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Biomedical subjects

F M Brown

Publications and source records attributed to F M Brown.

At least 19 recordsLinked to original sources
PubMed2003

Biotransformation of beta-ketosulfides to produce chiral beta-hydroxysulfoxides.

The biotransformations of a series of substituted phenylthio-2-propanone and benzylthio-2-propanone were carried out using Helminthosporium sp. NRRL 4671, Mortierella isabellina ATCC 42613, or Rhodococcus erythropolis IGTS8. Several products gave microbial oxidation of sulfide to sulfoxide and reduction of carbonyl to secondary alcohol, producing beta-hydroxysulfoxides in medium to high enantiomeric and diastereomeric purities. Fungal biotransformations using Helminthosporium sp. and M. isabellina resulted in the opposite sulfoxide configurations of various beta-hydroxysulfoxide products.

Biotransformation↗
PubMed2001

Extensively keratinized squamous intraepithelial lesions of the cervix are difficult to grade.

We tested the hypothesis that extensively keratinized squamous intraepithelial lesions (SILs) are difficult to grade precisely by identifying 100 Papanicolaou smears with a keratinizing SIL that had been originally judged difficult to grade. Of these, 65 were confirmed as low-grade SIL (LSIL) or high-grade SIL (HSIL) on subsequent biopsy. The 65 smears were reviewed independently by 3 cytopathologists who graded each case as LSIL or HSIL (by Bethesda System criteria). The accuracy of the grade was determined by the subsequent biopsy results; accuracy was compared with that of a historic control group of SILs with biopsy follow-up. In the study group, biopsies showed LSIL in 41 cases and HSIL in 24. The mean accuracy for a smear diagnosis of LSIL was 60% for the study group and 92% for the control group. For a smear diagnosis of HSIL, the accuracy was 60% for the study group and 95% for the control group. The overall kappa value for the study group confirmed poor interobserver agreement. Some keratinizing SILs are difficult if not impossible to grade precisely using standard criteria. For such lesions, the diagnosis "SIL, grade cannot be determined due to extensive keratinization" is justified.

Adolescent↗
PubMed2001

Gestational diabetes mellitus.

In summary, much controversy exists surrounding the diagnosis, treatment, and even existence of GDM. At present, there is not enough evidence to advocate the Carpenter and Coustan criteria over the NDDG criteria. In univariate analysis, the Toronto Tri-Hospital Study demonstrated an increased incidence of cesarean section, macrosomia, and preeclampsia with increasing carbohydrate intolerance in those who did not meet NDDG criteria for GDM. Multivariate analysis, however, showed that this contribution is small relative to other nonmodifiable risk factors. A shift to the Carpenter and Coustan criteria would identify a larger population of patients with GDM and increase treatment costs. In addition, although treatment of these borderline GDM patients might reduce macrosomia, there is no evidence to indicate that it reduces the cesarean section rate. The precise threshold at which glucose intolerance adversely affects pregnancy outcomes and increases the risk for the development of type 2 diabetes in the mother is unknown. The perinatal risks associated with hyperglycemia seem to increase continuously with increasing maternal hyperglycemia. More randomized intervention trials are needed to define the effects of graded increases in glucose intolerance on maternal and fetal morbidity.

Diabetes, Gestational↗
PubMed2000

Urine cytology. It is still the gold standard for screening?

