Efficacy and tolerability of albiglutide versus placebo or pioglitazone over 1 year in people with type 2 diabetes currently taking metformin and glimepiride: HARMONY 5.

AIMS: To investigate the efficacy and tolerability of albiglutide, a weekly glucagon-like peptide-1 receptor agonist, when added to metformin and glimepiride in a triple therapy regimen in people with type 2 diabetes mellitus. METHODS: This was a 156-week, randomized, double-blind, parallel-group, multicentre study. In the present paper we describe the primary results, namely those at 52 weeks. Adult participants (n = 685) were randomly assigned to albiglutide (30 mg/week), pioglitazone (30 mg/day) or placebo. If needed, blinded uptitration of albiglutide (to 50 mg/week) and pioglitazone (to 45 mg/day) was allowed. The participant's current dose of metformin (>1500 mg/day) was maintained throughout. The glimepiride dose (4 mg/day), standardized before randomization, could be decreased if persistent hypoglycaemia occurred. RESULTS: The week 52 model-adjusted difference in change of glycated haemoglobin (primary endpoint) for albiglutide versus placebo was -0.87 [95% confidence interval (CI) -1.07, -0.68]%-units (p < 0.001), and for albiglutide versus pioglitazone it was 0.25 (95% CI 0.10, 0.40)%-units; therefore, not non-inferior. In the albiglutide group only, fasting plasma glucose reduced rapidly in the first 2 weeks. Confirmed hypoglycaemia occurred in 14% of participants on albiglutide, 25% on pioglitazone and 14% on placebo. The mean (± standard error) weight change was -0.42 (±0.2) kg with albiglutide, +4.4 (±0.2) kg (p < 0.001) with pioglitazone, and -0.40 (±0.4) kg with placebo and serious adverse events occurred in 6.3, 9.0 and 6.1% of participants in the respective groups. Injection site reactions occurred in 13% of participants on albiglutide and resulted in treatment discontinuation for four participants (1.4%). CONCLUSIONS: Albiglutide, as part of triple therapy, provided effective glucose-lowering and was generally well tolerated.

Albiglutide does not impair the counter-regulatory hormone response to hypoglycaemia: a randomized, double-blind, placebo-controlled, stepped glucose clamp study in subjects with type 2 diabetes mellitus.

AIM: To determine if the glucagon-like peptide-1 (GLP-1) receptor agonist albiglutide, once weekly, impairs counter-regulatory responses during hypoglycaemia. METHODS: We conducted a randomized, double-blind, parallel, placebo-controlled study in subjects with type 2 diabetes mellitus. A single dose of albiglutide 50 mg (n = 22) or placebo (n = 22) was administered on day 1. Glucose was clamped on day 4 (to coincide with the approximate albiglutide maximum plasma concentration) at 9.0, 5.0, 4.0, 3.3 and 2.8 mmol/l (162, 90, 72, 59.4 and 50.4 mg/dl), with a post-clamp recovery period to 3.9 mmol/l (70 mg/dl). Hormone measurements were made at each plateau and adverse events (AEs) were recorded. RESULTS: The counter-regulatory hormones glucagon, epinephrine, norepinephrine, growth hormone and cortisol were appropriately suppressed when plasma glucose levels were >4.0 mmol/l (>72 mg/dl), but increased in the albiglutide and placebo groups with glucose levels <3.3 mmol/l (<59.4 mg/dl) in response to hypoglycaemia. The area under the curve geometric mean ratios (albiglutide : placebo), calculated from the clamped plateau of 4.0 mmol/l (72 mg/dl) to the glucose recovery point, were not significantly different for any of the counter-regulatory hormones. When plasma glucose levels were >5.0 mmol/l (>90 mg/dl), albiglutide increased pancreatic ß-cell secretion of C-peptide in a glucose-dependent manner to a greater extent than did placebo, and it was suppressed in each group when levels were <4.0 mmol/l (<72 mg/dl). No significant difference between groups was observed in the recovery time to glucose level ≥3.9 mmol/l (≥70 mg/dl). There were no clinically relevant differences in AEs or other safety variables. CONCLUSIONS: A single 50-mg dose of albiglutide was well tolerated and did not impair the counter-regulatory response to hypoglycaemia. These data provide mechanistic evidence supporting the low intrinsic hypoglycaemic potential of albiglutide.

The human rosette-forming cell as a marker of a population of thymus-derived cells.

