bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Tetracaine on Voltage-activated Calcium Sparks in Frog Intact Skeletal Muscle Fibers
Authors: Hollingworth Stephen , Chandler W. Knox , Baylor Stephen M.
Published: February 2006

The properties of Ca2+ sparks in frog intact skeletal muscle fibers depolarized with 13 mM [K+] Ringer's are well described by a computational model with a Ca2+ source flux of amplitude 2.5 pA (units of current) and duration 4.6 ms (18 °C; Model 2 of Baylor et al., 2002). This result, in combination with the values of single-channel Ca2+ current reported for ryanodine receptors (RyRs) in bilayers under physiological ion conditions, 0.5 pA (Kettlun et al., 2003) to 2 pA (Tinker et al., 1993), suggests that 1–5 RyR Ca2+ release channels open during a voltage-activated Ca2+ spark in an intact fiber. To distinguish between one and greater than one channel per spark, sparks were measured in 8 mM [K+] Ringer's in the absence and presence of tetracaine, an inhibitor of RyR channel openings in bilayers. The most prominent effect of 75–100 μM tetracaine was an approximately sixfold reduction in spark frequency. The remaining sparks showed significant reductions in the mean values of peak amplitude, decay time constant, full duration at half maximum (FDHM), full width at half maximum (FWHM), and mass, but not in the mean value of rise time. Spark properties in tetracaine were simulated with an updated spark model that differed in minor ways from our previous model. The simulations show that (a) the properties of sparks in tetracaine are those expected if tetracaine reduces the number of active RyR Ca2+ channels per spark, and (b) the single-channel Ca2+ current of an RyR channel is ≤1.2 pA under physiological conditions. The results support the conclusion that some normal voltage-activated sparks (i.e., in the absence of tetracaine) are produced by two or more active RyR Ca2+ channels. The question of how the activation of multiple RyRs is coordinated is discussed.
Developmental Differences in Spinal Cyclooxygenase 1 Expression after Surgical Incision
Authors: Ririe Douglas G. , Prout Heather D. , Barclay David , Tong Chuanyo , Lin Marina , Eisenach James C.
Published: February 2006

Background

Systemic administration of a cyclooxygenase 1 (COX-1) inhibitor reduces hypersensitivity to mechanical stimuli after incisional paw surgery in 4-week-old, but not 2-week-old, animals. The purpose of the current study was to test whether this developmental difference was reflected by differences in COX-1 expression in the spinal cord after surgery.

Methods

Rats 2 and 4 weeks of age, paralleling infant and child human neurologic developmental stages, were used. A paw incision was made under general anesthesia and the withdrawal thresholds were measured before and after systemic and intrathecal administration of a COX-1 selective inhibitor (SC560). Immunohistochemistry was used to assess COX-1 protein in the spinal cord, and real-time polymerase chain reaction was used to quantify gene expression of COX-1 mRNA.

Results

Systemic and intrathecal administration of SC560 produced an increase in withdrawal threshold in the 4-week-old, but not in the 2-week-old, animals. Intrathecal SC560 increased withdrawal thresholds in the 4-week-old animals at a dose 100-fold less than with systemic administration. Cyclooxygenase 1 protein in the spinal cord was increased ipsilateral to surgery in the 4-week-old, but not in the 2-week-old, animals. Cyclooxygenase 1 mRNA was increased in the 4-week-old animals in the spinal cord ipsilateral to surgery relative to the contralateral side of the spinal cord, but not in the 2-week-old animals.

