Biomedical subjects
Publications and source records attributed to G Miller.
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CONTEXT: The I1307K mutation of the APC gene is found in approximately 6% of the Ashkenazi Jewish population and is associated with elevated risk of colorectal cancer. The incidence of the mutation in patients with colorectal adenomas is unknown. OBJECTIVES: To determine the carrier rate of the I1307K mutation in Ashkenazi Jewish patients with a history of colorectal polyps but without colorectal cancer and to compare phenotypic characteristics and family history of carriers vs noncarriers. DESIGN, SETTING, AND PATIENTS: A total of 231 patients who had at least 1 large bowel polyp diagnosed between January 1, 1992, and January 31, 1999, at 1 of 5 centers in Boston, Mass, were included, of whom 183 were Ashkenazi Jewish. DNA was isolated from cheek swab samples. MAIN OUTCOME MEASURES: Presence of the I1307K variant in the APC gene. RESULTS: The I1307K variant was identified in 22 (14%) of 161 Ashkenazi Jewish patients with a history of adenomatous polyps and in 1 (5%) of 20 Ashkenazi Jewish patients with hyperplastic polyps. The phenotypic features of adenomas, family history of polyps, colorectal cancer, and other cancers were indistinguishable between I1307K carriers and noncarriers. CONCLUSIONS: The frequency of the APC I1307K mutation is elevated in Ashkenazi Jewish patients with adenomatous polyps, but not hyperplastic polyps. The I1307K mutation represents a novel paradigm for cancer-predisposing genes, as it is associated with moderately increased risk of neoplasia without other associated distinguishing phenotypic features. JAMA. 2000;284:857-860
Kaposi's sarcoma-associated herpesvirus (KSHV) is the first human virus known to encode dihydrofolate reductase (DHFR), an enzyme required for nucleotide and methionine biosynthesis. We have studied the purified KSHV-DHFR enzyme in vitro and analyzed its expression in cultured B-cell lines derived from primary effusion lymphoma (PEL), an AIDS-associated malignancy. The amino acid sequence of KSHV-DHFR is most similar to human DHFR (hDHFR), but the viral enzyme contains an additional 23 amino acids at the carboxyl-terminus. The viral DHFR, overexpressed and purified from E. coli, was catalytically active in vitro. The K(m) of KSHV-DHFR for dihydrofolate (FH(2)) was 2.4 microM, which is significantly higher than the K(m) of recombinant hDHFR (rhDHFR) for FH(2) (390 nM). K(m) values for NADPH were similar for the two enzymes, about 1 microM. KSHV-DHFR was inhibited by folate antagonists such as methotrexate (K(i): 200 pM), aminopterin (K(i): 610 pM), pyrimethamine (K(i): 29 nM), trimethoprim (K(i): 2.3 microM), and piritrexim (K(i): 3.9 nM). In all cases, K(i) values for these folate antagonists were higher for KSHV-DHFR than for rhDHFR. The viral enzyme was expressed at levels two- to tenfold higher than hDHFR in PEL cell lines as an early lytic cycle gene. KSHV-DHFR mRNA and protein appeared from 6 to 24 h after chemical induction of the KSHV lytic cycle. Epitope-tagged KSHV-DHFR and rhDHFR both localized to the nucleus of transfected cells, while other KSHV nucleotide metabolism genes localized to the cytoplasm. DHFR activity was not essential for viral replication in cultured PEL cells. Since hDHFR was not detectable in peripheral blood mononuclear cells (PBMCs), KSHV-DHFR may function to provide increased DHFR activity in vivo in infected cells that have little or none of their own enzyme.
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The objective of this study was to identify phenotypic parameters that could distinguish among seemingly homogeneous non-syncytium-inducing (NSI) viruses and that might provide a surrogate marker for clinical progression in pediatric human immunodeficiency virus type 1 (HIV-1) infection. We undertook a pilot analysis of 15 independent HIV-1 isolates collected prospectively from two mothers and their four children who displayed a spectrum of disease stages ranging from CDC categories A1 to C3. Viruses were evaluated for their ability to replicate in primary cells (including monocyte-derived macrophages [MDM]) and cell lines, for their co-receptor preference and for genetic features of the V3 hypervariable domain of env. Virtually all isolates displayed NSI phenotypes that were restricted in their capacity to replicate in cell lines and displayed V3 loops with uniformly low net positive charges. NSI viruses from two symptomatic children and one mother were macrophage-tropic, whereas NSI isolates from two asymptomatic children were unable to replicate in MDM and were designated primary lymphotropic viruses. Only one isolate was syncytium-inducing (SI), replicated in a variety of cell lines and in MDM, used multiple co-receptors, and was dual tropic, rather than a mixture of T-cell tropic and M-tropic viruses, as assessed by genetic analysis. Phenotypic heterogeneity among NSI viruses is revealed in the ability of isolates to replicate in MDM. This characteristic is related to disease stage and provides a potentially new in vitro criterion to distinguish among NSI isolates that is unlinked to other surrogate markers.
