bluuebunny/crossref_metadata_2025 huggingface dataset:
Immusorba TR and Immusorba PH: Basics of Design and Features of Functions
Authors: Yoshida Makoto , Tamura Yuichi , Yamada Yukihiro , Yamawaki Naokuni , Yamashita Yasuhiko
Published: March 2003

Abstract: Guest Editor's Introduction: Selective adsorption of target substances can be achieved based upon the application of physical and chemical interactions as well. Asahi Medical Co. developed 2 types of selective adsorbent columns, Immusorba PH‐350, and Immusorba TR‐350. These adsorbents consist of crosslinked polyvinyl alcohol gel beds with microporous structures for the base material, which immobilized a specific amino acid with hydrophobic property. Immusorba PH‐350 has phenylalanines as the ligand, which adsorbs the pathogenic substances such as immune complexes and anti‐DNA antibody. Tryptophan is immobilized in the Immusorba TR‐350, which adsorbs antiacetylcholine receptor antibodies. This paper describes the basic designs, adsorption characteristics, and summary of clinical applications of these adsorbents. This paper was printed in Therapeutic Apheresis, vol 2, page 185–192 (1998), and reprinted here with permission.

Immusorba was reported by Yamazaki et al. to be the world's first practical immunoadsorbent in 1982. Since then, this immunoadsorbent has accumulated an abundance of clinical achievements. Immusorba has such unique functions that it is used in treating various diseases and holds possibilities for application to more diseases. Immusorba was designed as an artificial receptor for rheumatoid factor (RF) based on structural analysis of heat‐denaturated globulin. Subsequently, new substances that it can adsorb have been found as seen in reports on the adsorption performance of Immusorba to anti‐acetylcholine receptor antibodies (anti‐AChR Abs) and antiganglioside antibodies. Along with this, Immusorba has been used in treating a wide range of diseases. The greatest characteristic of Immusorba is that its adsorption capability is selective rather than specific, making it effective against a great number of diseases.
Recent Advances of Therapeutic Apheresis in Guillain‐Barré Syndrome
Authors: Haupt W.F.
Published: March 2003

Abstract: Acute idiopathic demyelinating polyneuritis (AIDP), commonly known as the Guillain‐Barré syndrome (GBS), is an immune‐mediated demyelinating disease of the peripheral nerve and nerve roots. A number of immunological mechanisms were described, but the exact pathomechanism has not been explained fully. Presumably, a variety of immunological processes lead to a relatively uniform clinical phenotype. Two large multicenter studies showed that plasma exchange (PE) was significantly superior to supportive treatment only. Selective adsorption (SA) also was employed as a method of therapeutic apheresis, and various smaller studies established that both PE and SA are equally effective treatments for GBS. Recently, it was demonstrated that the number of apheresis treatments should be adapted to the severity of disease. A large multicenter controlled study established equal efficacy of PE and intravenous immunoglobulin treatment (IVIg) as well as the combination of PE and IVIg. Since that time, the use of apheresis for the treatment of GBS declined in many countries due to the easier application of IVIg. The number of patients treated in larger hospitals with long‐standing experience in the treatment of GBS also has declined.
The Six Year Experience of Plasmapheresis in Patients with Myasthenia Gravis
Authors: Chiu Hou‐Chang , Chen Wei‐Hung , Yeh Jiann‐Hong
Published: March 2003

Abstract: Plasmapheresis (PP) effectively removes autoantibodies in various autoimmune diseases. The use of PP in the treatment of myasthenia gravis (MG) has been widely accepted since the 1970s. The treatment protocol, however, has not been standardized. For the last 6 years, we collected a total of 94 MG patients, 38 males and 56 females aged 14–80 years, who received 175 courses of PP treatment for a total of 823 sessions. The methods we used were double filtration plasmapheresis (DF), immunoadsorption plasmapheresis (IA), and plasma exchange (PE). There were 167 courses of DF, 6 courses of IA, and 2 courses of PE. Each course of treatment consists of 4 to 5 sessions of apheresis. The processed volume of plasma is 1 calculated plasma volume. All patients tolerated PP well although 2.3% of them experienced hypotension. Our experiences are summarized as follows. Both DF and IA effectively ameliorate symptoms and signs of MG. IA removes acetylcholine receptor antibody more effectively than DF does, but clinical effects between these 2 methods are similar. A daily schedule seems more effective than an alternate daily schedule. The optimal number of PP sessions for each course is 4. The factors correlating with better clinical response are high MG score, nonthymoma patients, younger age at onset, and higher removal rate for immunoglobulin G.
The Presence of Superantigens and Complex Host Responses in Severe Sepsis May Need a Broad Therapeutic Approach
Authors: Stegmayr Bernd G.
Published: March 2003

Abstract: Patients with sepsis can progress into septic shock, disseminated intravascular coagulation, and multiorgan dysfunction syndrome. Various materials secreted by or released from microorganisms such as bacteria initiate these processes. In some bacteria, certain antigens and toxins may cause a 100‐fold greater or supernormal activation of monocytes and T lymphocytes, leading to activation of the cascade systems in the host. This can explain the extremely rapid progress of the sepsis into septic shock seen in some patients. In Group A streptococci, more than 100 different toxins have been identified, about 5 of which (superantigens) cause an extremely fast immunological response. Because the toxins and antigens can activate so many different cascade systems in the host, the clinical picture is extremely complex, and little benefit is derived from therapy, which interferes with only 1 or 2 of the parameters in the patient with sepsis. Instead, reversal of the septic shock requires the removal or inhibition of several toxins or substances activating the cascade systems. A broader therapeutic approach may be the use of apheresis (plasma exchange).
Antibody Reactivity of a Standardized Human Serum Protein Solution Against a Spectrum of Microbial Pathogens and Toxins: Comparison with Fresh Frozen Plasma
Authors: Schmidt Herbert , Lissner Reinhard , Struff Wilhelm , Thamm Oliver , Karch Helge
Published: March 2003

