A rare partnership: patient community and industry collaboration to shape the impact of real-world evidence on the rare disease ecosystem.

People with rare lysosomal storage diseases face challenges in their care that arise from disease complexity and heterogeneity, compounded by many healthcare professionals being unfamiliar with these diseases. These challenges can result in long diagnostic journeys and inadequate care. Over 30 years ago, the Rare Disease Registries for Gaucher, Fabry, Mucopolysaccharidosis type I and Pompe diseases were established to address knowledge gaps in disease natural history, clinical manifestations of disease and treatment outcomes. Evidence generated from the real-world data collected in these registries supports multiple stakeholders, including patients, healthcare providers, drug developers, researchers and regulators. To maximise the impact of real-world evidence from these registries, engagement and collaboration with the patient communities is essential. To this end, the Rare Disease Registries Patient Council was established in 2019 as a partnership between the Rare Disease Registries and global and local patient advocacy groups to share perspectives on how registry data are used and disseminated. The Patient Council has resulted in a number of patient initiatives including patient representation at Rare Disease Registries advisory boards; development of plain language summaries of registry publications to increase availability of real-world evidence to patient communities; and implementation of digital innovations such as electronic patient-reported outcomes, and patient-facing registry reports and electronic consent (in development), all to enhance patient engagement. The Patient Council is building on the foundations of industry-patient advocacy group collaboration to fully integrate patient communities in decision-making and co-create solutions for the rare disease community.

COVID-19 vaccination and breakthrough infections in patients with cancer.

BACKGROUND: Vaccination is an important preventive health measure to protect against symptomatic and severe COVID-19. Impaired immunity secondary to an underlying malignancy or recent receipt of antineoplastic systemic therapies can result in less robust antibody titers following vaccination and possible risk of breakthrough infection. As clinical trials evaluating COVID-19 vaccines largely excluded patients with a history of cancer and those on active immunosuppression (including chemotherapy), limited evidence is available to inform the clinical efficacy of COVID-19 vaccination across the spectrum of patients with cancer. PATIENTS AND METHODS: We describe the clinical features of patients with cancer who developed symptomatic COVID-19 following vaccination and compare weighted outcomes with those of contemporary unvaccinated patients, after adjustment for confounders, using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19). RESULTS: Patients with cancer who develop COVID-19 following vaccination have substantial comorbidities and can present with severe and even lethal infection. Patients harboring hematologic malignancies are over-represented among vaccinated patients with cancer who develop symptomatic COVID-19. CONCLUSIONS: Vaccination against COVID-19 remains an essential strategy in protecting vulnerable populations, including patients with cancer. Patients with cancer who develop breakthrough infection despite full vaccination, however, remain at risk of severe outcomes. A multilayered public health mitigation approach that includes vaccination of close contacts, boosters, social distancing, and mask-wearing should be continued for the foreseeable future.

Granulomatosis with polyangiitis and pregnancy: A case report and review of the literature.

The association of granulomatosis with polyangiitis and pregnancy is rare and therapeutic options are limited by the risk of teratogenicity and fetotoxicity. There is a paucity of published literature to guide clinical decision-making in these cases. We report the case of a 26-year-old woman with no medical history who presented at 21 weeks of gestation with a bilateral sudden loss of hearing and erosive rhinitis. The diagnosis of granulomatosis with polyangiitis was confirmed radiologically and biologically. Corticosteroids were not enough to stabilize the disease and she received intravenous immunoglobulins with remission. A successful delivery of a healthy male newborn was done at 36 weeks. A review of all published literature on granulomatosis with polyangiitis in pregnancy between 1970 and 2017 is presented. Trial registration: Not applicable.

Removal and recovery of U(VI) from aqueous effluents by flax fiber: Adsorption, desorption and batch adsorber proposal.

Flax fiber (Linen fiber), a valuable and inexpensive material was used as sorbent material in the uptake of uranium ion for the safe disposal of liquid effluent. Flax fibers were characterized using BET, XRD, TGA, DTA and FTIR analyses, and the results confirmed the ability of flax fiber to adsorb uranium. The removal efficiency reached 94.50% at pH 4, 1.2 g adsorbent dose and 100 min in batch technique. Adsorption results were fitted well to the Langmuir isotherm. The recovery of U (VI) to form yellow cake was investigated by precipitation using NH4OH (33%). The results show that flax fibers are an acceptable sorbent for the removal and recovery of U (VI) from liquid effluents of low and high initial concentrations. The design of a full scale batch unit was also proposed and the necessary data was suggested.

