Journal of the Peripheral Nervous System 7:65–69 (2002)

© 2002 Peripheral Nerve Society, Inc.

65

Blackwell Science Publishers

PERIPHERAL NEUROPATHY IN SYSTEMIC LUPUS ERYTHEMATOSUS - A LONGITUDINAL STUDY

Omdal R, Loseth S, Torbergsen T, Koldingsnes W, Husby G,

Mellgren SI

.

Acta Neurologica Scandinavica 103: 386–391,2001. Reprinted with permission from Munksgaard Interna-tional Publishers, Ltd.

Objective - Peripheral neuropathy (PN) is reported tooccur in 5–27% of patients with systemic lupus erythematosus(SLE) mostly as a length-dependent sensorimotor axonopa-thy. Studies over time have not been performed. Design -Longitudinal study. Subjects and methods - Thirty-three Cau-casian SLE patients consented to participate in the studyand were subjected to clinical examination, laboratory tests,and nerve conduction velocity (NCV) studies. At the follow-up 7 years later, 7 patients (21%) were dead, 4 refused toparticipate, and 2 did not want to perform NCV studies.Twenty patients were thus available for longitudinal study.Results - When all SLE patients were considered on a groupbasis at follow-up, 8 (33%) out of 24 NCV parametersshowed significant deterioration despite correction for time,while 16 (67%) were unchanged. Analysis of change frombaseline showed that, except for F-responses, several NCVchanges were highly dependent (negative regression coeffi-cients) on baseline levels at start of study. No demographic,laboratory, or disease associated quantitative factor wasassociated with these changes in NCV parameters overtime. Nor was a consistent effect on NCV parameters fromany qualitative demographic or disease associated factorconfirmed by Repeated Measures ANOVA analyses. Conclu-sions - A modest progressive neuropathic process exists inpatients with SLE. Important is also the finding that, overtime, the abnormalities of NCV parameters fluctuate in theindividual patients, and the impairments are not necessarilyirreversible. This study also shows no association to medica-tion, demographic-, or other disease associated factors.

BONE MARROW TRANSFER FROM WILD-TYPE MICE REVERTS THE BENEFICIAL EFFECT OF GENETICALLY MEDIATED IMMUNE DEFICIENCY IN MYELIN MUTANTS

Maurer M, Schmid CD, Bootz F, Zielasek J, Toyka KV, OehenS, Martini R

.

Molecular and Cellular Neuroscience 17: 1094–1101, 2001. Reprinted with permission from Academic Press, Inc.

Inherited demyelinating neuropathies are chronically dis-abling human disorders caused by various genetic defects,including deletions, single site mutations, and duplications inthe respective myelin genes. We have shown in a mousemodel of one distinct hereditary demyelinating neuropathy

(heterozygous PO-deficiency, PO

�

) that an additional nullmutation in the recombination activating gene-1 (RAG-1--)leads to a substantially milder disorder, indicating a diseasemodifying role of T-lymphocytes. In the present study, weaddressed the role of lymphocytes in the mouse model byreconstituting bone marrow of PO

�

/RAG-1-- mice with bonemarrow from immunocompetent wild-type mice. We com-pared the pathology and nerve conduction in double mutantmice (PO

�

/RAG-1-- on a C57BL/6 background) with that indouble mutants after receiving a bone marrow transplant.We found that the milder demyelination seen in the lympho-cyte-deficient PO

�

/RAG-1-- mutants was reverted to themore severe pathology by reestablishing a competentimmune system by bone marrow transfer. These data cor-roborate the concept that the immune system contributessubstantially to the pathologic process in this mouse modeland may open new avenues to ameliorate human hereditaryneuropathies by exploiting immunosuppressive treatments.

ACUTE ONSET OF INFANTILE SPINAL MUSCULAR ATROPHY

Ravid S, Topper L, Eviatar L

.

Pediatric Neurology 24: 371–372,2001. Reprinted with permission from Elsevier Science, Inc.