Urine cytology remains the gold standard for bladder cancer screening. It is the test against which all others are compared when evaluating potential bladder tumor markers. The answer to whether urine cytology possess the optimal combination of sensitivity and specificity to retain consideration as the best screening device depends on the goals of the clinical practice. Urine cytology has excellent specificity with few false-positive cases. Its overall sensitivity is poor, but this drawback is explained for the most part by poor criteria for identifying well-differentiated, low-grade TCC. The natural history of such lesions is the occurrence of multiple superficial recurrences in 70% to 80% of patients, with only a minority (10% to 15%) progressing to muscle invasive or metastatic disease. Because patients with low-grade TCC are at low risk for progression, they are monitored primarily for the development of a subsequent tumor. One might argue that the detection of new low-grade lesions is of secondary importance to the early detection of disease progression. The performance characteristics of urine cytology in this regard are much improved. Urine cytology often results in the identification of high-grade malignant cells even before a cystoscopically distinguishable gross lesion is present. Routinely diagnosing grade I TCC may be clinically irrelevant. Ancillary techniques to improve the sensitivity of urine cytology have been insufficiently additive to have much clinical value. Several promising bladder tumor markers have been investigated as potential screening tools and are summarized in Table 3. BTA, nuclear matrix proteins, and fibrin/fibrinogen degradation products share lower specificities than urine cytology and may have high rates of false positivity. Telomerase is highly sensitive and highly specific but is not readily available as a point-of-service test. Hyaluronidase and hyaluronic acid are promising prognostic markers, but hyaluronidase does not detect grade I TCC. Early results from studies of this marker await verification. Combining some of these new markers may optimize their performance status, allowing the advantages of one test to correct the shortcomings of another. Likewise, their combination with urine cytology may prove beneficial. Although adding urine cytology has not increased the sensitivity of some point-of-service tests, few studies have addressed the effect on specificity. Until an obvious winner is declared in the race to find a bladder tumor marker, urine cytology will remain the gold standard screening method because of its comfortable familiarity.

Antigens, Neoplasm↗
PubMed2000

Problems in grading soft tissue sarcomas.

Clinicians, particularly medical oncologists, place increasing importance on histologic grading as a means of informing their treatment decisions in patients with soft tissue sarcoma. Numerous different grading systems (with a variable number of grades) have been described. Although these have often used different parameters, it is nevertheless generally accepted that histologic grade, however derived, is probably the best prognostic indicator in these sarcoma patients. Unfortunately, however, there is no consensus as to the best grading system, and even those schemes that are most widely applied (those of the French National Cancer Centers and the National Cancer Institute in the United States) have important and acknowledged limitations. Furthermore, assessment of many of the most popular grading parameters is necessarily subjective, and, to date, potentially more objective measures of proliferative activity and ploidy (eg, using immunohistochemistry or DNA flow cytometry) have not improved on experienced morphologic grading. In addition, the confounding (and often misleading) effect on histologic grade of preoperative therapy, which is increasingly used, has not been addressed in any meaningful way. This overview highlights the limitations, problems, and concerns regarding histologic grading of soft tissue sarcomas.

Humans↗
PubMed2000

Myxoid neoplasms of the adrenal cortex: a rare histologic variant.

The myxoid variant of adrenocortical carcinoma is a rare neoplasm described previously in only two case reports. Because of the rarity of these lesions, the presence of myxoid changes in adrenal cortical neoplasms usually raises the possibility of malignancy. We studied the histopathologic features of 14 cases of myxoid adrenocortical neoplasms, including six adenomas and eight carcinomas. All patients with adenomas with sufficient follow-up (n = 5) were alive with no recurrence of their tumors or evidence of metastatic disease. Four patients with carcinomas died of their disease, two were alive with metastatic disease, and one was alive with no evidence of recurrence or metastatic disease. Histologically, the 14 tumors varied in their myxoid composition, ranging from 10% to 95%. The myxoid foci stained positively with Alcian blue and were usually negative with periodic acid-Schiff and mucicarmine stains. As a group, the immunophenotype of the lesions was typical of other adrenal cortical neoplasms, with positive immunostaining for vimentin, synaptophysin, and alpha-inhibin. One tumor was focally positive for keratin. Myxoid adrenal cortical neoplasms should be included in the differential diagnosis of myxoid retroperitoneal neoplasms. Myxoid changes in adrenal cortical neoplasms may be present in both adenomas and carcinomas, and the usual clinical and histopathologic features for adrenocortical neoplasms should be used to diagnose these neoplasms.

Adolescent↗
PubMed1999

Oral, inactivated, whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine: results of the initial evaluation in children. PRIDE Study Group.