Synthetic peptide optimization improves the inhibition of dengue NS2B-NS3 protease and dengue replication in vitro.

Dengue virus (DENV) infection is one of the most widely-spread flavivirus infections with no effective antiviral drugs available. Peptide inhibitors have been considered as one of the best drug candidates due to their high specificity, selectivity in their interactions and minimum side effects. In this study, we employed computational studies using YASARA, HADDOCK server and PyMOL software to generate short and linear peptides based on a reference peptide, CP5-46A, to block DENV NS2B-NS3 protease. The inhibition potencies of the peptides were evaluated using in-house DENV2 serine protease and fluorogenic peptide substrates. In vitro analyses were performed to determine the peptides cytotoxicity and the inhibitory effects against DENV2 replication in WRL-68 cells. Our computational analyses revealed that the docking energy of AYA3, a 16 amino acid (aa) (-81.2 ± 10.6 kcal/mol) and AYA9, a 15 aa peptide (-83.8 ± 6.8 kcal/mol) to DENV NS2B-NS3 protease were much lower than the reference peptide (46 aa; -70.9 ± 7.8 kcal/mol) and the standard protease inhibitor, aprotinin (58 aa; -48.2 ± 10.6 kcal/mol). Both peptides showed significant inhibition against DENV2 NS2B-NS3 protease activity with IC50 values of 24 µM and 23 µM, respectively. AYA3 and AYA9 peptides also demonstrated approximately 68% and 83% of viral plaque reduction without significantly affecting cell viability at 50 µM concentration. In short, we generated short linear peptides with lower cytotoxic effect and substantial antiviral activities against DENV2. Further studies are required to investigate the inhibitory effects of these peptides in vivo. Keywords: peptide inhibitors; dengue virus; NS2B-NS3 protease; plaque reduction.

[Preliminary study on the feasibility of robot-assisted double mesh sacrocolpopexy in comparison to the laparoscopic approach]. / Étude préliminaire sur la faisabilité de la double promontofixation robotique comparée à la voie cœlioscopique.

OBJECTIVES: The aim of our study was to demonstrate the feasibility of the laparoscopic robot-assisted anterior and posterior mesh sacrocolpopexy compared to the laparoscopic approach. MATERIALS AND METHODS: Between November 2009 and August 2011, 36 women underwent sacrocolpopexy with anterior and posterior mesh, 16 by a robot-assisted approach and 20 by laparoscopy. The cases were systematically evaluated at 1 and 12 months postoperatively. All cases were contacted 6 months later to evaluate the functional results. RESULTS: Both groups were comparable in terms of age, ASA score, Body Mass Index, surgical history and grades of pelvic organ prolapse preoperatively. There was no difference in terms of hospital stay, per- and postoperative complications, especially concerning the rate of postoperative constipation. The mean operating time was significantly more important in the Robot group (P=0.001) with 318 min for the Robot group versus 260 min for the laparoscopic group. With a mean follow-up of 12 months, the anatomic result was satisfactory without recurrence in 97.2% of the cases. The urinary and sexual results, the restart of a sexual activity postoperatively, the surgical satisfaction and the return to daily activities were comparable between both groups. CONCLUSION: Robot-assisted laparoscopic sacrocolpopexy seems to be a reliable technique with morbidity, anatomic and functional outcomes comparable to that of laparoscopy.

[Uterine necrosis following pelvic arterial embolisation for postpartum haemorrhage: case report]. / Nécrose utérine après embolisation pelvienne pour hémorragie du postpartum : à propos d'un cas.

We report a case of uterine necrosis in a 38 year-old patient, who underwent a caesarean section for placenta praevia and an embolisation of the uterine arteries for postpartum haemorrhage. The pelvic embolisation was performed with absorbable gelatine sponge pledgets. This woman presented with abdominal pain and fever three weeks after delivery and a computed tomography scan revealed the presence of gas in the myometrium and endometrium and allowed the diagnosis of uterine necrosis. A total abdominal hysterectomy was performed with adnexal conservation and the diagnosis of uterine necrosis was confirmed histologically. The complications of pelvic embolization and the risks of surgical procedures for the management of intractable obstetric hemorrhage are described.