Abstract: In this study, we compared a standardized solution of human serum protein (HSP) and fresh frozen plasma (FFP) with regard to the antibody specificity against a number of microbial pathogens and some important pathogenicity factors of bacterial pathogens. Due to the clinical use of HSP and FFP for therapeutical plasma exchange, we have chosen a spectrum of microbial pathogens for serological analysis that is critical in clinical settings. With the enzyme‐linked immunosorbent assay technique, we could show that HSP contains marked IgG antibody reactivity against antigens of Escherichia coli, Campylobacter jejuni, Enterobacter sakazakii, Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, Enterococcus faecalis, Chlamydia pneumoniae, and Candida albicans. Although no IgM antibodies against the pathogens tested could be detected in HSP, moderate IgA reactivity was found against 4 of 12 microbial antigens. Immunoblot analysis demonstrated specific IgA and IgG responses against the endoproteinase Glu‐C and the superantigens enterotoxin A and B of S. aureus, the IgA‐protease of Neisseria gonorrhoeae, and Shiga toxin 2 of enterohemorrhagic E. coli. By using 3 different HSP batches in parallel, we could demonstrate antibody reactivity against important microbial pathogens and toxins. This antibody profile is essentially more homogeneous than that of 3 batches of FFP.
On‐Line Hemodiafiltration in Critical Care
Authors: Kawanishi Hideki
Published: March 2003

Abstract: On‐line products of substitution fluid permits virtually unlimited fluid volume exchange during continuous hemodiafiltration (CHDF) to critical care. In on‐line hemodiafiltration (HDF), endotoxin free dialysate obtained using pyrogen cut filters is infused into the blood circuit, and HDF is automatically performed using the closed‐loop balancing system of the dialysis machine. On‐line CHDF is the application of this on‐line HDF to continuous renal replacement therapy in the critical care field. We performed on‐line CHDF on 376 acute renal failure patients during a 5 year period, and the mean survival rate was 62.5%. We concluded that the on‐line CHDF system is safe and effective at maintaining acute renal failure patients.
A Patient with Severe Acute Pancreatitis Successfully Treated with a New Critical Care Procedure
Authors: Moriguchi Takeshi , Hirasawa Hiroyuki , Oda Shigeto , Shiga Hidetoshi , Nakanishi Kazuya , Matsuda Ken‐ichi , Nakamura Masataka , Yokohari Kennji , Hirano Takeshi , Hirayama Yoh , Watanabe Eizo
Published: March 2003

Abstract: It has been accepted widely that excessive humoral mediators play important roles in the pathogenesis of organ failure in patients with severe acute pancreatitis (SAP) and that infection of the pancreas due to bacterial translocation (BT) is the most frequent cause of death in SAP. On the other hand, it has been reported that continuous hemodiafiltration (CHDF) removes humoral mediators on hypercytokinemic patients such as those with systemic inflammatory response syndrome. Furthermore, several clinical studies have demonstrated that selective digestive decontamination (SDD) effectively eliminates aerobic Gram‐negative bacteria from the intestinal tract and reduces the incidence of septic complications in SAP. Herein we report a case of SAP who was treated successfully with intensive care including CHDF and SDD. Thus, this case report suggests that CHDF aimed at removing causative humoral mediators and SDD for the prevention of BT are useful new tools for the management of SAP.
Blood Purification Procedures and Their Related Short‐ and Long‐Term Effect on Patients
Authors: Nosé Yukihiko
Published: March 2003

Abstract: At present, approximately 1 million patients are on chronic hemodialysis in the world. Some patients have been dialyzed for more than 20 years. However, chronic hemodialysis produces a new type of disease known as chronic hemodialysis syndrome. Procedurally induced immunomodulation may be the cause of this syndrome. Hematological changes imposed by this extracorporeal circulation for hemodialysis are discussed in this article. A comparison with procedurally induced immunomodulation by apheresis procedures is also provided. This repeated exposure of the blood‐to‐blood purification device with a large foreign surface produces quite substantial immunological effects to the patient. Thus, further studies were necessary to analyze more clearly the adaptation mechanism of the human defense system. On the basis of these studies, the following conclusion could be derived. Typically, Stage 1, human adaptation to the implanted or applied man‐made machine, would be 48 h and could be divided into 3 phases. They would be Phase I (15–30 min) leukocyte storage, Phase II (2–24 h) leukocyte release, and Phase III (24–48 h) completion of the proper leukocyte response. To adapt hematologically in 48 h, the patient may experience 3 phases of adaptation reactions. When patients are subjected to extracorporeal circulation, the immunosuppressive state of hemodialysis is hypothesized through these studies.
Establishment of Transplants on Machine‐Graded Ski Runs Above Timberline in the Swiss Alps
Authors: Fattorini Marzio
Published: March 2003

The suitability of 24 native species for restoration above the timberline in Switzerland was assessed with demographic monitoring of their populations after transplanting. The plots were laid out in 1985–1986 and 1995–1996 on machine‐graded ski runs using a total of 8,603 transplants of native grasses, legumes and forbs. Establishment conditions were improved with biodegradable wood‐fiber mats and a small addition of garden soil. Transplant survival rates were generally good after 12 years. The regeneration of mixed stands was clearly recognizable because some transplants successfully reproduced by seed, and colonizers immigrated from the adjacent natural vegetation and neighboring restoration plots. Comparative studies of reproductive parameters in transplants and their donor population revealed that differences in seed production may become nonsignificant within a short time span. These fitness features have important diagnostic value for assessing restoration success and provide information on the performance of the same or closely related genotypes in their natural populations and in the restoration site. The plants studied showed species‐specific traits in establishment after transplanting. Most species can be recommended for restoration in the alpine vegetation belt. The risk of restoration failure can be considerably reduced by using species with different life‐history characteristics. From an ecological point of view, this method is a valid alternative to commercial revegetation using seed mixtures of non‐native species and large amounts of fertilizers.
Linking Habitat Restoration to Meaningful Units of Animal Demography
Authors: Smallwood K. Shawn
Published: March 2003

