How long does it take to diagnose young-onset dementia? A comparison with late-onset dementia.

INTRODUCTION: Dementia occurring in young people may be difficult to recognize. We compared the time to diagnosis between young- (YOD, age < 65) and late-onset dementia (LOD). METHODS: Time between the onset of symptoms and the diagnosis was measured in YOD and LOD patients consecutively seen in a cognitive neurology clinic. Multivariable regression analyses were performed to identify determinants of time to diagnosis. RESULTS: Mean time to diagnosis in 95 YOD patients was 11.2 months longer than in 73 LOD patients (p = 0.022). The delay was driven by a longer time taken by YOD patients to be seen in the specialist centre, which in turn was related to the presence of language disturbances and coexisting depression. DISCUSSION: Young people take longer than elderly people to receive a dementia diagnosis because they take longer to be referred to dementia specialist centres. More awareness on YOD is needed in primary care and the public.

Incomplete penetrance in familial Alzheimer's disease with PSEN1 Ala260Gly mutation.

Presenilin1 (PSEN1) gene is the most common known genetic cause of early-onset familial Alzheimer's disease. We describe an Italian family with the known p.Ala260Gly mutation in PSEN1 gene. The presence of an asymptomatic 64-year-old male carrying the mutation provides evidence of a possible incomplete penetrance leading to a wider range of age at onset. In order to evaluate whether or not epigenetic modifications could contribute to the phenotypic heterogeneity, we assessed global DNA methylation levels which resulted significantly higher in the three females than in their presymptomatic brother. The study suggests that DNA methylation can contribute to slowing down or possibly protecting from the manifestation of symptoms even in monogenic diseases, emphasizing the great complexity of familial Alzheimer's disease.

Oro-facial evaluation of women with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an aggressive articular autoimmune disease that causes deformities and disability. The temporomandibular joint (TMJ) might be affected by this disease. Few controlled studies have evaluated bite force (BF) and oro-facial manifestations of this disease. To characterise oro-facial alterations in patients with RA, correlate these results with clinical and disease activity parameters and correlate BF with hand strength (HS). A cross-sectional study of 150 women was performed, (75 RA patients (RA group) and 75 healthy individuals (control group). The presence of articular sounds, pain on palpation of masseter, temporal and TMJ lateral pole, changes in occlusion, range of mandibular motion, measurement of BF in the incisor and molar regions and assessment of HS were evaluated. In relation to oro-facial evaluation there were statistical differences between the groups. There was correlation between BF and HS, in the RA group, this correlation was consistent in patients with natural teeth. Patients with RA had lower scores (P < 0·05) in the HAQ, DASH and OHIP-14 questionnaires than the control group. Inverse correlations were found between BF and HAQ, but not between BF and DAS-28, DASH and OHIP-14 questionnaires in the RA group. The women with RA presented more signs and symptoms in the oro-facial region and had a lower BF than the women in the control group. BF was inversely correlated with the overall function (evaluated by the HAQ) in the patients with RA, and there were correlations between BF and HS in the RA patients and in the control group.

Exposure to anaesthetic trace gases during general anaesthesia: CobraPLA vs. LMA classic.

BACKGROUND: To prospectively investigate the performance, sealing capacity and operating room (OR) staff exposure to waste anaesthetic gases during the use of the Cobra perilaryngeal airway (CobraPLA) compared with the laryngeal mask airway classic (LMA). METHODS: Sixty patients were randomly assigned to the CobraPLA or the LMA group. Insertion time, number of insertion attempts and airway leak pressures were assessed after induction of anaesthesia. Occupational exposure to nitrous oxide (N(2)O) and Sevoflurane (SEV) was measured at the anaesthetists' breathing zone and the patients' mouth using a photoacoustic infrared spectrometer. RESULTS: N(2)O waste gas concentrations differed significantly in the anaesthetist's breathing zone (11.7+/-7.2 p.p.m. in CobraPLA vs. 4.1+/-4.3 p.p.m. in LMA, P=0.03), whereas no difference could be shown in SEV concentrations. Correct CobraPLA positioning was possible in 28 out of 30 patients (more than one attempt necessary in five patients). Correct positioning of the LMA classic was possible in all 30 patients (more than one attempt in three patients). Peak airway pressure was higher in the CobraPLA group (16+/-3 vs. 14+/-2 cmH(2)O, P=0.01). The average leak pressure of the CobraPLA was 24+/-4 cmH(2)O, compared with 20+/-4 cmH(2)O of the LMA classic (P<0.001; all values means+/-SD). CONCLUSION: Despite higher airway seal pressures, the CobraPLA caused higher intraoperative N(2)O trace concentrations in the anaesthetists' breathing zone.

