Effect of early addition of rosiglitazone to sulphonylurea therapy in older type 2 diabetes patients (>60 years): the Rosiglitazone Early vs. SULphonylurea Titration (RESULT) study.

AIM: To compare the efficacy, safety and tolerability of adding rosiglitazone (RSG) vs. sulphonylurea (SU) dose escalation in older type 2 diabetes mellitus (T2DM) patients inadequately controlled on SU therapy. METHODS: A total of 227 T2DM patients from 48 centres in the USA and Canada, aged > or =60 years, were randomized to receive RSG (4 mg) or placebo once daily in combination with glipizide 10 mg twice daily for 2 years in a double-blind, parallel-group study. Previous SU monotherapy was (1/4) to (1/2) maximum recommended dose for > or =2 months prior to screening with fasting plasma glucose (FPG) > or =7.0 and < or =13.9 mmol/l. Treatment options were individualized, and escalation of study medication was specifically defined. RESULTS: Disease progression (time to reach confirmed FPG > or =10 mmol/l while on maximum doses of both glipizide and study medication or placebo) was reported in 28.7% of patients uptitrating SU plus placebo compared with only 2.0% taking RSG and SU combination (p < 0.0001). RSG + SU significantly decreased HbA(1c), FPG, insulin resistance, plasma free fatty acids and medical care utilization and improved treatment satisfaction compared with uptitrated SU. CONCLUSIONS: Addition of RSG to SU in older T2DM patients significantly improved glycaemic control and reduced disease progression compared with uptitrated SU alone but without increasing hypoglycaemia. These benefits were associated with increased patient treatment satisfaction and reduced medical care utilization with regards to emergency room visits and length of hospitalization. Early addition of RSG is an effective treatment option for older T2DM patients inadequately controlled on submaximal SU monotherapy.

An unusual incident: breached 22Na sealed source.

A typical laboratory contamination with radioactive materials in an academic institution is the result of a spill or other handling errors with unsealed radioactive materials. An unusual incident occurred in late January 2002 at our institution when a 22Na sealed source was breached, and a small portion of the contents accidentally migrated to various locations in the very large laboratory. Damage control provided a challenge to radiation safety personnel. Resources of the Radiation Safety Office were severely taxed during both the immediate reaction and the subsequent several months of decontamination prior to release of the laboratory for unrestricted use of radioactive materials once again. Salient features of this incident are described in conjunction with a portrayal of measures taken during early damage control and the following deliberate remediation.

Rosiglitazone reduces urinary albumin excretion in type II diabetes.

This study examines the effect of rosiglitazone on urinary albumin excretion (UAE) in patients with type II diabetes. Urinary albumin: creatinine ratio (ACR) was measured in a 52-week, open-label, cardiac safety study comparing rosiglitazone and glyburide. Patients were randomised to treatment with rosiglitazone 4 mg b.i.d. or glyburide. ACR was measured at baseline and after 28 and 52 weeks of treatment. Statistically significant reductions from baseline in ACR were observed in both treatment groups at week 28. By week 52, only the rosiglitazone group showed a significant reduction from baseline. Similar results were observed for the overall study population and for the subset of patients with baseline microalbuminuria. For patients with microalbuminuria at baseline, reductions in ACR did not correlate strongly with reductions in glycosylated haemoglobin, or fasting plasma glucose, but showed strong correlation with changes in mean 24-h systolic and diastolic blood pressure for rosiglitazone-treated patients (deltaACR vs deltamean 24-h systolic blood pressure, r=0.875; deltaACR vs deltamean 24-h diastolic blood pressure, r=0.755; P < 0.05 for both). No such correlation was observed for glyburide-treated patients. In conclusion, rosiglitazone treatment was associated with a decrease in urinary albumin excretion. These findings suggest a potential beneficial effect of rosiglitazone in the treatment or prevention of renal and vascular complications of type II diabetes.

Use of reproductive health services among young men, 1995.

