli↗
Failure to diagnose hereditary colorectal cancer and its medicolegal implications: a hereditary nonpolyposis colorectal cancer case.
PURPOSE: We describe a patient who had precancerous colonic symptoms and a positive family history of multiple occurrences of early-onset colorectal cancer in her first-degree and second-degree relatives consistent with hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer diagnosis had not been made before her diagnosis of carcinoma of the cecum with liver metastasis. She died at age 20, leading to litigation. Controversies about standards of care, their malpractice implications, and pertinent legal issues are discussed. METHODS: Review of the medical and family history was made by the expert witness (HTL) with appropriate documentation of the chronology of symptoms, as derived from depositions. These documents revealed that the patient's mother had repeatedly discussed with the caregivers her concern about the family history of colon cancer and the need for appropriate surveillance. RESULTS: The patient's colonic symptoms progressed for a period of three years. Flexible sigmoidoscopy was performed by a nonphysician. The physician who ordered the procedure considered this appropriate because isolated polyps were reported in the patient's father and paternal uncle, which apparently led him to believe that the diagnosis was familial adenomatous polyposis. During litigation procedures, a pedigree was constructed and found to be consistent with hereditary nonpolyposis colorectal cancer. The case was settled in favor of the plaintiff before trial. CONCLUSION: It is essential to understand the natural history of hereditary nonpolyposis colorectal cancer, inclusive of the need for surveillance colonoscopy in patients at increased risk by virtue of their position in their family pedigree.
Adenomatous Polyposis Coli↗
Toward designing the optimal total cavopulmonary connection: an in vitro study.
BACKGROUND: Understanding the total cavopulmonary connection (TCPC) hemodynamics may lead to improved surgical procedures which result in a more efficient modified circulation. Reduced energy loss will translate to less work for the single ventricle and although univentricular physiology is complex, this improvement could contribute to improved postoperative outcomes. Therefore to conserve energy, one surgical goal is optimization of the TCPC geometry. In line with this goal, this study investigated whether addition of caval curvature or flaring at the connection conserves energy. METHODS: TCPC models were made varying the curvature of the caval inlet or by flaring the anastomosis. Steady flow pressure measurements were made to calculate the power loss attributed to each connection design over a range of pulmonary flow splits (70:30 to 30:70). Particle flow visualization was performed for each design and was qualitatively compared to the power losses. RESULTS: Results indicate that curving the cavae toward one pulmonary artery is advantageous only when the flow rate from that cavae matches the flow to the pulmonary artery. Under other pulmonary flow split conditions, the losses in the curved models are significant. In contrast, fully flaring the anastomosis reduced losses over the range of pulmonary flow splits. Power losses were 56% greater for the curving as compared to flaring. Fully flaring without caval offset reduced losses 45% when compared to previous models without flaring. If flaring on all sides was implemented with caval offset, power losses reduced 68% compared to the same nonflared model. CONCLUSIONS: The results indicate that preferentially curving the cavae is only optimal under specific pulmonary flow conditions and may not be efficient in all clinical cases. Flaring of the anastomosis has great potential to conserve energy and should be considered in future TCPC procedures.
Anastomosis, Surgical↗
RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids.
The RNA-binding/dimerization domain of the NS1 protein of influenza A virus (73 amino acids in length) exhibits a novel dimeric six-helical fold. It is not known how this domain binds to its specific RNA targets, one of which is double-stranded RNA. To elucidate the mode of RNA binding, we introduced single alanine replacements into the NS1 RNA-binding domain at specific positions in the three-dimensional structure. Our results indicate that the dimer structure is essential for RNA binding, because any alanine replacement that causes disruption of the dimer also leads to the loss of RNA-binding activity. Surprisingly, the arginine side chain at position 38, which is in the second helix of each monomer, is the only amino-acid side chain that is absolutely required only for RNA binding and not for dimerization, indicating that this side chain probably interacts directly with the RNA target. This interaction is primarily electrostatic, because replacement of this arginine with lysine had no effect on RNA binding. A second basic amino acid, the lysine at position 41, which is also in helix 2, makes a strong contribution to the affinity of binding. We conclude that helix 2 and helix 2', which are antiparallel and next to each other in the dimer conformation, constitute the interaction face between the NS1 RNA-binding domain and its RNA targets, and that the arginine side chain at position 38 and possibly the lysine side chain at position 41 in each of these antiparallel helices contact the phosphate backbone of the RNA target.
