Search

Learning-related plasticity at excitatory synapses in the mammalian brain requires the trafficking of AMPA receptors and the growth of dendritic spines. However, the mechanisms that couple plasticity stimuli to the trafficking of postsynaptic cargo are poorly understood. Here we demonstrate that myosin Vb (MyoVb), a Ca2+-sensitive motor, conducts spine trafficking during long-term potentiation (LTP) of synaptic strength. Upon activation of NMDA receptors and corresponding Ca2+ influx, MyoVb associates with recycling endosomes (REs), triggering rapid spine recruitment of endosomes and local exocytosis in spines. Disruption of MyoVb or its interaction with the RE adaptor Rab11-FIP2 abolishes LTP-induced exocytosis from REs and prevents both AMPA receptor insertion and spine growth. Furthermore, induction of tight binding of MyoVb to actin using an acute chemical genetic strategy eradicates LTP in hippocampal slices. Thus, Ca2+-activated MyoVb captures and mobilizes REs for AMPA receptor insertion and spine growth, providing a mechanistic link between the induction and expression of postsynaptic plasticity.

Bubble chambers were the dominant technology used for particle detection in accelerator experiments for several decades, eventually falling into disuse with the advent of other techniques. We report here on a new application for these devices. We operated an ultraclean, room-temperature bubble chamber containing 1.5 kilograms of superheated CF3I, a target maximally sensitive to spin-dependent and -independent weakly interacting massive particle (WIMP) couplings. An extreme intrinsic insensitivity to the backgrounds that commonly limit direct searches for dark matter was measured in this device under operating conditions leading to the detection of low-energy nuclear recoils like those expected from WIMPs. Improved limits on the spin-dependent WIMP-proton scattering cross section were extracted during our experiments, excluding this type of coupling as a possible explanation for a recent claim of particle dark-matter detection.

Objectives: To demonstrate a potentially life-threatening complication following tonsillectomy in a diabetic patient and discuss the possible pathogenesis., Methods: Case report and review of the world literature concerning parapharyngeal abscess post-tonsillectomy., Case Report: A 20-year-old female patient underwent an uneventful tonsillectomy following a history of recurrent tonsillitis. She re-presented 14 days post-surgery with a large erythematous tender right mid cervical neck swelling. Clinical and radiological evaluation confirmed a parapharyngeal abscess. She proceeded to have an incision and drainage of the abscess through a horizontal skin crease incision and subsequent intravenous antibiotic therapy. She was discharged home well three days post-surgery., Conclusion: Diabetes mellitus is a well-recognised systemic disease that may leave an individual more susceptible to infection. We report the first case in a young healthy diabetic patient and highlight a potential serious complication following a routine tonsillectomy.

Background: Increased incidence of pertussis has been noted among infants too young to be immunized. We studied the disease burden of pertussis in pediatric intensive care units and the source of infection in several Asian, European and Latin American countries., Methods: The study was conducted in 7 countries from September 2001 to January 2004. Children <1 year of age were enrolled from pediatric intensive care units (PICU) and pediatric wards if they presented with respiratory failure, apnea, bradycardia, or cough accompanied by paroxysms, vomiting, whoop or cyanosis. Household members of pertussis-positive index cases were asked to answer a questionnaire and provide diagnostic specimens., Results: Pertussis was confirmed in 99 infants (12%) of 823 infants included in the analysis: 10 of 90 (11%) in Brazil, 9 of 88 (10%) in Costa Rica, 11 of 145 (8%) in Germany, 13 of 147 (9%) in Singapore, 29 of 67 (43%) in Spain, 2 of 86 (2%) in Taiwan and 25 of 200 (13%) in Uruguay. However, sensitivity analysis indicated that these figures were conservative. The mean (+/- SD) average age of infection was 2.6 +/- 2.2 months. Pertussis was found among 96 of 269 (36%) of household contacts investigated. At least one household contact was identified as the source of infection in 24 of 88 (27%) of the PICU cases and mothers were identified as being the most frequent source of infection., Conclusion: Although regional differences exist, severe pertussis represents a considerable global disease burden. Since most infants are infected before vaccination and concomitant protection is completed, household contacts should be targeted for booster vaccination to reduce the pertussis reservoir.