Sheep red blood cells can surround, in vitro, some human peripheral blood lymphocytes in a formation called a rosette. The number of rosetteforming cells (RFC) in 50 normal persons had a wide range (4-40%). The organs of 13 human fetuses (11-19 wk conceptional age) were examined for the presence of RFC. The thymus possessed the highest percentage of RFC, the maximum being 65% of total thymocytes in two 15-16 wk fetal specimens. Blood RFC were always present and their number slightly increased in the oldest fetuses. The bone-marrow showed 0-8% in the six fetuses studied. RFC were found in the spleen around the 13th wk and in the liver around the 17th wk of gestation. These observations lead to the hypothesis that human blood RFC may be chiefly thymic derived. Studies of patients with immunological disorders support this hypothesis: one patient with Nezelof syndrome had no blood RFC and four patients with Wiskott-Aldrich syndrome had a low number of blood RFC (1 and 1.5%). Patients with acquired hypogammaglobulinemia showed a normal percentage of RFC. With the fetal thymocytes, the percentage of inhibition with anti-mu serum increased with the fetal age to become complete in the oldest fetuses studied. Incubation of the oldest fetal thymocytes or the blood lymphocytes with anti-gamma serum of anti-mu serum completely inhibited the rosette formation. These results suggest that mu-chain determinants are present on human fetal thymocytes and blood RFC. The significance of the presence of gamma-chain determinants on these cells is unclear.

How do they get here: Does the method of transportation impact salvage for patients with testicular torsion?

INTRODUCTION: A growing number of patients are arriving at our tertiary care center for evaluation of possible testicular torsion using ambulance or helicopter transport. In many cases the parents arrive by car before the patient arrives. Are these advanced methods of medical transport worth the expense and risk in the case of suspected testicular torsion? OBJECTIVE: We evaluated the total number of patients presenting to our emergency room for suspected testicular torsion to see if the means of transport affected testicular survival. STUDY DESIGN: Retrospective. RESULTS: As shown below in the table, the means of transport did not impact on testicular salvage. DISCUSSION: It is understandable that many patients with scrotal pain seek treatment closer to home because of their pediatrician's recommendation and/or family preference. However once evaluated many patients are transferred because of a lack of urologists willing to evaluate and treat the pediatric patients in community settings or because of a lack of anesthesia support. These patients are often transported by ambulance or helicopter. Our data would suggest that there is no improvement in the testicular salvage rate seen with these more advanced means of medical transportation compared with transfer by private car even when we restrict the analysis to patients traveling from over 40 miles away. We suspect that important time is lost while waiting to make such transfer arrangements. Furthermore transfer by ambulance or helicopter is more expensive and these costs are often passed on to families. Transfer by helicopter is also riskier. While an argument can be made in favor of medical transport over long distances or long driving times, this data suggests that many of these transfers could be accomplished by car with no effect on testicular salvage rates. CONCLUSION: The rate of testicular salvage was not affected by the means of transport to our tertiary facility. Only 4 patients would have required advanced of medical transport if this were limited to those facilities over 100 miles or 1.5 hours driving time away. This would achieve a substantial cost savings with no measurable change in outcome.

Contribution of hepatic lipase, lipoprotein lipase, and cholesteryl ester transfer protein to LDL and HDL heterogeneity in healthy women.

Hepatic lipase (HL) and cholesteryl ester transfer protein (CETP) have been independently associated with low density lipoprotein (LDL) and high density lipoprotein (HDL) size in different cohorts. These studies have been conducted mainly in men and in subjects with dyslipidemia. Ours is a comprehensive study of the proposed biochemical determinants (lipoprotein lipase, HL, CETP, and triglycerides) and genetic determinants (HL gene [LIPC] and Taq1B) of small dense LDL (sdLDL) and HDL subspecies in a large cohort of 120 normolipidemic, nondiabetic, premenopausal women. HL (P<0.001) and lipoprotein lipase activities (P=0.006) were independently associated with LDL buoyancy, whereas CETP (P=0.76) and triglycerides (P=0.06) were not. The women with more sdLDL had higher HL activity (P=0.007), lower HDL2 cholesterol (P<0.001), and lower frequency of the HL (LIPC) T allele (P=0.034) than did the women with buoyant LDL. The LIPC variant was associated with HL activity (P<0.001), HDL2 cholesterol (P=0.034), and LDL buoyancy (P=0.03), whereas the Taq1B polymorphism in the CETP gene was associated with CETP mass (P=0.002) and HDL3 cholesterol (P=0.039). These results suggest that HL activity and HL gene promoter polymorphism play a significant role in determining LDL and HDL heterogeneity in healthy women without hypertriglyceridemia. Thus, HL is an important determinant of sdLDL and HDL2 cholesterol in normal physiological states as well as in the pathogenesis of various disease processes.