Amino Acid Sequence↗
Reduction in hMSH2 mRNA levels by premature translation termination: implications for mutation screening in hereditary nonpolyposis colorectal cancer.
We have used single-strand conformational polymorphism (SSCP) and heteroduplex analysis to examine DNA from 50 colorectal carcinoma patients coming from families meeting the Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC) or having developed colorectal carcinoma at age 45 or younger. We identified mutations in 12 of these patients, with seven of these being novel mutations. We examined four of the truncating mutations using in vitro transcription and translation (IVTT) assays and determined that the mutation causing an in-frame deletion of exon 5 could easily be detected by the IVTT assay, but the three mutations resulting in premature translation termination were not detected because the steady-state levels of the mutant allele transcripts are too low. Our findings suggest that some but not all mutant hMSH2 alleles have significantly lower steady-state mRNA levels than the normal allele. Under ideal circumstances, where lymphoblastoid cell lines are available for RNA extraction, IVTT may be useful for detecting truncating mutations. However, our data suggest that caution should be taken in using IVTT in routine screening of clinical samples for truncating HNPCC mutations, as many mutations may go undetected.
Colorectal Neoplasms, Hereditary Nonpolyposis↗
Electroencephalographic and psychomotor effects of chlorpromazine and risperidone relative to placebo in normal healthy volunteers.
AIMS: To investigate the effects of single oral doses of chlorpromazine (50 mg) and risperidone (2 mg) relative to placebo on topographical electroencephalometry (CATEEMTM ) and psychomotor tests in 12 healthy male volunteers. METHODS: A double-blind, placebo-controlled, three-way crossover design using a double dummy blinding technique was utilized. Chlorpromazine was selected as representative of the 'typical' neuroleptics, being also highly sedative. Risperidone has been suggested as representative of the newer 'atypical' neuroleptics and is claimed to be only minimally sedative. Volunteers were dosed on 3 separate days with a minimum of 7 days interval between trial days. On each trial day volunteers were dosed twice. Dose 1 consisting of either chlorpromazine 50 mg or placebo to chlorpromazine, and dose 2 either risperidone 2 mg or placebo to risperidone. The volunteers were randomized so that each received either chlorpromazine or risperidone (or neither), but not both on an individual trial day. A 17 electrode quantitative topographical electroencephalograph (EEG) recording was taken for each volunteer before and after each dosing period. Seven psychomotor function tests were used to determine the effects of each treatment on psychomotor performance. RESULTS: The data confirm the cited reports of sedation following single oral doses of chlorpromazine 50 mg. However, 7 of the 12 volunteers dosed with risperidone 2 mg also reported drowsiness/lethargy which was of greater severity and duration than 5 of the 12 volunteers who reported somnolence following dosing with chlorpromazine 50 mg. Objective assessment of psychomotor impairment using a short battery of psychomotor function tests mirrored the subjective reports of somnolence in that the impairment in volunteers dosed with risperidone 2 mg was greater in extent and magnitude than in volunteers dosed with chlorpromazine 50 mg. With respect to the cortical quantitative electroencephalogram, both chlorpromazine (50 mg) and risperidone (2 mg) increased power (4.75-6.75 Hz) in keeping with cited effects of other neuroleptics on the quantitative EEG. In addition, there was a statistically significant increase (P<0.05) in alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.5 Hz) wavebands in volunteers dosed with risperidone 2 mg. Furthermore, based on estimates of variability, we propose that a 3 min eyes open and 3 min eyes closed quantitative EEG recording is sufficient to maintain adequate power for this technique, whilst allowing its application to early volunteer trials of novel neuroleptic agents. CONCLUSIONS: This study demonstrates that quantitative EEG can be utilized in the profiling of neuroleptic agents, and could be readily applied to the early profiling of novel neuroleptics in limited numbers of volunteers, early in drug development. The chosen battery of psychomotor tests has clearly demonstrable sensitivity to the quantification of the subjective reports of somnolence secondary to both chlorpromazine and risperidone.