Background: Multiple chemical sensitivity (MCS) has an estimated American prevalence of 15%, and no consistently abnormal laboratory tests are available to assist in its diagnosis. Some physicians treating MCS patients have observed changes in intra-erythrocytic minerals (IEMs). As co-factors, minerals could influence detoxication of xenobiotics., Aim: To test whether IEM differed comparing MCS cases with controls., Methods: A total of 408 women meeting validated inclusion and exclusion criteria for MCS participated in this case-control study., Results: No statistically significant differences were observed. However, for copper, chromium, magnesium, molybdenum, sulphur and zinc, mean detectable levels were all lower in cases. No dose-response relationships were found., Conclusion: IEM measurements do not appear to provide useful diagnostic markers for MCS.

Background: The purpose of the present study was to assess the value of fine-needle aspiration cytology (FNAC) in parotid masses., Methods: A retrospective review was carried out of FNAC results in parotid masses and the findings compared to histology on subsequent parotidectomy., Results: One hundred parotid masses were investigated. Eighty-six had the cytological diagnosis confirmed by histology, 14 had a different diagnosis at histology. In two of these 14, a malignancy was found where a non-neoplastic condition had been detected. In the other 12, various non-malignant lesions were wrongly identified by FNAC. Squamous cell carcinoma was the commonest parotid malignancy in the present study., Conclusion: Fine-needle aspiration cytology was found to be an effective diagnostic tool in the hands of experienced pathologists at Christchurch Hospital, NZ.

Background: Impaired metabolism of toxic chemicals is a postulated mechanism underlying multiple chemical sensitivity (MCS). Because genetic variation alters the rate of chemical metabolism, this study was designed to determine if MCS cases differed from controls for genetic polymorphisms in drug-metabolizing enzymes., Methods: Female Caucasian participants (203 cases and 162 controls) were drawn from a larger case-control study based on a reproducible and validated case definition. Common polymorphisms for CYP2D6, NAT1, NAT2, PON1, and PON2 were genotyped., Results: Comparing cases and controls, significant differences were found in genotype distributions for CYP2D6 (P = 0.02) and NAT2 (P = 0.03). Compared with the referent homozygous inactive (CYP2D6) or slow (NAT2) metabolizers, the odds for being CYP2D6 homozygous active (OR = 3.36, P = 0.01) and NAT2 rapid (OR = 4.14, P = 0.01) were significantly higher in cases than controls. The odds for being heterozygous for PON1-55 (OR = 2.05, P = 0.04) and PON1-192 (OR = 1.57, P = 0.04) were also significantly higher in cases., Conclusions: A genetic predisposition for MCS may involve altered biotransformation of environmental chemicals. The CYP2D6 enzyme activates and inactivates toxins; the NAT2 enzyme bioactivates arylamines to protein-binding metabolites. A gene-gene interaction between CYP2D6 and NAT2 suggested that rapid metabolism for both enzymes may confer substantially elevated risk (OR = 18.7, P = 0.002). Our finding parallels others' observation of a link between PON1 heterozygosity and neurological symptoms in Gulf War syndrome. This first demonstration of genetic variation in drug-metabolizing enzymes in association with MCS requires replication. However, it suggests new research directions on genetically variable toxin pathways that might be important in MCS.

Background: Multiple chemical sensitivity (MCS), although poorly understood, is associated with considerable morbidity., Aim: To investigate potential biological mechanisms underlying MCS in a case-control study., Methods: Two hundred and twenty-three MCS cases and 194 controls (urban females, aged 30-64 years) fulfilled reproducible eligibility criteria with discriminant validity. Routine laboratory results and serum levels of volatile organic compounds (VOCs) were compared. Dose-response relationships, a criterion for causality, were examined linking exposures to likelihood of case status., Results: Routine laboratory investigations revealed clinically unimportant case-control differences in means. Confounder-adjusted odds ratios (OR) showed MCS was negatively associated with lymphocyte count and total plasma homocysteine, positively associated with mean cell haemoglobin concentration, alanine aminotransferase and serum vitamin B6, and not associated with thyroid stimulating hormone, folate or serum vitamin B12. More cases than controls had detectable serum chloroform (P = 0.001) with the OR for detectability 2.78 (95% confidence interval = 1.73-4.48, P < 0.001). Chloroform levels were higher in cases. However, cases had significantly lower means of detectable serum levels of ethylbenzene, m&p-xylene, 3-methylpentane and hexane, and means of all serum levels of 1,3,5- and 1,2,3-trimethylbenzene, 2- and 3-methylpentane, and m&p-xylene., Conclusions: Our findings are inconsistent with proposals that MCS is associated with vitamin deficiency or thyroid dysfunction, but the association of lower lymphocyte counts with an increased likelihood of MCS is consistent with theories of immune dysfunction in MCS. Whether avoidance of exposures or different metabolic pathways in cases explain the observed lower VOC levels or the higher chloroform levels should be investigated.

