ELECTROANALYSIS, Issue 9 2008
Farook Ahmad
Abstract Monitoring of glucose in subcutaneous and brain striatum have been extensively studied in the past. While biocompatibility was one of the limitations, others included the messy measuring equipments preclude monitoring in a complex environment. This study tried to establish an amperometric measurement of glucose in pre- and post-insulin-administration on diabetic and hyperglycemia rats via wireless. The results have indicated that the wireless sensing kit used was capable of monitoring glucose in both subcutaneous and brain. The physiological data have also shown a new insight on the fabrication of implantable glucose sensors. [source]

The Anti-Inflammatory Effect of Bee Venom Stimulation in a Mouse Air Pouch Model Is Mediated by Adrenal Medullary Activity

JOURNAL OF NEUROENDOCRINOLOGY, Issue 1 2003
Y.-B. Kwon
Abstract Cutaneous electrical or chemical stimulation can produce an anti-inflammatory effect, which is dependent on adrenal medullary-sympathetic activation. We have previously shown that peripheral injection of bee venom (BV) also produces a significant anti-inflammatory effect that is neurally mediated. In the present study, we examined whether this anti-inflammatory effect is also dependent on the adrenal gland using the mouse inflammatory air pouch model. Subcutaneous (s.c.) BV injection produced a marked suppression of leucocyte migration and tumour necrosis factor (TNF)- , concentration induced by zymosan injection into the air pouch. The role of the adrenal gland in this suppression was evaluated in adrenalectomized mice. Adrenalectomy significantly reversed the suppression of leucocyte migration and TNF- , elevation caused by BV. Serum concentrations of corticosteroid were increased in mice with zymosan-induced air-pouch inflammation and this increase was reduced by BV administration, suggesting that adrenal corticosteroid release is not involved in mediating the anti-inflammatory effects of BV. To test this hypothesis, the corticosteroid receptor antagonist (RU486) was administered and found not to affect the BV-induced inhibition of leucocyte migration. By contrast, pretreatment with the , -adrenergic antagonist propranolol reversed the BV-induced inhibitory effect on leucocyte migration. These results suggest that the anti-inflammatory effect of s.c. BV administration is mediated in part by the release of catecholamines from the adrenal medulla. [source]

Extreme Subcutaneous, Intramuscular and Inhaled Insulin Resistance Treated by Pancreas Transplantation Alone

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010
J. R. Sa
Diabetes mellitus with resistance to insulin administered subcutaneously or intramuscularly (DRIASM) is a rare syndrome and is usually treated with continuous intravenous insulin infusion. We present here two cases of DRIASM in 16 and 18 years female patients that were submitted to pancreas transplantation alone (PTA). Both were diagnosed with type 1 diabetes as young children and had labile glycemic control with recurrent episodes of diabetic ketoacidosis. They had prolonged periods of hospitalization and complications related to their central venous access. Exocrine and endocrine drainages were in the bladder and systemic, respectively. Both presented immediate graft function. In patient 1, enteric conversion was necessary due to reflux pancreatitis. Patient 2 developed mild postoperative hyperglycemia in spite of having normal pancreas allograft biopsy and that was attributed to her immunosuppressive regimen. Patient 1 died 9 months after PTA from septic shock related to pneumonia. In 8 months of follow-up, Patient 2 presented optimal glycemic control without the use of antidiabetic agents. In conclusion, PTA may be an alternative treatment for DRIASM patients. [source]

Analysis of Subcutaneous (SQ) Alemtuzumab Induction Therapy in Highly Sensitized Patients Desensitized With IVIG and Rituximab

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2008
A. A. Vo
Here we report on our experience with subcutaneous (SQ) Alemtuzumab in an uncontrolled study in highly HLA-sensitized patients (HS). From 3/05,4/07, 54 HS patients received Alemtuzumab 30 mg SQ as induction. Patient and graft survival, AR episodes, serum creatinines, absolute lymphocyte counts, monthly PCR monitoring for viruses, AE/SAEs and infectious complications were monitored. No patient to date has developed acute injection-related reactions after SQ Alemtuzumab; however, bone marrow suppression was occasionally seen requiring reduction or elimination of mycophenolate mofetil approximately 1,2 months posttransplant. Patient and graft survival at 12 M was 98%/96%, respectively. AR episodes occurred in 35% with 20% being C4d+ AMR. Mean SCrs at 12 M were 1.4 ± 0.3 mg/dL. The nadir ALC was 0.17 ± 0.19 within 24 h and sustained up to 365 days posttransplant. Infections occurred in eight patients (five with polyoma BK viremia [PBK], one CMV/PBK and two CMV viremia). SQ Alemtuzumab was well tolerated and resulted in prolonged lymphocyte depletion. Compared to our previous experience with daclizumab and rabbit ATG induction in HS patients, single-dose SQ Alemtuzumab was more cost effective, showed similar infection rates and did not reduce the AMR rates posttransplant. Although uncontrolled, these observations suggest that induction therapy with Alemtuzumab appears feasible and indeed promising, but awaits more definitive study. [source]

Subcutaneous unfractionated heparin-induced hyperkalaemia in an elderly patient

AUSTRALASIAN JOURNAL ON AGEING, Issue 2 2009
Angela Aiping Liu
No abstract is available for this article. [source]