Comparison of economical aspects of interscalene brachial plexus blockade and general anaesthesia for arthroscopic shoulder surgery.

BACKGROUND: This study investigated the cost-effectiveness of ultrasonographic-guided interscalene brachial plexus blockade (ISB) in comparison with general anaesthesia (GA) for arthroscopic shoulder surgery. METHODS: Forty patients undergoing arthroscopic shoulder surgery received either an ultrasonographic-guided ISB or GA. ISB was performed outside the operation room (OR) and patients were transferred in the OR at the earliest 20 min after block performance. All drugs and disposables were recorded to evaluate the costs for both techniques. The following anaesthesia-related times were defined: ready for surgical preparation (from arrival in the OR until end of anaesthesia induction), OR emergence time (from end of dressing until leaving the OR), anaesthesia control time (from patient's arrival in the OR until readiness for positioning plus time from the end of surgery to patient's discharge from the OR), and post-anaesthesia care unit (PACU) time (from patient's arrival in the PACU to the eligibility for discharge to normal ward). Personnel costs were excluded from statistical analysis. RESULTS: The total costs were [mean (sd)] 33 (9)euro for patients with ISB and 41 (7)euro for those who received GA (P<0.01). The anaesthesia-related workflow was improved in the ISB group when compared with the GA group [ready for surgical preparation 8 (3) vs 13 (5) min, P<0.001; OR emergence time 4 (3) vs 10 (5), P<0.001; anaesthesia control time 12 (4) vs 23 (6), P<0.001; and PACU time 45 (17) vs 70 (20), P<0.001]. CONCLUSIONS: Ultrasonographic-guided ISB is a cost-effective method for arthroscopic shoulder surgery.

Evaluation of stroke volume variation obtained by arterial pulse contour analysis to predict fluid responsiveness intraoperatively.

BACKGROUND: Fluid management guided by oesophageal Doppler monitor has been reported to improve perioperative outcome. Stroke volume variation (SVV) is considered a reliable clinical predictor of fluid responsiveness. Consequently, the aim of the present trial was to evaluate the accuracy of SVV determined by arterial pulse contour (APCO) analysis, using the FloTrac/Vigileo system, to predict fluid responsiveness as measured by the oesophageal Doppler. METHODS: Patients undergoing major abdominal surgery received intraoperative fluid management guided by oesophageal Doppler monitoring. Fluid boluses of 250 ml each were administered in case of a decrease in corrected flow time (FTc) to <350 ms. Patients were connected to a monitoring device, obtaining SVV by APCO. Haemodynamic variables were recorded before and after fluid bolus application. Fluid responsiveness was defined as an increase in stroke volume index >10%. The ability of SVV to predict fluid responsiveness was assessed by calculation of the area under the receiver operating characteristic (ROC) curve. RESULTS: Twenty patients received 67 fluid boluses. Fifty-two of the 67 fluid boluses administered resulted in fluid responsiveness. SVV achieved an area under the ROC curve of 0.512 [confidence interval (CI) 0.32-0.70]. A cut-off point for fluid responsiveness was found for SVV > or =8.5% (sensitivity: 77%; specificity: 43%; positive predictive value: 84%; and negative predictive value: 33%). CONCLUSIONS: This prospective, interventional observer-blinded study demonstrates that SVV obtained by APCO, using the FloTrac/Vigileo system, is not a reliable predictor of fluid responsiveness in the setting of major abdominal surgery.

Morphine-induced spinal cholinergic activation: in vivo imaging with positron emission tomography.