Chronic ethanol ingestion leads to inhibition of proteasomal activity. As a consequence, proteins accumulate in liver cells. Cytokeratin accumulation as seen in alcoholic hepatitis could lead to the formation of Mallory bodies. In order to study the phenomenon of cytokeratin accumulation in liver cells, rats were fed ethanol or dextrose for 1 month and some were given the proteasome inhibitor, PS-341, to augment the inhibitory effect of ethanol feeding. This was done to study the involvement of proteasome inhibition in the process of cytokeratin accumulation. There was a marked increase in the accumulation of polyubiquitinated proteins, and heat shock proteins (hsp) 25 and 70 in the liver of rats treated with PS-341. Similarly, cytokeratin-8 (CK-8) levels were markedly increased in the liver homogenates of rats fed ethanol when given PS-341. When normal mouse cultured hepatocytes were transfected with cytokeratin-18 (CK-18) tagged with red fluorescent protein (RFP), CK-18 aggresomes formed because proteasome was overloaded. These data provide new evidence that proteasome inhibition is involved in cytokeratin accumulation, when aggresomes are formed in tissue culture. Accumulation of cytokeratin in this way may ultimately lead to Mallory body formation as seen in alcoholic hepatitis.

A glomus vagale is a rare lesion of paraganglionic cells in the vagal perineurium. Secretion of hormones by such a tumour is exceedingly uncommon, although associated metabolic processes have been demonstrated. Clinical effects of secretion reported previously have been minimal. We report a case where resistant hypertension was eventually found to be due to a secretory glomus vagale, and was greatly alleviated by removal of the lesion.

Aggresome formation in cells involves the failure of the ubiquitin-proteasome pathway to dispose of proteins destined for degradation by the 26S proteasome. UBB(+1) is present in Mallory bodies in alcoholic liver disease and in aggresomes formed in Alzheimer's desease. The present investigation focuses on the role that UBB(+1) plays in cytokeratin aggresome formation in Mallory bodies (MBs) in vitro. Immunoprecipitation with a monoclonal antibody to cytokeratin-8 (CK-8) was used. The immunoprecipitate was incubated for 24 h in the presence of different constituents involved in aggresome formation including ubiquitin, UBB(+1), the proteasome inhibitor PS341, an ATP generating energy source, a deubiquitinating enzyme inhibitor, a purified proteasome fraction, and an E(1-3) conjugating enzyme fraction. MB-like protein aggregates formed in the presence of ubiquitin, plus UBB(+1) or PS341. These aggregates stained positively for CK-8. UBB(+1), and a proteasome subunit Tbp7, as demonstrated on Western blots. A second approach was used to form MBs in vitro in cultured hepatocytes transfected with UBB(+1) protein using Chariot. The cells were double stained using CK-8 and ubiquitin antibodies. The two proteins colocalized in MB-like aggregates. The results support the possibility that aggresome formation is a complex multifactor process, which is favored by inhibition of the proteasome and by the presence of UBB(+1).

The dynamics of Mallory body (MB) formation are difficult to follow in vivo. Because of the lack of an in vitro mouse hepatocyte culture model, a cellular extract approach was developed. In this model an immunoprecipitate was obtained using an antibody to cytokeratin-8 (CK-8). The isolate contained a large number of compounds: CK-8, ubiquitin, a frameshift mutation of ubiquitin (UBB(+1)), proteasomal subunits beta5 (a catalytic subunit of the 20S proteasome) and Tbp7 (an ATPase subunit of the 26S proteasome), transglutaminase, tubulin, heat shock proteins 90 and 70, and MBs. In Western blots, CK-8 immunoprecipitates showed colocalization of these components in a complex of proteins colocalized in a high-molecular-weight smear. When the CK-8 immunoprecipitate was incubated with the isolate of proteasomes and an energy generating source (ATP), the components of the ubiquitinated protein smear increased. These observations taken together with the in vivo observation that these proteins colocalized at the edge of the MB shown in the present study suggest that these proteins form aggregates through covalent binding of CK-8, ubiquitin, and the proteasomes. Covalent aggregation is suggested by the fact that the protein complex found in the high-molecular-weight smear that forms in vitro fails to dissociate in SDS. This protein complex is present in the CK-8 immunoprecipitates of livers forming MBs but not in control livers. In conclusion, the results support the concept that Mallory bodies are aggresomes which form as the result of the failure of the ubiquitin-proteasome complex to adequately eliminate cytokeratins destined for proteolysis.