Sampling error is an inherent problem of prostate biopsy. Consequently, there are problems in determining whether a given carcinoma is clinically significant on the basis of biopsy results. This study assesses the factors that predispose to errors in biopsy grading, as well as the dimensions of sampling error due to these factors. Among 187 cases, biopsy grading error was retrospectively related to grade heterogeneity in the prostate and to biopsy-related factors. Clinically relevant biopsy grading errors occurred in a quarter of the cases. Of all grading errors, at least 17% resulted from misinterpretation by the pathologist only. Overall, prostates with grade heterogeneity revealed grading errors twice as frequently as specimens without grade heterogeneity. In most cases, however, grading error resulted from multiple factors, such as the number and length of cores obtained (p<0.05). This was an important finding because the mean core length was only 9.4 mm, whereas the biopsy needle is designed to obtain cores of 15 mm. Moreover, clinically relevant biopsy grading error had occurred in almost half of the cases when the Gleason score was based on a tumour deposit measvring less than 0.5 mm (p<0.05). The clinical consequences of these findings are important. Clinicians should try to obtain at least six biopsies, each 15 mm in length, to minimize grading error. Pathologists should be cautious in reporting Gleason scores based on tumour lesions smaller than 400x total magnification field. Interpretation could be refined, when necessary, by warning the urologist of the Limitations of the biopsy report.
AIMS/HYPOTHESIS: Peroxisome proliferator activated receptor alpha (PPARalpha) regulates genes involved in lipid metabolism, haemostasis and inflammation, in response to fatty acids and fibrates, making it a candidate gene for risk of dyslipidaemia, atherosclerosis and coronary artery disease. Plasma non-esterified fatty acids are increased in subjects with Type II (non-insulin-dependent) diabetes mellitus, suggesting that PPARalpha could link Type II diabetes and dyslipidaemia, and affect response to fibrates. This has been investigated in association studies in healthy and diabetic subjects and in vitro studies. METHODS: The human PPARalpha gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays. RESULTS: We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type II diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct. CONCLUSION/INTERPRETATION: Naturally occurring variation alters PPARalpha function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARalpha is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type II diabetes.
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BACKGROUND: Minimizing the number and scope of ports used to perform laparoscopic cholecystectomy attempts to build on the improvements in postoperative pain control, rapid return to activity and work, patient satisfaction, and cosmetic result achieved by the laparoscopic method. METHODS: We studied 141 patients in two sequential studies: the first a prospective randomized trial with 41 patients, and the second an examination of the more minimal procedure in 100 patients. In the randomized trial, patients underwent laparoscopic cholecystectomy with three ports: three 5-mm ports or two 10-mm ports and one 5-mm port. The 100 patients underwent the three 5-mm port procedure. RESULTS: In the randomized trial, differences were not statistically significant. However, on the average, the group with three 5-mm ports required less medication over less time, had less postoperative pain, and took less time to return to activity than the second group with larger ports. A statistically significant difference was found in incisional pain between the smaller group (21 patients) with two 10-mm ports and one 5-mm port and the larger group (100 patients) with three 5-mm ports, whether the measure was overall incisional pain (p = 0.014) or a comparison based on specific ports (p = 0.001). The percentage of cases requiring port enlargement to remove the gallbladder was not significantly different between the groups. There were no conversions to an open procedure, no fourth trocars added, and no complications. No patient required overnight hospitalization. CONCLUSIONS: Reducing the number and size of ports in laparoscopic cholecystectomy sustains or enhances the improvements initiated by performing laparoscopic rather than open cholecystectomy. In a comparison of microlaparoscopic procedures, patients undergoing the procedure with the shorter incisions experienced significantly less pain.