Subcutaneous and muscular abscesses due to Mycobacterium avium intracellulare in a patient with AIDS as a manifestation of immune restoration

BRITISH JOURNAL OF DERMATOLOGY, Issue 2 2004
C. Bachmeyer
No abstract is available for this article. [source]

Evaluation of tumor affinity of mono-[123I]iodohypericin and mono-[123I]iodoprotohypericin in a mouse model with a RIF-1 tumor

CONTRAST MEDIA & MOLECULAR IMAGING, Issue 3 2007
Humphrey Fonge
Abstract In this study we have compared the tumour-seeking properties of mono-[123I]iodoprotohypericin and mono-[123I]iodohypericin in C3H mice with a subcutaneous radiation-induced fibrosarcoma-1 tumor. After intravenous injection, both tracers were rapidly cleared from all organs and were retained by the tumors. There was no significant difference in tumor uptake of the two tracers at all studied time points (p,>,0.05). To study the plausible mechanism of hypericin and mono-iodohypericin uptake in tumor, their plasma binding profile was investigated. Both agents show high affinity for low-density lipoproteins and to a lesser extent high-density lipoproteins and other heavy proteins. Mono-[123I]iodohypericin appears to be more promising as a tumor diagnostic agent, given its faster clearance from all organs. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Sclerotherapy of Varicose Veins with Polidocanol Based on the Guidelines of the German Society of Phlebology

DERMATOLOGIC SURGERY, Issue 2010
EBERHARD RABE MD
BACKGROUND Sclerotherapy involves the injection of a sclerosing agent for the elimination of intracutaneous, subcutaneous, and transfascial varicose veins. OBJECTIVE To update guidelines for sclerotherapy of varicose veins. METHODS The guidelines for sclerotherapy of varicose veins of the German Society of Phlebology were updated and modified through a review of the available literature. RESULTS Published clinical series and controlled clinical trials provide evidence to support the elimination of intracutaneous and subcutaneous varicose veins using sclerotherapy. Allergic skin reactions occur occasionally as allergic dermatitis, contact urticaria, or erythema. Anaphylaxis is rare. Transient migraine headaches present more frequently in patients treated with foam sclerotherapy than liquid sclerotherapy. CONCLUSION Sclerotherapy is the method of choice for the treatment of small-caliber varicose veins (reticular varicose veins, spider veins). If performed properly, sclerotherapy is an efficient treatment method with a low incidence of complications. BioForm Medical provided financial support for formal formatting of this manuscript without any influence over the content of the manuscript. The authors have previously participated in two scientific studies with polidocanol (ESAF and EASI study) financed by Kreussler. [source]

Guidelines for Sclerotherapy of Varicose Veins (ICD 10: I83.0, I83.1, I83.2, and I83.9)

DERMATOLOGIC SURGERY, Issue 5 2004
E. Rabe MD
Background. Sclerotherapy is the targeted elimination of intracutaneous, subcutaneous, and/or transfascial varicose veins (perforating veins) as well as the sclerosation of subfascial varicose vessels in the case of venous malformation by the injection of a sclerosant. With duplex-guide sclerotherapy and foam sclerotherapy, modified methods came into use. Objective. The objective was to create a guideline, based on the available publications and on the European Consensus Document on foam sclerotherapy from April 2003. Methods. This guideline was drafted on behalf of the German Society of Phlebology (Deutsche Gesellschaft für Phlebologie) and adopted by the committee and scientific advisory board of the Deutsche Gesellschaft für Phlebologie on June 15, 2001, and amended on December 5, 2003. The guideline considers the present state of knowledge as reflected in the literature. Conclusions. This guideline represents the recent state of the art of sclerotherapy of varicose veins in Germany including foam sclerotherapy. [source]

The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes

DIABETES OBESITY & METABOLISM, Issue 1 2010
S. D. Luzio
Aim: Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). Methods: Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m2, haemoglobin A1c (HbA1c) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. Results: Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280,330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC0,6 h (910 ± 270 vs. 472 ± 245 pmol h/L; 950 ± 446 vs. 433 ± 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA1c, weight and triglycerides were observed. Conclusions: Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations. [source]

DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue

DIABETES OBESITY & METABOLISM, Issue 4 2009
K. Kos
Context:, Dipeptidyl peptidase IV (DPP-IV) inactivates the incretin hormone glucagon-like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY1,36) which is truncated by DPP-IV to NPY3,36, as a consequence NPY's affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP-IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways. Aims:, To investigate the in vitro effects of NPY with DPP-IV inhibition in isolated abdominal subcutaneous (AbdSc) adipocytes on fat metabolism, and assessment of NPY receptor and DPP-IV expression in adipose tissue (AT). Methods:,Ex vivo human AT was taken from women undergoing elective surgery (body mass index: 27.5 (mean ± s.d.) ± 5 kg/m2, age: 43.7 ± 10 years, n = 36). Isolated AbdSc adipocytes were treated with human recombinant (rh)NPY (1,100 nM) with and without DPP-IV inhibitor (1 M); glycerol release and tissue distribution of DPP-IV, Y1 and Y5 messenger RNA (mRNA) were measured and compared between lean and obese subjects. Results and conclusion:, rhNPY reduced glycerol release, an effect that was further enhanced by co-incubation with a DPP-IV inhibitor [control: 224 (mean ± s.e.) ± 37 ,mol/l; NPY, 100 nM: 161 ± 27 ,mol/l**; NPY 100 nM/DPP-IV inhibitor, 1 M: 127 ± 14 ,mol/l**; **p < 0.01, n = 14]. DPP-IV was expressed in AbdSc AT and omental AT with relative DPP-IV mRNA expression lower in AbdSc AT taken from obese [77 ± 6 signal units (SU)] vs. lean subjects (186 ± 29 SU*, n = 10). Y1 was predominantly expressed in fat and present in all fat depots but higher in obese subjects, particularly the AbdSc AT-depot (obese: 1944 ± 111 SU vs. lean: 711 ± 112 SU**, n = 10). NPY appears to be regulated by AT-derived DPP-IV. DPP-IV inhibitors augment the antilipolytic effect of NPY in AT. Further studies are required to show whether this explains the lack of weight loss in T2DM patients treated with DPP-IV inhibitors. [source]

