Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by increases in amyloid-beta (Abeta) peptides, neurofibrillary tangles, oxidative stress and cholinergic deficits. However, the selectivity of these deficits and their relation with the Abeta pathology or oxidative stress remain unclear. We therefore investigated amyloidosis-related changes in acetylcholine (ACh) and serotonin (5-HT) innervations of hippocampus and parietal cortex by quantitative choline acetyltransferase (ChAT) and 5-HT immunocytochemistry, in 6, 12/14 and 18 month-old transgenic mice carrying familial AD-linked mutations (hAPP(Sw,Ind)). Further, using manganese superoxide dismutase (MnSOD) and nitrotyrosine immunoreactivity as markers, we evaluated the relationship between oxidative stress and the ACh deficit in 18 month-old mice. Thioflavin-positive Abeta plaques were seen in both regions at all ages; they were more numerous in hippocampus and increased in number (>15-fold) and size as a function of age. A majority of plaques exhibited or were surrounded by increased MnSOD immunoreactivity, and dystrophic ACh or 5-HT axons were seen in their immediate vicinity. Counts of immunoreactive axon varicosities revealed significant decreases in ACh innervation, with a sparing of the 5-HT, even in aged mice. First apparent in hippocampus, the loss of ACh terminals was in the order of 20% at 12/14 months, and not significantly greater (26%) at 18 months. In parietal cortex, the ACh denervation was significant at 18 months only, averaging 24% across the different layers. Despite increased perivascular MnSOD immunoreactivity, there was no evidence of dystrophic ACh varicosities or their accentuated loss in the perivascular area. Moreover, there was virtually no sign of tyrosine nitration in ChAT nerve terminals or neuronal cell bodies. These data suggest that aggregated Abeta exerts an early, non-selective and focal neurotoxic effect on both ACh and 5-HT axons, but that a selective, plaque- and oxidative stress-independent diffuse cholinotoxicity, most likely caused by soluble Abeta assemblies, is responsible for the hippocampal and cortical ACh denervation.     

Inherited multicentric osteolysis with carpal-tarsal localisation mimicking juvenile idiopathic arthritis

Five patients with multicentric carpal-tarsal osteolysis are presented: a mother and her three children with an autosomal dominant mode of inheritance and one of the children with nephropathy, the fifth a sporadic case also with renal involvement. The main findings common to these five patients are symptoms and signs simulating arthritis of the wrists and/or ankles starting at a young age and mimicking juvenile idiopathic arthritis. Early signs of osteolysis and shortening of the carpus or tarsus are radiological characteristic. The disease may be associated with a peculiar face, but most importantly with nephropathy. The pathogenesis is still unknown. Conclusion: recognition of this disease and differentiation from juvenile idiopathic arthritis is important to avoid unnecessary investigations and treatment. Follow-up of renal function is indicated.Abbreviations JCA juvenile chronic arthritis - JIA juvenile idiopathic arthritis - MCTO multicentric carpal-tarsal osteolysis     

Perineal pain

The investigation of patients suffering from perineal pain when sitting led us to perform an anatomical study of the pudendal nerve. We dissected 50 cadavers and found areas of conflict for the nerve fibers. The nerve trunk can become entrapped at the level of the ischiatic spine, in the Alcock's canal and when it crosses the falciform process. Considering the clinical and neurophysiological data, this type of chronic pain may arise from compression of the nerve between the sacro-tuberal and the sacro-spinal ligaments, and/or in the fascia of the internal obturator muscle. Much like treatment of entrapment of the median nerve in the wrist, we decided to treat chronic perineal pain by nerve blocks, and later by surgery. We describe here the clinical symptoms, the neurophysiological data, and the technique of the nerve blocks. For patients with persistent pain, we propose a posterior surgical approach which has provided successful pain relief in two third of patients.     

