bluuebunny/crossref_metadata_2025 huggingface dataset:
Pseudoporphyria and Nonsteroidal Antiinflammatory Agents in Children with Juvenile Idiopathic Arthritis
Authors: De Silva Bernadette , Banney Leith , Uttley William , Luqmani Raashid , Schofield Olivia
Published: March 2003

Abstract: Pseudoporphyria is characterized by erythema, blistering, and scarring on sun‐exposed skin. Nonsteroidal antiinflammatory drugs (NSAIDs) are implicated in the etiology of this condition. In a 1‐year prospective study of children attending the pediatric rheumatology clinic in Edinburgh we found a prevalence of pseudoporphyria of 10.9% in children taking NSAIDs for juvenile idiopathic arthritis. Naproxen was the most commonly implicated NSAID, independent of dosage. Blue/gray eye color was an independent risk factor for the development of pseudoporphyria. We would advise caution in prescribing naproxen in these children to prevent disfiguring facial scarring.
Granular Parakeratosis in a Child
Authors: Trowers Andrea B. , Assaf Rich , Jaworsky Christine
Published: March 2003

Granular parakeratosis has only recently been described and typically occurs in adults. We report the first instance of this condition affecting a child.
Hypomelanosis of Ito with Sturge–Weber Syndrome‐like Leptomeningeal Angiomatosis
Authors: García Muret María Pilar , Puig Lluís , Allard Christophe , Alomar Augustín
Published: March 2003

Abstract: The term hypomelanosis of Ito (HI) is applied to individuals with skin hypopigmentation following the lines of Blaschko (type 1a of patterns indicative of somatic mosaicism as defined by Happle). Even though originally described as a purely cutaneous disease, subsequent reports of HI have included a 30–94% association with multiple extracutaneous manifestations. The frequency of extracutaneous associations has led many authors to consider HI to be neurocutaneous disorder. We report a male infant with cutaneous hypomelanosis along the lines of Blaschko distributed on the left half of the body who developed status epilepticus. Neuroimaging studies disclosed an angiomatous enlargement of the right choroid plexus and a gyral pattern of cortical and subcortical calcification in the right occipital region. Thus a diagnosis could be made of HI and associated Sturge–Weber syndrome‐like leptomeningeal angiomatosis. This previously unreported association lends further support to the consideration of hypomelanosis of Ito as a marker of somatic mosaicism with frequently associated neurologic abnormalities. A relationship between HI and Sturge–Weber syndrome, two neuroectodermal disorders with a genetic mosaicism basis, might be possible due to nonallelic twin‐spotting which in the embryologic period would define an abnormal development of neural, vascular, and cutaneous structures.
A Case of Factor VIII Inhibitor‐Positive Acquired Hemophilia Treated by Plasmapheresis
Authors: Narukawa Nobuhiko , Abe Takaya , Shouno Mineo , Kitabata Yukiko , Okamoto Masanori , Kobata Hirotugu , Akizawa Tadao
Published: March 2003

Abstract: We report on a case of factor VIII inhibitor‐positive acquired hemophilia in which combined therapy of plasma exchange (PE) and steroids was effective. The patient, a 68‐year‐old man, had undergone hemodialysis since April 1998, due to chronic renal failure caused by diabetic nephropathy. The hemostasis of blood access sites gradually became difficult after the initiation of dialysis and the prolongation of activated partial thromboplastin time (APTT) (74.5 s), and a decrease in factor VIII (0.02%) and an abnormally high concentration of factor VIII inhibitor (111 U/ml) were found. Under the diagnosis of factor VIII inhibitor‐positive acquired hemophilia, 3 consecutive PE were performed, followed by a large dose administration of gamma globulin. However, the effect of this therapy disappeared within 20 days. Then the PE therapy was performed again accompanied by pulse methylprednisolone therapy. After that, factor VIII inhibitor was suppressed and the patient's hemostatic defect continued to improve even after the reduction of the steroid dose. These results suggest that PE is very effective in treating factor VIII inhibitor‐positive acquired hemophilia.
Direct Adsorption of Lipoproteins from Whole Blood by DALI Apheresis: Technique and Effects
Authors: Bosch Thomas
Published: March 2003

Abstract:Low‐density lipoprotein (LDL) apheresis can drastically reduce atherogenic lipoproteins in coronary patients in whom LDL and lipoprotein (a) (Lp[a]) cannot be sufficiently reduced by conservative therapy. LDL and Lp(a) adsorption by polyacrylate/polyacrylamide (DALI) is the simplest procedure for clinical LDL apheresis to date. DALI was first applied in patients in 1994 and introduced into clinical routine in 1996. It is the first LDL‐hemoperfusion system, i.e., it adsorbs LDL and Lp(a) directly from whole blood. This markedly simplifies the extracorporeal circuit, the handling of the system, and reduces significantly staff time and, especially at higher blood flow rates, treatment time. Its features are high selectivity and capacity of lipoprotein removal (maximum about 8 g low‐density lipoprotein cholesterol per session). Using citrate anticoagulation, good biocompatibility is evidenced by the lack of cell losses, hemolysis, thrombotic events, and complement activation. Some clotting factors of the intrinsic system are also adsorbed. There is significant bradykinin activation that, however, does not cause problems in most patients if angiotensin converting enzyme inhibitor medication is avoided. In a first long‐term study, 93% of sessions were uneventful. Major side effects were citrate‐induced paresthesias (1.3%) and hypotension (0.8%). To date, more than 25,000 DALI sessions have been performed all over the world.
Improvement of Multiple Organ Functions in Hepatorenal Syndrome During Albumin Dialysis with the Molecular Adsorbent Recirculating System
Authors: Mitzner Steffen R. , Klammt Sebastian , Peszynski Piotr , Hickstein Heiko , Korten Gero , Stange Jan , Schmidt Reinhard
Published: March 2003