Adipocyte prolactin: regulation of release and putative functions

DIABETES OBESITY & METABOLISM, Issue 4 2007
T. Brandebourg
Pituitary-derived prolactin (PRL) is a well-known regulator of the lactating mammary gland. However, the recent discovery that human adipose tissue produces PRL as well as expresses the PRL receptor (PRLR) highlights a previously unappreciated action of PRL as a cytokine involved in adipose tissue function. Biologically active PRL is secreted by all adipose tissue depots examined: breast, visceral and subcutaneous. The expression of adipose PRL is regulated by a non-pituitary, alternative superdistal promoter. PRL expression and release increases during early pre-adipocyte differentiation and is stimulated by cyclic AMP activators, including , adrenergic receptor agonists. PRL release from subcutaneous adipose explants is attenuated during obesity, suggesting that adipose PRL production is altered by the metabolic state. Several lines of evidence indicate that PRL suppresses lipid storage as well as the release of adipokines such as adiponectin, interleukin-6 and possibly leptin. PRL has also been implicated in the regulation of adipogenesis. A newly developed PRL-secreting human adipocyte cell line, LS14, should allow comprehensive examination of the regulation and function of adipocyte-derived PRL. Collectively, these studies raise the prospect that PRL affects energy homeostasis through its action as an adipokine and is involved in the manifestation of insulin resistance. [source]

Unlocking the opportunity of tight glycaemic control

DIABETES OBESITY & METABOLISM, Issue 2005
Innovative delivery of insulin via the lung
As the incidence of diabetes reaches epidemic proportions, the use of new, alternative routes of insulin delivery to manage glycaemic control is becoming an ever more active area of research. The high permeability and large surface area of the lung make it an attractive alternative to subcutaneous (SC) insulin injections. This review discusses the technical factors that influence the efficacy of pulmonary drug delivery and describes how an appreciation of these issues has enabled the design of Exubera®, a novel, non-invasive, pulmonary dry-powder human insulin delivery system currently in development by Pfizer and the sanofi-aventis Group in collaboration with Nektar Therapeutics. While clinical trials of this novel aerosol delivery of insulin are still ongoing in patients with diabetes, the results so far suggest it is simple to use and can provide reproducible doses of insulin in therapeutic amounts with only a few inhalations per dose. In addition, it has been shown to be comparable in terms of efficacy and safety to a conventional SC insulin injection regimen. Delivering aerosolized drugs via the lungs avoids the necessity for SC injections and thereby may increase the patient's acceptability of an insulin-based therapeutic regimen. [source]

Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2009
R. P. Radermecker
Abstract The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence, but not completely suppressed, the development of anti-insulin antibodies (IAs). Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), continuous peritoneal insulin infusion (CPII) and more recently inhaled insulin administration, appear to significantly increase circulating levels of immunoglobulin G (IgG) anti-IAs in diabetic patients. However, the increase is usually moderate and mostly transient as compared to previous observations with poorly purified animal insulin preparations. The clinical impact of these circulating anti-IAs remains unclear. Nevertheless, several studies have suggested that antibodies could retard insulin action, leading to a worsening of postprandial hyperglycaemia and/or serve as a carrier, thus leading to unexpected hypoglycaemia. CPII may be associated with more marked and sustained increase in IAs levels, possibly related to the use of an unstable insulin and the formation of immunogenic aggregates of insulin. The possible clinical consequences of these high levels of IAs remain to be evaluated because a low-glucose morning syndrome or severe insulin resistance with ketone bodies production have been reported in some cases. In conclusion, even if CSII and CPII may promote the development of circulating IAs, this increase does not lead to immunological insulin resistance, compared to that previously described with animal non-purified insulin preparations, and seems to have only marginal influence on blood glucose control or complications in most diabetic patients. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Glucose-induced release of tumour necrosis factor-alpha from human placental and adipose tissues in gestational diabetes mellitus