Two patients with acute generalized weakness andareflexia are presented. The electrophysiologic studies inboth revealed evidence of decreased conduction velocityand mixed axonal and demyelinating neuropathy, suggestiveof the diagnosis of Guillain-Barré syndrome. The young agesof the patients and their failure to respond to immunoglobu-lin therapy were the major clues to the final diagnosis of spi-nal muscular atrophy type I. Blood for DNA study revealedhomozygous deletion mutation in exons 7 and 8 of the sur-vival motor neuron gene. This diagnosis should be consid-ered in every child under 1 year of age who presents withacute weakness because Guillain-Barré syndrome in this agegroup is rare.

METHYLPREDNISOLONE MAY IMPROVE LUMBOSACRAL RADICULOPLEXUS NEUROPATHY

Dyck PJB, Norell JE, Dyck PJ

.

Canadian Journal of Neuro-logical Sciences 28: 224–227, 2001. Reprinted with permissionfrom the Canadian Journal of Neurological Sciences, Inc.

Objective: To report on an open trial of intravenousmethylprednisolone (IV MP) in nondiabetic lumbosacralradiculoplexus neuropathy (LSRPN). Background. Lumbosac-ral radiculoplexus neuropathy is a subacute, unilateral orasymmetric syndrome of pain, weakness, and paresthesia

Abstracts of selected articles recently published in the medical literature

Neuropathy Abstracts

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of the lower extremity, which is attributed to ischemic injuryfrom microvasculitis in lumbosacral roots, plexus, and nerves.Methods: Eleven nondiabetic patients with worsening LSRPNwere treated - ten with infusions of IV MP (1 gm/wk) for 8 to16 weeks and one with an equivalent dosage of oral pred-nisone. The main endpoints evaluated were: 1) the Neuro-pathy Impairment Score (NIS), and 2) the NeuropathySymptoms and Change (NSC) scores. Results: The medianage of our patients was 67 years, range 49 to 86 years. Sevenpatients were women. All 11 patients reported improvementduring treatment—nine reported marked improvement. Themedian NIS improved from 42 points (range 9 to 106 points)before treatment, to 20 points (range 5 to 57 points) (p =0.005) after treatment. Pain was completely resolved in fourpatients and much improved in seven. The change subscoreand the severity subscore of the NSC were statistically signif-icantly improved after treatment. Prior to treatment, allpatients had significant weakness with six confined towheelchairs and four using mechanical devices to aid inambulation. After treatment, the weakness was markedlyimproved in nine patients; only one still required a wheelchairand six walked independently (p = 0.03). Conclusions: 1) InLSRPN, pain and neurological deficits improved (often dra-matically) with IV MP treatment. 2) Although our resultsshould be interpreted with caution since this trial is uncon-trolled, IV MP may favorably affect the natural history ofLSRPN. 3) The results are sufficiently promising to provide arationale for prospective, sham controlled, double blind tri-als.

STATUS OF CURRENT CLINICAL TRIALS INDIABETIC POLYNEUROPATHY

Bril V

.

Canadian Journal of Neurological Sciences 28: 191–198, 2001. Reprinted with permission from the CanadianJournal of Neurological Sciences, Inc.

Peripheral polyneuropathy is the most frequent compli-cation of diabetic mellitus. In spite of many clinical trials ofdifferent specific interventions for diabetic polyneuropathy,intensive glycemic control remains the only effective spe-cific therapy currently available for this troublesome compli-cation. This systematic overview reports the status of currentclinical trials in diabetic polyneuropathy with an emphasis onthose interventions directed towards specific pathophysio-logical derangements. A discussion of clinical trials of agentsdirected towards relieving painful symptoms of diabetic poly-neuropathy concludes this overview.

PROGRESS IN CLINICAL NEUROSCIENCES: CHARCOT-MARIE-TOOTH DISEASE AND RELATED INHERITED PERIPHERAL NEUROPATHIES

Benstead TJ, Grant IA

.

Canadian Journal of NeurologicalSciences 28: 199–214, 2001. Reprinted with permissionfrom the Canadian Journal of Neurological Sciences, Inc.