Abstract: Recently, significant improvement of renal function and prolongation of survival were reported in hepatorenal syndrome (HRS) patients treated with the Molecular Adsorbent Recirculating System (MARS). As no impact on extrarenal organ function was documented, this trial looked into multiple organ function changes during MARS in HRS patients. Eight HRS patients (4 male, mean age 42. 1 years, range 30–58, all United Network for Organ Sharing [UNOS] status 2A) were treated intermittendly 4–14 times (total 47, mean 5.9 ± 3.4) between 4 and 8 h/single treatment. The following changes were observed pre‐ and posttreatment: bilirubin 466 ± 146 to 284 ± 134 γmol/L, creatinine 380 ± 182 to 163 ± 119 μmol/L, urea 26.4 ± 10.3 to 12.9 ± 4.9 mmol/L, plasma sodium 127.5 ± 7.7 to 137.5 ± 4.8 mmol/L (all p < 0.01). Mean arterial pressure (MAP) increased from 71.9 ± 12.8 to 95.6 ± 7.8 Torr (p < 0.001). Oliguria or anuria, present in all patients, was successfully reverted. Ascites, present in all patients, was not detectable after the treatment period. The hepatic encephalopathy grade decreased from 2.8 ± 0.8 to 0.8 ± 0.7 (p < 0.0001). Child‐Index decreased from 13.25 ± 1.3 to 9.4 ± 1.8 (p < 0.001). The hospital survival rate was 62%. One man underwent successful liver transplantation 18 months after the treatment. We conclude that MARS can improve multiple organ functions in patients with HRS.
Plasmapheresis in Thrombotic Microangiopathy‐Associated Syndromes: Review of Outcome Data Derived from Clinical Trials and Open Studies
Authors: Von Baeyer Hans
Published: March 2003

Abstract: Current reimbursement policy of health insurance for therapeutic plasmapheresis requires proof of efficacy using the concept of evidence‐based medicine. The aim of this paper is to review the outcome of plasmapheresis used to treat thrombotic microangiopathy (TMA)‐associated syndromes in the last decade to provide scientific evidence to back up reimbursement applications. The strength of evidence of each reviewed study was assessed using the five levels of evidence criteria as defined by the American Society of Hematology in 1996 for assessment of the treatment of immune thrombocytopenia. The level Experimental indication was added for situations where only case reports or small series supported by pathophysiological reasoning are available. The definitions of evidence used in this paper are as follows: Level I, randomized clinical trial with low rates of error (p < 0.01); Level II, randomized clinical trial with high rates of error (p < 0.05); Level III, nonrandomized studies with concurrent control group; Level IV, nonrandomized studies with historical control group; Level V, case series without a control group or expert opinion; and Experimental, case reports and pathophysiological reasoning. The results of this analysis based on the published data is summarized as follows: The indication of plasmapheresis is assigned to Level IV evidence for thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS); cancer/chemotherapy‐associated TTP/HUS is assigned to Level V evidence; and TTP/HUS refractory to standard plasma exchange and post‐bone marrow transplantation TTP/HUS are assigned to Experimental indication. For both subsets, protein A immunoadsorption is reportedly successful. The other TMA‐associated syndromes, hemolysis elevated liver enzymes low platelets and HUS in early childhood, are no indication of plasmapheresis. Two randomized clinical trials were performed in order to demonstrate the superiority of plasma exchange/fresh frozen plasma (PEX/FFP) over plasma transfusion in the management of TTP/HUS. The results prove the greater clinical success of the latter type of plasma administration. Standard PEX/FFP has reduced the mortality of TTP/HUS from 94.5% to 13%.
Endotoxin and Cytokine Removal in Sepsis
Authors: Tetta Ciro , Bellomo Rinaldo , Inguaggiato Paola , Wratten Mary Lou , Ronco Claudio
Published: March 2003

Abstract: Sespis, the leading cause of mortality in intensive care units, is a complex series of interrelated effects caused by the overproduction of multiple mediators and their unrestrained biological activity. Both proinflammatory and antiinflammatory mediators participate in the high complexity of sepsis and explain the failure of specific therapies to improve survival. Continuous extracorporeal therapies have been proposed as therapeutic options and as tools for blood purification in sepsis. Along these lines and in order to achieve higher clearances and mass removal rates, we studied the effects of plasmafiltration coupled with adsorption and provided in vitro and in vivo evidence that adsoprtion of multiple cytokines, activated complement components, and lipid mediators such as the platelet‐activating factor occurs. We also showed that such treatment may lead to improved survival in a rabbit model of sepsis and to improved hemodynamics, reduced norepinephrine dose, and restoration of near‐to‐normal responsiveness of blood leukocytes to endotoxin in humans. It is anticipated that treatment of plasma, as a modular device to conventional hemofiltration, may pave the way to innovative approaches in the extracorporeal treatment of septic patients.
Membranes for Therapeutic Apheresis
Authors: Nakaji Shuhei , Yamamoto Tsuneatsu
Published: March 2003