To restore habitat is to restore the functional aspects of a place where one or more species are intended to live. However, habitat restored with the right structural elements can still fail to support the species due to insufficient space and spatial contiguity (e.g., movement corridors) with nearby habitat. The spatial extent of habitat determines its capacity to support various demographic units, such as a breeding pair of individuals, a true population, or a metapopulation. In scatter‐plots of published density estimates and their corresponding study area sizes, I found consistent patterns that appeared to represent spatial scale domains, in which subpopulations, populations, and multiple populations exist for each species. These spatial scale domains can help guide habitat restoration by indicating the minimum area needed to support apopulation.The effectiveness of restored habitat, considered alone or in combination with existing habitat, should be judged by the habitat's capacity to sustain a functioning population, which includes the population's membership in a metapopulation. Additionally, the evidence increasingly demonstrates that habitat must include sufficient space for the population(s) to periodically relocate as resources are depleted locally. The spatial extent of proposed habitat restoration can now be linked to the likely demographic unit of the species that can be supported there. I provide two examples of proposed habitat conservation and their likely effectiveness based on their spatial areas.
Effect of Planting Unit Size and Sediment Stabilization on Seagrass Transplants in Western Australia
Authors: Van Keulen Mike , Paling Eric I. , Walker C. J.
Published: March 2003

Abstract The effect of increasing planting unit size and stabilizing sediment was examined for two seagrass planting methods at Carnac Island, Western Australia in 1993. The staple method (sprigs) was used to transplant Amphibolis griffithii (J. M. Black) den Hartog and the plug method was used to transplant A. griffithii and Posidonia sinuosa Cambridge and Kuo. Transplant size was varied by increasing the number of rhizomes incorporated into a staple and increasing the diameter of plugs. Planting units were transplanted into bare sand, back into the original donor seagrass bed, or into a meadow of Heterozostera tasmanica, which is an important colonizing species. Sprigs of A. griffithii were extracted from a monospecific meadow; tied into bundles of 1, 2, 5, and 10 rhizomes; and planted into unvegetated areas. Half the units were surrounded by plastic mesh and the remainder were unmeshed. All treatments were lost within 99 days after transplanting, and although larger bundles survived better than smaller ones, no significant differences could be attributed to the effects of mesh or sprig size. Plugs of P. sinuosa and A. griffithii were extracted from monospecific meadows using polyvinyl chloride pipe of three diameters, 5, 10, and 15 cm, and planted into unvegetated areas nearby. Half the units were surrounded by plastic mesh and the remainder were unmeshed. Posidonia sinuosa plugs were also placed within a meadow of H. tasmanica (Martens ex Aschers.) den Hartog. Only 60% of A. griffithii plug sizes survived 350 days after transplanting back into the donor bed; however, survival of transplants at unvegetated areas varied considerably, and analysis of variance indicated a significant two‐way interaction between treatment and plug size. Transplants survived better when meshed (90% survived) and survival improved with increasing plug size. Posidonia sinuosa transplants survived poorly (no plugs survived beyond 220 days in bare or meshed treatments) regardless of size. Survival of 10‐ and 15‐cm plugs was markedly better than the 5‐cm plugs in vegetated areas, including the H. tasmanica meadow. The use of large seagrass plugs may be appropriate for transplantation in high‐energy wave environments.
Severe polyneuropathy in a patient with Churg‐Strauss syndrome
Authors: Bazzi Paola , Tancredi Lucia , Scarpini Elio , Messina Stefano , Sciacco Monica , Livraghi Simona , Vanoli Massimo , Prelle Alessandro , Scarlato Guglielmo , Moggio Maurizio
Published: March 2003

Abstract  We describe the clinicopathologic features of a 56‐year‐old woman affected with Churg‐Strauss syndrome with major peripheral nerve involvement. The patient presented with a 1‐month history of mainly distal upper‐limb symmetrical paresthesias and hypostenia (bilateral “wrist drop”), palpable purpura and eosinophilia. Multiple pulmonary infiltrates and asthma had been present since the age of 52. Skin biopsy demonstrated an eosinophilic necrotizing vasculitis. During the hospitalization she was submitted to cardiac, bronchopulmonary, renal, and gastrointestinal evaluation and EMG. Peripheral nerve and skeletal muscle biopsies were performed. Sural nerve biopsy showed a marked degree of demyelination. A perivascular cellular infiltrate within the epineurium was immunoreactive for T lymphocytes and macrophages. Strong HLA‐DR immunostaining was present in the endoneurium. IgM, IgE and fibrinogen deposition was found in some epi‐ and endoneurial vessels. Muscle biopsy showed neurogenic changes and 1 thrombosed vessel surrounded by mononuclear cells. Membrane attack complex (MAC) deposition was present in a few capillaries and major histocompatibility complex products I (MHCP I) was expressed at the subsarcolemmal level in a few isolated perivascular muscle fibers. After immunosuppressive therapy, the patient showed progressive improvement of both clinical symptoms and neurophysiological parameters.
Inexcitability of nerves in a fulminant case of Guillain‐Barré syndrome
Authors: Vital Claude , Vital Anne , Arne Pierre , Hilbert Gilles , Gruson Didier , Gbikpi‐Benissan Georges , Cardinaud Jean‐Pierre , Petry Klaus
Published: March 2003