The classification of Charcot-Marie-Tooth disease andrelated hereditary motor and sensory neuropathies hasevolved to incorporate clinical, electrophysiological and bur-geoning molecular genetic information that characterize themany disorders. For several inherited neuropathies, the gene

product abnormality is known and for others, candidate geneshave been identified. Genetic testing can pinpoint a specificinherited neuropathy for many patients. However, clinical andelectrophysiological assessments continue to be essential toolsfor diagnosis and management of this disease group. This articlereviews clinical, electrophysiological, pathological and molecularaspects of hereditary motor and sensory neuropathies.

NERVE GROWTH FACTOR RESCUE OF CISPLATIN NEUROTOXICITY IS MEDIATED THROUGH THE HIGH AFFINITY RECEPTOR: STUDIES IN PC12 CELLS AND P75 NULL MOUSE DORSAL ROOT GANGLIA

Fischer SJ, Podratz JL, Windebank AJ

.

Neuroscience Let-ters 308: 1–4, 2001. Reprinted with permission from ElsevierScience Ireland, Ltd.

Nerve growth factor (NGF) rescues dorsal root ganglionneurons and PC12 cells from cisplatin-induced cell death.Two model systems were used to demonstrate that rescueis mediated through the high affinity NGF receptor. In dorsalroot ganglion (DRG) neurons isolated from p75(

�

/

�

) andcontrol mice, 20 ng/ml NGF completely prevented cisplatin-induced death. In PC12 cells, we overexpressed receptorchimeras between the tumor necrosis factor and NGF recep-tors. We demonstrated that activation of the intracellulardomain of Trk A is responsible for the NGF rescue effect.

LATE-ONSET GM2 GANGLIOSIDOSIS PRESENTING AS BURNING DYSESTHESIAS

Chow GCS, Clarke JTR, Banwell BL

.

Pediatric Neurology 25:59–61, 2001. Reprinted with permission from Elsevier Sci-ence, Inc.

Two brothers with a painful neuropathy as a componentof late-onset GM2 gangliosidosis of the Sandhoff type arepresented. A dramatic response of the severe dysesthesiasto amitriptyline and gabapentin is described. Symptomaticsensory neuropathy may be a component of late-onset GM2gangliosidosis.

DIAGNOSTIC INVESTIGATION OF PATIENTS WITH CHRONIC POLYNEUROPATHY: EVALUATION OF A CLINICAL GUIDELINE

Rosenberg NR, Portegies P, de Visser M, Vermeulen M

.

Journal of Neurology Neurosurgery and Psychiatry 71: 205–209, 2001. Reprinted with permission from the British Medi-cal Journal Publishing Group.

Objective: (1) To evaluate a clinical guideline for thediagnostic investigation of patients presenting with signsand symptoms (present for longer than 6 weeks) suggest-ing a chronic polyneuropathy. (2) To investigate the contribu-tion of electrophysiological studies to a focused search foraetiology in these patients. Methods: A chart review wascarried out of a consecutive group of outpatients in 1993-7at a university department of neurology, with signs andsymptoms suggesting a polyneuropathy in whom the diag-nostic investigation had been carried out according to arecently introduced guideline. Diagnostic tests were per-formed and final diagnoses were made. Results: Unneces-

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sary investigations were carried out in 108 (51%) of 213patients and too few tests in 23 (11%) of these patients. In82 (48%) of the 172 patients who fulfilled the inclusion cri-teria neurophysiological tests did not contribute to the finaldiagnosis. Neurophysiological criteria for demyelination werefulfilled in only 13 (8%) of the 172 patients. Conclusion: Inpatients presenting with signs and symptoms of chronicpolyneuropathy the number of tests in the diagnostic investi-gation can be considerably reduced. In patients with signsand symptoms of polyneuropathy, providing the clinical phe-notype is typical, in the presence of diabetes mellitus, renalfailure, HIV infection, alcoholism, or use of potentially neu-rotoxic drugs further investigations are non-contributory.The significance of electrophysiological studies in the inves-tigation of patients with polyneuropathy is rather to separatesensorimotor neuropathies from pure sensory neuropathiesthan to distinguish between demyelinating and axonal neuro-pathies.