Laparoscopic treatment for Crohn's disease

AIM: Several studies have demonstrated the feasibility and safety of laparoscopic surgery for Crohn's disease. A trend towards less morbidity as compared to laparotomy has been suggested. However, problems noted early in the experience may have prevented the optimal benefit from having been conferred. Accordingly, the aim of this study was to evaluate perioperatively those patients. METHODS: All 51 patients with Crohn's disease who underwent an intestinal resection at Cleveland Clinic Florida between January 1997 and December 1998 were analyzed. RESULTS: Seventeen patients underwent laparoscopic treatment: there were no significant differences between the 2 groups as to age, gender, incidences of comorbidity, prior laparotomy, or the use of anti-inflammatory and immunosuppressive agents. Similarly, there were no significant differences between the 2 groups as to either surgical indication, intraoperative findings, or procedure performed. Moreover, there were no significant differences concerning total anesthetic time or surgical operative time, the incidence of intraoperative morbidity or need for enterolysis or stoma construction, use of intraoperative endoscopy, or need for transfusion. Significant differences were noted in the duration of patient controlled analgesic usage (3.1 days in the laparoscopic group vs 3.9 days, respectively; p = 0.03), the incidence of postoperative morbidity (7/17 patients in the laparoscopic group vs 27/34 patients: p = 0.01), and length of hospital stay (6.4 days in the laparoscopic group vs 9.6 days, respectively; p = 0.05). CONCLUSIONS: In this retrospective cohort comparative study, laparoscopic intestinal resection for Crohn's disease, when compared to laparotomy, was associated with a short duration of patient controlled analgesic usage, a lower incidence of postoperative morbidity and a shorter hospital stay, without significantly increased operative time.     

The effect of ankle injury on subtalar motion

BACKGROUND: Injuries to the medial and lateral ankle ligaments have been implicated in subtalar joint instability. Lateral injury increased subtalar joint varus and anterior translation, while deltoid injury increased external rotation and valgus in studies using static, non-physiologic testing. METHODS: The current study employed a physiologically accurate ankle model using phasic force-couples attached to the muscle-tendon units to reproduce ankle motion. Six-degree-of-freedom kinematics of the tibia, talus, and calcaneus were measured using a VICON motion analysis system under the following experimental conditions: 1) intact ligaments 2) complete lateral ligament injury with subsequent repair, 3) superficial deltoid injury with subsequent repair, and 4) deep deltoid injury without repair in eight harvested lower extremities. Statistical analysis was by repeated measures analyses of variance. RESULTS: At heel-strike, the subtalar joint is in internal rotation, dorsiflexion, and varus. As the leg progresses to foot-flat, there is external rotation, plantarflexion, and valgus rotation. From foot-flat to heel-rise, there is little subtalar joint motion, while at toe-off, there is slight internal rotation, dorsiflexion, and varus rotation. The total rotations amounted to 9.0 degrees (SD 5.0 degrees) external rotation, 6.1 degrees (SD 2.5 degrees) plantarflexion, and 7.8 degrees (SD 5.5 degrees) valgus. Disruption of the superficial deltoid increased plantarflexion (p < .001) and valgus (p < .05). The additional lateral injury increased both external rotation (p < .001) and valgus (p < .02). Lateral injury alone had no significant effect on subtalar joint motion. CONCLUSION: Unlike most previous reports, this study showed no significant influence of isolated lateral ankle injury on subtalar joint motion, probably because the current study examined subtalar joint motion under physiologic loading and motion rather than by static stress testing. This calls into question the relevance of static stress testing to the in situ function of the subtalar joint. The increased external rotation and valgus seen with deltoid injury in the current study is consistent with previous reports.     

Laulimalide and paclitaxel: a comparison of their effects on tubulin assembly and their synergistic action when present simultaneously

Previous work has shown that laulimalide, a sponge-derived natural product, resembles paclitaxel in enhancing tubulin assembly and in its effects on cellular microtubules. The two compounds, however, seem to have distinct binding sites on tubulin polymer. Nearly equimolar amounts of tubulin, laulimalide, and paclitaxel are recovered from microtubules formed with both drugs. In the present study, we searched for differences between laulimalide and paclitaxel in their interactions with tubulin polymer. Laulimalide was compared with paclitaxel and epothilone A, a natural product that competes with paclitaxel in binding to microtubules, for assembly properties at different temperatures and for effects of GTP and microtubule-associated proteins on assembly. Although minor differences were observed among the three drugs, their overall effects were highly similar, except that aberrant assembly products were observed more frequently with paclitaxel and that the polymers formed with laulimalide and epothilone A were more stable at 0 degrees C. The most dramatic difference observed between laulimalide and epothilone A was that only laulimalide was able to enhance assembly synergistically with paclitaxel, as would be predicted if the two drugs bound at different sites in polymer. Because stoichiometric amounts of laulimalide and paclitaxel can cause extensive tubulin assembly, maximum synergy was observed at lower temperatures under reaction conditions in which each drug alone is relatively inactive. Laulimalide-induced assembly, like paclitaxel-induced assembly, was inhibited by drugs that inhibit tubulin assembly by binding at either the colchicine- or vinblastine-binding site. When radiolabeled GTP is present in a reaction mixture with either laulimalide or paclitaxel, nucleotide hydrolysis occurs with incorporation of radiolabeled GDP into polymer.     