Alterações renais em diabetes mellitus do tipo 2 descrição da histologia em estudo de necrópsia / Renal disease in type 2 diabetes mellitus a renal histological description in autopsies

Introdução: As alterações histológicas renais encontráveis no paciente com Diabetes Mellitus do tipo 2 (DM2) ainda não estão bem estabelecidas, comoo foram aquelas do diabetes tipo l. Acreditamos que esse fato se deve, em parte, à indicação de biópsia renal em DM2 que se restringe aos casos commanifestações clínicas atípicas, como proteinúria nefrótica, função renal comprometida sem retinopatia ou rápida progressão para insuficiência renal.Objetivos: Descrever as alterações da histologia renal presentes em pacientes diabéticos tipo 2 submetidos à necrópsia após óbito por qualquer causa.Métodos: Análise histológica renal pela microscopia comum de 61 rins de humanos diabéticos necropsiados num período de dez anos (janeiro de 1994 ajaneiro de 2004), no Hospital Universitário em Londrina-PR. Resultados: Dos 61 casos analisados, a glomeruloesclerose diabética clássica, comproliferação nodular, se fez presente em tão somente 49,2%, encontrando-se doença glomerular superimposta à glomeruloesclerose diabética em 6,6%,alterações crônicas com predomínio vascular em 13,1% e outra doença glomerular isolada em 31,1%. Discussão: À semelhança de nossos resultados,em três outros estudos também nos rins obtidos por necrópsias em DM2 houve predomínio da nefroesclerose diabética, por vezes associada a outraspatologias renais. Em nosso material de estudo, 44,2% dos casos apresentavam lesão não diabética composta por outra glomerulopatia em 31,1% enefroesclerose hipertensiva em 13,1%. Conclusões: A análise histológica de rins de pacientes com DM2, obtida por necrópsia, encontra-se emconsonância com os dados da literatura mundial. A biópsia renal em diabéticos com nefropatia certamente permitirá reconhecer, nesse contexto, patologiaseventualmente curáveis.

Background: The structural lesions associated with the signs and symptoms of renal disease in type 2 diabetes mellitus are not as well defined as thoseof type 1; the literature refers to findings other than the typical glomerulosclerosis, but the true prevalence of lesions remains to be established. In general,there is a restrictive biopsy policy in the diabetic patient, indicated only in the presence of heavy proteinuria or renal dysfunction with the absence of retinalchanges. Methods: in the department of pathology of our University Hospital we examined by light microscopy the renal tissue of 61 diabetic type 2 patientswho died from different causes to assess the presence and type of renal changes. Results: 30/61 (49.2%) of the patients had classical diabeticglomerulosclerosis; concomitant diabetic lesion and glomerulonephritis was present in 6.6%;isolated glomerulonephritis in 31.1% and predominant vasculardamage in 1.,1%. Discussion: In our study as well as in three other published studies regarding renal autopsy findings of type 2 diabetic patients, almosthalf of the cases presented a non- classic diabetic glomerular lesion and was represented by hypertensive nephrosclerosis or a potentially curableglomerulonephritis. Conclusions: Our findings with respect to the autopsied diabetic type 2 renal histology are in accordance with the medical literature.Prospectively unrestricted kidney biopsy of type 2 diabetic patients should be stimulated to establish the causes of the renal dysfunction and find treatablelesions, thus enabling us to prevent deterioration is some cases.

Id3 induces a caspase-3- and -9-dependent apoptosis and mediates UVB sensitization of HPV16 E6/7 immortalized human keratinocytes.

Inhibitor of differentiation/DNA binding (Id) proteins comprise a class of helix-loop-helix transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. We have shown that while Id2 is induced by UVB in primary keratinocytes, Id3 is upregulated only in immortalized cells. We have now determined that the consequences of ectopic expression of Id3 protein are strikingly different between immortalized and primary keratinocytes. Overexpression of Id3 induces a significant increase in apoptotic cells as revealed by Annexin V positivity as well as proteolytic processing of caspase-3 in immortalized, but not in primary keratinocytes. Id3-green fluorescent protein (GFP)-positive cells exhibited a fivefold increase in apoptotic nuclear fragmentation compared to Id3-GFP-negative cells. These apoptotic responses were accompanied by activation of caspase-3, as shown by immunocytochemical staining with antibodies to active caspase-3. Immunostaining with antibodies to the active form of caspase-9 as well as to the active form of Bax further revealed that induction of apoptosis in Id3-overexpressing keratinocytes occurred via a mitochondrial-caspase-9-mediated pathway. Coexpression of dominant-negative caspase-9 with Id3 significantly suppressed apoptotic nuclear fragmentation, indicating that caspase-9 activation is essential for Id3-induced cell death. This response was also markedly attenuated by coexpression with the Bax antagonist antiapoptotic protein Bcl2, confirming a role for Bax activation in this apoptotic response. Id3-induced Bax activation may result from increased expression of Bax protein. Furthermore, reduction of Id3 expression by small interfering RNAs abrogated the UVB-induced proteolytic activation of caspase-3 in these cells. These data together suggest that UVB-induced apoptosis of immortalized keratinocytes is at least in part due to Id3 upregulation in these cells.