Two randomized, double-blinded trials assessed the safety and immunogenicity of an oral, killed enterotoxigenic Escherichia coli (ETEC) plus cholera toxin B subunit vaccine in Egyptian children. Two doses of vaccine or E. coli K-12 were given 2 weeks apart to 105 6- to 12-year-olds and 97 2- to 5-year-olds. Safety was monitored for 3 days after each dose. Blood was collected before immunization and 7 days after each dose to measure immune responses. Few children reported postdosing symptoms, with no differences in the frequency of symptoms between treatment groups. Most vaccinees had an IgA antibody-secreting cell response against colonization factor antigen I (100%, 6-12 years; 95%, 2-5 years), coli surface antigen 2 (92%, 6-12 years; 83%, 2-5 years), and coli surface antigen 4 (93%, 6-12 years). Vaccination evoked a >/=4-fold rise in antitoxic IgA and IgG titers in 93% and 81% of children, respectively. In conclusion, the oral ETEC vaccine was safe and immunogenic in 2- to 12-year-old children, justifying further evaluation in infants.

Administration, Oral↗
PubMed1999

LSIL biopsies after HSIL smears. Correlation with high-risk HPV and greater risk of HSIL on follow-up.

Can the risk associated with a high-grade cervical smear be disregarded when followed by a low-grade biopsy? We examined the distribution of human papillomavirus (HPV) types in such cases to see whether they segregated preferentially with low-risk or high-risk viruses and compared the distribution with that reported in the literature for women with high-grade squamous intraepithelial lesions (HSILs) and low-grade squamous intraepithelial lesions (LSILs). We identified 48 cases of HSIL smears with corresponding LSIL biopsy specimens. Biopsy specimens were tested and typed for HPV by polymerase chain reaction amplification with consensus primers followed by restriction fragment length polymorphism analysis, and HPVs were scored as low-risk or high-risk types. Thirty-seven cases scored positive for HPV DNA: 2 for low-risk HPV types, 17 for high-risk types, and 18 for types of unknown oncogenicity. The prevalence of high-risk HPV was significantly higher than that of low-risk HPV. There was a higher rate of high-risk HPV than that seen in historic unselected LSIL cases. Cases of HSIL cytology/LSIL histology represent a group distinct from unselected LSILs by virtue of their higher prevalence of high-risk HPV types and, therefore, warrant closer clinical follow-up.

Biopsy↗
PubMed1999

Azithromycin versus ciprofloxacin for treatment of uncomplicated typhoid fever in a randomized trial in Egypt that included patients with multidrug resistance.

To compare clinical and bacteriological efficacies of azithromycin and ciprofloxacin for typhoid fever, 123 adults with fever and signs of uncomplicated typhoid fever were entered into a randomized trial. Cultures of blood were positive for Salmonella typhi in 59 patients and for S. paratyphi A in 3 cases; stool cultures were positive for S. typhi in 11 cases and for S. paratyphi A in 1 case. Multiple-drug resistance (MDR; resistance to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole) was present in isolates of 21 of 64 patients with positive cultures. Of these 64 patients, 36 received 1 g of azithromycin orally once on the first day, followed by 500 mg given orally once daily on the next 6 days; 28 patients received 500 mg of ciprofloxacin orally twice daily for 7 days. Blood cultures were repeated on days 4 and 10 after the start of therapy, and stool cultures were done on days 4, 10, and 28 after the start of therapy. All patients in both groups improved during therapy and were cured. Defervescence (maximum daily temperatures of </=38 degrees C) occurred at the following times [mean +/- standard deviation (range)] after the start of therapy: 3.8 +/- 1.1 (2 to 7) days with azithromycin and 3.3 +/- 1.0 (1 to 5) days with ciprofloxacin. No relapses were detected. Cultures of blood and stool during and after therapy were negative in all cases, except for one patient treated with azithromycin who had a positive blood culture on day 4. These results indicated that azithromycin and ciprofloxacin were similarly effective, both clinically and bacteriologically, against typhoid fever caused by both sensitive organisms and MDR S. typhi.