Background & Aims: Molecular misreading of the ubiquitin B gene has been documented in the cerebral cortex of patients with Alzheimer's disease and Down syndrome. This novel process consists of the unfaithful conversion of genomic information into aberrant transcripts and its subsequent translation into +1 proteins., Methods: Because Mallory bodies (MBs) also contain ubiquitinated proteins, we stained 11 autopsied and 6 biopsied MB-containing livers from patients with steatohepatitis with an antibody to ubiquitin(+1) to look for the presence of mutant (ubiquitin(+1)) protein. Antibodies to wild-type ubiquitin were used to document the presence of MBs in all cases., Results: Ubiquitin(+1) immunoreactivity was detected in all MB-containing livers with steatohepatitis; no ubiquitin(+1) immunoreactivity was found in 13 MB-free liver controls. A subpopulation (about one third of the MBs) of the MB-containing hepatocytes in autopsied livers showed ubiquitin(+1) immunoreactivity (i.e., ubiquitin and ubiquitin(+1) colocalized in MBs). MB-containing liver biopsy specimens showed colocalization of ubiquitin and ubiquitin(+1) in every MB. Western blot analysis showed an ubiquitin(+1) band of 11 kilodaltons. Molecular misreading of the ubiquitin B gene (DeltaGU) was shown in one of the livers, which contained numerous MBs using an expression cloning strategy., Conclusions: The results showed that molecular misreading of the ubiquitin B gene occurred in hepatocytes in virtually all of the MB-containing livers tested. Ubiquitin(+1) protein was only found within the MBs and therefore may act by interfering with the degradation of the MBs because ubiquitin(+1) may inhibit proteolytic function of the proteasome.

Fifty patients received 151 short, porous-surfaced implants in the partially edentulous maxilla. Periotest values (PTV) were recorded at baseline and after 6 months and 1 and 2 years. For this, prostheses were removed and a standard abutment attached and tightened (20-Ncm force) to each implant. Data analysis indicated significant relationships between time in function vs PTV and implant diameter (3.5, 4.1, or 5.0 mm) vs PTV There was no relationship between PTV and implant length. PTVs were more favorable in the posterior than anterior maxilla, and better PTVs were obtained with nonsplinted as opposed to splinted implants.

Our purpose was to characterize the relationship between EMG mean power frequency (MPF) or median frequency (MF) and rate of torque development in voluntary ballistic and electrically elicited isometric contractions. Twenty-three healthy adults participated in two sets of experiments performed on elbow flexor muscles. For Experiment 1, subjects were asked to generate voluntary ballistic contractions by reaching four different target torque levels (20, 40, 60 and 100% of the maximal voluntary contraction (MVC)) as fast as they could. For Experiment 2, electrical (M-waves) and mechanical (twitches) responses to electrical stimulation of the nerves supplying the biceps brachii and brachioradialis muscles were recorded with the subjects at rest and with a background isometric contraction of 15% MVC. MPF, MF and rate of torque development (% MVC/s) were calculated for both voluntary and elicited contractions. Significant positive correlations were observed between MPF and rate of torque development for the voluntary contractions, whereas significant negative correlations were observed between the two variables for elicited contractions. This suggests that factors other than muscle fiber composition influence the frequency content of EMG signals and/or the rate of torque development, and that the effect of these factors will vary between voluntary and elicited contractions.

The intragastric tube feeding model of alcoholic liver disease in the rat induces significant liver histopathology, including steatohepatitis and fibrosis. The question is, if the same low-carbohydrate diet is fed ad lib, will the same pathology develop? Rats were fed a liquid diet with ethanol ad lib that was low in calories derived from carbohydrates for 2 months. The urinary ethanol levels (UALs) were monitored at hourly, daily, and weekly intervals, and the growth of the rats was charted. The liver histopathology and blood transaminase levels were determined. Rats fed ethanol grew 1 g/day, which was 2 g/day less than when they were fed the same diet intragastrically. UALs varied hourly between 150 and 500 mg%, daily between 120 and 360 mg%, and weekly between 0 and 500 mg%. Individual rat UALs showed no predictable pattern. The pair-fed controls ate all of their daily ration within 12 h, then fasted until the next day. The histopathology and blood alanine aminotransferase were similar to those seen with the intragastric tube feeding of the same diet, except that necrosis, inflammation, and fibrosis did not develop. The conclusion was that the oral feeding of a low-carbohydrate diet produces less liver injury than that produced by the same diet fed intragastrically. The UALs varied hourly, daily, and weekly in individual rats, making it difficult to synchronize UALs at the time of sacrifice., (Copyright 2001 Academic Press.)