Abstract: Kuraray has developed many kinds of apheresis devices, such as plasma separators, plasma fractionators, and apheresis monitors. In this article, apheresis membranes, especially double filtration plasmapheresis (DFPP) and plasma fractionators used in DFPP are introduced. DFPP is both clinically and cost effective apheresis therapy, and it has been used widely for the treatment of many kinds of diseases. Several types of plasma separators with various pore sizes are available. It is important to select the proper plasma separator with suitable pore size, determined by the size of the pathogenic substances to be removed. The Evaflux 5A ethylene‐vinyl alcohol copolymer plasma fractionator efficiently separates low‐density lipoprotein from high‐density lipoprotein. DFPP with the Evaflux 5A is effective for the treatment of familiar hyperlipidemia.
Extracorporeal Photochemotherapy for the Treatment of Graft‐Versus‐Host Disease
Authors: Dall'Amico R. , Messina C.
Published: March 2003

Abstract: Photopheresis (extracorporeal photochemotherapy, ECP) is a new type of photochemotherapy used for the treatment of oncological and autoimmune diseases. Additionally, recent reports indicate that this therapy is promising in both pediatric and adult patients who develop graft versus host disease (GVHD) resistant to conventional protocols after bone marrow transplantation (BMT). In this paper, we review 31 studies where ECP was used in the treatment of acute and chronic GVHD. A total of 76 (32% female) acute GVHD patients have been considered in 11 series. Fifty‐nine patients presented with skin involvement; 47 had liver involvement, and 28 had gastrointestinal manifestations. Treatment duration ranged from 1 to 24 months. A regression of skin manifestations was observed in 83% of the patients with a complete response in 67%. A complete regression of liver and gut manifestations was reported in 38% and 54% of the patients, respectively. The overall patient survival was 53%. Of the 43 patients alive, 8 developed chronic GVHD manifestations. The immunosuppressive therapy was discontinued in 28% of cases and reduced in 46%. A total of 204 (45% female) chronic GVHD patients treated with ECP 1 to 110 months from transplantation have been considered in 20 series. One hundred twenty‐eight patients presented with skin involvement, 84 with liver, 31 with lung, and 59 with oral manifestations. Treatment duration ranged from 3 to 40 months. A regression of skin manifestations was observed in 76% of patients with a complete response in 38%. An improvement of liver and lung involvement was reported in 48% and 39% of the patients, respectively. Of the 59 patients with oral manifestations, an improvement was obtained in 63% of cases. The overall patient survival was 79%. ECP is a nonaggressive treatment that may benefit patients with both acute and chronic GVHD who do not respond to standard immunosuppressive therapy.
Termite‐ and Mulch‐Mediated Rehabilitation of Vegetation on Crusted Soil in West Africa
Authors: Mando A. , Brussaard L. , Stroosnijder L.
Published: March 2003

The rehabilitation of vegetation on structurally crusted soils by triggering termite activity through mulch was studied on three soil types in northern Burkina Faso, West Africa. A split‐plot design was used in a fenced environment for the experiment. Insecticide (Dieldrin) was used at a rate of 500 g a.i. (active ingredient)/ha to create nontermite and termite plots. Three mulch types consisting of straw (Pennisetum pedicellatum), woody material (Pterocarpus lucens), and a composite mulch (straw and woody material) applied at a rate of 3, 6, and 4 tons/ha, respectively, were used to trigger termite activity. The grasses and woody species on the plots were surveyed. Nontermite plots responded weakly to mulch treatments, but even in the first year vegetation established on termite + mulch plots. Termite activity resulted in the increase of plant cover, plant species number, phytomass production, and rainfall use efficiency. Infiltrated water use efficiency and plant diversity were not statistically different among treatments during the first 2 years but were in the third. Woody species established only on termite plots. The three types of mulch plots showed greater vegetation development than bare plots, which remained bare throughout the experiment. Analysis of the termite and mulch interaction indicated that mulch plots without termites did not perform better than bare plots, especially in the case of woody plant regeneration. Vegetation rehabilitation was best with composite and straw mulches with termites, followed by woody mulch with termites; it was worst on bare plots.
Effects of Established Perennial Grasses on Introduction of Native Forbs in California
Authors: Brown Cynthia S. , Bugg Robert L.
Published: March 2003

Prairie restoration is not complete without the establishment of both grasses and forbs. However, if desirable forbs and grasses are seeded simultaneously, control of broadleaf weeds is problematic. If possible, a two‐step process of introducing forbs after establishing grasses would allow use of broadleaf‐specific herbicides at the critical early stages of grass growth. We conducted experiments to investigate methods for introducing forbs into previously restored native perennial grasslands on rural roadsides in the Sacramento Valley of California. In one experiment, we studied the effects of background vegetation (established perennial grasses or tilled ground) on seven native forb species planted from seed. In a second experiment, we evaluated the effects of background vegetation (existing perennial grasses or tilled ground) and container size (36 ml or 105 ml) with excavation technique (excavation by core removal [core] or by creating an impression [dibble]) on the growth of transplants of the native perennial forbs Asclepias fascicularis and Sisyrinchium bellum. The presence of established perennial grasses reduced the growth of seeded forbs, but did not affect transplants, indicating the vulnerability of seedling forbs to interference. When compared to control plots that had been tilled in the autumn, weed canopy cover was significantly lower in the presence of perennial grasses if seeded with forbs, but not in the presence of perennial grasses alone. Both transplanted species grew better in the large container/core treatment than the small container/dibble treatment; however, existing grasses eliminated these positive effects. Asclepias fascicularis performed better when grown in large containers than in small containers, but its growth was not affected by excavation method; S. bellum performed better when planted with the core method than the dibble method of excavation, but container size made no difference. We attribute differences in the responses of the species to interactions between phenological differences and expansive clay soils that naturally de‐compact upon drying.
Influence of Nutrient Availability on the Interaction Between Spotted Knapweed and Bluebunch Wheatgrass
Authors: Herron Gretchen J. , Sheley Roger L. , Maxwell Bruce D. , Jacobsen Jeffrey S.
Published: March 2003