Abstract  A 45‐year‐old woman presented with a recent sensorimotor deficiency in all 4 limbs, and the next day she was totally paralyzed. A slight motor improvement began on day 27. The cerebrospinal fluid had normal cellularity, but the protein varied from 90 mg/dL on the first day to 800 mg/dL on day 15, and then 290 mg/dL on day 33. Electrophysiologic studies performed on days 15 and 23 revealed a universal peripheral nerve inexcitability. A superficial peroneal nerve biopsy was performed on day 23. Nine fascicles were examined on semi‐thin sections and myelinated fiber damage varied greatly from one fascicle to another. At ultrastructural examination, certain axons were severely damaged, but the others were quite well preserved and were naked or wrapped in a myelin sheath presenting a multivesicular degeneration. A few fibers had a better‐preserved myelin sheath that was sometimes dissociated by elongated processes from an invading histiocyte. Six cases of fulminant Guillain‐Barré syndrome with inexcitability of nerves and ultrastructural examination of nerve fragments have been reported. Electrophysiologic study is often ambiguous and cannot determine the precise origin of such an axonal degeneration. Therefore, ultrastructural analysis of a nerve biopsy is mandatory in this setting.
Electrophysiological Changes In Diabetic Neuropathy: From Subclinical Alterations To Disabling Abnormalities
Authors: Baba M.
Published: March 2003

Clinical spectrum of diabetic neuropathy is variable; it may be asymptomatic, but once established, it becomes irreversible and disabling. Some investigators suggested that earliest change in diabetic nerve function is alteration in axonal excitability due to alterations in ion conductance of axon membrane, although these functional changes of ion channels necessarily cause permanent damage or degeneration of nerve fibers. Among various parameter of nerve conduction study in diabetics, prolonged F‐wave latency in the peroneal and tibial nerve seems the commonest abnormality in asymptomatic patients. Decrease in amplitude of compound sensory action potential of sural nerve is another earlier abnormality, which is, then, accompanied by a fall in motor amplitude of peroneal and tibial nerves in advanced patients. In disabled patients no motor response is often elicited in the legs. Previous electrophysiological studies could not make clear if central axons were involved or not in diabetic neuropathy. Recently, our group has demonstrated that somatosensory central conduction from the spinal cord to the sensory cortex is delayed in diabetics as well as in the peripheral conduction, which might be partly responsible for the irreversible clinical presentation of diabetic neuropathy.
Evaluation Of Diabetic Neuropathy By Skin Biopsy
Authors: Yasuda H.
Published: March 2003

Instead of nerve biopsy which is most reliable method for diagnosing diabetic neuropathy but rather harmful, we have examined the usefulness of skin biopsy to evaluate the grade of diabetic neuropathy and therapeutic effects of given compounds. Nerve fibers immunostained by antibodies against protein gene product (PGP)9.5 and labeled with streptavidin fluorescein isothiocyanate and measured under confocal laser scanning microscopy were significantly shorter in the epidermis and dermis and around sweat glands in diabetic patients than in healthy subjects. Sural nerve conduction velocity was significantly correlated with dermal nerve fiber length (NFL) (p < 0.05) in diabetic patients. Patients with higher aldose reductase (AR) level of erythrocytes (>10.8 ng/Hg) showed shorter dermal NFL than those with lower AR level (<10.8)(p < 0.05). Using this technique, we evaluated the therapeutic effect of AR inhibitor (ARI) epalrestat during approximately 13 months in diabetic patients with neuropathy (19, epalrestat‐treated; 12, control). The number of patients whose percent change of dermal NFL exceeded its mean ± 2SD in the control group was significantly higher in the ARI group than in the control group (p < 0.05, 8/9 vs 1/12). These results suggest that quantitation of cutaneous nerves using biopsied skin samples may provide important information about the severity of diabetic neuropathy and that epalrestat can elongate dermal unmyelinated nerve fibers in at least part of diabetic patients.
Increased Depolarization‐Induced Cytosolic CA2+ Signal In Rat Dorsal Root Ganglion Neurons Under High Glucose With Suppressed NA+/K+ Pump Activity
Authors: Sanada M , Yasuda H , Omatsu‐Kanbe M , Matsuura H , Kikkawa R.
Published: March 2003

Hyperglycemia and its associated Na+/K+ pump activity has been implicated in the development of diabetic neuropathy. We recently reported that high glucose in the presence of ouabain induced a progressive increase in the delayed K+ current which was suppressed by a blocker of Ca2+‐activated K+ channels and blockers of Ca2+ channels in rat single myelinated nerve fibers, suggesting an increase of cytosolic free Ca2+ concentration ([Ca2+]i). However, the influences of high glucose with ouabain on [Ca2+]i in sensory neurons remain to be elucidated. The present study was undertaken to examine the modulation of depolarization‐induced Ca2+ transients by high glucose and ouabain in isolated adult rat dorsal root ganglion (DRG) neurons using the fluorescent Ca2+ indicator fura‐2. Bath application of KCl (50 mM) evoked a rapid increase in [Ca2+]i through voltage dependent Ca2+ channels ([Ca2+]i: 154.2 ± 22.5 nM). This increase was enhanced under high glucose (30 mM D‐glucose) in the presence of ouabain (100 M) ([Ca2+]i: 764.8 ± 210.1 nM). We conclude that a combination of high glucose and decreased Na+/K+ pump activity leads to an increase in [Ca2+]i in rat DRG neurons, thereby resulting in nerve dysfunction.
Effect Of Protein Kinase C‐β Inhibition On Diabetic Neuropathy In Otsuka Long‐Evans Tokushima Fatty Rats
Authors: Kato K , Nakamura J , Kasuya Y , Kamiya H , Akiyama N , Watanabe G , Kawamura T , Hotta N.
Published: March 2003

