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Biomedical subjects

W R Kennedy

Publications and source records attributed to W R Kennedy.

At least 19 recordsLinked to original sources
PubMed2006

Morphological features of nerves in skin biopsies.

Skin biopsy is an effective test for diagnosis of peripheral nerve disorders. The most commonly reported indication of abnormality in a skin biopsy is reduction of epidermal nerve density. Morphological changes of epidermal nerves and the underlying subepidermal nerve plexus provide added evidence for the presence of neuropathy. We determined the prevalence of epidermal axon swellings, dermal axon swellings, and a unique type of epidermal nerve that we call a crawler, in a group of normal subjects, diabetic subjects, and patients with idiopathic small fiber neuropathy. Other morphologic features examined include thinning of the subepidermal nerve plexus, sprouts at nerve terminals, encapsulated endings, and immunoreactive basal cells.

Adult↗
PubMed2003

Diagnosis of diabetic autonomic neuropathy: a multivariate approach.

AIM/HYPOTHESIS: In the diagnosis of diabetic autonomic neuropathy (DAN) various autonomic tests are used. We took a novel statistical approach to find a combination of autonomic tests that best separates normal controls from patients with DAN. METHODS: Twenty-four patients with Type-1 diabetes mellitus considered as having mild to moderate DAN as well as 10 normal, nondiabetic control subjects were analysed, searching for a test or a combination of tests that would optimally discriminate Type-1 diabetes mellitus from controls. Variations of heart rate during deep breathing (deltaR6) and during a Valsalva manoeuvre (VR), the number of reactive sweat glands on the foot (testing sympathetic sudomotor function), and the response of human pancreatic polypeptide to hypoglycaemia [ln(deltahPP+1)] were evaluated. RESULTS: Respective values for respective sensitivity and specificity values were: deltaR6, 96 and 70%; VR, 96 and 60%; sweat gland function, 71 and 90%; and ln(deltahPP+1), 71 and 90%. In a multivariate analysis approach a single discriminant function separating patients with Type-1 diabetes mellitus from nondiabetic controls was generated [Logit P=288.5-[14.7 deltaR6]-[26.6 ln(deltahPP+1)]]. This function allowed complete separation of patients with Type-1 diabetes mellitus from normal controls. CONCLUSION/INTERPRETATION: We conclude that the combined determination of deltaR6 and of ln (deltahPP+1) optimally separates subjects with parasympathetic impairment from normal subjects. In addition, this combination of tests may serve as a sensitive method for the assessment of DAN.

Adult↗
PubMed2001

Functional interactions between tumor and peripheral nerve: changes in excitability and morphology of primary afferent fibers in a murine model of cancer pain.

We used a murine model to investigate functional interactions between tumors and peripheral nerves that may contribute to pain associated with cancer. Implantation of fibrosarcoma cells in and around the calcaneus bone produced mechanical hyperalgesia of the ipsilateral paw. Electrophysiological recordings from primary afferent fibers in control and hyperalgesic mice with tumor revealed the development of spontaneous activity (0.2-3.4 Hz) in 34% of cutaneous C-fibers adjacent to the tumor (9-17 d after implantation). C-fibers in tumor-bearing mice exhibited a mean decrease in heat threshold of 3.5 +/- 0.10 degrees C. We also examined innervation of the skin overlying the tumor. Epidermal nerve fibers (ENFs) were immunostained for protein gene product 9.5, imaged using confocal microscopy, and analyzed in terms of number of fibers per millimeter of epidermal length and branching (number of nodes per fiber). Divergent morphological changes were linked to tumor progression. Although branching of ENFs increased significantly relative to control values, in later stages (16-24 d after implantation) of tumor growth a sharp decrease in the number of ENFs was observed. This decay of epidermal innervation of skin over the tumor coincided temporally with gradual loss of electrophysiological activity in tumor-bearing mice. The development of spontaneous activity and sensitization to heat in C-fibers and increased innervation of cutaneous structures within the first 2 weeks of tumor growth suggest activation and sensitization of a proportion of C-fibers. The decrease in the number of ENFs observed in later stages of tumor development implicates neuropathic involvement in this model of cancer pain.

Animals↗
PubMed2001

Small fibers involvement in Friedreich's ataxia.

Although the involvement of large myelinated sensory fibers in Friedreich's ataxia (FA) is well documented, an impairment of unmyelinated fibers has not been described. We demonstrate an involvement of cutaneous unmyelinated sensory and autonomic nerve fibers in FA patients. We performed a morphological and functional study of cutaneous nerve fibers in 14 FA patients and in a population of control subjects. We used immunohistochemical techniques and confocal microscopy applied to punch skin biopsies from thigh, distal leg, and fingertip, and compared the density of epidermal nerve fibers (ENFs) with the results of mechanical pain sensation and thermal and tactile thresholds performed on hand dorsum, thigh, distal leg, and foot dorsum. We observed in our patients a statistically significant loss of ENFs, a reduced innervation of sweat glands, arrector pilorum muscles and arterioles, and an impairment of thermal and tactile thresholds and mechanical pain detection.