PURPOSE: To analyze the extent to which teenage males receive preventive reproductive health services and identify demographic and health factors associated with their receipt. METHODS: Bivariate and multivariate analyses of nationally representative data from the 1995 National Survey of Adolescent Males were conducted using logistic regression to determine which factors predicted whether teenagers had a physical examination and whether they discussed reproductive health topics with a medical professional, had a human immunodeficiency virus (HIV) test, or had a sexually transmitted disease (STD) test. RESULTS: Although 71% of males aged 15-19 years received a physical examination in the past year, only 39% of them received any of the three reproductive health services. Less than one-third of all young men discussed reproductive health with their doctor or nurse. Among sexually experienced males, one-sixth had an STD test and one-quarter an HIV test. In multivariate analysis, males who had a physical examination were more likely to have an STD or HIV test, but were no more likely to discuss reproductive health topics. Minority and low-income youth were more likely to receive these reproductive health services, as were young men with multiple sex partners and those with health problems. CONCLUSIONS: In general, the proportion of teenage men receiving reproductive health services is low, although levels are higher among minority youth and certain groups at risk. To reduce rates of teen pregnancy and STDs, physicians and nurses need to incorporate reproductive health care into routine health services for teenage males, as well as females.

Does the peak-end phenomenon observed in laboratory pain studies apply to real-world pain in rheumatoid arthritics?

Laboratory studies and investigations of patients undergoing painful procedures have compared recalled pain to an average of multiple momentary reports taken throughout the painful experience. This work has shown that recalled ratings of pain are more closely associated with a combination of peak pain and pain proximal to the recall ratings than an average of all momentary reports. However, these studies have examined recalled pain over relatively short periods, usually under 1 hour. In this study of 32 patients with rheumatoid arthritis, momentary pain ratings taken over a 7-day period were compared with pain recalled on the eighth day. Analyses confirmed that a combination of peak and recent pain was a better predictor of recalled patient pain than was a simple average of all momentary pain reports. These results extend our understanding of how individuals remember pain and suggest alternative methods for assessing recalled pain.

The paradox of the low-renin state in diabetic nephropathy.

Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.

Laparoscopic biopsy for suspected abdominal lymphoma.

This study retrospectively reviewed the findings in laparoscopic biopsy specimens from 51 consecutive patients with suspected abdominal lymphoproliferative disorders. Histologic evaluation was supplemented (as necessary) by paraffin-section or frozen-section immunohistochemical analysis or by Southern blot hybridization. The laparoscopic procedure was diagnostic of a lymphoproliferative disorder in 24 patients (47%), of other neoplasms in 5 patients (10%), and of reactive tissue in 11 patients (22%); no tissue could be obtained for technical reasons (adhesions and inaccessible lesions) in 11 patients (22%). The 24 patients with lymphoproliferative disorders diagnosed by laparoscopic techniques included 14 patients with a new diagnosis of lymphoma and 10 patients with recurrent disease; pathologic findings were diagnostic of diffuse large cell lymphoma (11 patients), follicular lymphoma (11 patients), chronic lymphocytic leukemia (1 patient), and lymphocyte-predominant Hodgkin's disease (1 patient). Previous abdominal cytologic or core-needle biopsy specimens from 11 lymphoma patients did not yield an unequivocal diagnosis or subtype of lymphoma. The 11 patients (22%) in whom laparoscopic techniques did not produce a tissue sample needed laparotomy (10 patients) or femoral lymph node biopsy (1 patient) to document the diagnosis of large cell lymphoma (2 patients), follicular lymphoma (5 patients), composite lymphoma (1 patient), myeloma (1 patient), neurofibroma (1 patient), and reactive lymph nodes (1 patient). In the majority of patients with suspected abdominal lymphoma, laparoscopic techniques provide sufficient tissue for the diagnosis and classification of lymphoma and for the diagnosis of other causes of abdominal lymphadenopathy.

Obesity, salt intake, and renal perfusion in healthy humans.