Adolescent↗
An Internet-based law and medicine curriculum for residents.
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Connecticut↗
Multidrug therapy.
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Drug Administration Schedule↗
Accelerated recombinant protein purification process development automated, robotics-based integration of chromatographic purification and analysis.
Recovery of recombinant proteins from endogenous, host molecules can be an experimentally intensive and time-consuming task. Often the time to analyze material during development of recovery procedures is the rate-limiting step. Nowadays, modern techniques and equipment are being specifically engineered to make this effort much more efficient. We present a case study to illustrate how a new, automation tool, designed for easy, systematic methods development, can be used for very rapid process and analytical optimization. This tool uses robotics to integrate process development with rapid LC-based analysis requiring no user intervention. The methods and procedures described can be generalized to any recombinant protein recovery campaign.
Chromatography, High Pressure Liquid↗
Palliation of malignant dysphagia and fistulae with coated expandable metal stents: experience with 101 patients.
BACKGROUND: Insertion of coated expandable esophageal stents is the preferred endoscopic palliative treatment for malignant dysphagia and digestive-respiratory fistulae. METHODS: One hundred one patients with malignant dysphagia and digestive-respiratory fistulae, 83 due to esophageal cancer and 18 due to metastatic disease, underwent placement of a coated expandable metal stent. Thirteen patients had a digestive-respiratory fistula. The stricture location (99 patients) was proximal in 11, mid in 29, distal in 37, and at the gastroesophageal junction in 24. The endoscopic appearance was exophytic in 80, infiltrative in 19, single ulcer in 1, and normal in 1. The mean stricture length was 6.7 cm. RESULTS: Initial stent placement was successful in 100 patients; a second stent was required in 1. The median dysphagia grade improved from 3.6 to 1.4 and sealing-off of the digestive-respiratory fistula was successful in all cases. The overall complication rate was 37.9%. Life-threatening complications occurred in 7.9%. There were no procedure-related deaths. During a mean follow-up of 201 days, 99 patients died-none from stent-related problems. CONCLUSIONS: This large series confirms the efficacy of the coated metal expandable stent in the palliation of malignant dysphagia and digestive-respiratory fistula with an acceptable complication rate.
Adult↗
Perceived organizational support and police performance: the moderating influence of socioemotional needs.
Police patrol officers were surveyed to investigate how the strength of socioemotional needs affects the relationship between perceived organizational support (POS) and work performance. The association of POS with driving-under-the-influence arrests and speeding citations generally increased with strength of the needs for esteem, affiliation, emotional support, and social approval. Patrol officers with strong socioemotional needs, but not those with weak needs, showed a positive relationship between POS and performance. The findings are consistent with social exchange views that maintain (a) work effort is encouraged by the receipt of socioemotional resources, (b) POS fulfills a variety of socioemotional needs, and (c) the value of POS and the obligation to reciprocate with high performance increase with the strength of socioemotional needs.
Adult↗
Outpatient waiting times: indicators of hospital performance?
We monitored outpatient waiting times at UK military hospitals over an 18-month period (September 1996-March 1998). The highest mean waiting times for Consultant appointment were in urology (19 weeks) and orthopaedics (18 weeks). The lowest mean waiting times were in psychiatry (3 weeks), ENT surgery (5 weeks) and rheumatology (6 weeks). Waiting times for surgical specialties were around 50% higher than for medical specialties. The inter-hospital variability in waiting times was 260%. Military waiting list initiatives were introduced in 4 key specialties, but the majority of these initiatives only had a temporary impact in reducing outpatient waiting times. Waiting times reflect the accessibility of a hospital's services, and are a crude but easily measured indicator of one aspect of patient care. With a military population base, outpatient waiting times should be reduced to the lowest practicable level. The keys to achieving a long-term reduction in waiting times are proper staffing levels and the efficient management of clinics.
