Does Inflammation in an Autoimmune Disease Differ from Inflammation in Neurodegenerative Diseases? Possible Implications for Therapy

Accumulating evidence suggests that neurodegenerative diseases of the central nervous system (CNS) are associated with a local inflammatory response. CNS autoimmune diseases are also associated with inflammation. Does this mean that all neurodegenerative diseases are autoimmune in nature? Does it imply that autoimmune and neurodegenerative diseases are both eligible for the same therapy? What distinguishes between the two types of disease? Do they differ both in etiology and in pathology, or do they have different etiologies but similar pathology and progression? In this minireview we offer a new view of the inflammatory differences between neurodegenerative and autoimmune diseases in the CNS and discuss the implications for therapy.     

CHEK2-positive breast cancers in young Polish women.

PURPOSE: To investigate the contribution of CHEK2 mutations to early-onset breast cancer in Poland and to establish the characteristic features of these cancers. EXPERIMENTAL DESIGN: We studied 3,228 women diagnosed with breast cancer under the age of 51 years and 5,496 population controls. CHEK2 mutations were detected by RFLP-PCR or allele-specific oligonucleotide-PCR assays. Clinical and pathologic features of CHEK2-positive cases and CHEK2-negative cases were compared. RESULTS: A truncating CHEK2 mutation (1100delC or IVS2+1G>A) was seen in 47 of 3,228 cases and in 34 of 5,496 controls (odds ratio, 2.4; P = 0.0001). The CHEK2 I157T missense mutation was present in 207 of 3,228 cases, compared with 264 of 5,496 controls (odds ratio, 1.4; P = 0.002). Breast cancers in women with a CHEK2 mutation were more commonly of lobular histology (21.5% versus 15.8%; P = 0.05), of size >2 cm (54.8% versus 43.5%; P = 0.01), or of multicentric origin (28.7% versus 19.5%; P = 0.01) than were cancers from women without a CHEK2 mutation. Bilateral cancers were equally common in both subgroups. CONCLUSION: Three founder alleles in CHEK2 contribute to early-onset breast cancer in Poland. Breast tumors which arise in carriers of CHEK2 mutations seem to be similar to those of breast cancers in the population at large.     

Possible morphological substrates for GABA-mediated presynaptic inhibition in the lamprey spinal cord

Gamma-aminobutyric acid (GABA) neurons intrinsic to the lamprey spinal cord are known to modulate synaptic transmission from interneurons active during locomotion and from mechanosensory dorsal cells. Many of these physiological effects are presynaptic. To establish the morphological substrates for these axo-axonic interactions, an ultrastructural analysis was performed with an antiserum to fixed GABA. The GABA immunoreactivity (ir) was detected by postembedding peroxidase-antiperoxidase and immunogold techniques. GABA-ir terminals were found to make appositions with unlabelled axons located in the dorsal columns and in the ventrolateral aspect of the spinal cord. In the ventrolateral part of the cord, similar appositions between different GABA-ir terminals were also observed. The immunolabelled terminals contained spherical to pleomorphic synaptic vesicles, and also glycogen granules and dense core vesicles. In some cases, the fine structure of the contacts between immunogold-labelled terminals and unlabelled axons suggested a synaptic relationship. Such a relation was found in a relatively small proportion (2–3%) of the appositions studied. These specializations were always observed in close relation to an output synapse of the postsynaptic axon. It is suggested that the axo-axonal contacts described may provide an effective modulation of the synaptic transmission from axons in the lamprey spinal cord. © 1993 Wiley-Liss, Inc.     

p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized renal cell carcinoma

PURPOSE: We determined which clinical and molecular variables can predict cancer recurrence in patients following surgical management for localized renal cell carcinoma (RCC). MATERIALS AND METHODS: From a custom kidney cancer tissue microarray containing tumors specimens from 350 patients 193 undergoing nephrectomy for localized RCC at our institution between 1989 and 2000 were identified. The array was then analyzed by immunohistochemistry for certain molecular markers, namely CA9, CA12, Ki67, gelsolin, p53, EpCAM, pTEN and vimentin. The medical records of these patients were then reviewed for age, sex, TNM stage, tumor size, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status, recurrence status and, when applicable, time to recurrence. Cox regression analyses were done to determine clinical and molecular predictors of time to tumor recurrence. RESULTS: Of the patients 15% demonstrated evidence of tumor recurrence following nephrectomy (29 of 193). Univariate Cox regression demonstrated that tumor size, T stage, grade, ECOG performance status, Ki67, EpCAM and p53 were significantly associated with recurrence (p <0.05). A multivariate Cox regression model showed that T stage (p = 0.018), ECOG (p = 0.004) and p53 (p = 0.003) were the 3 most significant predictors. p53 expression correlated significantly with nuclear grade (Pearson correlation 0.22, p = 0.023) but not with any other clinical factors. Patients with localized tumors demonstrating mean p53 staining values above and below 20% of cells had recurrence rates of 37.7% and 14.4%, respectively (RR = 3.28, p = 0.018). CONCLUSIONS: p53 is a significant molecular predictor of tumor recurrence, as identified in patients undergoing treatment for localized RCC.     