PERIPHERAL NEUROPATHY IN CHRONIC OCCUPATIONAL INORGANIC LEAD EXPOSURE: A CLINICAL AND ELECTROPHYSIOLOGICAL STUDY

Rubens O, Logina I, Kravale I, Eglite M, Donaghy M

.

Journal of Neurology Neurosurgery and Psychiatry 71: 200–204, 2001. Reprinted with permission from the British Medi-cal Journal Publishing Group.

Background and Objectives: Traditionally the neuromus-cular disorder associated with lead poisoning has beenpurely motor. This study assessed peripheral nerve functionclinically and electrophysiologically in 46 patients with neuro-pathic features out of a total population of 151 workers withraised blood and/or urinary lead concentrations. Results:Average duration of occupational exposure for the neuro-pathic group ranged from 8–47 years (mean 21.7). Their meanblood lead concentration (SD) was 63.9 (18.3) microg/dl (nor-mal

�

40), urinary lead 8.6 (3.3) microg/dl (normal

�

5.0), uri-nary coproporphyrins 66.7 (38.4) microg/g creatinine (20–80), urinary aminolaevulinic acid 1.54 (0.39) mg/g creatinine(0.5–2.5). All 46 had distal paraesthesiae, pain, impaired pinprick sensation, diminished or absent ankle jerks, and auto-nomic vasomotor or sudomotor disturbances. Reduced vibra-tion sensation and postural hypotension were present in all20 studied. None of these 46 patients had motor abnormali-ties. Motor conduction velocity and compound muscle actionpotential amplitudes were normal, with marginally prolongeddistal motor latencies. Sensory nerve action potential ampli-tudes lay at the lower end of the normal range, and the distalsensory latencies were prolonged. No direct correlation wasfound between the biochemical variables, and the clinical orelectrophysiological data. Conclusions: One additional patientwas seen with shorter term exposure to lead fumes withsubacute development of colicky abdominal pain, severe limbweakness, and only minor sensory symptoms. Unlike thepatients chronically exposed to lead, he had massively raisedporphyrins (aminolaevulinic acid 21 mg/g creatinine, copropo-rhyrins 2102 microg/g creatinine). Patients with unusuallylong term inorganic lead exposure showed mild sensory andautonomic neuropathic features rather than the motor neu-

ropathy classically attributed to lead toxicity. It is proposedthat the traditional motor syndrome associated with sub-acute lead poisoning is more likely to be a form of leadinduced porphyria rather than a direct neurotoxic effect oflead.

EFFECTS OF LISINOPRIL ON STREPTOZOTOCIN-INDUCED DIABETIC NEUROPATHY IN RATS

Aggarwal M, Singh J, Sood S, Arora B

.

Methods and Find-ings in Experimental and Clinical Pharmacology 23: 131–134,2001. Reprinted with permission from Prous Science, SA.

Streptozotocin (STZ)-induced diabetic neuropathy in ratswas monitored by measuring the motor nerve conductionvelocity (MNCV) and histopathology of the tibial nerve. Pre-treatment with lisinopril (2 mg/kg p.o., 5 days prior to STZand continued for 10 weeks) significantly (p

�

0.01) pre-vented deterioration of MNCV ms compared to STZ-diabeticanimals. Nerve sections from the lisinopril pretreated grouprevealed less structural damage as compared to STZ-diabeticrats. However lisinopril had no effect on blood sugar i.e., itdid not alter the diabetic state. It is concluded that lisinoprilprevents the development of experimental diabetic neuro-pathy in STZ-induced diabetic rats.

HEREDITARY SENSORY NEUROPATHY TYPE I: HAPLOTYPE ANALYSIS SHOWS FOUNDERS IN SOUTHERN ENGLAND AND EUROPE

Nicholson GA, Dawkins JL, Blair IP, Auer-Grumbach M,Brahmbhatt SB, Hulme DJ

.

American Journal of HumanGenetics 69: 655–659, 2001. Reprinted with permissionfrom the University of Chicago Press, http://www.journals.uchicago.edu/AJHG.