The contribution of intraabdominal fat to gender differences in hepatic lipase activity and low/high density lipoprotein heterogeneity.

Hepatic lipase (HL) hydrolyzes triglyceride and phospholipid in low and high density lipoprotein cholesterol (LDL-C and HDL-C, respectively), and elevated HL activity is associated with small, dense atherogenic LDL particles and reduced HDL2-C. Elevated HL activity is associated with increasing age, male gender, high amounts of intraabdominal fat (IAF), and the HL gene (LIPC) promoter polymorphism (C nucleotide at -514). We investigated the mechanisms underlying the difference in HL activity between men (n = 44) and premenopausal women (n = 63). Men had significantly more IAF (144.5 +/- 80.9 vs. 66.5 +/- 43.2 cm(2), respectively; P < 0.001), higher HL activity (220.9 +/- 94.7 vs.129.9 +/- 53.5 nmol/mL.min; P < 0.001), more dense LDL (Rf, 0.277 +/- 0.032 vs. 0.300 +/- 0.024; P = 0.01), and less HDL2-C (0.19 +/- 0.10 vs. 0.32 +/- 0.16 mmol/L; P < 0.001) than women. After adjusting for IAF and the LIPC polymorphism, men continued to have higher (but attenuated) HL activity (194.5 +/- 80.4 vs.151.0 +/- 45.2, respectively; P = 0.007) and lower HDL2-C (0.23 +/- 0.11 vs. 0.29 +/- 0.14 mmol/L; P = 0.02) than women. Using multiple regression, HL activity remained independently related to IAF (P < 0.001), gender (P < 0.001), and the LIPC genotype (P < 0.001), with these factors accounting for 50% of the variance in HL activity. These data suggest that IAF is a major component of the gender difference in HL activity, but other gender-related differences, perhaps sex steroid hormones, also contribute to the higher HL activity seen in men compared with premenopausal women. The higher HL activity in men affects both LDL and HDL heterogeneity and may contribute to the gender difference in cardiovascular risk.

The numerical development of lymphoid cells during human embryogenesis.

We have studied the cellular growth rates in the fetal thymus, spleen, and bone marrow of 12 human fetuses ranging in gestational age from 7 to 20 weeks. In all instances growth rates were linear when plotted logarithmically. However, the spleen had a biphasic growth curve. These data are useful in predicting the cellular yields which can be obtained from human fetal lymphoid organs which are to be used for transplantation in immune deficiency diseases and other clinical conditions.

Detection of human androgen receptor mRNA expression abnormalities by competitive PCR.

A competitive polymerase chain reaction (PCR) method for analysis of androgen receptor (AR) mRNA expression is described. The technique involves the use of an in vitro-transcribed RNA (cRNA) corresponding to a region of the AR mRNA transcript as a competitor in reverse transcription and PCR (RT-PCR) using total cellular RNA. The competitor RNA contains a site-directed mutation that produces a restriction fragment length polymorphism after RT-PCR and endonuclease digestion. We demonstrate that incorporation of the competitor RNA into RT-PCR reactions allows rapid semiquantitative determination of relative AR mRNA levels without the necessity of following PCR product formation kinetically; reaction products are assessed at the conclusion of the reaction sequence and without the use of radioactive probes or other specialized detection systems. We have used competitive PCR to demonstrate low levels of AR mRNA in an androgen-unresponsive human prostate cell line (PC3). In addition, we have also used this method to confirm that genital fibroblasts obtained from a subject with penoscrotal hypospadias (a non-intersex masculinization defect) that exhibit low levels of high-affinity androgen binding also exhibit abnormally low AR mRNA levels. These last results suggest that some non-intersex malformations of the urogenital tract are associated with abnormalities in the expression of the androgen receptor.

Chlamydiae, cervicitis, and abnormal Papanicolaou smears.

Cervical abnormalities accompanied by Papanicolaou Class II or Class III cytologic results are commonly encountered in gynecologic office practice. Chlamydiae are a common cause of genital tract infection, with or without manifest symptoms or signs. An immunofluorescence method was used to determine the presence of antichlamydial antibodies in cervical secretions. Eleven of 15 patients in whom such antibodies were found (73.3%) had Papanicolaou Class II or Class III smears, in contrast to only 3 of 18 patients (16.7%) without antichlamydial antibodies. The determination of antichlamydial antibodies in cervical mucus was highly reproducible, and specimens were readily collected in the office, without the need of prompt laboratory procedures. In selected patients, tetracycline treatment of early chlamydial infection resulted both in the disappearance of the antibody from cervical secretions and in the reversion of the Papanicolaou smear from Class II or Class III to Class I.