Although increased protein kinase C (PKC) activity has been invoked in the pathogenesis of diabetic retinopathy, nephropathy and macroangiopathy, the role of PKC in neuropathy remains unclear. We reported that total PKC activity in sciatic nerves of STZ‐induced diabetic rats was not altered compared with that of normal rats, and that PKC‐β inhibitor, LY‐333531 (LY) ameliorated neural dysfunction and reduced endoneurial blood flow without affecting PKC activity, suggesting that this effect of LY would be mediated through its action on endoneurial microvasculature. In this study, effect of LY on diabetic neuropathy was investigated in Otsuka Long‐Evans Tokushima fatty (OLETF) rats, an animal model of type 2 diabetes. Three‐month‐old male OLETF rats and Long‐Evans Tokushima Otsuka (LETO) rats as normal control rats were divided into 5 groups as follows: 1) LETO control, 2) OLETF control, 3) LY (1 mg/kg/day)‐treated OLETF, 4) sucrose‐fed OLETF, and 5) sucrose‐fed OLETF treated with LY. After 21‐month treatment, motor nerve conduction velocity (MNCV) in tail nerves, sciatic nerve blood flow (SNBF) and protein expression of phosphorylated PKC in sciatic nerves were measured. 1) MNCV: OLETF rats demonstrated a significant delay in MNCV, which was enhanced by sucrose feeding, and these deficits were prevented by LY. 2)
SNBF: reduced SNBF in OLETF and sucrose‐fed OLETF rats was ameliorated by LY. 3)
PKC: phosphorylated PKC expression was decreased in OLETF rats, which was more prominent in sucrose‐fed OLETF rats. Treatment with LY increased phosphorylated PKC expression in both groups of OLETF rats. These observations suggest that diabetes with long duration and poor glycemic control decreases phosphorylated PKC in nerve tissues, which would contribute to the development of diabetic neuropathy, and that PKC‐β inhibition would be beneficial for the prevention of this neuropathy.
Meeting American Diabetes Association Guidelines In Endocrinologist Practice
Authors: Miller C.D. , Phillips L.S. , Tate M.K. , Porwoll J.M. , Rossman S.D. , Cronmiller N. , Gebhart S.S.P.
Published: March 2003

OBJECTIVE—To determine whether American Diabetes Association (ADA) guidelines can be met in the context of routine endocrinology practice. RESEARCH DESIGN AND METHODS—Charts were reviewed for a group of patients who were examined in 1998, followed for greater than or equal to 1 year, and had two or more visits during that year. Process measures and metabolic outcomes were studied for patients with type 2 diabetes, and glycemic control was assessed for patients with type 1 diabetes. RESULTS—A total of 1.21 patients with type 2 diabetes had a mean age of 63 years, a mean BMI of 31 kg/m(2), and a mean duration of diabetes of 12 years. Many had comorbidities or complications: 80% had hypertension, 64% had hyperlipidemia, 78% had neuropathy, 22% had retinopathy, and 21% had albuminuria. Management of type 2 diabetic patients was complex: 38% used oral hypoglycemic agents alone (54% of these were using two or more agents), 31% used oral hypoglycemic agents and insulin, and 26% used insulin alone, 42% of patients taking insulin therapy injected insulin three or more times per day. Within 12 months, 74% of patients had dilated eye examinations, 70% had lipid profiles, and 55% had urine albumin screening. Of the patients, 87% had a foot examination at their last visit. Blood pressure levels averaged 133/72 mmHg, cholesterol levels averaged 4.63 mmol/l, triglyceride levels averaged 1.99 mmol/l. HDL cholesterol levels averaged 1.24 mmol/l, and LDL cholesterol levels averaged 2.61. mmol/l. Random blood glucose levels averaged 8.0 mmol/l, and HbA(1c) levels averaged 6.9 +/− 0.1%. A total of 87% of patients had HbA(1c) levels less than or equal to 8.0%. A total of 30 patients with type 1 diabetes had mean age of 44 years, a mean BMI of 26 kg/m(2), and a mean duration of diabetes of 20 years. All type 1 diabetic patients used insulin and averaged 3.4 injections a day, their average HbA(1c) level was 7.1 +/− 0.2%, and 80% had HbA(1c) levels less than or equal to 8.0%. CONCLUSIONS—Although endocrinologists must manage patients with multifaceted problems, complex treatment regimens yield glycemic control levels comparable with the Diabetes Control and Complications Trial and allow ADA guidelines to be met in a routine practice setting.
Clinical And Neuropathological Parameters Affecting The Diagnostic Yield Of Nerve Biopsy
Authors: Deprez M. , Ceuterick‐de Groote C. , Gollogly L. , Reznik M. , Martin J.J.
Published: March 2003

The value of nerve biopsy in the investigation of peripheral neuropathies is an important and controversial issue, partially obscured by the large variations in the diagnostic yield routinely reported for this procedure. The aim of this study was to evaluate the clinical and neuropathological parameters affecting the yield of nerve biopsy. We compared the experience of two independent neuropathology laboratories with different patient recruitment and neuropathological methods over 11 years (01/1987–12/1997). Clinicopathological correlations were studied retrospectively in 355 patients. Using the same criteria of evaluation, contributive biopsies accounted for 35.5% in one laboratory and 47.3% in the other. Clinical parameters affecting the yield of nerve biopsy were: (a) the presumptive diagnosis at time of referral for biopsy: (b) the distribution of symptoms, and (c) the interval between disease onset and biopsy. Greater yield was associated with clinically suspected vasculitis, inflammatory demyelinating neuropathy or hereditary sensorimotor neuropathies. Contributive findings were more often reported with multifocal or asymmetrical presentations, and onset‐to‐biopsy interval of less than 6 months. The contribution of nerve biopsy varied according to neuropathological techniques: (a) serial sections on frozen, paraffin‐embedded and resin‐embedded material improved sensitivity for interstitial pathology, (b) combined muscle biopsy increased sensitivity in the detection of vasculitis, and (c) teasing of nerve fibers added critical information to other classical techniques in only 4/102 cases.
SYM‐2081 A Kainate Receptor Antagonist Reduces Allodynia And Hyperalgesia In A Freeze Injury Model Of Neuropathic Pain
Authors: Ta L.E. , Dionne R.A. , Friction J.R. , Hodges J.S. , Kajander K.C.
Published: March 2003