Conclusions

These results suggest that developmental differences in COX-1 expression in the spinal cord likely explain the lack of efficacy of COX-1 inhibitors in the 2-week-old rats. Whether this reflects a deficit in factors that stimulate COX-1 expression or a difference in response to these factors is not addressed, but should similar deficits occur in humans, COX-1 inhibitors may exhibit reduced efficacy in infants.
Obesity in Diabetic Patients Undergoing Coronary Artery Bypass Graft Surgery Is Associated with Increased Postoperative Morbidity
Authors: Pan Wei , Hindler Katja , Lee Vei-Vei , Vaughn William K. , Collard Charles D.
Published: February 2006

Background

Despite the fact that obesity is a known risk factor for cardiovascular disease, many studies have failed to demonstrate that obesity is independently associated with an increased risk of cardiovascular morbidity and mortality in nondiabetic patients undergoing coronary artery bypass graft surgery. The authors investigated the influence of obesity on adverse postoperative outcomes in diabetic and nondiabetic patients after primary coronary artery bypass surgery.

Methods

A retrospective cohort study of patients undergoing primary coronary artery bypass surgery (n = 9,862) between January 1995 and December 2004 at the Texas Heart Institute was performed. Diabetic (n = 3,374) and nondiabetic patients (n = 6,488) were classified into five groups, according to their body mass index: normal weight (n = 2,148), overweight (n = 4,257), mild obesity (n = 2,298), moderate obesity (n = 785), or morbid obesity (n = 338). Multivariate, stepwise logistic regression was performed controlling for patient demographics, medical history, and preoperative medications to determine whether obesity was independently associated with an increased risk of adverse postoperative outcomes.

Results

Obesity in nondiabetic patients was not independently associated with an increased risk of adverse postoperative outcomes. In contrast, obesity in diabetic patients was independently associated with a significantly increased risk of postoperative respiratory failure (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.41-3.61; P < 0.001), ventricular tachycardia (OR, 2.27; 95% CI, 1.18-4.35; P < 0.02), atrial fibrillation (OR, 1.56; 95% CI, 1.03-2.38; P < 0.04), atrial flutter (OR, 2.38; 95% CI, 1.29-4.40; P < 0.01), renal insufficiency (OR, 1.66; 95% CI, 1.10-3.41; P < 0.03), and leg wound infection (OR, 5.34; 95% CI, 2.27-12.54; P < 0.001). Obesity in diabetic patients was not independently associated with an increased risk of mortality, stroke, myocardial infarction, sepsis, or sternal wound infection.

Conclusion

Obesity in diabetic patients is an independent predictor of worsened postoperative outcomes after primary coronary artery bypass graft surgery.
Safety and Efficacy of the Cyclooxygenase-2 Inhibitors Parecoxib and Valdecoxib after Noncardiac Surgery
Authors: Nussmeier Nancy A. , Whelton Andrew A. , Brown Mark T. , Joshi Girish P. , Langford Richard M. , Singla Neil K. , Boye Mark E. , Verburg Kenneth M.
Published: February 2006

Background

Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures.

Methods

The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects.

Results

Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01).

Conclusions

Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.
Alcohol‐attributable mortality and potential years of life lost in Canada 2001: implications for prevention and policy
Authors: Rehm Jürgen , Patra Jayadeep , Popova Svetlana
Published: February 2006

Background Alcohol is one of the most important risk factors for burden of disease.

Objective To estimate the number of deaths and the years of life lost attributable to alcohol for Canada 2001 using different ways to measure alcohol exposure.

Methods Distribution of exposure was taken from a major national survey of Canada, the Canadian Addiction Survey, and corrected for per capita consumption from production and sales. For chronic disease, risk relations were taken from the published literature and combined with exposure to calculate age‐ and sex‐specific alcohol‐attributable fractions (AAFs). For injury, AAFs were taken directly from available statistics. Information on mortality, with cause of death coded according to the International Classification of Diseases version 10 (ICD‐10) was obtained from Statistics Canada.

Results For Canada in 2001, 4010 of all deaths in the group below 70 years of age were attributable to alcohol, 3132 in men and 877 in women. This constituted 6.0% of all deaths in Canada in this age group, 7.6% for men, and 3.5% for women. The 4010 deaths are a net figure, already taking into account the deaths prevented by moderate consumption of alcohol. Main causes of alcohol‐attributable death were unintentional injuries, malignant neoplasms and digestive diseases. Ischaemic heart disease (IHD) was the biggest cause of death prevented by alcohol, with 78.7% of all alcohol‐attributable prevented deaths in the age groups of 70 years and above. A total of 144 143 years of life were lost prematurely in Canada in that year, 113 079 years in men and 31 063 years in women.