DIABETIC MEDICINE, Issue 11 2001
M. T. Coughlan
Abstract Aims, The cytokine tumour necrosis factor-alpha (TNF-,) has been implicated in the pathogenesis of insulin resistance in Type 2 diabetes mellitus, but limited data are available in relation to gestational diabetes mellitus (GDM), a disease in which similar biochemical abnormalities exist. We investigated the effect of exogenous glucose on the release of TNF-, from placental and adipose (omental and subcutaneous) tissue obtained from normal pregnant women, and women with GDM. Methods, Human tissue explants were incubated for up to 24 h and TNF-, concentration in the incubation medium quantified by ELISA. The effect of normal (5 mmol/l) and high (15 and 25 mmol/l) glucose concentrations on the release of TNF-, was assessed. Results, In placental and subcutaneous adipose tissues obtained from women with GDM (n = 6), TNF-, release was significantly greater under conditions of high glucose compared with normal glucose (placenta, 25 mmol/l 5915.7 ± 2579.6 and 15 mmol/l 4547.1 ± 2039.1 vs. 5 mmol/l 1897.1 ± 545.5; subcutaneous adipose tissue, 25 mmol/l 423.5 ± 207.0 and 15 mmol/l 278.5 ± 138.7 vs. 5 mmol/l 65.3 ± 28.5 pg/mg protein; P < 0.05). In contrast, there was no stimulatory effect of high glucose on TNF-, release by tissues obtained from normal pregnant women (n = 6) (placenta, 25 mmol/l 1542.1 ± 486.2 and 15 mmol/l 4263.3 ± 2737.7 vs. 5 mmol/l 5422.4 ± 1599.0; subcutaneous adipose tissue, 25 mmol/l 189.8 ± 120.4 and 15 mmol/l 124.5 ± 32.3 vs. 5 mmol/l 217.9 ± 103.5 pg/mg protein). Conclusions, These observations suggest that tissues from patients with GDM release greater amounts of TNF-, in response to high glucose. As TNF-, has been previously implicated in the regulation of glucose and lipid metabolism, and of insulin resistance, these data are consistent with the hypothesis that TNF-, may be involved in the pathogenesis and/or progression of GDM. Diabet. Med. 18, 921,927 (2001) [source]

Development of Prototype Wireless Transmission Measurement for Glucose in Subcutaneous and Brain Striatum

PRECLINICAL STUDY: Mechanisms of respiratory insufficiency induced by methadone overdose in rats

ADDICTION BIOLOGY, Issue 1 2010
Lucie Chevillard
ABSTRACT Methadone may cause respiratory depression. We aimed to understand methadone-related effects on ventilation as well as each opioid-receptor (OR) role. We studied the respiratory effects of intraperitoneal methadone at 1.5, 5, and 15 mg/kg (corresponding to 80% of the lethal dose-50%) in rats using arterial blood gases and plethysmography. OR antagonists, including intravenous 10 mg/kg-naloxonazine at 5 minutes (mu-OR antagonist), subcutaneous 30 mg/kg-naloxonazine at 24 hours (mu1-OR antagonist), 3 mg/kg-naltrindole at 45 minutes (delta-OR antagonist) and 5 mg/kg-Nor-binaltorphimine at 6 hours (kappa-OR antagonist) were pre-administered. Plasma concentrations of methadone enantiomers were measured using high-performance liquid chromatography coupled to mass-spectrometry. Methadone dose-dependent inspiratory time (TI) increase tended to be linear. Respiratory depression was observed only at 15 mg/kg and characterized by an increase in expiratory time (TE) resulting in hypoxemia and respiratory acidosis. Intravenous naloxonazine completely reversed all methadone-related effects on ventilation, while subcutaneous naloxonazine reduced its effects on pH (P < 0.05), PaCO2 (P < 0.01) and TE (P < 0.001) but only partially on TI (P < 0.001). Naltrindole reduced methadone-related effects on TE (P < 0.001). Nor-binaltorphimine increased methadone-related effects on pH and PaO2 (P < 0.05) Respiratory effects as a function of plasma R -methadone concentrations showed a decrease in PaO2 (EC50: 1.14 µg/ml) at lower concentrations than those necessary for PaCO2 increase (EC50: 3.35 µg/ml). Similarly, increased TI (EC50: 0.501 µg/ml) was obtained at lower concentrations than those for TE (EC50: 4.83 µg/ml). Methadone-induced hypoxemia is caused by mu-ORs and modulated by kappa-ORs. Additionally, methadone-induced increase in TE is caused by mu1- and delta-opioid receptors while increase in TI is caused by mu-ORs. [source]

PRECLINICAL STUDY: Route of administration affects the ability of naltrexone to reduce amphetamine-potentiated brain stimulation reward in rats

ADDICTION BIOLOGY, Issue 4 2009
Mark S. Todtenkopf
ABSTRACT Opioid receptor antagonism has been shown to attenuate behavioral and neurochemical effects of amphetamine in humans and rodents. The effects of acute (oral or subcutaneous) or extended-release naltrexone (XR-NTX) were tested on the reward-enhancing effects of amphetamine using the intracranial self-stimulation (ICSS) paradigm. Acute exposure to drugs of abuse reduces the locus of rise (LOR) in the ICSS procedure, reflecting enhanced brain stimulation reward (BSR). Rats were treated once a day with naltrexone orally (PO; 5.0 mg/kg) or subcutaneously (SC; 0.5 mg/kg) for four consecutive days and tested with D-amphetamine (0.5 mg/kg, intraperitoneal) in the ICSS paradigm 30 minutes later on days 1 and 4. Separate groups of rats received XR-NTX (50 mg/kg, SC) or placebo microspheres (similar mass to XR-NTX, SC) on day 0 and tested with D-amphetamine in the ICSS paradigm on days 4, 14, 21, 28 and 41 after administration. Naltrexone plasma concentrations were determined for each amphetamine testing session using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). In rats pretreated with naltrexone acutely, amphetamine-potentiated BSR did not differ from vehicle-pretreated rats on either day 1 or day 4 (25,30% decrease in LOR). In XR-NTX-pretreated rats, amphetamine-potentiated BSR was reduced by 64 and 70% on days 4 and 14, respectively, compared to placebo microsphere-treated controls. This effect dissipated by day 21. Naltrexone plasma concentrations were comparable across all treatment groups (14,30 ng/ml) on days 1, 4 and 14. In summary, an extended-release formulation of naltrexone results in significant attenuation of psychostimulant-enhanced BSR that is not observed with acute naltrexone. [source]