Adolescent↗
PubMed2001

Lessons learned from more than 1,000 pancreas transplants at a single institution.

OBJECTIVE: To determine outcome in diabetic pancreas transplant recipients according to risk factors and the surgical techniques and immunosuppressive protocols that evolved during a 33-year period at a single institution. SUMMARY BACKGROUND DATA: Insulin-dependent diabetes mellitus is associated with a high incidence of management problems and secondary complications. Clinical pancreas transplantation began at the University of Minnesota in 1966, initially with a high failure rate, but outcome improved in parallel with other organ transplants. The authors retrospectively analyzed the factors associated with the increased success rate of pancreas transplants. METHODS: From December 16, 1966, to March 31, 2000, the authors performed 1,194 pancreas transplants (111 from living donors; 191 retransplants): 498 simultaneous pancreas-kidney (SPK) and 1 simultaneous pancreas-liver transplant; 404 pancreas after kidney (PAK) transplants; and 291 pancreas transplants alone (PTA). The analyses were divided into five eras: era 0, 1966 to 1973 (n = 14), historical; era 1, 1978 to 1986 (n = 148), transition to cyclosporine for immunosuppression, multiple duct management techniques, and only solitary (PAK and PTA) transplants; era 2, 1986 to 1994 (n = 461), all categories (SPK, PAK, and PTA), predominantly bladder drainage for graft duct management, and primarily triple therapy (cyclosporine, azathioprine, and prednisone) for maintenance immunosuppression; era 3, 1994 to 1998 (n = 286), tacrolimus and mycophenolate mofetil used; and era 4, 1998 to 2000 (n = 275), use of daclizumab for induction immunosuppression, primarily enteric drainage for SPK transplants, pretransplant immunosuppression in candidates awaiting PTA. RESULTS: Patient and primary cadaver pancreas graft functional (insulin-independence) survival rates at 1 year by category and era were as follows: SPK, era 2 (n = 214) versus eras 3 and 4 combined (n = 212), 85% and 64% versus 92% and 79%, respectively; PAK, era 1 (n = 36) versus 2 (n = 61) versus 3 (n = 84) versus 4 (n = 92), 86% and 17%, 98% and 59%, 98% and 76%, and 98% and 81%, respectively; in PTA, era 1 (n = 36) versus 2 (n = 72) versus 3 (n = 30) versus 4 (n = 40), 77% and 31%, 99% and 50%, 90% and 67%, and 100% and 88%, respectively. In eras 3 and 4 combined for primary cadaver SPK transplants, pancreas graft survival rates were significantly higher with bladder drainage (n = 136) than enteric drainage (n = 70), 82% versus 74% at 1 year (P =.03). Increasing recipient age had an adverse effect on outcome only in SPK recipients. Vascular disease was common (in eras 3 and 4, 27% of SPK recipients had a pretransplant myocardial infarction and 40% had a coronary artery bypass); those with no vascular disease had significantly higher patient and graft survival rates in the SPK and PAK categories. Living donor segmental pancreas transplants were associated with higher technically successful graft survival rates in each era, predominately solitary (PAK and PTA) in eras 1 and 2 and SPK in eras 3 and 4. Diabetic secondary complications were ameliorated in some recipients, and quality of life studies showed significant gains after the transplant in all recipient categories. CONCLUSIONS: Patient and graft survival rates have significantly improved over time as surgical techniques and immunosuppressive protocols have evolved. Eventually, islet transplants will replace pancreas transplants for suitable candidates, but currently pancreas transplants can be applied and should be an option at all stages of diabetes. Early transplants are preferable for labile diabetes, but even patients with advanced complications can benefit.

Adolescent↗
PubMed2000

Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis.

OBJECTIVES: A case of a 10-year-old girl with congenital insensitivity to pain with anhidrosis (CIPA) is reported. METHODS AND RESULTS: Parents referred several hyperpyretic episodes without sweating occurring since birth, and insensitivity to pain, noticed when the child was 2 years old. Her body had many bruises and scars, bone fractures and signs of self-mutilation. Neurological examination was normal except for insensitivity to pain. Her IQ was 52. Electrical and tactile sensory nerve conduction velocities were normal. The patient was unable to detect thermal stimuli. Histamine injection evoked a wheal but not a flare; pilocarpine by iontophoresis did not induce sweat. Microneurography showed neural activity from A-beta sensory fibers while nociceptive and skin sympathetic C fiber nerve activity was absent. No small myelinated fibers and very rare unmyelinated fibers were found in the sural nerve. Immunohistochemistry showed a lack of nerve fibers in the epidermis and only few hypotrophic and uninnervated sweat glands in the dermis. CONCLUSIONS: The lack of innervation of the skin (C and A-delta fibers) appears to be the morphological basis of insensitivity to pain and anhidrosis, and is consistent with the loss of unmyelinated and small myelinated fibers in the sural nerve biopsy.