Adolescent↗
PubMed1999

The effect of hormonal replacement therapy on the vascular reactivity and endothelial function of healthy individuals and individuals with type 2 diabetes.

Estrogens protect healthy women from cardiovascular disease. However, epidemiological data suggest that women with diabetes are denied the cardioprotection associated with estrogens. Whether or not hormonal replacement therapy (HRT) confers cardiovascular benefits in postmenopausal women with diabetes is not known. The aim of this study was to examine the effects of HRT on the microvascular reactivity and endothelial function of individuals with and without diabetes. We studied the following groups of individuals: premenopausal healthy women [n = 28, age 41 +/- 8 yr (mean +/- SD)], premenopausal women with type 2 diabetes (n = 16, age 43 +/- 6 yr); postmenopausal healthy women (n = 12, age 57 +/- 4 yr), postmenopausal women with diabetes (n = 17, age 62 +/- 5 yr); postmenopausal healthy women on HRT (n = 13, age 51 +/- 5 yr), postmenopausal women with diabetes on HRT (n = 11, age 57 +/- 7 yr). We used laser Doppler flowmetry to measure forearm cutaneous vasodilatation in response to iontophoresis of 1% acetylcholine (endothelium dependent) and 1% sodium nitroprusside (endothelium independent). The endothelium-dependent vasodilation was significantly higher in premenopausal healthy women (180 +/- 67%; increase over baseline) compared to premenopausal diabetic women (87 +/- 41%; P < 0.001). endothelium-dependent vasodilation was also higher in postmenopausal healthy women on HRT (143 +/- 52) compared with postmenopausal diabetic women on HRT (86 +/- 61), postmenopausal healthy women without HRT (104 +/- 43), and postmenopausal diabetic women without HRT (74 +/- 28; P < 0.001). A similar pattern of responses was observed in the endothelium-independent vasodilation (premenopausal healthy women, 126 +/- 56; premenopausal diabetic women, 88 +/- 26; postmenopausal healthy women on HRT, 121 +/- 37; postmenopausal diabetic women on HRT, 88 +/- 41; postmenopausal healthy women without HRT, 84 +/- 36; and postmenopausal diabetic women without HRT, 73 +/- 36; P < 0.001). Soluble intercellular adhesion molecule (sICAM) was also measured among all the women with diabetes. Premenopausal women with diabetes (248.9 +/- 56 ng/ml) and postmenopausal women with diabetes on HRT (257.7 +/- 49 ng/ml) had lower sICAM levels compared with the postmenopausal diabetic women without HRT (346.4 +/- 149 ng/ml; P < 0.05). We conclude that menopausal status and type 2 diabetes are associated with impaired microvascular reactivity. HRT substantially improves microvascular reactivity in postmenopausal healthy women. In contrast, the effect of HRT on the microvascular reactivity of postmenopausal diabetic women is less apparent. However, the use of HRT among women with diabetes is associated with lower sICAM levels, suggesting an attenuation in endothelial activation.

Acetylcholine↗
PubMed1998

Safety and immunogenicity of an oral, killed enterotoxigenic Escherichia coli-cholera toxin B subunit vaccine in Egyptian adults.

Enterotoxigenic Escherichia coli (ETEC) is the leading cause of bacterial diarrhea in young children in developing countries. The safety and immunogenicity of a killed, oral ETEC vaccine consisting of whole cells plus recombinantly produced cholera toxin B subunit (rCTB) was evaluated in Egypt, which is endemic for ETEC diarrhea. Seventy-four healthy Egyptian adults (21-45 years old) were randomized and received two doses of the ETEC/rCTB vaccine (E003) or placebo 2 weeks apart. The frequency of adverse events after either dose did not differ by treatment group, and no severe adverse events were reported. After vaccination, peripheral blood IgA B cell responses to CTB (100%) and to vaccine colonization factor antigens CFA/I (94%), CS4 (100%), CS2 (81%), and CS1 (69%) were significantly higher than response rates for the placebo group. These favorable results in Egyptian adults indicate that the ETEC/rCTB vaccine is a promising candidate for evaluation in younger age groups in this setting.