Discussion Regardless of the assumptions made, alcohol is a major contributor to mortality in Canada. The impact of alcohol on social life is not confined to mortality, as other studies indicated that alcohol is linked even more strongly to disability and social harm. Alcohol‐attributable harm could be substantially reduced, however, if known effective policies were introduced.
What drug policies cost. Drug policy spending in the Netherlands in 2003
Authors: Rigter Henk
Published: February 2006

Aim  To estimate the public spending on drug policy in the Netherlands.

Methods  Calculation and extrapolation of expenditures from 2003 budgets of all Ministries of the national government, annual reports from other governments and agencies and White Papers, supported by interviews with and information obtained otherwise from policy makers. Expenditures were allocated to four drug policy functions, i.e. prevention, treatment, harm reduction and enforcement. Where exact data on expenditures were lacking, approximations were made representing expert judgement.

Results  The total drug policy spending estimate in 2003 was 2185 million Euros. Allocation to functions amounted to 42 million Euros for prevention, 278 million for treatment, 220 million for harm reduction and 1646 million for enforcement.

Conclusions  Drug law enforcement is clearly the dominant expenditure. This can be said with certainty despite the noted pitfalls in estimating drug policy expenditures. Many of the available data are not precise. To achieve better figures, a much more detailed analysis would be needed (which is not planned for the foreseeable future). Even then, it would be hard to separate the drug component from more general budgets.
Highly active antiretroviral therapy (HAART) among HIV‐infected drug users: a prospective cohort study of sexual risk and injecting behaviour
Authors: Smit Colette , Lindenburg Karen , Geskus Ronald B. , Brinkman Kees , Coutinho Roel A. , Prins Maria
Published: February 2006

Aims  To study sexual risk and injecting behaviour among HIV‐infected drug users (DU) receiving highly active antiretroviral therapy (HAART). 

Design and setting  As part of an ongoing prospective cohort study, HIV‐infected DU who commenced HAART (n = 67) were matched with those not starting HAART (n = 130) on CD4 cell counts, duration of cohort participation, age and calendar year of visit. Immunological and virological responses of the HAART‐treated DU were compared with the HAART‐treated homosexual men from the same cohort (n = 212).

Measurements  Trends in behaviour and therapeutic response were tested with a logistic regression model adjusted for repeated measurements and a piecewise random effects model, respectively.

Findings  Non‐HAART users reported more episodes of injecting than HAART users. In both groups injecting declined over time with no effect of HAART initiation. Before HAART initiation an increase in sexual risk behaviour was observed among those who had been assigned to receive HAART; their sexual risk behaviour declined thereafter. No change in sexual risk behaviour was found among non‐HAART users. Relative to homosexual men, DU had a similar initial therapeutic response, but DU started HAART at lower CD4 cell counts and higher viral load levels.

Conclusion  DU who are treated with HAART are not increasing their risk behaviour, and their early response to HAART is similar to homosexual men. However, before the treated DU received HAART they were seen to inject less often than those not treated with HAART. This suggests that selection of potential HAART starters is based on limited drug use. Although the DU who commence HAART are a selected group, our results show that HIV‐infected DU can be treated effectively.
Substance use and other psychiatric disorders in first‐degree relatives of opioid‐dependent males: a case–controlled study from India
Authors: Prasant M. Phani , Mattoo Surendra K. , Basu Debasish
Published: February 2006

Aim  To assess the prevalence of substance use and other psychiatric disorders in first‐degree relatives of males with opioid dependence compared to normal controls. 

Design  Observational, case–control study using family history method. 

Setting  A drug addiction treatment centre in northern India. 

Participants  First‐degree relatives of 100 male probands with opioid dependence and no comorbidity (n = 493) and those of 50 matched probands from normal population (n = 254).