Renal perfusion rises as obesity develops during short-term overfeeding in animal studies. In humans, the assessment is complicated by the need to normalize renal perfusion for body size. We made use of the fact that radioactive xenon washout measures renal perfusion per unit of tissue mass to address this issue by comparing 45 moderately obese and 147 lean healthy potential kidney donors. All were disease free. The rationale for involving kidney donors reflects the fact that the xenon method for measuring renal perfusion demands injection of the xenon directly into the renal artery, which can be accomplished during the arteriogram that is a necessary part of potential kidney donor evaluation. In 21 obese subjects (body mass index [BMI], 29.1+/-0.9) in balance on a 10-mmol sodium intake, renal perfusion (352+/-16 mL x 100 g(-1) x min(-1)) was significantly higher than predicted from findings in the 95 lean control subjects (313+/-3 mL x 100 g(-1) x min(-1); P=0.035) after adjustment for age. With a high sodium intake (200 mmol), however, renal perfusion was not significantly different in 24 obese subjects (BMI, 28.8+/-0.7; 323+/-13 mL x 100 g(-1) x min(-1)) in comparison to 52 lean controls (341+/-10 mL x 100 g(-1) x min(-1) after adjustment for age. Systolic and diastolic blood pressures were similar in obese and age- and gender-matched lean control subjects. Renal vasodilation was seen in association with sustained obesity in humans. While the mechanisms of obesity-related vasodilation are unclear, the dependence on sodium intake in this study is consistent with a role for the renin-angiotensin system. The findings are not in accordance with a reduction in renal perfusion reported in healthy obese humans in whom measured renal perfusion was indexed for body size.

T cell activation and retargeting using staphylococcal enterotoxin B and bispecific antibody: an effective in vivo antitumor strategy.

The aim of this work was to test for cure and immunity in a micrometastatic tumor model using in vivo T cell activation with staphylococcal enterotoxin B (SEB) and retargeting with antitumor x anti-CD3 F(ab')2 bispecific antibodies (bsAb). All studies were performed in C3H/HeN mice using syngeneic tumor cell lines. For survival studies, mice were injected intravenously on day 0 with CL62 (a p97-transfected clone of the K1735 murine melanoma tumor). Day-3 treatments included saline (control), SEB (50 gamma g intraperitoneal) with or without bsAb (5 micrograms i.v.). Cured mice, surviving beyond 60 days, were rechallenged with subcutaneous CL62, K1735, or a nonmelanoma control, AG104. SEB activation studies were performed with pulmonary tumor-infiltrating lymphocytes isolated from 10-day established CL62 tumors. Maximal tumor-infiltrating lymphocyte cytotoxicity was demonstrated 24 h following SEB injection, therefore bsAb treatments were administered 24 h after SEB. When survival was examined at 60 days, there were significantly more survivors in the group receiving SEB plus bsAb (70%) compared to the group receiving SEB alone (30%), and the controls (0%) (P = 0.02 and P < 0.01, respectively). Mice cured of CL62 using SEB alone or with bsAb demonstrated equal immunity to CL62, however, mice treated with SEB plus bsAb were more often immune to the p97-parental cell line, K1735(P = 0.001). Ag104 consistently grew in all mice. Results of these studies demonstrate that SEB plus bsAb can be effective, not only in curing tumors but also in providing protective immunity against targeted and non-targeted tumor antigens.

Analysis of bacterial carbapenem antibiotic production genes reveals a novel beta-lactam biosynthesis pathway.

Carbapenems are beta-lactam antibiotics which have an increasing utility in chemotherapy, particularly for nosocomial, multidrug-resistant infections. Strain GS101 of the bacterial phytopathogen, Erwinia carotovora, makes the simple beta-lactam antibiotic, 1-carbapen-2-em-3-carboxylic acid. We have mapped and sequenced the Erwinia genes encoding carbapenem production and have cloned these genes into Escherichia coli where we have reconstituted, for the first time, functional expression of the beta-lactam in a heterologous host. The carbapenem synthesis gene products are unrelated to enzymes involved in the synthesis of the so-called sulphur-containing beta-lactams, namely penicillins, cephamycins and cephalosporins. However, two of the carbapenem biosynthesis genes, carA and carC, encode proteins which show significant homology with proteins encoded by the Streptomyces clavuligerus gene cluster responsible for the production of the beta-lactamase inhibitor, clavulanic acid. These homologies, and some similarities in genetic organization between the clusters, suggest an evolutionary relatedness between some of the genes encoding production of the antibiotic and the beta-lactamase inhibitor. Our observation are consistent with the evolution of a second major biosynthetic route to the production of beta-lactam-ring-containing antibiotics.

Analysis of bacterial carbapenem antibiotic production genes reveals a novel ß-lactam biosynthesis pathway.

