Small- and large-fiber neuropathy after 40 years of type 1 diabetes associations with glycemic control and advanced protein glycation: the Oslo Study

OBJECTIVE To study large- and small-nerve fiber function in type 1 diabetes of long duration and associations with HbA1c and the advanced glycation end products (AGEs) N-&#949-(carboxymethyl)lysine (CML) and methylglyoxal-derived hydroimidazolone. RESEARCH DESIGN AND METHODS In a long-term follow-up study, 27 persons with type 1 diabetes of 40 &#177 3 years duration underwent large-nerve fiber examinations, with nerve conduction studies at baseline and years 8, 17, and 27. Small-fiber functions were assessed by quantitative sensory thresholds (QST) and intraepidermal nerve fiber density (IENFD) at year 27. HbA1cwas measured prospectively through 27 years. Serum CML was measured at year 17 by immunoassay. Serum hydroimidazolone was measured at year 27 with liquid chromatography– mass spectrometry. RESULTS Sixteen patients (59%) had large-fiber neuropathy. Twenty-two (81%) had smallfiber dysfunction by QST. Heat pain thresholds in the foot were associated with hydroimidazolone and HbA1c. IENFD was abnormal in 19 (70%) and significantly lower in diabetic patients than in age-matched control subjects (4.3 &#177 2.3 vs. 11.2 &#177 3.5 mm, P , 0.001). IENFD correlated negatively with HbA1c over 27 years (r = 20.4, P = 0.04) and CML (r = 20.5, P = 0.01). After adjustment for age, height, and BMI in a multiple linear regression model, CML was still independently associated with IENFD. CONCLUSIONS Small-fiber sensory neuropathy is a major manifestation in type 1 diabetes of 40 years duration and more prevalent than large-fiber neuropathy. HbA1c and the AGEs CML and hydroimidazolone are important risk factors in the development of large- and small-fiber dysfunction in long-term type 1 diabetes

Les Médecins de Louis XlV : un mémoire sur la médecine du 17ème siècle, la santé et les médecins de Louis XlV ainsi que ses initiatives pour le développement de la médecine

Résumé : Le but de ce mémoire est de décrire la santé à la cour de Louis XlV et plus précisément la santé du roi lui- même, la pratique de ses médecins et les traitements qui lui sont ordonnés, ainsi que de tenter d’analyser le rôle de la médecine au 17ème siècle. La médecine du 17ème siècle était une médecine impuissante, sans réelle capacité de guérir les patients. De l’Antiquité à la fin du 17ème siècle, les connaissances médicales étaient sans fondement scientifique. Au temps de Louis XlV, il régnait une ignorance presque totale. Basée sur les idées d’Hippocrate et Galien, on a cru que la santé était une harmonie entre des humeurs, et que la maladie représentait une déséquilibre. Les traitements consistaient à redresser l’harmonie entre ces humeurs, ce qu’on faisait avec des purges, des lavements et des saignées, associés à des drogues ou préparations les plus fantaisistes. La médecine était sans lien avec la réalité physiologique ou même le simple bon sens. Mais, une évolution de la pensée scientifique et l’emploi systématique de la méthode expérimentale a déjà commencé au 16ème siècle, et au 17ème siècle on assiste à une évolution rapide des connaissances, connue sous le nom de Révolution scientifique. De nombreuses découvertes importantes ont été faites, comme la circulation du sang, du lymphatique. Grâce au microscope on découvre les « cellules », et les spermatozoïdes. Mais les nouvelles découvertes n’ont pas changé les traitements thérapeutiques, ni augmenté l’espérance de vie qui est restée inférieure à 25 ans. Louis XlV souffrait, contrairement à ce qu’on peut imaginer à cause de sa longévité (77 ans), d’un grand nombre de maladies et risqua à plusieurs reprises de mourir. Il est traité en accord avec les doctrines de son temps, en particulier avec des saignées, des lavements et des purges. Il a survécu grâce à sa constitution robuste et malgré les traitements de ses médecins. L’éducation médicale était au 17ème siècle en France dispersée dans de nombreuses facultés qui formaient les étudiants d’une manière non conforme. Louis XlV a joué un rôle considérable pour l’amélioration de l’éducation médicale et l’exercice de la médecine dans son royaume, en ayant créé l’Académie de Sciences en 1666. Au 17ème siècle, les seuls gestes thérapeutiques venaient de la chirurgie. Louis XlV est en particulier responsable, en collaboration avec ses premiers chirurgiens, de l’augmentation de la réputation de la chirurgie française. Leurs efforts ont été indispensables pour la fondation de L’académie royale de la chirurgie en 1731

Cold allodynia is correlated to paroxysmal and evoked mechanical pain in complex regional pain syndrome (CRPS)