Hereditary sensory neuropathy type I (HSN1) is themost common dominantly inherited degenerative disorderof sensory neurons. The gene mutation was mapped tochromosome 9 in a large Australian family, descended froman ancestor from southern England who was a convict.Dawkins et al. recently reported gene mutations in theSPTLC1 gene, in this and other families. The first descriptionof hereditary sensory neuropathy, by Hicks, was in a familyfrom London and Exeter. To determine if the families in thepresent study that have SPTLC1 mutations are related toEnglish families with HSN1 and, possibly, to the family stud-ied by Hicks, we performed haplotype analysis of four Aus-tralian families of English extraction, four English families,and one Austrian family. Three Australian families of Englishextraction and three English families (two of whom havebeen described elsewhere) had the 399T

→

G SPTLC1 muta-tion, the same chromosome 9 haplotype, and the same phe-notype. The Australian and English families may thereforehave a common founder who, on the basis of historical infor-mation, has been determined to have lived in southernEngland prior to 1800. The sensorimotor neuropathy pheno-type caused by the 399T

→

G SPTLC1 mutation is the sameas that reported by Campbell and Hoffman and, possibly, thesame as that originally described by Hicks.

Abstracts Journal of the Peripheral Nervous System 7:65–69 (2002)

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CORTICOSPINAL TRACT INVOLVEMENT IN A VARIANT OF GUILLAIN-BARRÉ SYNDROME

Oshima Y, Mitsui T, Endo I, Umaki Y, Matsumoto T

.

EuropeanNeurology 46: 39–42, 2001. Reprinted with permission fromKarger.

To determine the involvement of the corticospinal tractin Guillain-Barré syndrome (GBS), we examined central motorconduction in patients with GBS-like symptoms and hyperre-flexia using a magnetic stimulation technique. The subjectswere 3 patients who exhibited ascending muscle weakness2–4 weeks after preceding infections. Deep tendon reflexeswere exaggerated in all four limbs of the 3 patients. Theresults of cerebrospinal fluid examinations revealed proteinelevation without pleocytosis. The serum anti-GM(1) anti-body titer was elevated in 2 patients. The results of nerveconduction study revealed axonal motor neuropathy and nor-mal F-wave conduction. Central motor conduction time (CMCT)in patients with hyperreflexia was significantly delayed com-pared to that in patients with GBS and areflexia (p

�

0.001),and the delayed CMCTs were significantly improved in therecovery periods (p

�

0.001). Although hyperreflexia is a con-troversial symptom in patients with GBS, these findings indi-cate that there is functional corticospinal tract involvement inpatients with a GBS variant.

PARAPROTEINEMIC NEUROPATHIES

Vital A.

Brain Pathology 11: 399–407, 2001. Reprinted withpermission from the International Society of Neuropathology.

The occurrence of a peripheral neuropathy (PN) in asso-ciation with a monoclonal gammopathy is quite commonand suggests that monoclonal proteins may play a pathoge-netic role in peripheral nervous system damage. In fact,paraproteinemic PN constitute an heterogeneous group ofdisorders related to various pathogenetic factors, and thehistopathologic features in peripheral nerve biopsies differfrom one condition to another. In several well defined disor-ders, the responsibility of the monoclonal component in thedevelopment of the PN has been evidenced. This is the casefor most of the PN associated with an IgM monoclonal gam-mopathy, either a monoclonal gammopathy of undeterminedsignificance (MGUS) or Waldenstrom’s macroglobulinemia.The responsibility of the monoclonal protein in the occur-rence of amyloid neuropathy related to multiple myeloma isalso recognized. However, most IgG or IgA MGUS, as wellas the monoclonal component in POEMS syndrome, havean uncertain causal relationship with the neuropathy. PNassociated with monoclonal cryoglobulin (type 1) are occa-sional and differ from those associated with mixed cryoglob-ulins (types 2 or 3).

THERAPEUTIC POTENTIAL OF PKC INHIBITORS IN PAINFUL DIABETIC NEUROPATHY

Kamei J, Mizoguchi H, Narita M, Tseng LF

.