Laparoscopic and histologic evaluation of the inguinal vanishing testis.

OBJECTIVES: Visual inspection of the spermatic cord vessels and vas deferens during laparoscopy now frequently determines further treatment. We set out to explore the implications of atretic spermatic cord vessels and vas deferens entering the inguinal ring, a finding noted on laparoscopic examination in some patients with a nonpalpable testis, and that we refer to as the inguinal vanishing testis. METHODS: We reviewed our series of 35 patients with nonpalpable testes with regard to the laparoscopic, surgical, and histopathologic findings of the involved gonadal structures. RESULTS: We noted atretic vessels and vas deferens entering the inguinal ring in 14 patients in this series. All 14 patients underwent open inguinal exploration. Histopathologic findings revealed fibrosis and hemosiderin deposits alone in 13 patients. One specimen had a microscopic focus of residual seminiferous tubules. No specimen contained dysgenetic gonadal tissue. CONCLUSIONS: We submit that patients with inguinal vanishing testes do not need to undergo inguinal exploration to remove residual testicular tissue. Only rarely will viable seminiferous tubules be found, so the risk of malignant degeneration is remote. The histopathologic findings suggest that the inguinal vanishing testis occurs secondary to a vascular accident in utero or in the neonatal period.

Congenital posterior urethral perineal fistulae: a unique form of urethral duplication.

Three unique cases of urethral duplication, often referred to as congenital posterior urethral perineal fistulae, are presented. Presenting signs and symptoms, evaluation, and treatment are discussed, and the literature is reviewed. Although labeled as a fistula in the literature, this entity most likely represents a distinct type of urethral duplication. A functional dorsal urethra separates it from the other forms of urethral duplication.

Complete primary closure of bladder exstrophy. Epispadias and bladder exstrophy repair.

Bladder exstrophy remains one of the most challenging problems in pediatric urology. Recent efforts have focused on primary reconstruction rather than urinary diversion to treat exstrophy. Complete primary closure appears to offer improved continence and decreases the number of surgical procedures required to treat exstrophy.

Changes in LDL density across the menopausal transition.

BACKGROUND: The risk of coronary artery disease increases in women after menopause. This increased risk may be associated with alterations in the lipid profile characterized by changes in LDL particle size and buoyancy. Characterization of lipoprotein levels and LDL buoyancy across the stages of the menopausal transition has yet to be reported. METHODS: Plasma lipoprotein concentrations, LDL buoyancy, and body mass index (BMI) were studied cross-sectionally in five groups of women: premenopausal women (n = 42), women in early menopausal transition (n = 35), middle menopausal transition (n = 19), late menopausal transition (n = 20), and postmenopausal women (n = 14). No women were taking estrogen. RESULTS: The postmenopausal women had significantly higher low-density lipoprotein cholesterol (LDL-C) and total cholesterol than premenopausal women (P < 0.05). LDL-C and Apo B was significantly higher in women in the late menopausal transition compared to premenopausal women (P < 0.05). All women in the menopausal transition and postmenopause had significantly more dense LDL than premenopausal women (P < 0.05). Multiple regression analysis revealed that the change in LDL buoyancy associated with the menopausal transition period could be explained by changes in triglyceride and HDL-C, related to changes in body mass index. CONCLUSIONS: These data suggest that the menopausal transition is associated with more dense LDL and higher LDL-C levels in comparison to premenopausal women. It appears that whereas LDL-C may change late in the menopausal transition, the production of denser LDL particles appears early in the menopausal transition, both acting to worsen the lipoprotein profile. Increased triglyceride and decreased HDL appeared to account for the shift toward small, dense LDL, presumably related to increased BMI. The change in LDL density may contribute to the higher incidence of atherosclerosis in postmenopausal women.

[Urethral valves. Fate of the bladder and upper urinary tract]. / UrethralklappenSchicksal der Blase und des oberen Harntrakts.