Child↗
PubMed1999

A skin blister method to study epidermal nerves in peripheral nerve disease.

Skin is a reservoir of sensory and autonomic nerve fibers that are potential indicators of peripheral nerve disease. Biopsies of skin have shown that sensory nerves in the most superficial layer of skin, the epidermal nerve fibers (ENFs), are reduced in patients with polyneuropathy. This report describes a minimally invasive skin blister method to isolate, image, and obtain quantitative analysis of ENFs. Blisters are made by applying a suction capsule to skin. The epidermal roof of the blister is excised, immunostained, whole mounted, and analyzed for ENF number and distribution. A reduction in number and abnormal distribution of ENFs are early indicators of peripheral nerve disease. Illustrations of skin blister and skin biopsy specimens from patients with different types of peripheral nerve disorders are included. These patients were chosen because their findings demonstrate the complementary information obtained by the blister and biopsy methods and the potential of the blister procedure to evaluate single nerve lesions and polyneuropathy and to follow the progress of ENF degeneration and regeneration.

Adult↗
PubMed1999

Magnetically aligned collagen gel filling a collagen nerve guide improves peripheral nerve regeneration.

Bioresorbable collagen nerve guides filled with either magnetically aligned type I collagen gel or control collagen gel were implanted into 4- or 6-mm surgical gaps created in the sciatic nerve of mice and explanted 30 and 60 days postoperation (dpo) for histological and immunohistochemical evaluation. The hypothesis was that contact guidance of regenerating axons and/or invading nonneuronal cells to the longitudinally aligned collagen fibrils would improve nerve regeneration. The criterion for regeneration was observation of regenerating myelinated fibers distal to the nerve guide. Consistent with previous studies showing poor regeneration in 6-mm gaps at 60 dpo with entubulation repair, only one of six mice exhibited regeneration with control collagen gel. In contrast, four of four mice exhibited regeneration with magnetically aligned collagen gel, including the appearance of nerve fascicle formation. The numbers of myelinated fibers were less than the uninjured nerve in all groups, however, which may have been due to rapid resorption of the nerve guides. An attempt to increase the stability of the collagen gel, and thereby the directional information presented by the aligned collagen fibrils, by crosslinking the collagen with ribose before implantation proved detrimental for regeneration.

Animals↗
PubMed1999

Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation.

Capsaicin applied topically to human skin produces itching, pricking and burning sensations due to excitation of nociceptors. With repeated application, these positive sensory responses are followed by a prolonged period of hypalgesia that is usually referred to as desensitization, or nociceptor inactivation. Consequently, capsaicin has been recommended as a treatment for a variety of painful syndromes. The precise mechanisms that account for nociceptor desensitization and hypalgesia are unclear. The present study was performed to determine if morphological changes of intracutaneous nerve fibers contribute to desensitization and hypalgesia. Capsaicin (0.075%) was applied topically to the volar forearm four times daily for 3 weeks. At various time intervals tactile, cold, mechanical and heat pain sensations were assessed in the treated and in contralateral untreated areas. Skin blisters and skin biopsies were collected and immunostained for protein gene product (PGP) 9.5 to assess the morphology of cutaneous nerves and to quantify the number of epidermal nerve fibers (ENFs). Capsaicin resulted in reduced sensitivity to all cutaneous stimuli, particularly to noxious heat and mechanical stimuli. This hypalgesia was accompanied by degeneration of epidermal nerve fibers as evidenced by loss of PGP 9.5 immunoreactivity. As early as 3 days following capsaicin application, there was a 74% decrease in the number of nerve fibers in blister specimens. After 3 weeks of capsaicin treatment, the reduction was 79% in blisters and 82% in biopsies. Discontinuation of capsaicin was followed by reinnervation of the epidermis over a 6-week period with a return of all sensations, except cold, to normal levels. We conclude that degeneration of epidermal nerve fibers contributes to the analgesia accredited to capsaicin. Furthermore, our data demonstrate that ENFs contribute to the painful sensations evoked by noxious thermal and mechanical stimuli.

Administration, Topical↗
PubMed1998

Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function.