Objectives Mechanisms of complex regional pain syndrome (CRPS) are still debated. Identifying subgroups of patients have been attempted in the hope of linking clinical findings to possible mechanisms. The aim of the present study was to investigate whether subgroups of CRPS (based on quantitative sensory testing (QST)-results) differed with respect to different characteristics of pain like spontaneous ongoing or paroxysmal pain and mechanical dynamic allodynia. Methods 61 CRPS-patients (type 1 and 2) were examined clinically and with QST, in affected and contralateral extremity, with assessment of thresholds for warmth, cold and heat-and cold pain. Results 43 patients (20 men, 23 men) were diagnosed with CRPS 1 (70.5%) and 18 patients (8 women and 10 men) with CRPS 2 (29.5%). Three subgroups were defined based on thermal thresholds; A (thermal allodynia 22.9%), B (thermal hyposensitivity 37.3%), C (thermal allodynia and hyposensitivity 39.3%). Paroxysmal pain was more prevalent in patients with thermal allodynia (merging group A + C, 25/38–65.8%) compared to patients without thermal allodynia (group B, 5/23–21.7%) (p-value=0.00085). Conclusions We suggest that cold allodynia is based on hyper-excitability of very superficial skin nociceptors. The correlation between paroxysmal pain, allodynia to light touch and cold allodynia suggests that activity in those peripheral nociceptors can drive both, paroxysmal pain and spinal sensitization leading to stroke evoked allodynia. Mechanistically, the physical cold stimulus can unmask disease-related hyperexcitability by closure of temperature-sensitive potassium channels or induction of resurgent currents. Small fiber degeneration alone may not be the crucial mechanism in CRPS, nor explain pain

Pathological nociceptors in two patients with erythromelalgia-like symptoms and rare genetic Nav 1.9 variants

Introduction: The sodium channel Nav 1.9 is expressed in peripheral nociceptors and has recently been linked to human pain conditions, but the exact role of Nav 1.9 for human nociceptor excitability is still unclear. Methods: C-nociceptors from two patients with late onset of erythromelalgia-like pain, signs of small fiber neuropathy, and rare genetic variants of Nav 1.9 (N1169S, I1293V) were assessed by microneurography. Results: Compared with patients with comparable pain phenotypes (erythromelalgia-like pain without Nav-mutations and painful polyneuropathy), there was a tendency toward more activity-dependent slowing of conduction velocity in mechanoinsensitive C-nociceptors. Hyperexcitability to heating and electrical stimulation were seen in some nociceptors, and other unspecific signs of increased excitability, including spontaneous activity and mechanical sensitization, were also observed. Conclusions: Although the functional roles of these genetic variants are still unknown, the microneurography findings may be compatible with increased C-nociceptor excitability based on increased Nav 1.9 function

Mild phenotype in an adult male with X-linked adrenoleukodystrophy – case report

Key Clinical Message X-linked adrenoleukodystrophy may present with a deceptively mild phenotype, even in adult males. Tight collaboration between clinicians, geneticists, biochemists, and other specialists is increasingly required for clarification of diagnosis in cases with atypical presentation

Milde phenotype in an adult male With X-linked adrenoleukodystrophy

Key Clinical Message:X-linked adrenoleukodystrophy may present with a deceptively mild phenotype, even in adult males. Tight collaboration between clinicians, geneticists, biochemists, and other specialists is increasingly required for clarification of diagnosis in cases with atypical presentation

Maximum axonal following frequency separates classes of cutaneous unmyelinated nociceptors in the pig

Using extracellular single‐fibre recordings from the saphenous nerve in pig in vivo, we investigated peak following frequencies (5–100 Hz) in different classes of C‐nociceptors and their modulation by nerve growth factor. Classes were defined by sensory (mechano‐sensitivity) and axonal characteristics (activity dependent slowing of conduction, ADS). Mechano‐insensitive C‐nociceptors (CMi) showed the highest ADS (34% ± 8%), followed only 66% ± 27% of 75 pulses at 5 Hz and increasingly blocked conduction at higher frequencies. Three weeks following intradermal injections of nerve growth factor, peak following frequency increased specifically in the sensitized mechano‐insensitive nociceptors (20% ± 16% to 38% ± 23% response rate after 72 pulses at 100 Hz). In contrast, untreated polymodal nociceptors with moderate ADS (15.2% ± 10.2%) followed stimulation frequencies of 100 Hz without conduction failure (98.5% ± 6%). A distinct class of C‐nociceptors was exclusively sensitive to strong forces above 150 mN. This class had a high ADS (27.2% ± 7.6%), but displayed almost no propagation failure even at 100 Hz stimulation (84.7% ± 17%). Also, among human mechanosensitive nociceptors (n = 153) those with thresholds above 150 mN (n = 5) showed ADS typical of silent nociceptors. C‐fibres with particularly high mechanical thresholds and high following frequency form a distinct nociceptor class ideally suited to encode noxious mechanical stimulation under normal conditions when regular silent nociceptors are inactive. Sensitization by nerve growth factor increases maximum discharge frequency of silent nociceptors, thereby increasing the frequency range beyond their physiological limit, which possibly contributes to excruciating pain under inflammatory conditions

Abnormal Function of C-Fibers in Patients with Diabetic Neuropathy

The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36–67 years old), and these were compared with 77 C-fibers from healthy controls (41–64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was ~2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechano-responsive nociceptors. Copyright © 2006 Society for Neuroscienc

Neurobiology of Disease Abnormal Function of C-Fibers in Patients with Diabetic Neuropathy

The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36 -67 years old), and these were compared with 77 C-fibers from healthy controls (41-64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was ϳ2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechanoresponsive nociceptors

Abstracts from The Cold Weather Operations Conference 2021

A common effort for both military and civil healthcare is to achieve knowledge-based health care in cold weather injuries and fatal accidents in harsh arctic environment. The Cold Weather Operations Conference in November 2021, having more than 300 participants from 20 countries, was addressing the prevention and treatment of injuries and trauma care in cold weather conditions and the challenges for military prehospital casualty care. The intention of the programme was to stimulate further research and systematic knowledge-based clinical work. The abstracts from the conference present cold weather research and clinical experience relevant for readers of the International Journal of Circumpolar Health