Measurement  Family interview of probands and family members, using the Family Interview for Genetic Studies. The main outcome measure was relative risk (expressed as odds ratio after controlling for confounding variables using logistic regression) of familial aggregation of psychiatric and substance use disorders.

Findings  First‐degree relatives of opioid‐dependent males were more likely to have a psychiatric disorder than those of normal controls [adjusted odds ratio (OR) 4.47; 95% confidence interval (CI) 1.97–10.11; P < 0.001], especially for opioid use disorders in the brothers (adjusted OR 6.55; 95% CI 1.44–29.88; P = 0.015) and for alcohol use disorders in the fathers of the probands (adjusted OR 5.64; 95% CI 2.39–13.24; P < 0.001). Other disorders (major depression, chronic psychosis and obsessive compulsive disorder) did not have significant aggregation in the first‐degree relatives of opioid‐dependent subjects.

Conclusions  This study provides further evidence for the higher rates of alcohol and opioid dependence in first‐degree relatives of opioid‐dependent patients. The exact pattern of this familial aggregation may be influenced by the gender of the relatives and their relation to the proband.
Effectiveness of drug and alcohol counselling during methadone treatment: content, frequency, and duration of counselling and association with substance use outcomes
Authors: Gossop Michael , Stewart Duncan , Marsden John
Published: February 2006

Aims  The study investigates the relationship between the type and severity of drug and alcohol use problems, and the provision of drug‐ and alcohol‐counselling in methadone programmes. The study also specifically investigates the relationship between content, frequency and duration of counselling provided during the first month of treatment, and heroin, cocaine, and alcohol use outcomes at 6 months. 

Design, setting and participants  The sample comprised 276 patients receiving outpatient methadone treatment who were followed‐up 6 months after treatment entry.

Measurements  Data on client characteristics, drug and alcohol problems and on counselling received were collected by structured face‐to‐face interviews.

Findings  Drug‐focused counselling was associated with less frequent heroin and cocaine use at follow‐up, but was not related to pre‐treatment drug use. Alcohol‐focused counselling was provided for those with higher levels of drinking at admission but was not significantly associated with drinking outcome at 6 months.

Conclusions  Results indicate that there are complex interactions between presenting substance use problems, provision of counselling and treatment outcomes. These interactions differ by substance type.
Transjugular intrahepatic portosystemic shunt for portal vein thrombosis with and without cavernous transformation
Authors: SENZOLO M. , TIBBALS J. , CHOLONGITAS E. , TRIANTOS C. K. , BURROUGHS A. K. , PATCH D.
Published: February 2006

Background

Treatment options for patients with portal vein thrombosis are limited.

Aim

To evaluate the feasibility and efficacy of transjugular intrahepatic portosystemic shunt for portal vein thrombosis with/without cavernomatous transformation.

Methods

A survey of such patients, referred for transjugular intrahepatic portosystemic shunt between 1994 and 2005, was performed. Success rates, complications, transjugular intrahepatic portosystemic shunt patency and clinical progression were examined.

Results

Transjugular intrahepatic portosystemic shunt was attempted in 28 patients (13 cirrhotics). Indications were: presurgery/transplantation (2), worsening of ascites (2), variceal bleeding (15 – 8 elective), refractory ascites (3), portal biliopathy (3) and portal vein thrombosis complicating Budd–Chiari syndrome (2). Transjugular intrahepatic portosystemic shunt was placed successfully in 19 of 28 (73%); 23 of 28 had complete portal vein thrombosis and 9 of 23 had cavernous transformation and transjugular intrahepatic portosystemic shunt was successfully placed in six of these. In the 19 patients with transjugular intrahepatic portosystemic shunt, the mean follow‐up was 18.1 months (range 5–70): six patients had stent revisions; three had liver transplantation, one died of bleeding. Most cirrhotic patients had an improvement in the Child‐Pugh score. In the failed transjugular intrahepatic portosystemic shunt group, two of nine died, and three had further bleeding.