Adult↗
PubMed1997

Immunogenicity of recombinant hepatitis B vaccine among infants of mothers with active schistosomiasis.

A study of the immunogenicity of a recombinant hepatitis B vaccine was conducted among 385 Egyptian infants, 191 (49.6%) of whom were born to mothers with moderately active Schistosoma mansoni infection (mean egg count = 224 eggs/g of feces). All mothers were seronegative for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen. Infants were vaccinated with a 2.5-microg dose of this vaccine, given along with diphtheria, tetanus, and pertussis (DTP) vaccine, at the ages of two, four, and six months. Serum samples taken from each infant at nine months of age were tested for HBsAg, antibody to hepatitis B core antigen, and quantitatively for antibody to hepatitis B surface antigen (anti-HBs). There was no significant difference (P = 0.1) between anti-HBs titers in infants of S. mansoni-infected mothers (mean = 539 mIU/ml) and in infants of noninfected mothers (mean = 377 mIU/ml). This study shows that there was no apparent effect of maternal schistosomiasis infection on the immune response of these infants to vaccination.

Adult↗
PubMed1996

Expression and biochemical characterization of iron regulatory proteins 1 and 2 in Saccharomyces cerevisiae.

Iron-regulatory proteins (IRPs) 1 and 2 are cytosolic RNA-binding proteins that bind to specific stem-loop structures, termed iron-responsive elements (IREs) that are located in the untranslated regions of specific mRNAs encoding proteins involved in iron metabolism. The binding of IRPs to IREs regulates either translation or stabilization of mRNA. Although IRP1 and IRP2 are similar proteins in that they are ubiquitously expressed and are negatively regulated by iron, they are regulated by iron by different mechanisms. IRP1, the well-characterized IRP in cells, is a dual-function protein exhibiting either aconitase activity when cellular iron is abundant or RNA-binding activity when cellular iron is scarce. In contrast, IRP2 lacks detectable aconitase activity and functions exclusively as an RNA-binding protein. To study and compare the biochemical characteristics of IRP1 and IRP2, we expressed wild-type and mutant rat IRP1 and IRP2 in the yeast Saccharomyces cerevisiae. IRP1 and IRP2 expressed in yeast bind the IRE RNA with high affinity, resulting in the inhibition of translation of an IRE-reporter mRNA. Mutant IRP2s lacking a 73 amino acid domain unique to IRP2 and a mutant IRP1 containing an insertion of this domain bound RNA, but lacked detectable aconitase activity, suggesting that the presence of this domain prevents aconitase activity. Like IRP1, the RNA-binding activity of IRP2 was sensitive to inactivation by N-ethylmaleimide (NEM) or 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), indicating IRP2 contains a cysteine(s) that is (are) necessary for RNA binding. However, unlike IRP1, where reconstitution of the 4Fe-4S cluster resulted in a loss in RNA-binding activity, the RNA-binding activity of IRP2 was unaffected using the same iron treatment. These data suggested that IRP2 does not contain a 4Fe-4S cluster similar to the cluster in IRP1, indicating that they sense iron by different mechanisms.

Aconitate Hydratase↗
PubMed1995

Characterization and expression of iron regulatory protein 2 (IRP2). Presence of multiple IRP2 transcripts regulated by intracellular iron levels.

Iron regulatory proteins (IRP1 and IRP2) are RNA-binding proteins that bind to stem-loop structures, termed iron-responsive elements (IREs), present in either the 5'- or 3'-untranslated regions of specific mRNAs. The binding of IRPs to 5'-IREs inhibits translation of mRNA, whereas the binding of IRPs to 3'-IREs stabilizes mRNA. To study the structure and regulation of IRP2, we isolated cDNAs for rat and human IRP2. The derived amino acid sequence of rat IPR2 is 93% identical with that of human IRP2 and is present in lower eukaryotes, indicating that IRP2 is highly conserved. IRP1 and IRP2 share 61% overall amino acid identity. IRP2 is ubiquitously expressed in rat tissues, the highest amounts present in skeletal muscle and heart. IRP2 is encoded by multiple mRNAs of 6.4, 4.0, and 3.7 kilobases. The 3'-untranslated region of rat IRP2 contains multiple polyadenylation signals, two of which could account for the 4.0-kb and 3.7-kb mRNAs. The 3.7-kb mRNA is increased in iron-depleted cells and occurs with a reciprocal decrease in the 6.4-kb transcript. These data suggest that the 3.7-kb mRNA is produced by alternative poly(A) site utilization in iron-depleted cells.