Cholinergic modulation of visuospatial responding in central thalamus

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007
Lori A. Newman
Abstract Central thalamus has extensive connections with basal ganglia and frontal cortex that are thought to play a critical role in sensory-guided goal-directed behavior. Central thalamic activity is influenced by cholinergic projections from mesopontine nuclei. To elucidate this function we trained rats to respond to lights in a reaction time (RT) task and compared effects of muscarinic (2.4, 7.3, 22 nmol scopolamine) and nicotinic (5.4, 16, 49, 98 nmol mecamylamine) antagonists with the GABAA agonist muscimol (0.1, 0.3, 1.0 nmol) in central thalamus. We compared this with subcutaneous (systemic) effects of mecamylamine (3.2, 9.7, 29 µmol/kg) and scopolamine (0.03, 0.09, 0.26 µmol/kg). Subcutaneous scopolamine increased omissions (failure to respond within a 3-s response window) at the highest dose tested. Subcutaneous mecamylamine increased omissions at the highest dose tested while impairing RT and per cent correct at lower doses. Intrathalamic injections of muscimol and mecamylamine decreased per cent correct at doses that did not affect omissions or RT. Intrathalamic scopolamine increased omissions and RT at doses that had little effect on per cent correct. Anatomical controls indicated that the effects of mecamylamine were localized in central thalamus and those of scopolamine were not. Drug effects did not interact with attention-demanding manipulations of stimulus duration, proximity of stimulus and response locations, or stimulus array size. These results are consistent with the hypothesis that central thalamus mediates decisional processes linking sensory stimuli with actions, downstream from systems that detect sensory signals. They also provide evidence that this function is specifically influenced by nicotinic cholinergic receptors. [source]

Route of Administration Differentially Affects Fevers Induced by Gram-Negative and Gram-Positive Pyrogens in Rabbits

EXPERIMENTAL PHYSIOLOGY, Issue 3 2002
T. Cartmell
We have investigated the febrile responses of New Zealand White rabbits to a Gram-negative pyrogen (bacterial lipopolysaccharide (LPS) from Salmonella typhosa), commonly associated with systemic infection, and a Gram-positive pyrogen (Staphylococcus aureus), more frequently associated with superficial soft tissue infection, each administered via one of four different routes (intravenous, intramuscular, subcutaneous or intraperitoneal) at each of three different doses (LPS: 0.1, 1 and 10 ,g kg,1; S. aureus: 1.5 × 107, 1.5 × 108 and 1.5 × 109 cell walls kg,1). Intravenous administration of LPS evoked rapid, dose-dependent biphasic fever. Injection of LPS by the other routes also evoked dose-dependent fever. However, these fevers were monophasic, had increased latency of onset, and were of lower amplitude. It is important to note that a dose of approximately 10 and 100 times that of the standard intravenous dose was required to produce a similar peak rise in temperature when administered subcutaneously and intraperitoneally, respectively. Intravenous injection of the highest dose of S. aureus evoked dose-dependent biphasic fever, with short latency of onset, which was very similar to that induced by intravenous LPS. At lower doses, intravenous S. aureus induced monophasic fever. No fever occurred when the same doses of S. aureus were administered by any other route. We conclude that any of the four routes may be used for the study of LPS-induced fever, provided that the doses are adjusted. However, studies of S. aureus -induced fever, and detection of contamination with either pyrogen, requires intravenous injection. [source]

Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytes

GLIA, Issue 15 2008
Thomas Calzascia
Abstract T cell mediated immunotherapies are proposed for many cancers including malignant astrocytoma. As such therapies become more potent, but not necessarily more tumor-specific, the risk of collateral autoimmune damage to normal tissue increases. Tumors of the brain present significant challenges in this respect, as autoimmune destruction of brain tissue could have severe consequences. To investigate local immune reactivity toward a tumor-associated antigen in the brain, transgenic mice were generated that express a defined antigen (CW3170,179) in astroglial cells. The resulting six transgenic mouse lines expressed the transgenic self-antigen in cells of the gastrointestinal tract and CNS compartments, or in the CNS alone. By challenging transgenic mice with tumor cells that express CW3, self/tumor-specific immune responses were visualized within a normal polyclonal T cell repertoire. A large expansion of the endogenous CW3170,179 -specific CD8 T cell population was observed in nontransgenic mice after both subcutaneous and intracerebral implantation of tumor cells. In contrast, CW3170,179 -specific immune responses were not observed in transgenic mice that exhibited extracerebral transgene expression. Importantly, in certain groups of mice in which transgene expression was restricted to the CNS, antigen-specific immune responses occurred when tumor was implanted subcutaneously, but not intracerebrally. This local immune tolerance in the brain was induced via peripheral (extrathymic) rather than central (thymic) tolerance mechanisms. Thus, this study highlights the role of regional immune regulation in the prevention of autoimmunity in the brain, and the potential impact of these mechanisms for brain tumor immunotherapy. © 2008 Wiley-Liss, Inc. [source]