Cold‐freeze injury at −4 degrees C to the rat sciatic nerve produces mechanical allodynia and thermal hyperalgesia [M.A. Kleive, P.S. Jungbluth, J.A. Uhlenkamp, K.C. Kajander, Cold injury to rat sciatic nerve induces thermal hyperalgesia or analgesia, 8th World Congress on Pain, Vancouver, BC, Canada, August 1996 (Abstract).]. The NMDA receptor, an excitatory amino acid (EAA) receptor, appears to be involved in the development of allodynia and hyperalgesia following nerve injury. The role, if any, of the kainate receptor, another EAA receptor, remains unknown. In the current study, we evaluated whether (2S,4R)‐4‐methylglutamic acid (SYM‐2081), a recently developed kainate receptor antagonist, attenuates increased responsiveness following cold injury to the sciatic nerve. During baseline testing, Sprague‐Dawley rats were evaluated for frequency of withdrawal from van Frey filaments and latency of withdrawal from a radiant thermal source. Animals were then anesthetized, the left sciatic nerve was exposed, and the nerve was cooled to −4 degrees C for 15 min (n = 24). For control rats (n = 24), all procedures were identical except that the nerve was maintained at 37 degrees C. Testing resumed on the third day following surgery. On the fifth post‐operative day, SYM‐2081 (150 or 100 mg/kg), fentanyl citrate (0.04 mg/kg) or vehicle was injected intraperitoneally. Injury to the rat sciatic nerve induced a significant increase in withdrawal frequency and a significant decrease in withdrawal latency (ANOVA, p < 0.05). SYM‐2081 and fentanyl significantly reduced these responses (p < 0.05). These results suggest that kainate and opioid receptors are involved in the mechanical allodynia and thermal hyperalgesia that develop following cold injury to the sciatic nerve.
Cold Exposure Enhances Tactile Allodynia Transiently In Mononeuropathic Rats
Authors: Kauppila T.
Published: March 2003

A laser and erythrosin‐B‐induced sciatic nerve injury decreases thresholds of a mechanically induced paw withdrawal reflex and enhances cold‐induced withdrawal behavior of the affected limb. Exposure of the affected paw to a normally innocuous cold stimulus results in a transient decrease in the threshold of the mechanically evoked paw withdrawal reflex in neuropathic but not in intact rats. The present data suggest that in an experimental neuropathic state a normally innocuous cold stimulus may further sensitize spinally mediated withdrawal reflexes to stimuli of another stimulus modality, in this case, to innocuous tactile stimuli. Therefore, testing mechanical allodynia in neuropathic rats immediately after testing cold allodynia may produce artifactual results.
Neurotrophins In Diabetic Neuropathy
Authors: Fernyhough P.
Published: March 2003

The recent Genentech/Roche sponsored FDA phase III clinical trial of nerve growth factor (NGF) for the treatment of diabetic neuropathy failed. The aim of this talk is to discuss the reasons for this failure and based upon the lessons learned identify if there remain any other viable avenues for studies on neurotrophins in diabetic neuropathy. The presentation will briefly introduce the basic biology of the neurotrophins and their putative role in the aetiology and/or treatment of diabetic neuropathy. Some details of the NGF clinical trials will be presented and reasons for failure assessed. The main part of the talk will focus on future strategies for neurotrophin work with an emphasis on the possible roles of neurotrophin‐3 and brain‐derived neurotrophic factor. Alternative approaches based upon regulation of endogenous neurotrophin expression and use of neurotrophin trk receptor agonists will also be discussed. The aim of the talk is to show that lessons learned from the failed NGF trial should lead to a re‐invigoration of studies directed at determining alternative methods for optimising neurotrophic support of sensory neurones in diabetes.
Skin Sympathetic Response In Subclinical Diabetic Neuropathy
Authors: Kucera P , Krahulec B , Strbová  , L.
Published: March 2003

Skin sympathetic response (SSR)—a method of assessing sudomotor sympathetic fibres dysfunction—is absent in 9–83% of diabetic patients with distal symmetrical sensorimotor neuropathy (1,2). There are only few reports in the literature about SSR in subclinical stages of diabetic neuropathy. We therefore measured SSR in 73 diabetic patients (49 patients with clinically evident diabetic neuropathy/assessed with pin prick test, light touch, 128 Hz tuning fork, ankle reflexes and 10 g monofilament/ and 24 patients without clinical signs of diabetic neuropathy, but with abnormal conduction studies of nervus suralis and peroneus) and 32 normal subjects at both feet and hands. We considered the SSR abnormal only when it was absent in two or more extremities. SSR was present in all normal subjects in all extremities (100%). SSR was absent in 47% of the whole group of diabetic patients. It was absent in 34.7% of the subgroup of patients with clinically evident diabetic neuropathy, and 20.8% in the subgroup without clinical signs of neuropathy. These differences were not statistically significant. Our results support the observations of higher vulnerability and early involvement of small unmyelinated peripheral sympathetic fibres in diabetes mellitus. We conclude, that measuring of SSR can be helpful in diagnosis of subclinical diabetic neuropathy and can extend spectrum of electrophysiological diagnostic methods.