Amino Acid Sequence↗
PubMed1995

Comparative study of the immunogenicity and safety of two dosing schedules of hepatitis B vaccine in neonates.

Healthy Egyptian neonates born to hepatitis B surface antigen (HBsAg)-seronegative mothers were randomly enrolled in one of three vaccination schedules. A dose of 2.5 micrograms of recombinant HB vaccine was given at birth, two, and six months of age (group A) or two, four, and nine months of age (group B). These two groups and a third control group (group C) also were given the other routine childhood vaccines (BCG, DPT, polio, and measles). Blood samples were taken one month after the third vaccine dose in groups A (seven months of age) and B (10 months of age), and a second follow-up blood sample was taken at the age of 18 months for all three groups. Sera were tested for HBsAg and antibody to hepatitis B core antigen, and quantitatively for antibody to hepatitis B surface antigen (anti-HBs) using commercial enzyme immunoassay kits. The vaccine was well tolerated and side effects were limited to local soreness, redness, or temporary swelling. Among 590 infants who were followed-up, good (51-300 mIU anti-HBs/ml) or excellent (> 300 mIU/ml) immune responses occurred in 85% of the infants in group A and in 96% in group B. Geometric mean titers of anti-HBs at the first and second follow-up were 306 and 55 mIU/ml in group A, and 1,492 and 147 mIU/ml in group B. The recombinant HB vaccine is safe and immunogenic when given in three doses of 2.5 micrograms in either regimen, but delay of the booster dose of the vaccine until nine months after birth produced a higher immune response.

Female↗
PubMed1994

Forskolin specifically inhibits the bacterial galactose-H+ transport protein, GalP.

Forskolin is a potent inhibitor of mammalian passive glucose transporters. Here we show that forskolin is a remarkably specific inhibitor of energized D-galactose transport by the GalP sugar-H+ symport protein of Escherichia coli. Surprisingly, it does not inhibit transport of L-arabinose or D-xylose by the related E. coli AraE and XylE transporters, even though the amino acid sequences of their proteins are 30-64% identical to GalP and to the mammalian GLUT family. However, unlike GLUT1, photoactivation of the [3H]forskolin-GalP complex fails to incorporate radioactivity covalently into the protein, in contrast to the effective incorporation of radioactivity from [3H]cytochalasin B into both proteins. However, 3-[125I]iodo-4-azidophenethylamido-7-O-succinyldesacetylforskol in ([125I]APS-forskolin), which labels GLUT1, is a potent labeling reagent for GalP and, to a lesser extent, for AraE. The appropriate sugar substrates of each transporter protect it against the [125I]APS-forskolin. Equilibrium binding studies using membranes from an E. coli strain that overexpresses GalP reveal a single set of high affinity binding sites for [3H]forskolin with a Kd of 1.3-1.4 microM, probably forming a 1:1 complex, compared with a value of 7.5 microM for GLUT1. Sugar substrates of GalP and cytochalasin B displace forskolin from the protein. The nonhomologous sugar-H+ symporters for L-rhamnose (RhaT), L-fucose (FucP) and lactose (LacY) in E. coli are insensitive to forskolin. Forskolin and [125I]APS-forskolin, therefore, constitute novel probes for exploring the structure-activity relationship of the bacterial GalP protein. GalP will provide an excellent model for the human glucose transporters and for elucidating the molecular basis of subtle differences in substrate and inhibitor recognition by individual members of this widespread family of transport proteins.

Affinity Labels↗