Centaurea maculosa (Lam.) (spotted knapweed) reduces wildlife and livestock habitat biodiversity and increases erosion. Nutrient availability to plants may be used to accelerate succession away from spotted knapweed. Early‐successional plant communities often have high nutrient availability, whereas late‐successional communities are often found on lower nutrient soils. We hypothesized that removal of nutrients would change the competitive advantage from spotted knapweed to Pseudoroegneria spicatum (bluebunch wheatgrass) (late seral). In two addition series matrices, background densities of Secale cereale (annual rye) and Elymus elimoides (bottlebrush squirreltail) (3,000 seeds/m2) were used to remove nutrients from the soil. In another set of addition series matrices, nitrogen (33 kg/ha) or phosphorus (33 kg/ha) were added to the soil. Nutrient analysis of soil and vegetation indicated that annual rye and bottlebrush squirreltail reduced nutrient availability in soils. In another matrix, neither a background density nor nutrients were added. Data were fit into Watkinson's curvilinear model to determine the competitive relationship between bluebunch wheatgrass and spotted knapweed. This allowed comparison of the equivalence ratios (C) generated from each addition series. The C parameters are the per‐plant equivalent of bluebunch wheatgrass or spotted knapweed and can be interpreted as the ratio of intra‐to‐interspecific competition. The C parameters are also the equivalence ratio of the number of spotted knapweed it takes to have equivalent effect on bluebunch wheatgrass or the number of bluebunch wheatgrass having the equivalent effect on spotted knapweed. Without nutrient manipulation, spotted knapweed was more competitive than bluebunch wheatgrass. The C for bluebunch wheatgrass was 0.17, indicating that 0.17 knapweed plants were competitively equivalent to one wheatgrass. Annual rye changed the competitive balance in favor of bluebunch wheatgrass (C = 9.9). Addition of nitrogen, phosphorus, or the mid‐seral species did not change the competitive relationship between the two species. This preliminary study suggests that succession from spotted knapweed to late‐seral bluebunch wheatgrass community may be accelerated by altering resource availability.
Aristida beyrichiana (Wiregrass) Establishment and Recruitment: Implications for Restoration
Authors: Mulligan Maureen K. , Kirkman L. Katherine , Mitchell R. J.
Published: March 2003

Restoration of the longleaf pine ecosystems of the southeastern United States has focused interest on the regeneration and establishment of Aristida sp. (wiregrass) as a means to reestablish ecological function and structure of the ecosystem. This study examined dispersal distance from planted adults and canopy cover and density effects on establishment and reproduction. In 1994 wiregrass plugs were planted in two densities (500 seedlings/100 m2 and 49 seedlings/100 m2) and three canopy‐thinning treatments (25 m2 basal area/ha, 16 m2 basal area/ha, and 8 m2 basal area/ha) were implemented in a 20‐year‐old longleaf plantation in southwestern Georgia. Due to the intense site preparation and the density of pines planted, virtually no understory vegetation was present. The site was burned in June 1995, which promoted seed production of the planted wiregrass. Results indicate that the 8 m2 basal area/ha treatment results in larger plants that in turn produce a greater number of seedling recruits. No seedling recruitment occurred in control plots. Dispersal distances of up to 594 cm were recorded. Natural seedling recruitment occurred at low‐density transplanting (5 plants/10 m2), denoting that high‐density planting similar to natural density (5 plants/m2) is not required for successful establishment or reproduction. However, overstory thinning in dense pine plantations is required for reproduction and increases the survival of individual plants due to changes in the environmental conditions at the forest floor.
Coral Transplantation: Regeneration and Growth of Acropora Fragments in a Nursery
Authors: Soong Keryea , Chen Tai‐an
Published: March 2003

Abstract Coral reef degradation has been widely reported for the past 20 years. Because the recovery rate is usually low, various methods of restoration have been explored in different regions of the world. Among the effective and commonly used methods to restore coral communities is the transplantation of coral colonies or fragments. In this investigation fragments of Acropora pulchra were used in a semiprotected nursery in southern Taiwan between 1996 and 1998 to test, in situ, the possible effects of different factors on the generation of new branches and the initial skeletal extension rates of transplants. The variables under study here were the origin and length of the fragments, their new orientation, presence of tissue injury, and position in the fragment. All these factors were found to make a difference in either one or both aspects of coral growth (i.e., branching frequency and skeletal extension rate). These two factors clearly determine the success rate of a small fragment developing into a large colony that has a much higher probability to survive and grow on its own. It is now obvious that the efficiency of coral generation through fragment culture can be enhanced if the variables examined here are taken into consideration. Once coral colonies are formed, they can be fragmented again to generate more corals or can be transplanted to a suitable site.
Detection of host and donor cells in sex‐mismatched rat nerve allografts using RT‐PCR for a Y chromosome (H‐Y) marker
Authors: Midha Rajiv , Ramakrishna Vankayalapati , Munro Catherine A. , Matsuyama Takeshi , Gorczynski Reginald M.
Published: March 2003