Positron emission tomography (PET) imaging of spinal cord in monkeys with a cholinergic tracer demonstrates increased spinal cholinergic activity in response to an analgesic dose of morphine, and this PET result correlates with measurement of acetylcholine spillover into spinal cord extracellular space induced by morphine, as measured by microdialysis. Previous studies in rats, mice, and sheep demonstrate activation of spinal cholinergic neurons by systemic opioid administration, and participation of this cholinergic activity in opioid-induced analgesia. Testing the relevance of this observation in humans has been limited to measurement of acetylcholine spillover into lumbar cerebrospinal fluid. The purpose of this study was to apply a recently developed method to image spinal cholinergic terminals non-invasively via PET and to test the hypothesis that the tracer utilized would reflect changes in local cholinergic activity. Following Animal Care and Use Committee approval, seven adult male rhesus monkeys were anesthetized on three separate occasions. On two of the occasions PET scans were performed using [(18)F] (+)-4-fluorobenzyltrozamicol ([(18)F]FBT), which selectively binds to the vesicular acetylcholine (ACh) transporter in the presynaptic cholinergic terminals. PET scans were preceded by injection of either saline or an analgesic dose of IV morphine (10 mg/kg). On the third occasion, microdialysis catheters were inserted in the spinal cord dorsal horn and acetylcholine concentrations in dialysates determined before and after IV morphine injection. Morphine increased cholinergic activity in the spinal cord, as determined by blood flow corrected distribution volume of [(18)F]FBT in the cervical cord compared to the cerebellum. Morphine also increased acetylcholine concentrations in microdialysates from the cervical cord dorsal horn. The one animal which did not show increased spinal cholinergic activity by PET from this dose of morphine also did not show increased acetylcholine from this morphine dose in the microdialysis experiment. These data confirm the ability to use PET to image spinal cholinergic terminals in the monkey spinal cord and suggest that acute changes in cholinergic activity can be imaged with this non-invasive technique. Following preclinical screening, PET scanning with [(18)F]FBT may be useful to investigate mechanisms of analgesic action in normal humans and in those with pain.

N-imidazolylchroman-4-ones, N-imidazolyl-1-tetralones, and their alcohols as hypolipemic agents raising high-density lipoproteins.

A series of 3-(1-imidazolyl)chroman-4-ones and 2-(1-imidazolyl)-1-tetralones II, some of their alcohols, and some related compounds were synthesized and tested for hypolipidemic activity. Compounds II, bearing appropriate lipophilic substituents on the phenyl ring, strongly reduced total serum cholesterol while raising high-density lipoprotein cholesterol in diet-induced hypercholesterolemic rats. 3-(1-Imidazolyl)chroman-4-ols and 2-(1-imidazolyl)-1-tetralols corresponding to II retained the hypolipidemic activity while removal of the carbonyl or hydroxy group adjacent to imidazole gave inactive compounds. Although many of the active compounds significantly increased liver weight, the one studied as a model, 6-chloro-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (5), caused no peroxisome proliferation. Compound 5 and the corresponding alcohol 40, as representatives of the ketone and alcohol series, showed significant hypolipidemic activity in normolipemic rats. Some of the compounds assayed in cholesterol biosynthesis inhibited acetate incorporation but none inhibited HMG-CoA reductase. 5-Bromo-6-hydroxy-2-(1-imidazolyl)-3,4-dihydro-1(2H)-naphthalenone (38), which showed strong activity but caused little hepatomegaly in the rat, was chosen for further pharmacological evaluation.

Formation of 6-nitro-norepinephrine from nitric oxide and norepinephrine in the spinal cord and its role in spinal analgesia.