Carbapenems are ß-lactam antibiotics which have an increasing utility in chemotherapy, particularly for nosocomial, multidrug-resistant infections. Strain GS101 of the bacterial phytopathogen, Erwinia carotovora, makes the simple ß-lactam antibiotic, 1-carbapen-2-em-3-carboxylic acid. We have mapped and sequenced the Erwinia genes encoding carbapenem production and have cloned these genes into Escherichia coli where we have reconstituted, for the first time, functional expression of the ß-lactam in a heterologous host. The carbapenem synthesis gene products are unrelated to enzymes involved in the synthesis of the so-called sulphur-containing ß-lactams, namely penicillins, cephamycins and cephalosporins. However, two of the carbapenem biosynthesis genes, carA and carC, encode proteins which show significant homology with proteins encoded by the Streptomycesclavuligerus gene cluster responsible for the production of the ß-lactamase inhibitor, clavulanic acid. These homologies, and some similarities in genetic organization between the clusters, suggest an evolutionary relatedness between some of the genes encoding production of the antibiotic and the ß-lactamase inhibitor. Our observations are consistent with the evolution of a second major biosynthetic route to the production of ß-lactam-ring-containing antibiotics.

Androgen receptor in human liver: characterization and quantitation in normal and diseased liver.

Liver is responsive to sex hormones. The role of androgens in normal human liver function is not well understood, although androgens have been implicated in several liver diseases. Because the human hepatic androgen receptor has not been adequately characterized, we analyzed cytosolic and nuclear fractions from normal human liver of both sexes for androgen-binding activity using multipoint saturation analysis with the androgenic radioligand methyltrienelone (R1881). Both cytosolic and nuclear fractions of both sexes displayed high affinity R1881 binding (dissociation constants = nanomolar range). The R1881 binding in both fractions is highly specific in that potent androgens compete well, and the antiandrogens hydroxyflutamide and cyproterone acetate show partial competition; other nonandrogenic steroid hormones do not compete. The cytosolic R1881 receptor displays physicochemical characteristics of androgen receptors in other tissues in that it is retained by heparin-Sepharose and by DNA cellulose after activation, and it displays a molybdate-stabilized 8S form on sucrose gradients and a 7.3-nm species on gel filtration chromatography. Receptor activity was also quantitated in specimens of hepatic adenoma, focal nodular hyperplasia and metastatic carcinoma to the liver and in samples of adjacent histologically normal specimens when available. In general, both the diseased and normal portions of the livers from the patients with hepatic adenoma and metastatic carcinoma to the liver, but not focal nodular hyperplasia, demonstrated reduced total androgen-receptor activity as compared with liver from normal individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of tamoxifen on hepatic regeneration in male rats.

A number of metabolic changes within the liver occur concurrent with hepatic regeneration. These processes suggest that the administration of an antiestrogen might alter the rate of hepatic regeneration. To examine this question, male Wistar rats were treated with tamoxifen (0.1 mg/rat/day or 1.0 mg/rat/day) or vehicle for three days prior to and after partial hepatectomy, and the anatomic and biochemical process of hepatic regeneration was assessed. Tamoxifen administration caused a dose-dependent decrease in the hepatic cytosolic estrogen receptor activity and, conversely, a dose-dependent increase in cytosolic androgen receptor activity. Despite these changes in baseline hepatic sex steroid receptor status, all receptor activities were comparable between the three groups within 24 hr of partial hepatectomy. Moreover, no differences in any of the parameters assessing hepatic regeneration following partial hepatectomy were evident: liver-body ratio, ornithine decarboxylase activity, and thymidine kinase activity. This lack of effect of tamoxifen treatment on hepatic regeneration suggests either that estrogens do not play a role in the modulation of liver growth after partial hepatectomy or that, once initiated, the regenerative process per se determines a series of events that regulate hepatocellular sex hormone receptor status independent of extrahepatic stimuli.

Androgen receptor in rat liver: characterization and separation from a male-specific estrogen-binding protein.