Conclusions

Transjugular intrahepatic portosystemic shunt should be considered for selected patients with symptomatic complete portal vein thrombosis with/without cavernous transformation, as clinical improvement and less rebleeding occur when transjugular intrahepatic portosystemic shunt placement is successful.
Acetic acid‐enhanced magnification endoscopy in the diagnosis of specialized intestinal metaplasia, dysplasia and early cancer in Barrett's oesophagus
Authors: FORTUN P. J. , ANAGNOSTOPOULOS G. K. , KAYE P. , JAMES M. , FOLEY S. , SAMUEL S. , SHONDE A. , BADRELDIN R. , CAMPBELL E. , HAWKEY C. J. , RAGUNATH K.
Published: February 2006

Background

Barrett's surveillance is prone to sampling error.

Aim

To determine whether enhanced magnification endoscopy using acetic acid instillation improves diagnostic accuracy of specialized intestinal metaplasia/dysplasia in Barrett's oesophagus.

Methods

We examined the detection rate of the specialized intestinal metaplasia/dysplasia in 64 consecutive patients with Barrett's oesophagus using acetic acid to enhance mucosal pit patterns. Histology was compared with the previous findings at recent conventional surveillance in 62 patients. We also examined the inter‐/intra‐observer agreement in the assessment of the enhanced magnification endoscopy pit pattern findings.

Results

Histology revealed columnar‐lined oesophagus in six (9%) patients, specialized intestinal metaplasia in 49 (77%), low‐grade dysplasia in five (8%), high‐grade dysplasia in one (2%), and adenocarcinoma in three (5%). There was discordance between the histologic findings from conventional surveillance with random biopsy. Fifteen patients (24%) had a histological upgrade with enhanced magnification endoscopy. There was a high detection rate of specialized intestinal metaplasia even in short segment Barrett's oesophagus (74%), and additionally, there were two cancers, one with 2‐cm Barrett's oesophagus and one ultra‐short (1 cm). The mean kappa values for inter‐ and intra‐observer agreement in assessing the pit patterns were 0.571 (0.041) and 0.709 (0.038), respectively.

Conclusions

Enhanced magnification endoscopy allows clear visualization of the epithelial pit patterns within Barrett's oesophagus, and targeted biopsy results in a high yield of specialized intestinal metaplasia and dysplasia.
Recurrence of Helicobacter pylori infection after several eradication therapies: long‐term follow‐up of 1000 patients
Authors: GISBERT J. P. , LUNA M. , GÓMEZ B. , HERRERÍAS J. M. , MONÉS J. , CASTRO‐FERNÁNDEZ M. , SÁNCHEZ‐POBRE P. , COSME A. , OLIVARES D. , PAJARES J. M.
Published: February 2006

Aim

To study the incidence of Helicobacter pylori recurrence, its chronological aspects, and the variables that might influence it.

Methods

A total of 1000 patients in whom H. pylori had been eradicated were prospectively studied. Therapies were classified as low and high efficacy regimens. Four to eight weeks after completion of therapy, 13C‐urea‐breath‐test was performed, and it was repeated yearly up to 5 years. In some patients, endoscopy with biopsies was also performed to confirm H. pylori eradication.

Results

A total of 1000 patients were included, giving 2744 patient‐years of follow‐up. Seventy‐one H. pylori recurrences were observed (2.6% per patient‐year). Probability of being H. pylori‐negative at 1 year was 94.7%, and at 5 years 90.7%. In the multivariate analysis, low age (OR: 1.84; 95% CI: 1.04–3.26) and low efficacy therapies (OR: 2.5; 1.23–5.04) correlated with 1‐year H. pylori recurrence. Differences were observed when Kaplan–Meier curves were compared depending on age and therapy regimen.

