Basic pathology of the peripheral nerve

Peripheral nerve pathology encompasses a complex array of disease processes that are poorly understood. This article provides a substrate for communication between pathologists and radiologists who are involved in the diagnosis and treatment of patients with peripheral neuropathy. The article is organized into sections on normal histology, routine morphologic techniques used in the study of peripheral nerve, and the basic disease patterns, followed by a brief discussion of selected neuropathies.     

Managing atypical squamous cells of undetermined significance (ASCUS): human papillomavirus testing, ASCUS subtyping,or follow-up cytology?

OBJECTIVE: This study related morphologic subtype, human papillomavirus status, and a second cytologic examination to the follow-up biopsy-proven high-grade squamous intraepithelial lesion (HSIL; grade II or III cervical intraepithelial neoplasia) after a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS). STUDY DESIGN: Seven hundred four liquid-based cervical cytology specimens were classified as normal, "ASCUS, favor reactive" (AFR), "ASCUS, not otherwise specified," "ASCUS, favor low-grade squamous intraepithelial lesion," "ASCUS, favor HSIL" (AFHS), low-grade squamous intraepithelial lesion, and HSIL. Human papillomavirus typing used polymerase chain reaction-restriction fragment length polymorphism analysis. A longitudinal review of the cytologic and histologic records of ASCUS cases with > or =1 follow-up test or biopsy ascertained the frequency of a follow-up diagnosis of biopsy-proven HSIL (grade II or III cervical intraepithelial neoplasia). RESULTS: Three hundred eighty-six cases (208 ASCUS, 68 normal, 86 with low-grade squamous intraepithelial lesions, and 24 with HSIL) were evaluated. High-risk human papillomavirus (HRHPV positive) was lowest with normal cytology (13%), highest with HSIL (71%), and was present in 29.8% of ASCUS cases, ranging from 22.2% (AFR) to 75% (AFHS). Most ASCUS tests (64%) were followed by a negative cytologic or histologic examination. Overall, 3.8% and 11% of ASCUS and HRHPV-positive ASCUS had histologic outcomes of HSIL. AFHS had the highest (25%) and AFR had the lowest (1.1%) proportion of HSIL outcomes. Sensitivity, specificity, and positive predictive values of human papillomavirus testing for biopsy-proven HSIL were 87.5%, 72.5%, and 11.3%, respectively. CONCLUSION: HSIL and AFHS are distinguished by the highest frequency of HRHPV types and higher rates of HSIL outcome. The remaining categories of ASCUS are heterogeneous with respect to human papillomavirus type and HSIL risk, and the value of subclassification of these entities is dependent on the practice. A human papillomavirus detection system based on polymerase chain reaction-restriction fragment length polymorphism identifies a smaller percentage of high-risk human papillomaviruses than mixed probe-based methods, probably because of the more precise exclusion of cross-reacting low-risk human papillomavirus. Negative HRHPV findings by either system show a markedly reduced risk of an HSIL outcome. However, the relative advantage of human papillomavirus testing over follow-up cytology will be influenced by the frequency of negative follow-up cytologic examination and sensitivity of liquid-based preparations in a given practice.     

Central amylin signaling and the regulation of energy homeostasis

Amylin is a 37-amino acid peptide hormone that is co-secreted with insulin by pancreatic B cells in response to food intake. Exogenous amylin potently and dose-dependently reduces feeding in rats and mice, with both central and peripheral sites being effective. Although amylin has been characterized as a satiety signal that regulates short-term food intake (i.e., meal size), recent data indicate that amylin may have long term effects on food intake and body weight. In fact, amylin shares many properties with the established adiposity signals, leptin and insulin. Like leptin and insulin, amylin is not synthesized within the brain, but is rapidly and efficiently transported across the blood-brain barrier (BBB) to a variety of discrete brain regions, including the hypothalamus, where populations of amylin binding sites are found. Further, amylin secretion and plasma levels are correlated with the degree of body adiposity, as is the case for leptin and insulin. In the following brief review, a summary of the findings from recent reports is presented supporting the hypothesis that amylin's role in the control of food intake is not limited to that of purely a satiety signal that brings individual bouts of ingestion to an end, but also serves as an adiposity signal acting within the brain to regulate long-term energy homeostasis.     