Spinally released norepinephrine is thought to produce analgesia in part by stimulating alpha(2)-adrenergic receptors, which in turn leads to nitric oxide synthesis. Also, nitric oxide is known to react with norepinephrine in vivo in the brain to form 6-nitro-norepinephrine, which inhibits neuronal norepinephrine reuptake. In the present study, we tested the hypothesis that formation of 6-nitro-norepinephrine occurs in the spinal cord and that intrathecal administration of 6-nitro-norepinephrine produces analgesia by stimulating norepinephrine release. 6-Nitro-norepinephrine was present in rat spinal cord tissue and microdialysates of the dorsal horn and intrathecal space. Intrathecal norepinephrine injection increased 6-nitro-norepinephrine. 6-Nitro-norepinephrine also stimulated norepinephrine release in dorsal spinal cord in vitro. Intrathecal injection of 6-nitro-norepinephrine produced antinociception and interacted additively with norepinephrine for antinociception. Spinal noradrenergic nerve destruction increased antinociception from intrathecally injected norepinephrine, but decreased antinociception from 6-nitro-norepinephrine. These results suggest a functional interaction between spinal nitric oxide and norepinephrine in analgesia, mediated in part by formation of 6-nitro-norepinephrine. Stimulation of auto-inhibitory alpha(2)-adrenergic receptors at noradrenergic synapses decreases norepinephrine release. Paradoxically, alpha(2)-adrenergic agonist injection increases and alpha(2)-adrenergic antagonist injection decreases norepinephrine release in the spinal cord. 6-Nitro-norepinephrine may be an important regulator of spinal norepinephrine release and could explain the positive feedback on norepinephrine release after activation of spinal alpha(2)-adrenergic receptors.

Is CT scan monitoring useful in patients with epithelial ovarian cancer and follow-up negative CA 125 serum levels?

We retrospectively reviewed our series of ovarian cancers to assess the benefit of routine follow-up abdominal computer tomography (CT) scans in asymptomatic patients with CA 125 levels <35 U/ml. A chart review was undertaken of all patients with a diagnosis of ovarian cancers treated and followed at the Institute of Obstetrics and Gynecology, University of Ancona, from January 1986 to January 1994. In asymptomatic patients, the routine follow-up consisted of physical examination and CA 125 serum level determination every three to four months for the first two years, and every six months thereafter for a minimum of 5 years. At each visit, a history and a bimanual vaginal examination were completed. The pelvic and abdomen CT scans were performed every six months for the first year and then annually. Inclusion criteria were CA 125 levels >35 U/ml prior to surgery or initial chemotherapy, and complete routine follow-up. Fifty-two patients (75%) satisfied the inclusion criteria. After surgery, 32 of the 52 CA 125 positive patients (61%) showed a decrease in CA 125 levels; 10 other patients showed a negativity of CA 125 after cisplatinum polychemotherapy. After a median time of 49 months (range 16-117 months), 9 of the 42 patients (21%) developed a relapse. The overall CA 125 sensitivity at the time of relapse was 78%, with a specificity of 94%; the sensitivity for early detection of relapses was 70%. Two-hundred and seventy-six abdominal and pelvic CT scans were performed and 8 were positive for tumor relapse, with an overall sensitivity of 89%. The sensitivity of CT scans was 33% for early detection of relapses. The routine performance of follow-up CT scans did not significantly improve the overall detection of early relapses in ovarian carcinoma. A longitudinal monitoring of serum CA 125 is a reliable method of follow-up. Abdominal and pelvic CT scans should be performed in patients who, after a period in which they have been classified as not having evidence of disease with normal CA 125 serum levels, show elevated and rising CA 125, with the aim of finding and characterizing relapses.

Determination of the affinity of drugs toward serum albumin by measurement of the quenching of the intrinsic tryptophan fluorescence of the protein.

Binding of new chemical entities to serum proteins is an issue confronting pharmaceutical companies during development of potential therapeutic agents. Most drugs bind to the most abundant plasma protein, human serum albumin (HSA), at two major binding sites. Excepting fluorescence spectroscopy, existing methods for assaying drug binding to serum albumin are insensitive to higher-affinity compounds and can be labour-intensive, time-consuming, and usually require compound-specific assays. This led us to examine alternative ways to measure drug-albumin interaction. One method described here uses fluorescence quenching of the single tryptophan (Trp) residue in HSA excited at 295 nm to measure drug-binding affinity. Unfortunately, many compounds absorb, fluoresce, or both, in this UV wavelength region of the spectrum. Several types of binding phenomenon and spectral interference were identified by use of six structurally unrelated compounds and the equations necessary to make corrections mathematically were derived and applied to calculate binding constants accurately. The general cases were: direct quenching of Trp fluorescence by optically transparent ligands with low or high affinities; binding of optically transparent, non-fluorescent ligands to two specific sites where both sites or only one site result in Trp fluorescence quenching; and chromophores whose absorption either overlaps the Trp emission and quenches by energy transfer or absorbs light at the Trp fluorescence excitation wavelength producing absorptive screening as well as fluorescence quenching. Unless identification of the site specificity of drug binding to serum albumin is desired, quenching of the Trp fluorescence of albumin by titration with ligand is a rapid and facile method for determining the binding affinities of drugs for serum albumin.