Subcutaneous Sumatriptan Pharmacokinetics: Delimiting the Monoamine Oxidase Inhibitor Effect

HEADACHE, Issue 2 2010
Anthony W. Fox
(Headache 2010;50:249-255) Background., The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96-100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after Tmax = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase-A (MAO-A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co-administration of an inhibitor of MAO-A (a MAOI-A) causes a 2-fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half-life. Objective., The objective of this study is to determine whether MAOI-A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds. Methods., Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92-050. Half-times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at Tmax, 1, 2, and 10 hours post-dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs). Results., The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2-fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI-A was 3.72 ng/mL (or <4% of Cmax). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC0-10h was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI-A. Conclusions., There are no pharmacokinetic grounds to deter co-administration of an MAOI-A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI-A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan. [source]

Adult Emergency Department Patients with Sickle Cell Pain Crisis: A Learning Collaborative Model to Improve Analgesic Management

ACADEMIC EMERGENCY MEDICINE, Issue 4 2010
Paula Tanabe PhD
Abstract Objectives:, The objectives were to report the baseline (prior to quality improvement interventions) patient and visit characteristics and analgesic management practices for each site participating in an emergency department (ED) sickle cell learning collaborative. Methods:, A prospective, multisite longitudinal cohort study in the context of a learning-collaborative model was performed in three midwestern EDs. Each site formed a multidisciplinary team charged with improving analgesic management for patients with sickle cell disease (SCD). Each team developed a nurse-initiated analgesic protocol for SCD patients (implemented after a baseline data collection period of 3.5 months at one site and 10 months at the other two sites). All sites prospectively enrolled adults with an acute pain crisis and SCD. All medical records for patients meeting study criteria were reviewed. Demographic, health services, and analgesic management data were abstracted, including ED visit frequency data, ED disposition, arrival and discharge pain score, and name and route of initial analgesic administered. Ten interviews per quarter per site were conducted with patients within 14 days of their ED discharge, and subjects were queried about the highest level of pain acceptable at discharge. The primary outcome variable was the time to initial analgesic administration. Variable data were described as means and standard deviations (SDs) or medians and interquartile ranges (IQR) for nonnormal data. Results:, A total of 155 patients met study criteria (median age = 32 years, IQR = 24,40 years) with a total of 701 ED visits. Eighty-six interviews were conducted. Most patients (71.6%) had between one and three visits to the ED during the study period. However, after removing Site 3 from the analysis because of the short data enrollment period (3.5 months), which influenced the mean number of visits for the entire cohort, 52% of patients had between one and three ED visits over 10 months, 21% had four to nine visits, and 27% had between 10 and 67 visits. Fifty-nine percent of patients were discharged home. The median time to initial analgesic for the cohort was 74 minutes (IQR = 48,135 minutes). Differences between choice of analgesic agent and route selected were evident between sites. For the cohort, 680 initial analgesic doses were given (morphine sulfate, 42%; hydromorphone, 46%; meperidine, 4%; morphine sulfate and ibuprofen or ketorolac, 7%) using the following routes: oral (2%), intravenous (67%), subcutaneous (3%), and intramuscular (28%). Patients reported a significantly lower targeted discharge pain score (mean ± SD = 4.19 ± 1.18) compared to the actual documented discharge pain score within 45 minutes of discharge (mean ± SD = 5.77 ± 2.45; mean difference = 1.58, 95% confidence interval = .723 to 2.44, n = 43). Conclusions:, While half of the patients had one to three ED visits during the study period, many patients had more frequent visits. Delays to receiving an initial analgesic were common, and post-ED interviews reveal that sickle cell pain patients are discharged from the ED with higher pain scores than what they perceive as desirable. ACADEMIC EMERGENCY MEDICINE 2010; 17:399,407 © 2010 by the Society for Academic Emergency Medicine [source]

HAEdb: A novel interactive, locus-specific mutation database for the C1 inhibitor gene,

HUMAN MUTATION, Issue 1 2005
Lajos Kalmár
Abstract Hereditary angioneurotic edema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous and submucosal edema and is caused by the deficiency of the activated C1 esterase inhibitor protein (C1-INH or C1INH; approved gene symbol SERPING1). Published C1-INH mutations are represented in large universal databases (e.g., OMIM, HGMD), but these databases update their data rather infrequently, they are not interactive, and they do not allow searches according to different criteria. The HAEdb, a C1-INH gene mutation database (http://hae.biomembrane.hu) was created to contribute to the following expectations: 1) help the comprehensive collection of information on genetic alterations of the C1-INH gene; 2) create a database in which data can be searched and compared according to several flexible criteria; and 3) provide additional help in new mutation identification. The website uses MySQL, an open-source, multithreaded, relational database management system. The user-friendly graphical interface was written in the PHP web programming language. The website consists of two main parts, the freely browsable search function, and the password-protected data deposition function. Mutations of the C1-INH gene are divided in two parts: gross mutations involving DNA fragments >1 kb, and micro mutations encompassing all non-gross mutations. Several attributes (e.g., affected exon, molecular consequence, family history) are collected for each mutation in a standardized form. This database may facilitate future comprehensive analyses of C1-INH mutations and also provide regular help for molecular diagnostic testing of HAE patients in different centers. Hum Mutat 25:1,5, 2005. © 2004 Wiley-Liss, Inc. [source]