1. Soliven B, Maselli R, Jaspan J, Green A, Graziano H, Petersen M, Spire J‐P: Sympathetic skin response in diabetic neuropathy. Muscle Nerve 10, 1987: 711–716.

2. Niakan E, Harati Y: Sympathetic skin response in diabetic peripheral neuropathy. Muscle Nerve 2, 1988: 261–264.
The Role Of C‐JUN N‐Terminal Kinase 3 (JNK3) In Sensory Nerve Regeneration
Authors: Lockwood Mf , Averill S , Priestley Jv , Tomlinson Dr , Fernyhough P
Published: March 2003

The c‐Jun N‐terminal protein kinase (JNK or SAPK1) signals downstream from the small GTPases Rac/Rho/Cdc42 that are known to regulate neurite outgrowth. JNK may also control alterations in sensory neuron phenotype induced by axotomy via activation of transcription factors such as AP‐1 and ATF2. The aim of this study was to use JNK3 knockout mice to determine the role of JNK3 in sensory neuron regeneration. Dissociated adult mouse and rat cultures were used and JNK levels probed by Western blot and immunohistochemistry using antibodies directed against total JNK, phospho‐JNK and JNK3. Total JNK was located in the nucleus, cytoplasm and axons. Phospho‐JNK was located primarily in the nucleus, with some axonal staining, and JNK3 displayed heavy staining in the cytoplasm. In vivo, DRG of adult rats exhibited JNK staining in neuronal soma, however, following axotomy of 2‐3 weeks duration there was enhanced staining for phospho‐JNK in satellite cells. In vitro, neurite outgrowth studies on dissociated DRG cultures from JNK3 knockout mice showed increased outgrowth by 1.75‐2.54‐fold at concentrations <0.1ng/ml of nerve growth factor (NGF) vs wild‐type (C57BL6). Increased neurite outgrowth was also observed in mouse DRG organ cultures of JNK3 knockout mice in the presence of NGF. The results suggest that JNK3 is a negative regulator of axonal outgrowth, possibly as part of the Rho pathway (Funded by a BBSRC PhD Studentship and Pfizer).
Pre‐Perceptual Pain Sensory Responses (N1 Component) In Type 1 Diabetes Mellitus (Dm): A Laser Evoked Potentials (LEPs) Study
Authors: Rossi P , Serrao M , Gabriele A , Morano A , Di Mario U , Pozzessere G
Published: March 2003

Background. LEPs may be a useful and sensitive diagnostic tool for assessing the function of small‐myelinated fibers (Aδ) in diabetic neuropathy (DN). This statement is based on recent studies measuring the N2‐P2 vertex potentials. This component is strongly influenced by attention processes and may reflect cognitive processing of nociceptive inputs. It represents a drawback of LEP studies. Recently, it has been demonstrated that a smaller N1 component is not influenced by attention shifts and is thought to be more specific for the sensory‐discriminative aspects of pain. Aim of the study. To evaluate the integrity of Aδ‐fibers in type 1 DM by measuring the N1 component of LEPs. Subjects. 12 healthy volunteers and 20 diabetics divided in two groups: Group 1 included 11 patients staged as N0; group 2 included 9 patients staged as N1 or N2. Methods. N1 component following hand (LEPH) and foot (LEPF) stimulation was measured using a simple fronto‐temporal derivation. Results. A clear N1 component was recorded in 12/12 of controls, 9/11 of patients in group 1 and 6/9 of patients in group 2. No significant difference was found for LEPH. LEPF was significantly prolonged in group 2 patients (controls = 202 ± 10.1 ms; group 1 = 208 ± 12.3 ms; group 2 = 240.4 ± 14.3 ms, p < 0.05). 2 patients in group 1, and 4 patients in group 2 presented abnormal LEPF values. Discussion. N1 component following foot stimulation is abnormally prolonged in type 1 diabetic patients with clinical or electrophysiological evidence of DN. A subclinical hypoalgesia was found in asymptomatic patients as well. These data suggest that LEP abnormalities are secondary to a small fiber dysfunction.
Instability Of Cerebral Blood Flow In Diabetic Patients With Cardiovascular Autonomic Neuropathy And Orthostatic Hypotension
Authors: Mankovsky Bn , Piolot R , Mankovsky O , Ziegler D.
Published: March 2003

Cardiovascular autonomic neuropathy (CAN) is a risk factor for stroke in people with diabetes mellitus, and orthostatic hypotension (OH) is a feature of CAN. Therefore, the purpose of this study was to evaluate the mean cerebral blood flow velocity (MFV) in response to standing up in patients with diabetes and OH. We studied 27 patients with diabetes mellitus, among whom 8 had CAN and OH (OH+, age: 46.4 ± 13.5 years, diabetes duration: 25.0 ± 11.0 years; mean ± SD), 7 had CAN but without orthostatic hypotension (OH‐, age: 47.3 ± 12.7, diabetes duration: 26.4 ± 12.1 years), 12 had no evidence of CAN (CAN‐, age: 44.1 ± 13.8, diabetes duration: 17.1 ± 10.2 years), and 14 control subjects (age: 42.6 ± 9.1 years). The MFV in the right middle cerebral artery was recorded using transcranial Doppler sonography in the supine position after 15 minutes of rest and immediately after standing up. The change from the supine position to standing resulted in a pronounced drop in mean blood pressure in the OH+ group (−14.0 ± 20.9 mmHg), while there were no significant changes in blood pressure in the other groups. MFV in the supine position was not different between the diabetic (either with or without CAN or OH) and control groups. However, the relative percentage changes in MFV immediately after standing up were −23.3 ± 17.2% in OH+, +0.6 ± 14.6% in OH‐, −2.3 ± 15.1% in CAN‐, and −10.5 ± 11.1% in the control group (p < 0.05 for OH+ vs. the other groups). Patients with diabetes mellitus complicated by CAN and OH may show instability in cerebral blood flow regulation on standing. Whether this finding is associated with a higher susceptibility to stroke in these patients remains to be established in prospective studies.
Langerhans Islet Implants in Diabetic Patients. Preliminary Results
Authors: Alcázar‐Montenegro H , Alvarado‐Vásquez N , Alc·zar‐Leyva S
Published: March 2003