[Talus bipartitus]. / Talus bipartitus.

Talus bipartitus is an exceptional congenital malformation consisting in the presence of two non-fused bony talar fragments. We report the case of an adolescent girl who complained of mechanical pain in the left ankle which became increasingly invalidating. Plain radiographs, CT-scan and MRI led to the diagnosis of this congenital anomaly: talus bipartitus. Surgical correction by subtalar arthrodesis provided improvement at the cost of reduced ankle mobility. Surgical treatment should be proposed for talus bipartitus in patients with invalidating pain or stiffness when rehabilitation fails to provide sufficient improvement.

p15(INK4b) in bladder carcinomas: decreased expression in superficial tumours.

The p15 gene which encodes a cyclin-dependent kinase inhibitor, is located in the 9p21 chromosomal region that is frequently deleted in human bladder transitional cell carcinomas (TCCs). The aim of the present paper is to study the potential involvement of the p15 gene in the evolution of TCCs. p15 mRNA expression was investigated by semi-quantitative RT-PCR in a series of 75 TCCs, 13 bladder cell lines and 6 normal bladder urothelia by semi-quantitative RT-PCR. p15 was expressed in the normal urothelium but p15 mRNA levels were significantly decreased in 66% of the superficial (Ta-T1) TCCs (P = 0.0015). In contrast, in muscle-invasive (T2-T4) TCCs, p15 expression differed widely between samples. p16 mRNA levels were also studied and there was no correlation between p15 and p16 mRNA levels, thus indicating that the two genes were regulated independently. Lower p15 expression in superficial tumours did not reflect a switch from quiescence to proliferative activity as normal proliferative urothelial controls did not present decreased p15 mRNA levels relative to quiescent normal urothelia. We further investigated the mechanisms underlying p15 down regulation. Homozygous deletions of the p15 gene, also involving the contiguous p16 gene, were observed in 42% of the TCCs with decreased p15 expression. No hypermethylation at multiple methylation-sensitive restriction sites in the 5;-CpG island of p15 was encountered in the remaining tumours. Our data suggest that decreased expression of p15 may be an important step in early neoplastic transformation of the urothelium and that a mechanism other than homozygous deletions or hypermethylation, may be involved in p15 down regulation.

Two dimerization domains in the trans-activation response RNA-binding protein (TRBP) individually reverse the protein kinase R inhibition of HIV-1 long terminal repeat expression.

Trans-activation response (TAR) RNA-binding protein (TRBP) is a cellular protein that binds to the human immunodeficiency virus-1 (HIV-1) TAR element RNA. It has two double-stranded RNA binding domains (dsRBDs), but only one is functional for TAR binding. TRBP interacts with the interferon-induced protein kinase R (PKR) and inhibits its activity. We used the yeast two-hybrid assay to map the interaction sites between the two proteins. We show that TRBP and PKR-N (178 first amino acids of PKR) interact with PKR wild type and inhibit the PKR-induced yeast growth defect in this assay. We characterized two independent PKR-binding sites in TRBP. These sites are located in each dsRBD in TRBP, indicating that PKR-TRBP interaction does not require the RNA binding activity present only in dsRBD2. TRBP and its fragments that interact with PKR reverse the PKR-induced suppression of HIV-1 long terminal repeat expression. In addition, TRBP activates the HIV-1 long terminal repeat expression to a larger extent than the addition of each domain. These data suggest that TRBP activates gene expression in PKR-dependent and PKR-independent manners.

The role of popliteal vein incompetence in the diagnosis of saphenous-popliteal reflux using continuous wave doppler.