The ability of capsaicin to excite and subsequently to desensitize a select group of small sensory neurons has made it a useful tool to study their function. For this reason, application of capsaicin to the skin has been used for a variety of painful syndromes. We examined whether intradermal injection of capsaicin produced morphological changes in cutaneous nerve fibers that would account for its analgesic properties by comparing cutaneous innervation in capsaicin-treated skin with psychophysical measures of sensation. At various times after capsaicin injection, nerve fibers were visualized immunohistochemically in skin biopsies and were quantified. In normal skin the epidermis is heavily innervated by nerve fibers immunoreactive for protein gene product (PGP) 9.5, whereas fibers immunoreactive for substance P (SP) and calcitonin gene-related peptide (CGRP) are typically associated with blood vessels. There was nearly complete degeneration of epidermal nerve fibers and the subepidermal neural plexus in capsaicin-treated skin, as indicated by the loss of immunoreactivity for PGP 9.5 and CGRP. The effect of capsaicin on dermal nerve fibers immunoreactive for SP was less obvious. Capsaicin decreased sensitivity to pain produced by sharp mechanical stimuli and nearly eliminated heat-evoked pain within the injected area. Limited reinnervation of the epidermis and partial return of sensation occurred 3 weeks after treatment; reinnervation of the epidermis was approximately 25% of normal, and sensation improved to 50-75% of normal. These data show that sensory dysfunction after capsaicin application to the skin results from rapid degeneration of intracutaneous nerve fibers.

Adult↗
PubMed1997

Immunohistochemical study of skin reinnervation by regenerative axons.

The time sequence of sensory and sudomotor nerve regeneration to the mouse footpad was studied between one and seven weeks after crush or section of the sciatic nerve. Protein gene product 9.5, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide were localized in thick sections by using indirect immunofluorescence techniques and imaged by confocal microscopy. Nerve regeneration was visually assessed in all nerves and quantified in sweat glands. After denervation, protein gene product 9.5 immunoreactivity remained as dim fluorescence within thick fibers of dermal nerve trunks, whereas thin nerve fibers to sweat glands and to epidermis disappeared. By 14 days postcrush and 35 days postsection, the first protein gene product 9.5 immunoreactive regenerating axons appeared in large nerve trunks, quickly extending to epidermis and sweat glands. Reinnervation of Meissner's corpuscles occurred nearly simultaneous with return of epidermal free nerve endings and sudomotor network. Calcitonin gene-related peptide, vasoactive intestinal peptide, and substance P immunoreactivity disappeared completely one week after denervation, then reappeared at 17-18 days postcrush and 35 days postsection. Fewer nerve fibers were immunoreactive to these peptides than to protein gene product 9.5. The overall density of reinnervation, although reduced, more closely resembled normal in the sweat glands and Meissner's corpuscles than in the epidermis. Reinnervation was more successful after crush than after nerve section. The time course for functional return of sweating paralleled the return of protein gene product 9.5 immunoreactivity, whereas appearance of vasoactive intestinal peptide was delayed by several days.

Animals↗
PubMed1997

Long-term effects of pancreatic transplantation on diabetic neuropathy.

Restoration of a long-lasting euglycemic state by a functioning pancreatic transplantation (PTx) is the most logical treatment for insulin-dependent diabetes mellitus and for amelioration of secondary complications, including neuropathy. We evaluated neurological function by clinical examination, nerve conduction studies, and autonomic function tests in 115 patients with a functioning PTx and in 92 control patients treated with insulin, at baseline and 1, 2, 3.5, 5, 7, and 10 years later. In control patients, neuropathy progressively worsened during follow-up. The clinical examination score and composite indices of abnormality of motor and sensory nerve conduction decreased significantly at all intervals tested. Autonomic function indices also decreased, but significantly only after 1 year. In patients who received a successful PTx the neuropathy improved. The motor and sensory nerve conduction indices increased significantly at all intervals after transplantation, whereas the clinical examination and autonomic tests improved only slightly. Patients who received either a PTx alone, a PTx after a kidney graft, or simultaneous pancreatic and kidney transplantations improved similarly over the follow-up. These results indicate that a functioning PTx halts the progression and improves the signs of diabetic polyneuropathy by restoration of a normoglycemic state.

Adult↗
PubMed1996

Neuropathy and mortality in diabetes: influence of pancreas transplantation.

We collected information on patient status and cause of death for 545 insulin-dependent diabetic subjects who had cardiorespiratory reflex and nerve conduction tests performed to determine if presence and severity of autonomic and somatic neuropathy is associated with mortality and if a functioning pancreas transplantation (PTx) influences mortality. Follow-up was 12-138 months. Abnormal cardiorespiratory reflexes were present in 417 patients and there was abnormal nerve conduction in 392 patients. Mortality rates for patients with abnormal tests were higher (P < 0.0001) than for patients with normal tests. A total neuropathy score that included cardiorespiratory and nerve conduction test scores predicted survival better than separate scores. Patients with moderate neuropathy, but not those with severe neuropathy, who retained a functioning PTx, had longer survival times than patients whose PTx failed in the first 3 months. Considering only patients transplanted after 1985, those with moderate neuropathy who retained a functioning PTx had even longer survival times than nontransplanted patients.

Adult↗