Posterior urethral valve is a condition that leads to characteristic changes in the bladder and upper tracts. The bladder develops hypertrophic changes including muscular hypertrophy, dilatation of the prostatic urethra (keyhole appearance), and progressive hydroureteronephrosis. The voiding cystourethrogram confirms the diagnosis and documents vesicoureteral reflux and accompanying bladder changes. The follow-up of the serum creatinine level is a parameter for renal recovery. In our opinion, primary endoscopic ablation of the valves followed by a wait-and-see attitude is the most efficacious management of posterior urethral valves. The development of the bladder function is controlled by ultrasound and voiding cystourethrogram. Urodynamics provide a formal and objective means of assessing bladder function, but should be carefully applied in infants. Valve ablation in a neonate with significant reflux and a markedly trabeculated bladder can remodel itself remarkably within the 1st year of life. The persistence of hydronephrosis, bladder wall thickening and trabeculation, and persistent elevation of serum creatinine can all be harbingers that a degree of bladder outlet obstruction persists and one needs to rule out a persistent anatomic obstruction. At what point a functional obstruction occurs and which management is reasonable are still issues of debate and require the vigilance of a pediatric urologist to sort out. Dysfunctions of the bladder such as hyperreflexia, hypertonic, small capacity bladder, sphincter incompetence and/or myogenic failure should be adequately treated.

Continent gastric pouch.

Between January 1985 and June 1995 a total of 12 patients (9 female, 3 male) underwent total reconstruction of the lower urinary tract using gastric tissue. Their mean age was 10 years (range, 5-25 years). Total gastric bladder substitution was performed in seven patients, whereas five other patients had composite continent reservoirs (stomach plus bowel) created. The diagnoses were cloacal exstrophy, classic bladder exstrophy, bladder rhabdomyosarcoma, bilateral ectopic ureters, and VACTERL association. The mean follow-up period was 4.5 years (range, 16 months to 9 years). The average bladder capacity was 309 ml, and the compliance averaged 12.9 ml/cmH2O. Continence was achieved in all patients, but the continence mechanism often required revision. Renal deterioration was noted only in one patient due to an obstruction at the site of a transureteroureterostomy. The complications included hyponatremic, hypochloremic metabolic alkalosis (two patients); prolapse of the neovagina (one patient); a ureterovesical junction obstruction (three patients); and revision of the neourethra or Mitrofanoff (six patients). Revision of the gastric tube used as the catheterizable channel was performed in three instances. Lengthening of the tube, including nippling in one instance, corrected persistent incontinence. Distal stenosis of a gastric tube required several plastic procedures for correction. A ureteral Mitrofanoff developed a distal stricture necessitating revision. Persistent leaking of an appendiceal Mitrofanoff was corrected with reimplantation. A tapered ileal neourethra required a tunneling procedure followed by Teflon injection to provide urinary continence. Complications seen most often involved the continence mechanism of these gastric neobladders or composite urinary reservoirs. Persistence, patience, and perseverance led to total urinary continence and adequate reservoirs for urine storage in all patients.

Overcoming the limitations of proprietary computerized billing systems to enhance patient care.

Most physician offices have proprietary computerized billing systems, but these are not designed for monitoring utilization or addressing patient care issues, and they are difficult or impossible to modify. These systems do, however, contain valuable diagnosis and demographic information. An open-ended, relational x-base system is described that downloads this billing information and combines it with additional input to provide the practitioner with: current problem lists; medication and allergy lists; health screening reminders that are age, sex and disease specific; and commonly used demographic information. Several popular query/reporting tools are used to generate standard reports and ad hoc inquiries that relate directly to patient care. Two studies, one involving alerting physicians to possible adverse medication effects on specific patients, and one investigating appropriate use and billing of stool occult blood testing are summarized. In the constantly evolving arenas of utilization, outcomes research and cost efficiency, such an open ended, time efficient system has unlimited potential to improve patient care.

Deoxyguanosine kinase. Distinct molecular forms in mitochondria and cytosol.

Two distinct deoxyguanosine kinase activities have been identified in calf thymus tissue. They can be differentiated by subcellular location, electrophoretic mobility, chromatographic behavior, nucleoside specificity, apparent Km values, and end product inhibition. After a 130-fold purification from mitochondrial extract, the newly discovered kinase was specific primarily for deoxyguanosine and deoxyinosine. Unlike the cytosol enzyme, which proved to be the broadly specific deoxycytidine kinase studied previously, the mitochondrial enzyme does not phosphorylate deoxycytidine. Its apparent Km for deoxyguanosine, 6 micromolar, is 2 orders of magnitude lower than that of the cytosol enzyme. The mitochondrial enzyme is strongly inhibited by dGTP and dITP and activated up to 6-fold by dTDP and UDP, whereas neither dCTP nor dATP had much effect.