Expert Opinionon Investigational Drugs 10: 1653–1664, 2001. Reprinted withpermission from Ashley Publications, Ltd.

Diabetic neuropathy accompanied by anomalies in painperception is one of the most frequent complications ininsulin-dependent diabetes in humans. Many clinical and

experimental studies have suggested that diabetes or hyper-glycaemia alters pain sensitivity. In humans, diabetic neuro-pathy can be associated with burning, tactile hypersensitivity.Behavioural reactions of hyperalgesia in animal models of dia-betes have been described. However, the aetiology of thesedisturbances is still unknown, although metabolic factorssuch as hyperglycaemia or neurotransmitter alteration maybe involved. Activation of protein kinase C (PKC) has beenimplicated in changes in pain perception. Phorbol esters,which activate PKC, enhance the thermal hyperalgesia in dia-betic mice and enhance nociceptive responses after tissueinjury induced by formalin. Electrophysiological experimentshave shown that activation of PKC leads to long-lastingenhancement of excitatory amino acid-mediated currents indorsal horn neurons and trigeminal neurons. Thus, activationof PKC may underlie the neuronal sensitisation that pro-duces hyperalgesia in diabetic neuropathy.

SEQUENCE TYPING CONFIRMS THAT CAMPYLOBACTER JEJUNI STRAINS ASSOCIATED WITH GUILLAIN-BARRÉ AND MILLER-FISHER SYNDROMES ARE OF DIVERSE GENETIC LINEAGE, SEROTYPE, AND FLAGELLA TYPE

Dingle KE, Van den Braak N, Colles FM, Price LJ, Wood-ward DL, Rodgers FG, Endtz HP, Van Belkum A, MaidenMCJ

.

Journal of Clinical Microbiology 39: 3346–3349, 2001.Reprinted with permission from the American Society forMicrobiology.

Guillain-Barré syndrome (GBS) and Miller-Fisher syndrome(MFS) are correlated with prior infection by Campylobacterjejuni in up to 40% of cases. Nucleotide sequence-based typ-ing of 25 C. jejuni isolates associated with neuropathypermitted robust comparisons with equivalent data fromapproximately 800 C. jejuni isolates not associated with neu-ropathy. A total of 13 genetic lineages and 20 flaA short vari-able region nucleotide sequences were present among the25 isolates. A minority of isolates (4 of 25) had the flaA shortvariable region nucleotide sequences that were previouslyproposed as a marker for GBS-associated isolates. These 4isolates probably represented the Penner serotype 19 lineage,which has been proposed to have an association with GBS.

PERIPHERAL VASCULAR AND NERVE FUNCTION ASSOCIATED WITH LOWER LIMB AMPUTATION IN PEOPLE WITH AND WITHOUT DIABETES

Carrington AL, Abbott CA, Griffiths J, Jackson N,Johnson SR, Kulkarni J, Van Ross ERE, Boulton AJM

.

Clinical Science 101: 261–266, 2001. Reprinted with permis-sion from Portland Press, © the Biochemical Society and theMedical Research Society.

Multiple factors, including peripheral vascular diseaseand neuropathy, contribute to the development and perpetu-ation of complications of the lower extremities in diabetes.The main aim of the present study was to assess the periph-eral vascular and nerve status of diabetic and non-diabeticsubjects that had undergone lower limb amputation. Variousnon-invasive tests of peripheral vascular and nerve functionwere carried out on subjects who had undergone unilaterallower limb amputation and were now attending a Rehabilita-

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tion Centre. The control group (n = 23), the diabetic amputeegroup (n = 64) and the non-diabetic amputee group (n = 32)were age-matched. Only the diabetic amputee group hadevidence of medial arterial calcification. Transcutaneous oxy-gen levels were significantly lower in the diabetic amputeegroup (median 43 mmHg; interquartile range 33–49 mmHg)than in the control (59; 56–74 mmHg) and non-diabeticamputee (57; 43–65 mmHg) groups (control compared withdiabetic amputee group, P