Abstract  The donor and host source of support cells, such as Schwann cells, in nerve allograft segments have been the subject of debate. The objective of the present study was to assess the utility of a molecular technique that probes for a Y chromosome expressed gene (H‐Y) in distinguishing host from donor tissue in sex‐mismatched nerve allograft segments. Forty‐two Lewis rats received bilateral syngeneic Lewis or allogeneic ACI rat peroneal nerve grafts, with or without cyclosporin A (CsA) treatment. At different times thereafter animals were sacrificed and samples were harvested. We transplanted males and females reciprocally, to study both survival of donor cells (persisting H‐Y mRNA in male grafts by transcription polymerase chain reaction (RT‐PCR), and graft infiltration by host cells (detectable H‐Y mRNA in female grafts). A kinetic analysis revealed a progressive loss of viable donor cells (loss of H‐Y mRNA signal) from allografts, beginning 2–3 weeks, and culminating at 4 weeks, with little detectable H‐Y in the absence of CsA treatment. CsA treatment led to prolonged survival of allograft cells, confirmed by detectable H‐Y mRNA. By studying female grafts in male rats we could confirm that loss of viable donor tissue in allografts was accompanied by infiltration of host (H‐Y mRNA positive) cells, whereas no H‐Y mRNA signal was seen in males receiving autografts from females or in immunosuppressed allograft segments. These data suggest that reverse RT‐PCR analysis for a Y chromosome gene product can be a valuable tool to assess the origin of viable cells in sex‐mismatched nerve allotransplantation tissue.
Autonomic Neuropathy In Sorbitol Dehydrogenase Inhibitor (Sdi)‐Treated Streptozotocin‐Diabetic Rats
Authors: Schmidt Re
Published: March 2003

We have developed an animal model of diabetic autonomic neuropathy characterized by neuroaxonal dystrophy (NAD) involving ileal mesenteric nerves and prevertebral sympathetic superior mesenteric ganglia (SMG) in chronic streptozotocin‐diabetic rats. We have examined the effect of SDI‐158, which interrupts the conversion of sorbitol to fructose (and reactions dependent on the second step of the polyol pathway), on NAD in control and diabetic rats. SDI‐treatment (SDI‐Rx) did not produce NAD in control animals despite the fact that sciatic nerve sorbitol levels reached the same levels as untreated diabetic animals. SDI‐Rx resulted in a dramatically increased frequency of NAD in ileal mesenteric nerves and SMG. SDI‐Rx diabetic rats developed lesions prematurely, after only one month of diabetes, and in greater numbers than untreated diabetics. SDI‐Rx for 1,2,3 and 6 months showed a statistically significant but progressively smaller effect on NAD. The ultrastructural appearance of SDI‐Rx ganglia and mesenteric nerves were identical to that previously reported in long‐term untreated diabetics; however, short term SDI‐Rx resulted in less compacted tubulovesicular elements in the SMG. Three month SDI‐Rx superior cervical ganglia failed to develop NAD in the same animals in which large numbers of lesions were found in the SMG. Dystrophic axons involved ileal mesenteric nerves while sparing those to the jejunum. Dystrophic tyrosine hydroxylase immunoreactive sympathetic axons were distributed to myenteric and submucosal ganglia within the gut wall but not to the mesenteric vasculature. Therefore, although SDI‐Rx diabetic rats show an exaggerated severity and accelerated time course of NAD compared to untreated diabetics, lesion appearance, immunoreactivity and distribution are comparable to those found in untreated STZ‐diabetic rats of much longer durations.
Cardiovascular Risk Factors Predict The Development Of Diabetic Peripheral Neuropathy
Authors: Tesfaye S , Chaturvedi N , Eaton Sem , Ward Jd , Fuller J.
Published: March 2003

Hypertension has recently been shown to be an important determinant of diabetic retinopathy and nephropathy. The relationship between cardiovascular risk factors and the incidence of peripheral neuropathy (PN) was examined in type 1 diabetic subjects from 27 centres participating in the EURODIAB Prospective Complications Study. PN was assessed at baseline and follow‐up using a standardised protocol involving combinations of neuropathic symptoms, tendon reflexes, age related vibration perception thresholds and autonomic function tests. Serum lipids/lipoproteins, HbA1c and albumin excretion rate (AER) were measured in a central laboratory. Of 986 subjects with no PN at baseline (mean age 31 years; mean duration 13 years), 24.6% developed PN over the follow up period (average 7.3 years). The incidence of PN was significantly positively associated with age, duration of diabetes and HbA1c at baseline. After statistical adjustment for these three factors the following baseline variables were significantly predictive of the development of PN; BMI, AER, triglyceride (p < 0.001), cholesterol and systolic BP (p < 0.01). This prospective study shows that over a 7‐year period, about one quarter of type 1 diabetic patients will develop peripheral neuropathy; age, duration of diabetes and poor glycaemic control being major determinants. The development of PN is also associated with potentially modifiable cardiovascular risk factors such as serum lipids, BP, BMI and AER supporting risk reduction strategies in its prevention. Furthermore, these findings support the role of vascular factors in pathogenesis of PN.
Expression Of O‐Acetyl Sialic Acid On Cerebral Microcirculation In A Glycine Or Taurine Treated Diabetic Rat Model
Authors: Noe A , Pedro Z , Ricardo L , Edgar Z , Alejandra B , Guillermo C.
Published: March 2003