[Urethrovesical morphology in continent women in spinal anesthesia]. / Urethrovesikale Morphologie bei kontinenten Frauen in Spinalanästhesie.

OBJECTIVE: To assess the influence of spinal anesthesia on bladder neck position and a clinical stress test in continent women. METHODS: In a prospective investigation, 14 women underwent urodynamic, sonographic and clinical assessment during spinal anesthesia. Results were compared to those obtained immediately preoperatively in the same patient. RESULTS: During spinal anesthesia, the bladder neck was found to be located significantly lower and more posterior, and in 4/7 parous patients (0/7 nullipara) the clinical stress test was positive. CONCLUSION: These data provide additional evidence for the importance of neuromuscular function in the etiology of pelvic floor dysfunction and genuine stress incontinence.

Effect of earplugs on propofol requirement and awareness with recall during spinal anesthesia.

UNLABELLED: investigator either placed or did not place earplugs into the patients' ears (PLUG or noPLUG groups, respectively). Propofol requirements for stable sedation guided by the bispectral index and incidence of postoperative recall of intraoperative events were assessed in a double-blinded fashion. RESULTS: We found high but comparable propofol requirements in both groups (PLUG 4.4+/-1.2 vs. noPLUG 4.2+/-1.0 mg kg-1 h-1, p=NS). The incidence of intraoperative awareness was lower in the PLUG compared to the noPLUG group (16 vs. 56%; P<0.001). CONCLUSION: Although no sedative-sparing effect could be found in patients who wore earplugs during elective orthopedic surgery under spinal anesthesia, we nevertheless recommend using single-use paraffin wax earplugs. Beside their beneficial effect against potential harmful intraoperative noise, they reduce the incidence of intraoperative awareness with recall.

Peritoneal macrophage cholesteryl ester content as a function of plasma cholesterol in rats.

Cholesterol accumulation in macrophages that have migrated in the subintimal space leads to foam cell formation, which is believed to be one of the initiating events in atherosclerosis. In this study we investigated the effect of cholesterol feeding on peritoneal monocyte/macrophage cholesterol content and peritoneal cavity lipoprotein composition in rats. A cholesterol (2%) and cholic acid (1%) diet caused significant hypercholesterolemia in plasma, and at the same time the cholesterol content of peritoneal monocytes/macrophages was increased. At day 7, the cellular cholesteryl ester content had risen to 30.1 micrograms/mg cellular protein from a baseline value of 9.2 micrograms/mg. The unesterified cholesterol content also increased by 56%. At this time, acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity was doubled, whereas neutral and acidic cholesteryl ester hydrolase activities were unchanged. Reversal to the regular chow diet after 7 days of the cholesterol-enriched diet normalized plasma cholesterol levels as well as peritoneal monocyte/macrophage cholesteryl ester content. ACAT activity also decreased toward normal levels. Analysis of the d less than 1.21 g/ml peritoneal lipoproteins isolated by ultracentrifugation revealed the presence, in both normal and hypercholesterolemic rats, of apolipoprotein A-I-rich lipid complexes with pre-beta mobility on agarose gel electrophoresis. The size of the peritoneal lipoproteins was smaller than that of plasmatic high density lipoproteins, and their chemical composition was also different from that of the major plasma lipoproteins. The cholesteryl ester content of peritoneal lipoproteins increased after feeding of the cholesterol-enriched diet. In conclusion, our results show that cholesterol feeding leads to rapid accumulation of cholesteryl esters in monocytes/macrophages. As soon as plasma cholesterol levels are returned to normal, cellular cholesterol content is also normalized.(ABSTRACT TRUNCATED AT 250 WORDS)

Results and implications of high-resolution surface dosimetry of ruthenium-106 eye applicators.