INTRODUCTION: continuous wave Doppler (CWD) has good discriminatory power at the groin in the assessment of saphenous femoral junction (SFJ); however, it is not as accurate as duplex ultrasound scanning (DUS) in the popliteal fossa for assessment of saphenous popliteal junction (SPJ) in patients with primary short saphenous vein incompetence. AIM: the aim of this study was to compare the findings of CWD with those of DUS at the SPJ and assess the role of popliteal vein incompetence in the accuracy of CWD. METHOD: prospective study of consecutive patients presenting to a vein clinic requiring a duplex scan of their SPJ. Each patient was examined by one surgeon using CWD and by one radiologist using DUS. Each observer was unaware of the other's findings. Additional information on the competence of the popliteal vein on DUS was also recorded. RESULTS: some 171 limbs in 128 patients with varicose veins were studied. One hundred and sixteen limbs had reflux at SPJ on CWD whilst 55 did not. Their mean age was 54 (range 18-85). Female to male ratio was 3:1. Spearman's rank correlation between CWD and DUS has 0.49 (p =0.0001). CWD has a sensitivity of 92% and specificity of 53% (PPV=62%, NPV=89%, accuracy=70%). Twenty-nine limbs had an incompetent popliteal vein (IPV). Of those, 12 limbs also had incompetence on CWD and competence on DUS at the SPJ, which represent 28% of the total number of limbs with these findings (n =43). CONCLUSION: CWD is sensitive in detecting incompetence at SPJ, though its specificity is low. In this study 17% (n =29) of all patients had incompetence of popliteal vein. Up to 25% ( n =12) of patients with SPJ incompetence on CWD (Doppler +) and competence on DUS (duplex -) had incompetence of the underlying popliteal vein, which may explain the low specificity. The presence of SPJ incompetence on CWD should be confirmed on DUS prior to surgery.

Characterization of TRBP1 and TRBP2. Stable stem-loop structure at the 5' end of TRBP2 mRNA resembles HIV-1 TAR and is not found in its processed pseudogene.

TRBP1 and TRBP2 cDNAs have been isolated based on the ability of the protein that they encode to bind HIV-1 TAR RNA. The two cDNAs have different 5' end-termini resulting in 21 additional amino acids for TRBP2 protein compared to TRBP1. The corresponding gene is conserved in mammalian species. By PCR amplification of a human library, we have isolated an additional 22 nucleotides in the 5' end of TRBP2 cDNA. Based on the addition of these 22 new nucleotides, the first 87 nucleotides of TRBP2 mRNA can fold into a stable stem-loop structure that resembles TAR RNA. We have also isolated the DNA sequence that represents the TRBP processed pseudogene. The absence of full alignment between TRBP2 full-length cDNA and this sequence suggests that the stem-loop structure could have prevented a complete reverse transcription during pseudogene formation. Using different antibodies, three forms of TRBP can be identified in primate cells at 40, 43 and 50 kD, suggesting a differential expression from the cDNAs and post-translational modifications. Both TRBP1 and TRBP2 activate the basal and the Tat-activated level of the HIV-1 LTR in human and murine cells. Our data indicate that TRBP proteins act at a level prior to Tat function. TRBP could contribute to improved HIV expression in murine models.

Effect of pre-conceptional external or internal irradiation of N5 male mice and the risk of leukemia in their offspring.

Male mice of the N5 strain were exposed to a unique external X-ray dose of 500 cGy, or to i.p. injections of tritiated water (HTO) over a 30 day period, which resulted in an estimated total internal exposure of 150 cGy. The paternal X-ray irradiation resulted in a marginally significant (P = 0.07) doubling of the leukemia/lymphoma rate in the offspring, over a 1 year observation period. The constitutive gene expression of granulocyte-macrophage colony stimulating factor (GM-CSF) and tumour necrosis factor (TNF) (two cytokines associated with hematopoiesis and immune response) spontaneously diminished between the ages of 6 months and 12 months in the bone marrows and in the spleens of these mice, and paternal X-ray exposure influenced the statistical significance of this diminution. Male exposure to HTO resulted in a statistically significant several-fold increase of leukemia incidence among the young offspring. However this increase tended to diminish as older mice were observed, and was no longer significant at 1 year of age. The overall leukemia incidence in the offspring of the HTO-exposed fathers was significantly dependent on the maturation stage of the sperm-forming cells during the HTO exposure, which suggests an influence of such an exposure.

Acute effects of oral glibenclamide on blood pressure and forearm vascular resistance in diabetics.