Expression of sialic acid is altered in Diabetes mellitus. This modification has also been involved with both vascular and neurologic diseases, and with the increase of no enzymatic glycosylation of proteins. In our opinion, the lectins were very useful with specificity for sialic acids in order to determine the level of sialic acid expression on cerebral microcirculation in a diabetic Wistar rat model with streptozotocin. In this model, the glycine (1%) and taurine (0.5%) aminoacids were placed in drinking‐water by six months. At the end of this time, the animals were sacrificed, their brains surgically removed and frozen in liquid nitrogen, and the specimens cut in serial sections. Immediately, the sections were incubated with different biotin‐labelled lectins specific to sialic acid using peroxidase‐labelled avidin as second ligand and H2O2 chromogen. The results showed greater O‐acetyl sialic acid expression in cerebral capillaries of untreated diabetic rats than in glycine‐, taurine‐treated diabetic rats or than in control animals. The minor sialic acid expression may be an indicator of degenerative diseases such as Alzheimer's or the vascular disease of diabetic patients and probably is related to cellular protective properties of the glycine and taurine aminoacids. These first protective characteristics that have been observed in both ischemia with cellular ATP depletion models, suggest the utilization of aminoacids glycine or taurine in diabetic patient in order to avoid the development of microinfarcts.
Effect Of Renal Denervation On Urinary TGF‐β1, Albuminuria And Renal Content Of Glut1 In Stz‐Induced Diabetic Rats
Authors: Schmid H , Schaan B , Bertolluci M , Lacchini S , Machado U , Irigoyen Mc
Published: March 2003

In long‐term Diabetes Mellitus (DM) the progression of nephropathy has been related to the occurrence of autonomic neuropathy and hypertension. The STZ‐diabetic rat was previously described by us as an animal model that develops albuminuria, as well as increased expression of cortical renal GLUT1 and of Transforming Growth Factor 1 (TGF1) and increased urinary excretion of TGF1. The aim of this study was to evaluate the effect of renal denervation (RD) upon urinary TGF‐β1 (UTGF‐β1) and cortical renal GLUT1 protein levels, relating these parameters to blood pressure (BP) levels and metabolic control. Streptozotocin injected rats (group D; n=13) and control animals (group C; n=13) were compared for their urinary albumin (UA), UTGF‐1, BP and for their renal cortical and medullar GLUT1 protein abundance 45 days after the beginning of hyperglycemia. The animals were submitted to surgical RD or sham procedure within 30 days of STZ injection, and evaluations were done 15 days after the surgery. The effects of RD were confirmed by intra‐renal decrease of norepinephrine levels. Results showed that RD determined no changes in UA or UTGF‐β1, in both D and C rats. Blood pressure levels were similar between D and C and did not change as an effect of denervation. These results are shown in the table.

In conclusion, in the STZ‐rat with albuminuria complicating diabetes, RD produces a normalization of previously elevated cortical GLUT1 protein and no effect upon UTGF ‐ β1 and UA, suggesting that these animals (with no hypertension) are protected from the deleterious effect of kidney denervation.
Alpha‐Lipoic Acid Effects And Combination Therapy With Gamma‐Linolenic Acid
Authors: Cameron Ne , Cotter Ma
Published: March 2003

Alpha‐lipoic acid (LPA) has marked effects in experimental diabetic neuropathy. Treatment for 2 weeks after 8 weeks of diabetes in rats corrected motor and sensory conduction velocity and endoneurial perfusion deficits with an ED50 of approximately 40 mg/kg. There was no difference in efficacy between R‐ and S‐enantiomers of LPA. When combined with the n‐6 essential fatty acid, gamma‐linolenic acid (GLA), either as a drug mixture or joint compound, there was a synergistic effect on neurovascular function, resulting in a 6‐fold increase in treatment efficacy. LPA has wide‐ranging actions on markers of endothelial damage, the coagulation system and lipids that are important risk factors for neuropathy and vascular disease in patients. Thus, 2 months of diabetes in rats caused 2.5‐ to 5.4‐fold elevations of von Willebrand factor, factor VII, triglycerides and LDL cholesterol, which were 41‐64% attenuated by 2 weeks of LPA treatment. Vascular effects are not restricted to endoneurial perfusion. Thus, the time taken for a fixed‐volume tail‐bleed was 4.2‐fold greater with diabetes and this was 79% attenuated by LPA treatment. Nitric oxide and endothelium‐derived hyperpolarizing factor dependent vasodilation were markedly reduced by diabetes in corpus cavernosum and mesenteric vasculature, LPA giving a high degree of protection. The function of small nerve fibres, exemplified by the nitrergic vasodilator innervation to corpus cavernosum, is greatly diminished by diabetes, high‐dose LPA having a protective effect. When LPA was combined with GLA, as for large fibres, there was a marked synergy for both the innervation and the endothelium of corpus cavernosum. Thus LPA alone, and particularly combined with GLA, has a broad spectrum of action highly relevant for the treatment of diabetic neuropathy and micro and macrovascular disease.
C‐Peptide Deficiency: An Important Pathogenetic Factor In Type 1 Diabetic Neuropathy
Authors: Sima Aaf , Sugimoto K , Murakawa Y , W‐X. Zhang
Published: March 2003