Background: Little longitudinal data are available on the general physical, psychological, and social problems experienced as a result of laryngectomy or on the preoperative status of patients in regard to these aspects. In particular, prospective longitudinal data gathered from the same group of subjects over time and examining a variety of such outcomes is rare. This descriptive study addresses these issues., Methods: The study investigates the progress of a group of 34 laryngectomees from the preoperative stage up to 6 months after surgery. Medical complications, communication, swallowing, diet, physical, and psychosocial adjustment were measured using both the Short-Form Health Survey (SF-36) and original outcome tools., Results: A large percentage of subjects demonstrated significant and persistent communication and swallowing problems throughout the period studied. Low preoperative and postoperative scores on the SF-36 demonstrate that this group had a poorer state of general health in many respects than those with serious medical conditions previously documented., Conclusions: The results suggest that communication and swallowing difficulties persist for many laryngectomees up to 6 months after surgery and still require further investigation. Poor preoperative and postoperative general health scores indicate that this group may require more long-term social support than is currently being offered to adjust to the laryngectomy.

Records are available on 27 patients who had vestibular nerve section between 1975 and 1987 giving a follow-up time of 10 to 22 years with a mean of 16 years. Episodic vertigo was fully controlled in 26 patients, one needing a labyrinthectomy 18 months later. In addition to the patient who had labyrinthectomy, one patient had immediate post-operative profound hearing loss so that long-term follow-up of hearing was possible in 25 patients. After six months there was an overall average improvement in hearing of 1 dB. Thereafter there were average deterioration of 7 dB at two years, 15 dB at 10 years, 23 dB at 15 years and 29 dB at 20 years. This deterioration was more marked in those who had better hearing at the time of surgery, with all 10 whose hearing was classified as good deteriorating to poor by 15 years. At 10 years hearing deteriorated by 25 dB in those with good hearing and by 7 dB in those with poor hearing. In 20 per cent of patients there was audiological evidence of eventual involvement of the other ear. Tinnitus became worse in five patients but was a major problem in only one patient. One patient suffered a facial paralysis with partial recovery and, in addition, in one the frontal branch was divided in the incision.

A 32-year-old man presented to the otolaryngology department with acute dysphagia after vomiting. Radiological investigation suggested a piece of meat lodged in the lower oesophagus and rigid oesophagoscopy was performed. However, a plastic shotgun cartridge was found and removed. This had gained access to the stomach when the patient had been shot at point-blank range 18 months previously, and appeared to have been forced into the oesophagus by the vomiting, where it caused obstruction.

Otalgia is often related to pathology in areas of the head and neck apart from the ear. This is due to the rich innervation of the ear via the fifth, seventh, ninth and tenth cranial nerves and the cervical plexus. It is estimated that 50% of ear pain is referred from non-otologic sites. A case is reported where otalgia was due to the presence of a bone in place of a ligament in the neck and was relieved by its removal.

The case of a 12-yr-old male exposed to a substantial amount of dicofol, a DDT analog, is presented. The patient was still contaminated 3 wk after exposure. Blood and fat analysis documented the presence of dicofol. The patient demonstrated subjective and objective evidence of neurological injury, which resolved. Other organ injury was not present. Cognitive and emotional difficulties persisted over an 18-mo period.

The T84 human colonic epithelial cell line retains the ability to produce secretagogue-responsive monolayer cultures with high transepithelial resistance when grown and maintained on collagen-coated permeable supports in media supplemented with 5% newborn calf serum. The addition of highly purified insulin to the basolateral but not the apical membrane side of established monolayers caused the transepithelial resistance to decline more than eightfold over a 3-4-d period. By comparing the transepithelial flux of 22Na with that of the extracellular space marker, [3H]mannitol, the decline in electrical resistance was shown to be due solely to an effect on tight junction-mediated paracellular permeability. The effect of insulin was dose dependent with a half-maximal effect at 3.9 ng/ml (approximately 0.7 nM) and fully reversible over a 10-d time course. Simultaneous addition of 2 microM cycloheximide prevented the insulin-induced decline in resistance; in fact, this combination caused a significant increase in electrical resistance. There was no effect on the short-circuit current response of insulin-treated monolayers to secretagogues so long as media was changed daily. While no gross morphological changes were apparent, there did appear to be a subtle condensation of the perijunctional actin ring as visualized using rhodamine-labeled phalloidin. These results demonstrate that insulin modulates the permeability of the occluding junction in T84 cell monolayers through a receptor mediated process which probably involves changes in protein synthesis and cytoskeletal structure. Insulin was also shown to produce similar effects on two other intestinal epithelial cell lines.