Does a Second-look Operation Improve Survival in Patients with Peritonitis due to Acute Mesenteric Ischemia? A Five-year Retrospective Experience

Second-look laparotomy is one of the mainstays of surgical treatment of acute mesenteric ischemia (AMI). The aim of this study was to analyze its role in the survival of patients with infarcted gangrenous bowel resulting from AMI. A retrospective chart review of all patients admitted over the study period was undertaken. The study population consisted of 41 patients with clinical evidence of peritonitis and gangrenous, perforated bowel on surgical exploration. Outcome was compared among patients who underwent second-look laparotomy and those who did not. Fifteen patients with an American Society of Anesthesiologists (ASA) score of less than 4 underwent second-look laparotomy. Six patients had residual necrotic bowel that required additional resection. Only one (17%) of them survived. Of the nine remaining patients, who had no evidence of necrosis, only two survived (22%). Overall survival in this group was 20%. Twenty-six patients were managed without second-look laparotomy. Nine of them, with an ASA score of 4–5, died soon after the operation. The decision not to operate on the remaining 17 patients with an ASA score <4 was made by an experienced surgeon. Eleven of those patients (65%) survived. Overall survival in the non-second-look group was 42%. Excluding the early deaths, the survival in the non re-explored group was significantly higher than in the second-look group (65% vs. 20%, p = 0.011). A selective approach to the surgical treatment of acute mesenteric ischemia based on the sound clinical judgment of an experienced surgeon may be as appropriate as its universal application.     

Comparison of radial forearm with fibula and scapula osteocutaneous free flaps for oromandibular reconstruction

OBJECTIVE: To compare our experience with the osteocutaneous radial forearm free flap (group 1) (n = 108) with other commonly used osteocutaneous free flaps (group 2) (n = 56) such as the fibula and scapula in single-stage oromandibular reconstruction. DESIGN: Retrospective case review. SETTING: Tertiary-care academic medical center. PATIENTS: One hundred sixty-three consecutive patients who underwent 164 mandibular reconstructions with osteocutaneous free flaps. MAIN OUTCOME MEASURES: Assessment of preoperative and intraoperative variables for both groups. We compared recipient-site complication rate, intensive care unit stay, total hospital stay, and postoperative function. RESULTS: The most common donor site used was the radius (n = 108 [66%]), followed by the fibula (n = 36 [22%]) and scapula (n = 20 [12%]). Mean follow-up was 29 months (range, 1-116 months). Group 2 patients had larger soft tissue and/or bony defects. Surgical and medical complication rates and major donor site morbidity in group 1 were similar or better when compared with those in group 2. The lengths of the intensive care unit (4 vs 7 days; P = .009) and hospital stays (13 vs 15 days; P = .06) were shorter in group 1. Although the microvascular success rate was similar in both groups, the local wound complication rate was significantly better for group 1. The difference for the length of intensive care unit stay was statistically significant and potentially amounts to more than 6000 dollars of savings. Functional outcomes, including the ability to tolerate oral diet, tracheostomy presence, and dental rehabilitation, were similar between the groups. CONCLUSIONS: The primary site long-term morbidity, donor site morbidity, and postoperative function of osteocutaneous radial forearm free flaps are comparable to those of other commonly used osteocutaneous free flaps such as the fibula and scapula when used in single-stage oromandibular reconstruction.     

Coordination of bowing and fingering in violin playing

Playing string instruments implies motor skills including asymmetrical interlimb coordination. How special is musical skill as compared to other bimanually coordinated, non-musical skillful performances? We succeeded for the first time to measure quantitatively bimanual coordination in violinists playing repeatedly a simple tone sequence. A motion analysis system was used to record finger and bow trajectories for assessing the temporal structure of finger-press, finger-lift (left hand), and bow stroke reversals (right arm). The main results were: (1) fingering consisted of serial and parallel (anticipatory) mechanisms; (2) synchronization between finger and bow actions varied from -12 ms to 60 ms, but these 'errors' were not perceived. The results suggest that (1) bow-finger synchronization varied by about 50 ms from perfect simultaneity, but without impairing auditory perception; (2) the temporal structure depends on a number of combinatorial mechanisms of bowing and fingering. These basic mechanisms were observed in all players, including all amateurs. The successful biomechanical measures of fingering and bowing open a vast practical field of assessing motor skills. Thus, objective assessment of larger groups of string players with varying musical proficiency, or of professional string players developing movement disorders, may be helpful in music education.     

Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective

'Protective autoimmunity' refers to a well-controlled anti-self response that helps the body resist neurodegeneration. The response is mediated by autoimmune T cells, which produce cytokines and growth factors. Using an in vitro assay of hippocampal slices, we show that the cytokines interferon-gamma and (especially) interleukin-4, characteristic of pro-inflammatory and anti-inflammatory T cells, respectively, can make microglia neuroprotective. Aggregated beta-amyloid, like bacterial cell wall-derived lipopolysaccharide, rendered the microglia cytotoxic. Cytotoxicity was correlated with a signal transduction pathway that down-regulates expression of class-II major histocompatibility proteins (MHC-II) through the MHC-II-transactivator and the invariant chain. Protection by interleukin-4 was attributed to down-regulation of tumor necrosis factor-alpha and up-regulation of insulin-like growth factor I. These findings suggest that beneficial or harmful expression of the local immune response in the damaged CNS depends on how microglia interpret the threat, and that a well-regulated T-cell-mediated response enables microglia to alleviate rather than exacerbate stressful situations in the CNS.