Background: C‐peptide has insulin‐like effects and ameliorates the acute nerve conduction defect (NCD) in experimental and human type 1 diabetic neuropathy (DN). Methods: In this study, diabetic BB/Wor‐rats were treated with rat C‐peptide (75 ng/kg) from onset of diabetes for 8 months (prevention‐group, PG). In a separate experiment, 5‐mo untreated diabetic BB/Wor‐rats were started on the same C‐peptide treatment continued to 8 mo of diabetes (intervention group, IG). Results: In the PG, the NCD was significantly decreased (p < 0.001) compared to untreated BB/Wor‐rats and was similar to that of normo‐C‐peptidemic and isohyperglycemic type 2 BBZ rats. This effect was associated with significant preventions of nodal changes (p < 0.001) including axo‐glial dysjunction (p < 0.001), which was not different from non‐diabetic control rats. Axonal atrophy and Wallerian degeneration were significantly prevented (both p < 0.05). In the IG, the NCD decreased significantly (p < 0.01) during the 3 mo treatment period. Associated with the functional improvement, nodal changes improved significantly (p < 0.001) as did axonal degenerative changes (p < 0.01). C‐peptide treatment in the IG resulted in a significant increase in the frequency of regenerating fibers (p < 0.001) compared with untreated 5 mo diabetic rats. Conclusion: These studies demonstrate that C‐peptide replacement in type 1 diabetes prevents the chronic NCD and structural changes. Furthermore, C‐peptide treatment significantly improves the already established functional and structural abnormalities of DN. This is the first demonstration of a therapeutic improvement of established neuropathy in experimental diabetes. We conclude that C‐peptide deficiency in type 1 diabetes is an important pathogenetic component of DN and that its replacement may provide a valuable adjunct to intensive insulin treatment.
Antioxidant Protection Mechanisms And Arachidonic Acid Synthesis Are Altered In Schwann Cells Grown In Elevated Glucose
Authors: Miinea C , Eichberg J.
Published: March 2003

Accumulating evidence points to oxidative stress as an important factor in the onset of diabetic neuropathy. We have investigated the status of antioxidant protection mechanisms in immortalized rat Schwann cells cultured in high (30 and 50 mM) concentrations of glucose. As compared to growth in 5 mM glucose, the cells contained 40% less reduced glutathione (n =8, p < 0.01). Total superoxide dismutase activity was diminished by more than 50% (n=3; p < 0.001), whereas catalase activity was unchanged. The cellular NADH/NAD+ ratio was progressively increased with increasing medium glucose concentrations. Our previous findings have established that upon exposure of cultured cells to elevated glucose, the proportions of arachidonic acid‐containing molecular species (ACMS) in phospholipids are decreased in a pattern similar to alterations exhibited by diabetic nerve. To examine whether biosynthesis of arachidonic acid might be perturbed, confluent cells maintained in either high or low glucose were incubated with either [14C]linoleic acid (18:2) or [14C]dihomo‐γ‐linolenic acid (20:3) and radioactivity incorporated into molecular species of major phospholipid classes was measured. The incorporation of 18:2 either as unchanged fatty acid or into ACMS did not differ as a function of glucose concentration. Negligible labeled 18:3 or 20:3 molecular species were detected. In contrast, the uptake of 20:3 into 18:1/20:4 and 16:0/20:4 phosphatidylcholine and 18:1/20:4 phosphatidylethanolamine, but not into 20:3‐containing molecular species, was significantly reduced in cells cultured in 30 mM glucose. These data imply that Δ5 desaturase activity is decreased in cells exposed to elevated glucose. This reduced enzyme activity could adversely affect polyunsaturated fatty acid metabolism and might arise as a consequence of impaired scavenging of reactive oxygen species. (Supported by NIH grant DK30577)
Assessing Quality Of Life In Diabetic Neuropathy: Condition‐Specific Or Generic Approach?
Authors: Vileikyte L , Boulton Ajm
Published: March 2003

Studies that assessed Quality of Life (QoL) in patients with diabetic peripheral neuropathy (DPN) used generic measures, focusing on extremes of DPN. This study compared the performance of the neuropathy‐specific QoL measure (NeuroQoL) with the generic SF36, in diabetic patients with varying severity of DPN. 120 DPN patients were included, mean age 61 years, diabetes duration 12 years. DPN severity was assessed by neuropathy disability score (NDS) and vibration perception threshold (VPT): symptom severity by neuropathy symptom score (NSS). All NeuroQoL domains showed significant differences (eg., social; interpersonal relationships p < 0.01) between patients subdivided into those with moderate/severe symptoms (NSS > =6) compared to those with mild (NSS < 6), in contrast to only 2 SF36 domains (mental health; bodily pain p < 0.05). Similarly, when patients were subdivided according to DPN severity (moderate/severe: VPT > =25 and NDS > =6; mild: VPT < 25; NDS < 6), NeuroQoL domains (eg., negative symptoms; sexual problems p < 0.05) demonstrated differences between the groups whereas virtually no differences were seen in SF36. Furthermore, NeuroQoL maintained its ability to differentiate between those with mild (VPT < 25); moderate (VPT:25 to 35) and severe (VPT > 35) DPN, whereas SF36's discriminatory power was lost. All significant differences remained after accounting for confounding variables. Thus, NeuroQoL detects more subtle differences between DPN patients and should therefore be more sensitive to change over time than the SF36.
Hyperalgesia Mediated By Spinal Prostaglandin E2 And Signalling Through The P38 Pathway In Diabetic Rats
Authors: Calcutt Na , Freshwater J , Campana Wm
Published: March 2003