Body protein does not vary despite seasonal changes in fat in the White Stork Ciconia ciconia

IBIS, Issue 1 2002
Delphine Michard-Picamelot
To understand how a large soaring bird, the White Stork Ciconia ciconia, copes with energy constraints, we compared changes in body mass in 14 captive adult storks with the body composition of 12 free-ranging adult storks found dead from accidents. The captive storks, already in an enclosure for several years, were fed ad libitum. They were weighed daily for 1.5,3.5 years using an automatic device. The bodies of the accidentally killed storks were analysed to determine total water, lipid, protein and ash contents, and to assess the biochemical composition of certain organs. Females were on average 20% lighter and 24% smaller than males, but the body mass of the sexes varied in parallel throughout the year. Body mass peaked in December and January (25,30% above minimal body mass), due essentially to large fat stores in subcutaneous and abdominal adipose tissues. Body mass and body lipid rapidly decreased from February to June, whether the storks reared chicks successfully or not, and remained minimal for a few days into July. In contrast to birds using flapping flight, no variation in body protein or pectoral muscle protein was observed while breeding, even though the moult occurred then, nor in August, before the time when wild storks migrate. An endogenous regulation of body fuels is discussed. [source]

Induction of an antitumour adaptive immune response elicited by tumour cells expressing de novo B7-1 mainly depends on the anatomical site of their delivery: the dose applied regulates the expansion of the response

IMMUNOLOGY, Issue 4 2003
Silvia Sartoris
Summary De novo expression of costimulatory molecules in tumours generally increases their immunogenicity, but does not always induce a protective response against the parental tumour. This issue was addressed in the mouse Sp6 hybridoma model, comparing different immunization routes (subcutaneous, intraperitoneal and intravenous) and doses (0·5 × 106 and 5 × 106 cells) of Sp6 cells expressing de novo B7-1 (Sp6/B7). The results can be summarized as follows. First, de novo expression of B7-1 rendered Sp6 immunogenic, as it significantly reduced the tumour incidence to ,15% with all delivery routes and doses tested, whereas wild-type Sp6 was invariably tumorigenic (100% tumour incidence). Second, long-lasting protection against wild-type Sp6 was mainly achieved when immunization with Sp6/B7 was subcutaneous: a dose of 0·5 × 106 Sp6/B7 cells elicited protection that was confined to sites in the same anatomical quarter as the immunizing injection. Repeated injections of the same dose extended protection against wild-type Sp6 to other anatomical districts, as well as a single injection of a 10-fold higher dose (5 × 106 cells). Finally, Sp6-specific cytotoxic T-lymphocyte activity was detected in draining lymph nodes, and the splenic expansion of Sp6-specific cytotoxic T-lymphocyte precursors quantitatively correlated with the dose of antigen. We conclude that activation of a protective immune response against Sp6 depends on the local environment where the immunogenic form of the ,whole tumour cell antigen' is delivered. The antigen dose regulates the anatomical extent of the protective response. [source]

The use of histone deacetylase inhibitor FK228 and DNA hypomethylation agent 5-azacytidine in human bladder cancer therapy

INTERNATIONAL JOURNAL OF CANCER, Issue 8 2007
Jose A. Karam
Abstract The long-term disease-free survival in patients with metastatic transitional cell carcinoma (TCC) is still considerably low. Novel chemotherapeutic agents are needed to decrease the morbidity and mortality of TCC. In this study, we have evaluated several epigenetic modifiers for their therapeutic application in bladder cancer. Both histone deacetylase inhibitors (FK228, TSA) and DNA hypomethylating agent (5-Azacytidine) were tested using in vitro assays such as cell viability, cell cycle analysis and western blot to determine their mechanisms of action. Drug combination experiments were also designed to study any additive or synergistic effects of these agents. In addition, two bladder cancer xenograft models (one subcutaneous and one orthotopic) were employed to assess the therapeutic efficacy of these agents in vivo. Three agents exhibited various growth inhibitory effects on 5 different TCC cell lines in a dose- and time-dependent manner. In addition to G2/M cell cycle arrest, FK228 is more potent in inducting apoptosis than the two other single agents, and combination of both FK228 and 5-Aza further enhances this effect. p21 induction is closely associated with FK228 or TSA but not 5-Aza, which is mediated via p53-independent pathway. Consistent with in vitro results, FK228 exhibited a significant in vivo growth inhibition of TCC tumor in both subcutaneous and orthotopic xenograft models. FK228 is a potent chemotherapeutic agent for TCC in vivo with minimal undesirable side effects. The elevated p21 level mediated via p53 independent pathway is a hallmark of FK228 mechanism of action. © 2007 Wiley-Liss, Inc. [source]

Subcutaneous lispro and intravenous regular insulin treatments are equally effective and safe for the treatment of mild and moderate diabetic ketoacidosis in adult patients