�

0.001; diabetic amputee com-pared with non-diabetic amputee group, P

�

0.01). The sametrend was found for carbon dioxide levels in the skin [mmHg:diabetic amputees, 25 (21–37); controls, 38 (32–42); non-dia-betic amputee, 34 (31–39)] (control compared with diabeticamputee, P

�

0.01; diabetic amputee compared with non-diabetic amputee, P

�

0.05). Vibration and pressure percep-tion measurements (which assess A beta nerve fibre func-tion) showed that both the diabetic amputee and non-diabeticamputee subjects had significantly greater impairment thanthe controls. However, measures of A alpha and C nerve fibrefunction were abnormal only in the diabetic amputee group.Thus the peripheral vascular and nerve functions of age-matched diabetic and non-diabetic subjects having undergonelower limb amputation show specific differences, with non-diabetic amputees exhibiting signs of neuropathy. This indi-cates that factors characteristic of diabetes (such as hypergly-caemia and non-enzymic glycation) are associated withcalcification, lower oxygen and carbon dioxide levels in theskin, and abnormal A alpha and C nerve fibre function.

STEROID EFFECTS ON THE GENE EXPRESSION OF PERIPHERAL MYELIN PROTEINS

Melcangi RC, Magnaghi V, Galbiati M, Martini L

.

Hormonesand Behavior 40: 210–214, 2001. Reprinted with permissionfrom Academic Press, Inc.

The present article summarizes recent observationsobtained in our laboratory which clearly indicate that sex ste-roids exert relevant effects on the peripheral nervous sys-tem. In particular, the following important points haveemerged: (1) Steroids exert stimulatory actions on the syn-thesis of the proteins proper of the peripheral myelin (e.g.,glycoprotein Po and peripheral myelin protein 22) in vivo andon the Schwann cells in culture; (2) in many cases the actionsof hormonal steroids are not due to their native molecularforms but rather to their metabolites (e.g., dihydroprogester-

one and tetrahydroprogesterone in the case of progesterone;dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol in the case of testosterone); (3) the mechanism ofaction of the various steroidal molecules may involve bothclassical (progesterone and androgen receptors) and nonclas-sical steroid receptors (GABA, receptor); and finally, (4) thestimulatory action of steroid hormones on the proteins of theperipheral myelin might have clinical significance in cases inwhich the rebuilding of myelin is needed (e.g., aging, periph-eral injury, demyelinating diseases, and diabetic neuropathy).

DERMAL NEUROVASCULAR DYSFUNCTION INTYPE 2 DIABETES

Vinik AI, Erbas T, Park TS, Stansberry KB, Scanelli JA, Pit-tenger GL

.

Diabetes Care 24: 1468–1475, 2001. Reprintedwith permission from the American Diabetes Association.

OBJECTIVE: To review evidence for a relationship betweendermal neurovascular dysfunction and other components of themetabolic syndrome of type 2 diabetes. RESEARCH DESIGNAND METHODS: We review and present data supporting con-cepts relating dermal neurovascular function to prediabetesand the metabolic syndrome. Skin blood flow can be easilymeasured by laser Doppler techniques. RESULTS: Heat andgravity have been shown to have specific neural, nitrergic,and independent mediators to regulate skin blood flow. Wedescribe data showing that this new tool identifies dermalneurovascular dysfunction in the majority of type 2 diabeticpatients. The defect in skin vasodilation is detectable beforethe development of diabetes and is partially correctable withinsulin sensitizers. This defect is associated with C-fiber dys-function (i.e., the dermal neurovascular unit) and coexistswith variables of the insulin resistance syndrome. The defectmost likely results from an imbalance among the endoge-nous vasodilator compound nitric oxide, the vasodilator neu-ropeptides substance P and calcitonin gene-related peptide,and the vasoconstrictors angiotensin 11 and endothelin.Hypertension per se increases skin vasodilation and does notimpair the responses to gravity, which is opposite to that ofdiabetes, suggesting that the effects of diabetes override andcounteract those of hypertension. CONCLUSIONS: Theseobservations suggest that dermal neurovascular function islargely regulated by peripheral C-fiber neurons and that dys-regulation may be a component of the metabolic syndromeassociated with type 2 diabetes.