Diabetic rats exhibit hyperalgesia following paw formalin injection, despite reduced spinal release of the excitatory neurotransmitters substance P and glutamate. In normal rats, spinal sensitization to sensory input involves local release of prostaglandin E2 (PGE2). We used microdialysis to measure spinal PGE2 release following paw formalin injection in conscious control and STZ‐diabetic rats. In control rats, there was an increase in spinal PGE2 levels to 260 ± 14% of basal (p < 0.01) in the first 5 minutes after paw formalin injection and thereafter levels were not different from basal. Diabetic rats showed a similar increase (254 ± 25%) but also exhibited a second period of release (266 ± 20%; p < 0.01 vs. basal) 15‐20 minutes after the stimulus. Systemic delivery of the NSAID indomethacin (10 mg/kg IP) or intrathecal delivery of an EP1 receptor antagonist (30 μg) prior to paw formalin injection both significantly reduced the number of paw flinches in diabetic rats 10‐40 minutes after injection (17 ± 9 and 20 ± 8, respectively) compared to vehicle treated diabetics (42 ± 8). Formalin‐evoked flinching was also significantly reduced by spinal delivery of the p38 stress‐activated protein kinase inhibitor SB203580 (1–30 μg IT) in both control and diabetic rats, with higher concentrations required for efficacy in diabetic rats. Hyperalgesia following paw formalin injection in diabetic rats is accompanied by increased spinal PGE2 release and activation of the EP1 receptor while signaling through the p38 pathway also participates in maintaining formalin‐evoked flinching.
High Dose Therapy With Alpha‐Lipoic Acid Improves Cutaneous Vasomotor Response In Patients With Diabetic Neuropathy
Authors: Tretjakovs P , Jurka A , Pirags V.
Published: March 2003

The aim of our study was to evaluate the effect of alpha‐lipoic acid on the postocclusive hyperaemic response in type 2 diabetes (NIDDM) patients with diabetic peripheral neuropathy. Subjects: 36 NIDDM patients with diabetic peripheral neuropathy were divided in two groups according to the dosage of alpha‐lipoic acid: 18 patients received 600 mg (D1) and 18 patients received 1800 mg (D2) alpha‐lipoic acid orally for 4 weeks. 20 healthy subjects were selected as controls (C). Patient groups were matched for age, sex, body mass index and HbA1c. Subjects with peripheral vascular disease, hypertension, microalbuminuria and dyslipidemia were excluded. Methods: Before and after therapy we recorded changes in the cutaneous blood flow induced by 3 min arterial occlusion (cuff above the knee) on the pulp of the big toe using laser Doppler (LD) fluxmetry (PeriFlux 4001, Perimed). Basal LD flux (b‐LDF; PU), the percent increase of b‐LDF (ΔLDF; %) and the time to peak LD flux (t‐LDF; s) were calculated (PeriSoft program). Results: Before therapy b‐LDF on the pulp was significantly higher (mean ± SD; Mann‐Whitney U test) in diabetic patients (D1: 116.1 ± 47.4, D2: 99.8 ± 55.6 vs C: 58.5 ± 22.0 PU, p < 0.01), LDF was decreased in diabetic patients, and t‐LDF was significantly shorter in diabetic patients (D1: 22.8 ± 8.6, D2: 24.5 ± 7.1 vs C: 39.8 ± 9.7 s, p < 0.05) in comparison to controls. Oral therapy for 4 weeks with a high dose (1800 mg daily) of alpha‐lipoic acid restored ΔLDF (111.8 ± 44.9% vs 72.7 ± 11.0% before therapy, p < 0.05). Conclusion: Our results suggest that high dose of alpha‐lipoic acid improves responsiveness of cutaneous microvessels to arterial occlusion test in diabetic patients with peripheral neuropathy.
Risk Factors For Guillain‐Barre Syndrome (Gbs) In Northern Italy: Analysis Of Anamnestic Antecedent Events And Serological Evidence Of Infections
Authors: Carpo M , Allaria S , Franciotta D , Citterio A , Bersano A , Scarlato G , Nobile‐Orazio E.
Published: March 2003

Antecedent gastrointestinal or respiratory infections are frequently reported in GBS patients where they have been often attributed to Campylobacter jejuni (CJ), Cytomegalovirus (CMV) or Ebstain‐Barr virus (EBV). In order to determine the relative risk (RR) for the development of GBS of anamnestic and/or serological evidence of an antecedent infection we analysed the anamnestic data and sera of 47 GBS patients, 45 neurological controls (NC) and 44 non‐neurological controls (NNC) in a prospective case‐control study in northern Italy. After receiving an informed consent, we analysed the preceding events reported by GBS patients and controls within 2 months before the onset of the neurological or non‐neurological disease leading to admission in the hospital by a questionnaire administered to each subject. Patients' sera were then screened by ELISA for reactivity with CJ, CMV, EBV, Herpes simplex virus (HSV), Mycoplasma Pneumoniae, Hepatitis A, B, C and HIV. The analysis of the questionnaires revealed that 9 GBS patients (19%) have had diarrhea compared to 3 NC and 3 NNC (7% each) (GBS vs. NC/NNC p < 0.05; RR 3.35). By ELISA only 2 of 47 GBS patients (4%), both with diarrhea (22% of GBS patients with diarrhea), and 1 (without diarrhea) of 89 NC and NNC had anti‐CJ IgG antibodies (RR: 3.91). An antecedent respiratory tract infection was reported by 32 GBS (68%), 16 NC and 16 NNC (35% and 36%, respectively) (GBS vs. NC/NNC p < 0.05; RR: 3.8). Serological data revealed that 28% and 30% of GBS had anti‐CMV and anti‐HSV IgM antibodies, respectively, in the acute sera compared to 4% and 11% of controls (p < 0.005 and <0.01, respectively; RR: 8.1 and 3.35, respectively). Anti‐CMV and anti‐HSV IgM antibodies were, however, similarly frequent in GBS patients with or without respiratory infection. No other antibody reactivity with virus or bacteria was detected in our population. Diarrhea and respiratory infections were the most frequent antecedent events of GBS in this Italian population. Even if serological evidences of CJ, CMV, and HSV infection were associated with an increased RR for GBS, their association with an history of antecedent infection in GBS was either infrequent (diarrhea) or elusive (respiratory infection).