Ambulatory Care↗
Production and characterization of fusion proteins containing transferrin and nerve growth factor.
To explore the ability to use genetic fusions of transferrin as a carrier for brain targeting and delivery, a series of fusion proteins containing both human nerve growth factor (NGF) and human transferrin was produced in mammalian cells. A protein in which the hinge region from human IgG3 joined the carboxyl terminus of NGF and the amino terminus of transferrin formed a covalent homodimer, bound human transferrin receptor, and retained full NGF in PC12 cells. In contrast, proteins in which polypeptide dimerization was not induced or in which NGF was fused through its amino terminus had greatly reduced NGF activity. The ability to maintain both biologically active NGF and transferrin as part of a fusion protein may offer a novel way to deliver NGF and other neurotrophic factors to the central nervous system.
Blood-Brain Barrier↗
A web-based risk management and medical-legal curriculum for graduate medical education.
An educational Web site on the topic of risk management and medical-legal issues was designed. The site incorporates a 25-question multiple-choice quiz where resident responses were stored in a database for quantitative analysis. Residents who browsed the educational module scored significantly higher on the quiz (81%) than those who did not (62%). The authors conclude that the Web site and accompanying quiz database offer a practical solution for the uniform delivery of risk management in graduate medical education.
Computer-Assisted Instruction↗
Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium.
OBJECTIVE: To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations in the BRCA1 or BRCA2 genes. PARTICIPANTS: A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by National Human Genome Research Institute (previously the National Center for Human Genome Research). EVIDENCE: Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to breast and ovarian cancer were identified using MEDLINE (National Library of Medicine) and from bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "breast cancer," "ovarian cancer," and "screening," or "surveillance" in combination with "cancer family" and "BRCA1" and "BRCA2." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. CONSENSUS PROCESS: The task force developed recommendations through discussions over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on expert opinion concerning presumptive benefit, early breast cancer and ovarian cancer screening are recommended for individuals with BRCA1 mutations and early breast cancer screening for those with BRCA2 mutations. No recommendation is made for or against prophylactic surgery (eg, mastectomy, oophorectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking, and case reports have documented the occurrence of cancer following prophylactic surgery. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
Antineoplastic Agents, Hormonal↗
Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium.
OBJECTIVE: To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations associated with hereditary nonpolyposis colon cancer (HNPCC). PARTICIPANTS: A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by the National Human Genome Research Institute (previously the National Center for Human Genome Research). EVIDENCE: Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to colon cancer were identified using MEDLINE and bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "colon cancer," and "screening" in combination with "cancer family" and "HNPCC." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. CONSENSUS PROCESS: The task force developed recommendations through discussions over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on observational studies, colonoscopy every 1 to 3 years starting at age 25 years is recommended for individuals known to have HNPCC-associated mutations. Endometrial cancer screening is also recommended, based on expert opinion concerning presumptive benefit. No recommendation is made for or against prophylactic surgery (ie, colectomy, hysterectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.
Adaptor Proteins, Signal Transducing↗
Bifunctional fusion between nerve growth factor and a transferrin receptor antibody.
The cDNAs encoding the variable regions of the heavy and light chains of a murine antibody specific for the human TfR were cloned and a human chimera (gamma1, kappa) was produced. A gene fusion was created by joining the 3' end of the coding region of the human nerve growth factor (NGF) precursor to the 5' end of the heavy chain variable region of the chimeric antibody. When expressed with the unmodified light chain in mammalian cells, the protein fusion is properly processed, assembled, and secreted. Subsequent purification and characterization established the uncompromised bifunctional activities of the protein, relative to the unmodified components, as demonstrated by its ability to both bind to the human TfR and induce neurite outgrowth in primary sympathetic or spinal ganglia and in trkA-transfected pheochromocytoma cells. The ability to generate biologically active NGF fused to a TfR targeting antibody, which was previously shown to cross the blood-brain barrier, may offer a novel way to deliver NGF and other neurotrophic factors to the central nervous system.
Animals↗