BACKGROUND: Small bowel obstruction (SBO) is a major cause of morbidity and financial expenditure in hospitals around the world. The leading cause of SBO in the western world has become adhesions. The goal of this study was to determine the causes of SBO. METHODS: The medical records of all patients admitted to one hospital between 1986 and 1996 with the diagnosis of SBO were reviewed retrospectively. This included 552 patients accounting for 1,001 admissions. RESULTS: The etiology of SBO was adhesions (74%), Crohn's disease (7%), neoplasia (5%), hernia (2%), radiation (1%), and miscellaneous (11%). Patients with Crohn's disease were younger than patients with other etiologies. Surprisingly, recurrence rates were similar for patients treated operatively as for those treated nonoperatively with the exception in the hernia group where higher recurrence rates were noted for patients initially treated in a nonoperative manner. CONCLUSION: The most common cause of SBO is adhesions followed by Crohn's disease and neoplasia.
Two patients with neck-tongue syndrome, a rare disorder of the upper cervical nerves that results in paroxysmal neck pain and paresthesia of the tongue, are described. Signs are the result of compression of the C2 root by disorders affecting the first two cervical vertebrae. Conservative management is effective in most cases if no masses are in the involved area. The disorder has been observed rarely in children. Clinical onset occurred at 6 and 11 years of age, respectively, in the reported patients.
Microsomal triglyceride transfer protein (MTP) plays a central role in the synthesis of lipoproteins by shuttling lipids between phospholipid membranes to apoB. We have examined the effect of three MTP gene variants, -493G > T, Q95H and H297Q, in 2831 healthy UK middle-aged men. The rare allele frequencies were: 0.25 (95% CI 0.24-0.26) for -493T, 0.054 (95% CI 0.05-0.06) for 95H and 0.32 (95% CI 0.31-0.33) for 297Q. The three variants were in strong allelic association in all pairwise combinations (p < 0.001). None of the variant sites were associated with significant differences in cholesterol, triglyceride, apoB or apoAI levels. When stratified by tertiles of triglycerides for the H297Q variant alone there was a significant effect on apoB levels in men in the top tertile (p = 0.01). Considering the -493G > T and H297Q genotype in combination on baseline levels, individuals with three or four rare alleles had 6.6% higher mean apoB levels compared to the rest (p = 0.007). Therefore, homozygosity for 297Q at higher triglyceride (Tg) levels, or in combination with -493G > T, is associated with a raising effect on apoB levels, suggesting the importance of modest differences in MTP activity in determining hepatic secretion of lipoproteins in healthy men.
Hepatic regimen-related toxicity (RRT) is a serious complication of stem cell transplantation. Cytokine activation may be involved in the pathogenesis. Corticosteroids are potent inhibitors of cytokine production, and, therefore could play a role in the treatment of hepatic RRT. Between January 1994 and June 1998, 28 of 782 consecutive transplant patients (3.6%) developed hepatic RRT (20 veno-occlusive disease (VOD) and eight liver dysfunction of uncertain etiology (LDUE) as defined by Seattle criteria), and were treated with high-dose methylprednisolone (MP, 500 mg/m2 i.v. every 12 h for six doses), initiated upon increase in serum total bilirubin to > or =4 mg/dl. Other causes of liver dysfunction were excluded. Response to therapy with high-dose MP was defined as reduction in total bilirubin by 50% within 10 days of initiation of MP. Overall, 17 patients (61%) responded to treatment (12 patients with VOD, five patients with LDUE). The bilirubin in responding patients decreased from a mean of 8.6 mg/dl (range, 4-17.9) at the start of MP to 4.1 mg/dl (range, 0.5-17.9) 10 days later. There were no statistically significant differences between responders and non-responders in the day treatment with high-dose MP was initiated (P = 0.38), total serum bilirubin (P = 0.17) and percent weight gain at the time high-dose MP was started (P = 0.10) or the calculated probability of fatal outcome from VOD (18% for responders, 23% for non-responders; P = 0.30). A lower pre-transplant DLCOc was observed among non-responders (P = 0.04). At 100 days post-transplant, hepatic RRT resolved in all 13 survivors who responded to high-dose MP, and in one non-responding patient. No serious toxicities due to high-dose MP were observed. We conclude that resolution of hepatic RRT occurred in the majority of patients treated with high-dose MP in this study; however, randomized controlled trials are required to determine the efficacy of high-dose MP for treatment of hepatic RRT.