Risk of non-medullary thyroid cancer influenced by polymorphic variation in the thyroglobulin gene

Benign thyroid disorders are strong risk factors for non-medullary thyroid cancer (NMTC). Germline variation in Tg (thyroglobulin) and TSHR (thyroid stimulating hormone receptor) confers an increased risk of benign thyroid disorders. To explore the hypothesis that polymorphic variation in these genes affects the risk of NMTC we compared the frequency of TgQ2511R, TSHR-P52T and TSHR-D727E genotypes in two series of NMTC cases and controls (group 1, Canadian 102 cases and 102 controls; group 2, British 202 cases and 298 controls). No significant association was seen with TSHR-P52T and TSHR-D727E genotypes and risk of NMTC. However, the frequency of the R-allele of TgQ2511R was over represented in NMTC cases in both study populations. The odds ratios associated with hetero- and homozygosity for the R-allele were 1.6 (95% confidence interval, 1.1-2.5) and 2.0 (95% confidence interval, 1.2-3.3), respectively. Although the risk of NMTC associated with the TgQ2511R R-allele is modest, its high prevalence in the general population suggests it may make a significant contribution to the incidence of NMTC.     

Assessing the value of weight loss among primary care patients

BACKGROUND: Modest weight loss of 10% of baseline weight is beneficial and achievable for overweight and obese patients. However, whether primary care patients value modest weight loss is unclear. OBJECTIVE: To quantify the value patients place on modest weight loss. DESIGN: Cross-sectional telephone survey. SETTING: Patients at a large hospital-based primary care practice. PARTICIPANTS: Three hundred sixty-five primary care patients (60% response rate). MEASUREMENTS: Utilities or value for weight loss estimated from willingness to risk death or trade time in exchange for losing different levels of weight (weight loss in pounds equivalent to a 5%, 10%, and 20% reduction in initial weight or to achieve a body mass index [BMI] of 25 kg/m2) using the standard gamble and time tradeoff formats. RESULTS: Of respondents, 15% of overweight (BMI, 25 to 29.9 kg/m2) and 42% of obese patients (BMI > or = 30 kg/m2) believed they needed to lose more than 10% of their weight to derive any health benefits. However, 18% of overweight and 33% of obese patients were willing to risk death to lose 10% of their weight. Patients with higher BMI valued higher degrees of weight loss. Among the overall sample, the utilities derived using standard gamble were 0.95 for current weight, 0.96 for 5% weight loss, 0.97 for 10% weight loss, and 0.98 for 20% weight loss; among obese patients, utilities were 0.88, 0.91, 0.93, and 0.96, respectively. Utilities derived using time tradeoff were lower but correlated with utilities derived from standard gamble. Utilities did not vary by education, gender, race, having comorbidities, or smoking. CONCLUSIONS: Many primary care patients value modest weight loss. The value placed on loss of 10% body weight among obese patients where utility improved from 0.88 to 0.93 is similar to recovery from major depression. Nevertheless, the majority of patients still do not highly value modest weight loss. Clinicians should emphasize the health benefits of modest weight loss when counseling about weight.     

Synthesis, cytotoxicity, and inhibitory effects on tubulin polymerization of a new 3-heterocyclo substituted 2-styrylquinazolinones

In order to study the influence of 3-substitution on the cytotoxic activity of 2-styrylquinazolinones, new 6-chloro-2-styryl-3-(heteroaryl)-4(3H)-quinazolinones were synthesized by refluxing equimolar amounts of 6-chloro-2-methyl-3-(heteroaryl)-4(3H)-quinazolinones and benzaldehyde in glacial acetic acid. At 1 microg ml(-1) concentration, almost all 2-styrylquinazolinones showed some cytotoxic activity against the L1210 and K562 leukemia cell lines. However, only 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone inhibited the growth of these cells by over 50%. This last compound was also the only member of the series that inhibited tubulin polymerization, with an IC(50) value of 5.8 versus 3.2 microM for colchicine. It was also examined for effects on the growth of human MCF7 breast carcinoma cells and Burkitt lymphoma CA46 cells, which had IC(50) values of 0.34 and 1.0 microM, respectively. At 10 microM 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone induced G2/M arrest (66%) in Burkitt cells, with a mitotic index of 20%. At 3.4 microM, it caused disruption of the cellular microtubule system of the MCF7 cells. Both these cellular effects are consistent with its mechanism of action resulting from its inhibitory effect on tubulin assembly.