Many liver processes are sexually dimorphic. In particular, the microsomal content of specific enzymes and the synthesis of specific proteins are under sex steroid hormone control. Because the liver of male rats is strikingly androgen responsive, we sought evidence for an androgen receptor in this tissue. We detected and characterized both cytosolic and nuclear androgen-binding proteins. Both forms bind [3H]R1881 (methyltrienolone, 17 beta-hydroxy-17 alpha-methyl-4,9,11-estratriene-3-one) with the high affinity, low capacity, and specificity for androgens and antiandrogens characteristic of androgen receptors. No high-affinity binding of [3H]DHT could be detected in unfractionated cytosol because of the rapid metabolism of this ligand; however, binding of a DHT metabolite to the high-capacity male-specific estrogen binder (MEB) of cytosol was observed. Both gel filtration and heparin-Sepharose affinity chromatography separate the cytosolic androgen receptor from MEB. Incubation of cytosol in the absence of sodium molybdate resulted in androgen-binding activity which was retained by DNA-cellulose. Castration of male rats results in a time-dependent loss of both cytosolic and nuclear androgen binding, as well as a loss in MEB activity. Androgen-binding activity is low in livers from female rats, but can be induced by testosterone treatment. An intact pituitary is necessary for maintenance of androgen-binding activity, as hypophysectomy results in complete loss of activity.

Liver regeneration in rats treated with the antiandrogen flutamide.

Previous studies have shown that male rat liver undergoes demasculinization during hepatic regeneration after partial hepatectomy. In the present study the effect of the antiandrogen flutamide on liver regeneration was assessed. Adult male Wistar rats were treated with flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for 3 days prior to and daily after partial hepatectomy. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. The rate of liver growth after partial hepatectomy in the three groups was similar at all time points examined. The increases in thymidine kinase activity and ornithine decarboxylase activity after partial hepatectomy were comparable throughout the study. Thus, administration of flutamide did not influence the regenerative response after partial hepatectomy.

Hepatic estrogen receptor in human liver disease.

Human liver contains estrogen receptors which render it sensitive to estrogen. Specific hormone binding to cytosol and nuclei from normal liver containing such receptors is of high affinity, low capacity, saturable, and specific for steroidal and nonsteroidal estrogens. Although estrogens alter metabolism and may produce disease, little data is available concerning estrogen receptor levels found in diseased liver. Herein we report estrogen receptor levels in human female liver containing diseases associated with oral contraceptives. Binding studies demonstrated cytosolic and nuclear estrogen receptors in human hepatic adenoma and focal nodular hyperplasia. Nuclear estrogen receptor levels in neoplastic tissue were greater than those in normal tissue. In addition, one hepatic adenoma resected from a patient taking tamoxifen contained no cytosolic estrogen receptor, and nuclear estrogen receptor levels were significantly lower than those found in normal tissue. These differences in binding capacity suggest a potential for greater hormone responsiveness in neoplastic liver tissue.

Pre- and intraoperative localization of small bowel arteriovenous malformation.

Patients with chronic gastrointestinal bleeding with no source found after standard radiographic and endoscopic procedures are diagnostic challenges. Since angiodysplasia is a frequent cause of such bleeding, selective angiography has become an essential diagnostic tool in identifying arteriovenous malformations (AVM) of the large and small bowel. In addition to preoperative identification, some method of intraoperative localization is essential to assure removal of the involved segment. In a patient with a 7-year history of gastrointestinal bleeding from an AVM of the small bowel, a technique of preoperative angiographic catheter placement with intraoperative confirmation of catheter position proved a useful way to find such small bowel lesions and insured adequate but not excessive resection.

Characterization and quantitation of human hepatic estrogen receptor.

Because the liver is an estrogen-sensitive organ and such sensitivity necessitates the presence of an hepatic estrogen receptor, we assayed whole human liver cytosol for the presence of estrogen receptor. Scatchard plot analysis of specific [3H]diethylstilbestrol binding to whole human liver cytosol from both sexes demonstrated hormone binding that is of high affinity (Kd = 10(-10)M) and low capacity (1-10 fmol/mg cytosol protein), and that is saturable and specific for steroidal and nonsteroidal estrogens, but not for other steroids. The protein can be further characterized as an estrogen receptor by its binding to heparin-Sepharose. In addition, gel filtration chromatography of [3H]estrogen-labeled cytosol on Sephadex G-100 indicates that potentially contaminating proteins, such as albumin and sex-steroid-binding globulin, do not bind [3H]estrogen in whole cytosol. We conclude that human liver from both sexes has estrogen receptor and that the presence of estrogen receptor in human liver explains the sensitivity of the human liver to estrogen.