1. To determine the effects of an acute oral dose of glibenclamide on blood pressure (BP), basal forearm vascular resistance (FVR) and FVR responses to the K+(ATP) channel activating vasodilator diazoxide, a placebo-controlled, double-blind cross-over study was performed in eight male volunteers with non-insulin-dependent diabetes mellitus. 2. Changes in vascular responses to progressively increasing concentrations of diazoxide (3.75-30 mg/kg per min) and noradrenaline (25-100 ng/kg per min) were measured by venous occlusion plethysmography. 3. Glibenclamide significantly lowered plasma glucose levels compared with placebo (P < 0.02) and attenuated the decrease in FVR (P < 0.05) and the decrease in systolic BP (P < 0.05) that followed a meal. However, vasodilator responses to diazoxide were potentiated by the administration of oral glibenclamide (P < 0.01). 4. Acute administration of oral glibenclamide attenuates the normal decrease in FVR and systolic BP that follows a meal and potentiates rather than inhibits forearm vasodilator responses to intra-arterial diazoxide, probably via indirect humoral effects. These results suggest that glibenclamide has direct or indirect vasoconstrictor effects that antagonize the normal increase in forearm blood flow that follows a meal and that the inhibition of vascular K+(ATP) channels following acute oral glibenclamide administration is clinically insignificant compared with other indirect vascular effects of the drug.

Acute effects of oral glibenclamide on blood pressure and forearm vascular resistance in diabetics.

1. To determine the effects of an acute oral dose of glibenclamide on blood pressure (BP), basal forearm vascular resistance (FVR) and FVR responses to the K+ATP channel activating vasodilator diazoxide, a placebo-controlled, double-blind cross-over study was performed in eight male volunteers with non-insulin-dependent diabetes mellitus. 2. Changes in vascular responses to progressively increasing concentrations of diazoxide (3.75-30 mg/kg per min) and noradrenaline (25-100 ng/kg per min) were measured by venous occlusion plethysmography. 3. Glibenclamide significantly lowered plasma glucose levels compared with placebo (P < 0.02) and attenuated the decrease in FVR (P < 0.05) and the decrease in systolic BP (P < 0.05) that followed a meal. However, vasodilator responses to diazoxide were potentiated by the administration of oral glibenclamide (P < 0.01). 4. Acute administration of oral glibenclamide attenuates the normal decrease in FVR and systolic BP that follows a meal and potentiates rather than inhibits forearm vasodilator responses to intra-arterial diazoxide, probably via indirect humoral effects. These results suggest that glibenclamide has direct or indirect vasoconstrictor effects that antagonize the normal increase in forearm blood flow that follows a meal and that the inhibition of vascular K+ATP channels following acute oral glibenclamide administration is clinically insignificant compared with other indirect vascular effects of the drug.

Comparative effects of glibenclamide and metformin on ambulatory blood pressure and cardiovascular reactivity in NIDDM.

OBJECTIVE: To compare the effects of chronic glibenclamide and metformin therapy on blood pressure (BP) and cardiovascular responsiveness in patients with NIDDM. RESEARCH DESIGN AND METHODS: Fourteen patients with NIDDM received metformin or glibenclamide for 1 month in a double-blind, randomized crossover study. At the end of each treatment period, patients were tested for forearm vascular responsiveness to intrabrachial arterial infusion of diazoxide (an ATP-sensitive potassium channel opener), acetylcholine, sodium nitroprusside, and norepinephrine, BP responses to intravenous infusions of NE and angiotensin II, BP responses to cold pressor testing and isometric exercise, and 24-h ambulatory BP monitoring. RESULTS: Metformin and glibenclamide produced similar glycemic control. Mean 24-h BPs did not differ between the two groups, but mean 24-h heart rates were significantly lower (75 +/- 6 bpm vs. 80 +/- 6 bpm) on glibenclamide therapy than on metformin. Plasma norepinephrine levels were significantly higher on glibenclamide (6.41 +/- 1.77 vs. 4.26 +/- 1.54 mmol/l, P < 0.01), and systolic BP responses to intravenous norepinephrine and angiotensin II were significantly higher on glibenclamide than on metformin (P < 0.02 and P < 0.05, respectively). Systolic BP responses to cold pressor testing appeared higher on glibenclamide than on metformin, but the difference did not quite achieve statistical significance (P = 0.052). Baseline forearm vascular resistance did not differ between the two drugs, nor did forearm vascular resistance responses to diazoxide, acetylcholine, sodium nitroprusside, and norepinephrine differ. CONCLUSIONS: Glibenclamide therapy is accompanied by greater systolic BP responses to norepinephrine and angiotensin II and higher plasma norepinephrine levels than those that occur on metformin therapy. Lower heart rates on glibenclamide therapy despite evidence of greater sympathetic activity suggests that glibenclamide may have negative chronotropic effects.