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 4 2006
H. Ö. Ersöz
Summary In this prospective, randomised, open trial, we wanted to evaluate the efficacy and safety of hourly subcutaneous (SC) insulin lispro administration in the treatment of diabetic ketoacidosis (DKA) in comparison with intravenous (IV) regular insulin treatment. Twenty patients were enroled in the study. The patients were randomly assigned into two groups. Following a bolus injection of 0.15 U/kg IV regular insulin, group L received half of this dose as hourly SC insulin lispro while group R was treated conventionally with IV regular insulin infusion. At the end of treatment period, time that needed for normalisation of serum glucose, ,-hydroxybutyrate, blood pH and urine ketone levels were not different in groups L and R. There was no mortality or serious side effects in both groups. In this study, we revealed that treatment of mild and moderate DKA with SC insulin lispro is equally effective and safe in comparison with IV regular insulin. [source]

Cutaneous sclerosing perineurioma of the digit

INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 9 2006
Toshitsugu Nakamura MD
An 11-year-old Japanese girl noticed a small nodule, with mild tenderness, on the right index finger 5 years before visiting our outpatient clinic. She had no familial history of neurofibromatosis or past history of traumatic injury at the site of the tumor. Physical examination revealed a slightly elevated, subcutaneous, nodular tumor in the volar aspect between the proximal and distal interphalangeal joints of the digit (Fig. 1A). By magnetic resonance imaging examination, the tumor showed low density on both T1- and T2-weighted images, and was located just adjacent to the tendon with no invasive signs. The tumor was extirpated; at operation, it was well circumscribed and mobile without adhesion to adjacent tendon or nerve, and was easily removed. Figure 1. (a) Slightly elevated subcutaneous tumor (arrow) on the volar aspect of the right index finger. (b) gross appearance of the extirpated tumor, showing a well-circumscribed, whitish solid nodule Grossly, the tumor was a well-circumscribed, firm nodule (10 mm × 8 mm × 5 mm in size) (Fig. 1B). The cut surface was whitish, homogeneous, and solid without cystic lesions. Histologically, it was an unencapsulated, paucicellular dense, fibrous nodule with a concentric circular arrangement of collagen bundles (Fig. 2A). Amongst the fibrous bundles, a small number of ovoid/epithelioid or plump spindle cells were arranged in a corded, trabecular, or whorled (onion bulb-like) pattern (Fig. 2B); a storiform pattern was not noted. These cells were relatively uniform and had a somewhat elongated, slightly hyperchromatic nucleus with fine granular chromatin. Neither nuclear pleomorphism nor multinucleated cells were evident, and necrosis and mitotic figures were not observed. Periodic acid,Schiff (PAS) stain after diastase digestion highlighted the corded or whorled pattern of the tumor cells by encasing them. For immunohistochemical examination, formalin-fixed, paraffin-embedded serial tissue sections were stained by a labeled streptavidin,biotin method. The tumor cells were positive for vimentin and epithelial membrane antigen (EMA) (Fig. 3A), and negative for pan-cytokeratin, carcinoembryonic antigen (CEA), CD34, ,-smooth muscle actin, desmin, and CD68. Type IV collagen and laminin (Fig. 3B) were detected along the cords or whorls of the tumor cells, similar to the staining pattern of the diastase-PAS reaction. Schwann cells and axonal components, immunoreactive for S100 protein and neurofilament, respectively, were focally detected just adjacent to the cords or whorls, although the tumor cells per se did not express these proteins. Consequently, the tumor was found to be perineurial in origin and was diagnosed as cutaneous sclerosing perineurioma. Figure 2. (a) Low-power view of the tumor, showing an unencapsulated, paucicellular, dense, fibrous nodule with a concentric circular arrangement of collagen bundles (hematoxylin and eosin stain: original magnification, ×15). (b) Higher magnification of the tumor, showing ovoid or epithelioid cells arranged in cords or whorls in the abundant collagen bundles (hematoxylin and eosin stain: original magnification, ×150) Figure 3. Immunohistochemical profiles of the tumor. The tumor cells are positive for epithelial membrane antigen (a) and are surrounded by laminin (b) (original magnification, ×150) [source]

Microcystic adnexal carcinoma: report of four cases treated with Mohs' micrographic surgical technique

INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 6 2005
Amor Khachemoune MD
Background, Microcystic adnexal carcinoma (MAC) is a rare and aggressive malignant tumor of the sweat glands. Clinically, it often presents as a firm subcutaneous nodule on the head and neck regions. On histology, MAC exhibits both pilar and sweat duct differentiation with a stroma of dense collagen. It often extends beyond the clinical margins with local spreading in the dermal, subcutaneous, and perineural tissue planes. It has a high local recurrence rate after standard excision. Recent preliminary reports have indicated more favorable cure rates with Mohs' micrographic surgery (MMS). Objective, To present our data on four cases of MAC treated by MMS. We also compared our findings with more recently reported series in the English language literature. Methods, We reviewed the medical records of four patients (two males and two females) with MAC treated by MMS over the last 3 years. We also obtained follow-up data. Results, In all four patients with MAC treated by MMS, there were no recurrences, with a mean follow-up of 1 year. Conclusion, We report an additional four MAC cases treated by MMS. The accumulated data continue to confirm that, if the diagnosis of MAC is made early, and if the anatomic location is accessible to excision by MMS, a favorable outcome can be expected. [source]