Glycolysis, the Krebs cycle, oxidative phosphorylation and the pentose cycle are blocked in diabetes mellitus (DM). This results in alterations in the production of ATP and an increase in free radicals which damage protein lipids and DNAmt. In 1981, Cerami et al. stated that an excess of glucose is the cause of the classical complications in diabetics. The transplanting of pancreatic beta cells was proposed as a method of control for diabetes mellitus. This procedure in animals and humans has given rise to encouraging results, but only in patients receiving immunosuppressive therapy for renal transplants. On an experimental basis, we have implanted pancreatic beta islets and have obtained a reduction in glucose levels. In the present paper we evaluate the clinical and laboratory response of diabetic patients who, prior treatment with a modified form of RNAt (RNAt HAM) to induce the synthesis of IFN, received parenteral implants of Langerhans islets extracted from sheep. Immediately after, patients were given parenteral injections of thiamine pyrophosphate (X‐2). Three days after the implant blood glucose levels had reduced. Clinical improvement was recorded through the disappearance of asthenia, adynamia and depression. The administration of hypoglycemic agents or insulin was reduced or suspended according to laboratory results. We conclude that the implanting of pancreatic islets is a good option for the treatment of DM, on condition that RNAt HAM is used to avoid rejection from immunological tolerance.
Arterial Rigidity And Cardiovascular Sympathetic Tone In Hypertensive Obese And Type 2 Diabetic Patients
Authors: Valensi P , Dabire H , Brahimi M , Platon P , Hadj‐Brahim F , Attali Jr
Published: March 2003

An increase of arterial rigidity and sympathetic activity has been suggested to contribute to essential hypertension. We have shown that vagal control of heart rate (HR) variations during standardized tests is similarly impaired in normotensive obese and type 2 diabetic patients. The aim was to compare cardiovascular vagosympathetic balance and the link between pulse pressure, an index of arterial rigidity, and sympathetic activity in normotensive and hypertensive obese and type 2 diabetic patients. Groups 1 and 2 consisted of 70 normotensive and 32 hypertensive obese patients, groups 3 and 4 of 18 normotensive and 14 hypertensive diabetic patients respectively. HR and blood pressure (BP) variations were studied with a plethysmographic system and spectral analysis (Finapres). During a 5 min‐period at a controlled breathing rate, in the 4 groups, the high frequency peak of HR variations (vagal control) was significantly lower than in controls (19 healthy subjects), and the mid/high frequency peak ratio of HR variations was significantly increased. During a standing test, the mid‐frequency peak of systolic BP variations (sympathetic activity) did not differ significantly in obese or diabetic patients, either normotensive or hypertensive, and in controls. This peak correlated significantly with pulse pressure in groups 2 and 4 and in the control group but not in groups 1 and 3. In conclusion, 1) spectral analysis confirms that in obese and diabetic patients vagal control of HR variations is similarly reduced and suggests that sympathetic activity is relatively increased ; 2) in hypertensive patients sympathetic tone is not higher than in normotensive ones, but may contribute to arterial rigidity.
One Year Follow‐Up In Diabetic Patients After Surgical Treatment Of Carpal Tunnel Syndrome
Authors: Reljanovic M , Barada A , Bilic R , Kovijanic J.
Published: March 2003

The aim of the study was to evaluate clinical and neurophysiological changes in diabetic patients who had the surgery of carpal tunnel syndrome (CTS). The group consisted of 61 diabetic patients with the clinical and neurophysiological signs of CTS, with mean age 50.3 (± 27.3) and diabetes duration 13.5 years (± 8.9). The response to treatment was evaluated using visual analogue scale (VAS) for pain and for paresthesias prior to surgery, as well as 3 and 12 months after. At the same time we compared the median motor distal latency, amplitude of motor nerve action potentials, sensory conduction velocity and amplitude of sensory nerve action potentials in distal segment of median nerve as well as vibration perception threshold. The improvement was found for pain (baseline VAS 4.5 cm vs. follow‐up VAS 1.5 cm; Wilcoxon p = 0.00365) and for paresthesias (baseline VAS 5.4 cm vs. follow‐up VAS 0.8 cm; Wilcoxon p = 0.00000) after 3 months. Subjective pain and paresthesias assessment remained at the improved level after 12 months of follow‐up. Neurophysiological parameters measured were shown to improve after 3 and 12 months of follow‐up period: median motor distal latency (baseline 5.9 ms/6 cm, 3 months 4.8 ms/6 cm, 12 months 4.1 ms/6 cm; ANOVA p < 0.00000), amplitude of median motor action potential (baseline 4.8 mV, 3 months 5.6 mV, 12 months 6.6 mV., ANOVA p < 0.01040), median sensory conduction velocity in distal segment (baseline 37.9 m/s, 3 months 43.0 m/s, 12 months 47.3 m/s, ANOVA p < 0.00464), vibration perception threshold (baseline 9.8 V, 3 months 7.6 V, 12 months 6.8 V; ANOVA p < 0.00006). Concerning our results, the clinical and neurophysiological parameters supported surgery as the effective treatment for CTS in diabetics.