Spinal cord malignant astrocytomas. Clinicopathologic features in 36 cases

BACKGROUND: Malignant astrocytomas of the spinal cord are uncommon neoplasms with a dismal prognosis. To the authors' knowledge, little information has been published to date regarding the prognostic impact of clinicopathologic factors. METHODS: The authors studied 36 cases to investigate the prognostic effect of the World Health Organization (WHO) tumor grade, tumor localization, cell proliferative activity, p53 expression, and therapy. RESULTS: Sixteen patients (44%) underwent biopsy alone, 11 (31%) underwent subtotal resection, and 7 (19%) underwent macroscopic total excision. For two patients, there were no data available regarding surgical treatment. Among the 36 patients (mean age, 32.4 years), there were 23 males (63%) and 13 (36%) females. Their initial biopsies showed 21 (63%) glioblastoma multiforme (GBM) cases (WHO Grade 4), 13 (36%) anaplastic astrocytomas (AA) (WHO Grade 3), and 2 (6%) astrocytomas (A) (WHO Grade 2). After initial surgery, 10 (29%) patients were treated with radiation therapy alone and 7 (19%) received radiation therapy with chemotherapy. Patterns of disease recurrence included extraneural metastases (two cases), brain metastases (five cases), local extension (one case), and diffuse spread along the neuraxis (six cases). Two A (100%) and six AA (46%) cases progressed to GBM. The overall median survival time was 33 months (range, 24-42 months) for A, 10 months (range, 1-84 months) for AA, and 10 months (range, 1-43 months) for GBM. CONCLUSIONS: Patients older than 40 years have a shorter survival period compared with younger patients. There is a high risk of central nervous system dissemination in patients with this disease.     

A randomized,double-blind,placebo-controlled,phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.     

Dichloroacetate increases skeletal muscle pyruvate dehydrogenase activity during acute limb ischemia

The purpose of this study was to evaluate the effects of dichloroacetate sodium (DCA), a drug that inactivates pyruvate dehydrogenase kinase (PDH-K), on pyruvate dehydrogenase (PDH) activity, lactate level, and function of skeletal muscle in an experimental model of acute limb ischemia. Thirty-two male Sprague-Dawley rats underwent right iliac artery ligation to produce hindlimb ischemia. After 2 hours of ischemia, 16 animals received intravenous DCA (15 mg/100 g body weight) and 16 control animals received an equivalent volume of normal saline. After an additional 1 hour of ischemia (total 3 hours) tibialis anterior muscle from the ischemic limb and contralateral nonischemic limb was excised, rapidly freeze-clamped with Wallenberg tongs cooled in liquid nitrogen, and stored at -70 degrees C. Muscles specimens were subsequently assayed for PDH activity and lactate level by use of spectrophotometric techniques. An additional 16 animals (DCA-treated, n = 8; control, n = 8) underwent ex-vivo gastrocnemius muscle fatigue testing with a 10 g tension preload after 3 hours of limb ischemia. In ischemic hind limbs, DCA treatment significantly (p = 0.025) increased PDH activity (19.6 +/-1.6 micromol/min/g dry weight) compared to controls (13.1 +/-1.3 micromol/min/g dry weight). DCA treatment did not increase (p = 0.13) skeletal muscle PDH activity in the nonischemic limbs (9.6 +/-1.1 micromol/min/g dry weight, controls; 13.2 +/-1.3 micromol/min/g dry weight, DCA group). In DCA-treated animals, hind limb ischemia resulted in no significant increase in muscle lactate levels compared to the nonischemic limb, while control animals demonstrated a significant (p = 0.005) elevation in lactate level in ischemic limbs compared to contralateral nonischemic limb. Ischemia induced a significant decrease in time to muscle fatigue in both DCA-treated and control animals (p = 0.002 and 0.001, respectively). Time to muscle fatigue in DCA-treated animals was increased compared to controls (2.6 +/-0.3 versus 2 +/-0.6 minutes; p < 0.05)in ischemic limbs but was not significantly different in nonischemic limbs (DCA = 3.3 +/-0.5 minutes; control = 3.1 +/-0.6 minutes). Treatment with DCA during acute limb ischemia reduced the depression of PDH activity and lactate level of skeletal muscle. Ischemic muscle function was also improved by DCA treatment. Further investigation of the potential beneficial effects of DCA treatment on muscle injury during ischemia and reperfusion is warranted.     

Pulmonary cystic hydatid disease in Ireland

Background Hydatid disease is rare in Ireland and its incidence and prevalence are unknown. Most cases are diagnosed by a combination of clinical findings, morphological features on imaging and by serological testing. Aims We describe an Irish case of pulmonary hydatid disease detected at bronchoscopy by bronchoalveolar lavage, and discuss the diagnosis and treatment of the disorder.     

Infections of the nervous system

This article surveys common causes and pathologic features of nervous system infections within the general population. Special consideration is given to infections in people with the HIV virus.