The dosimetry of 106Ru/106Rh beta-emitting eye applicators is still inadequate. Manufacturer's specifications of absolute dose rates are loaded with a +/- 30% error, and the relative distribution of activity on the surface is measured on a few points only, using a 3-mm plastic scintillation probe. While reducing the absolute error of dose rate measurements to +/- 15% by a method published earlier, we now present a phantom using small thermoluminescent dosimetry crystals for refined assessment of its distribution over the surface. Evaluation of two applicators revealed a 50% increase in activity in the midperiphery in one and a steep falloff of activity 1 mm within the margin of both specimens. The method and findings are demonstrated in detail and compared to those reported by other authors.

Intrathecal adenosine: interactions with spinal clonidine and neostigmine in rat models of acute nociception and postoperative hypersensitivity.

BACKGROUND: Spinal adenosine receptor agonists exert antinociception in animal models of acute and chronic pain, but adenosine itself has not been examined. The authors tested the antinociceptive and antihypersensitivity interactions of intrathecal adenosine and its interactions with intrathecal clonidine and neostigmine in rat models of acute thermal nociception and postoperative hypersensitivity. METHODS: Rats were prepared with lumbar intrathecal catheters. Responses to acute noxious stimulation were evaluated by latency to paw withdrawal from a radiant heat source focused on the hind paw. Postoperative hypersensitivity was measured after an incision in the rat hind paw by application of von Frey filaments to the heel adjacent to the wound. An isobolographic design was used to distinguish between additive and synergistic drug interactions. RESULTS: Spinal administration of clonidine and neostigmine, but not adenosine, produced dose-dependent antinociception to noxious thermal stimulation. Addition of adenosine enhanced the antinociceptive effect of clonidine but not neostigmine. In contrast, each of these three agents alone reversed postoperative hypersensitivity. Pretreatment with the alpha-adrenergic antagonist phentolamine completely reversed adenosine's antihypersensitivity action. Adenosine interacted synergistically with neostigmine and additively with clonidine in reducing postoperative hypersensitivity. CONCLUSIONS: These data indicate that intrathecal adenosine by itself has no antinociceptive properties to acute noxious thermal stimulation in rats, but enhances clonidine's antinociception. In contrast, intrathecal adenosine is active against postoperative hypersensitivity by an adrenergic mechanism. Different interactions between adenosine, clonidine, and neostigmine in acute nociception and postoperative hypersensitivity models are consistent with altered central processing of sensory information after peripheral injury.

Simulation of an epidural test dose with intravenous isoproterenol in awake and in halothane-anesthetized children.

BACKGROUND: An epidural test dose containing epinephrine does not reliably produce hemodynamic responses in children under halothane anesthesia. The purpose of this study was to determine hemodynamic responses to intravenous isoproterenol in both awake and halothane-anesthetized children. METHODS: After obtaining institutional review board approval and parental informed consent, 72 ASA physical status 1 or 2 children (2.8 +/- 1.7 yr) undergoing elective minor surgery were studied before and during anesthesia with 1.2 minimum alveolar concentration halothane. A bolus containing 0.25 mg/ kg bupivacaine and 0.05 microgram/kg, 0.075 microgram/kg, or 0.1 microgram/kg isoproterenol, or bupivacaine and saline was injected via a peripheral arm vein to simulate intravascular injection of an epidural test dose. RESULTS: Before induction of anesthesia, all patients showed a positive test response after isoproterenol injection (heart rate increase > or = 20 beats/min). During anesthesia, 79% of patients receiving 0.05 microgram/kg, 89% of patients receiving 0.075 microgram/kg, and 100% of patients receiving 0.1 microgram/kg met the criterion of a positive test response. Among each treatment group, all infants showed a positive test response. Blood pressure did not differ among the groups at any time. Transient benign dysrhythmias occurred in only one patient under halothane anesthesia receiving 0.075 microgram/kg isoproterenol. CONCLUSION: Isoproterenol at a dose of 0.1 microgram/kg is a sensitive indicator for intravascular injection of a test dose in children anesthetized with halothane and nitrous oxide. Isoproterenol at a dose of 0.05 microgram/kg approximates a minimal effective dose in awake children and in infants. After detailed studies on neural toxicity, isoproterenol could be of value as an epidural test agent in children.