BACKGROUND: Small bowel obstruction (SBO) is a major cause of morbidity and financial expenditure. The goals of this study were to determine factors predisposing to adhesive SBO, to note the long-term prognosis and recurrence rates for operative and non-operative treatment, to elicit the complication rate of operations and to highlight factors predictive of recurrence. METHODS: The medical records of all patients admitted to one hospital between 1986 and 1996 with the diagnosis of SBO were reviewed retrospectively. This included 410 patients accounting for 675 admissions. RESULTS: The frequency of previous operation by procedure type was colorectal surgery (24 per cent), followed by gynaecological surgery (22 per cent), herniorrhaphy (15 per cent) and appendicectomy (14 per cent). A history of colorectal surgery (odds 2.7) and vertical incisions (odds 2.5) tended to predispose to multiple matted adhesions rather than an obstructive band. At initial admission 36 per cent of patients were treated by means of operation. As the number of admissions increased, the recurrence rate increased while the time interval between admissions decreased. Patients with an adhesive band had a 25 per cent readmission rate, compared with a 49 per cent rate for patients with matted adhesions (P<0.004). At the initial admission 36 per cent of patients were treated surgically. Patients treated without operation had a 34 per cent readmission rate, compared with 32 per cent for those treated surgically (P not significant), a shorter time to readmission (median 0.7 versus 2.0 years; P<0.05), no difference in reoperation rate (14 versus 11 per cent; P not significant) and fewer inpatient days over all admissions (4 versus 12 days; P<0.0001). CONCLUSION: The likelihood of reobstruction increases and the time to reobstruction decreases with increasing number of previous episodes of obstruction. Patients with matted adhesions have a greater recurrence rate than those with band adhesions. Non-operative treatment for adhesions in stable patients results in a shorter hospital stay and similar recurrence and reoperation rates, but a reduced interval to reobstruction when compared with operative treatment.
Membranous nephropathy (MN) is a common cause of nephrotic syndrome. Optimal therapy for this disease is still debated. We report our experience using mycophenolate mofetil (MMF), an immunosuppressive agent widely used in transplant recipients, to treat 16 nephrotic patients with MN. All patients had biopsy-documented MN; secondary forms were ruled out. Fifteen patients had steroid-resistant disease; cytotoxic agents had failed in 6 patients and cyclosporine therapy had failed in 5 patients. Patients were treated with MMF (dose range, 500 to 2,000 mg) for a mean of 8 months. Six patients experienced a halving of proteinuria, which occurred after a mean duration of 6 months of therapy. Partial remissions occurred in 2 patients. There were no significant changes in mean values for serum creatinine, serum albumin, or proteinuria. Mean cholesterol levels were significantly less. Side effects of MMF were infrequent and generally mild. In summary, MMF appears to reduce proteinuria in some patients with idiopathic MN previously resistant to steroids, cytotoxic agents, or cyclosporine. Further trials with this agent are warranted.
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The classical statistics approach used in health physics for the interpretation of measurements is deficient in that it does not take into account "needle in a haystack" effects, that is, correct identification of events that are rare in a population. This is often the case in health physics measurements, and the false positive fraction (the fraction of results measuring positive that are actually zero) is often very large using the prescriptions of classical statistics. Bayesian statistics provides a methodology to minimize the number of incorrect decisions (wrong calls): false positives and false negatives. We present the basic method and a heuristic discussion. Examples are given using numerically generated and real bioassay data for tritium. Various analytical models are used to fit the prior probability distribution in order to test the sensitivity to choice of model. Parametric studies show that for typical situations involving rare events the normalized Bayesian decision level k(alpha) = Lc/sigma0, where sigma0 is the measurement uncertainty for zero true amount, is in the range of 3 to 5 depending on the true positive rate. Four times sigma0 rather than approximately two times sigma0, as in classical statistics, would seem a better choice for the decision level in these situations.
This article re-examines whether and how emotions are an aspect of solution-focused therapy. A major theme in the article focuses on the usual ways that therapists define and discuss emotions in solution-focused and other therapies. We argue that these discussions are a source of much confusion about emotions and about solution-focused therapy, including the confusing idea that emotions are neglected in solution-focused therapy. The second major theme describes an alternative approach to these issues, one that we believe better fits with the assumptions and concerns of solution-focused therapy. The approach is based on Wittgenstein's writings about language games, private experience, and how emotions are rule-following activities. Viewed from this perspective, solution-focused therapists take account of their clients' emotions by helping clients to create new emotion rules to follow.