Conclusion

Risk of posteradication H. pylori recurrence is higher during the first year, which suggests that most recurrences during this period are recrudescence and not true reinfections. H. pylori recurrence is more frequent in younger patients and in those treated with low efficacy therapies, but is exceptional if high efficacy therapies are used, in which case post‐therapy eradication can be safely confirmed at 4 weeks with 13C‐urea‐breath‐test.
Genomic variation in the mitochondrially encoded cytochrome b (MT‐CYB) and 16S rRNA (MT‐RNR2) genes: characterization of eight endangered Pecoran species
Authors: Guha S. , Goyal S. P. , Kashyap V. K.
Published: February 2006

In an effort to develop species‐specific identification markers, we examined genetic variants and molecular signatures within genes encoding mitochondrial cytochrome b and 16S rRNA in eight endangered Pecoran species endemic to the Indian peninsula. Our results revealed that the cytochrome b gene exhibited higher sequence diversity than the 16S rRNA gene, both between and within species. However, the 16S rRNA gene harboured a larger number of species‐specific mutation sites compared with the cytochrome b gene, suggesting that it could be useful for species identification. Indeed, we successfully used ‘forensically informative nucleotide sequencing’ (FINS) analysis of the 16S rRNA gene to identify two previously unknown biological specimens.
18Flurodeoxyglucose positron emission tomography in the localization of ectopic ACTH‐secreting neuroendocrine tumours
Authors: Kumar J. , Spring M , Carroll P. V. , Barrington S. F. , Powrie J. K.
Published: February 2006

Objective  Neuroendocrine tumours (NET) are a rare cause of Cushing's syndrome. These tumours can be very small and therefore difficult to identify. Current localization techniques include CT, MRI and radioisotope scanning, but in a proportion of cases the NET remains occult. Positron emission tomography (PET) scanning, is a relatively new imaging modality that is increasingly used to detect and monitor lesions with high metabolic activity. We report on the use of PET scanning in the evaluation of the ectopic ACTH syndrome.

Patients  Three patients with ectopic ACTH‐dependent Cushing's syndrome with varying difficulty in NET localization are included in the report.

Measurement  Positron emission tomography scanning using 18flurodeoxyglucose (FDG) identifies tissue with high metabolic activity. 18FDG‐PET scanning was used in each of these patients and the imaging is presented along with biochemical data.

Results  In each case the NET was easily identified using 18FDG‐PET, aiding clinical decision making and therapeutic outcome. A cure was identified by clinical resolution of symptoms and undetectable ACTH levels postsurgery.

Conclusions  18FDG‐PET assisted in localizing small metabolically active NETs, suggesting this imaging modality may have a useful role in identifying NET causing Cushing's syndrome as a result of ectopic ACTH production.
Cerebral glutamate metabolism during hypoglycaemia in healthy and type 1 diabetic humans
Authors: Bischof M. G. , Brehm A. , Bernroider E. , Krššák M. , Mlynárik V. , Krebs M. , Roden M.
Published: February 2006

Background  The mechanisms responsible for the progressive failure of hypoglycaemia counterregulation in long‐standing type 1 diabetes are poorly understood. Increased brain glucose uptake during hypoglycaemia or alterations of brain energy metabolism could effect glucose sensing by the brain and thus contribute to hypoglycaemia‐associated autonomic failure.

Materials and methods  Type 1 diabetic patients (T1DM) and healthy volunteers (CON) were studied before, during and after a hypoglycaemic (50 mg dL−1) hyperinsulinaemic (1·5 mU kg−1 min−1) clamp test. The 1H magnetic resonance spectroscopy of the occipital lobe of the brain was performed employing the STEAM localization technique. The water signal was suppressed by the modified SWAMP method. All spectra were acquired on a 3 Tesla scanner (80 cm MEDSPEC‐DBX, Bruker Medical, Ettlingen, Germany) using a 10‐cm diameter surface coil.

Results  During hypoglycaemia, T1DM showed blunted endocrine counterregulation. At baseline the brain tissue glucose : creatine ratio was lower in CON than in T1DM (CON 0·13 ± 0·05 vs. T1DM 0·19 0·11; P < 0·01). During hypoglycaemia glucose : creatine ratios decreased in both groups (CON 0·07 ± 0·08, P < 0·05; T1DM 0·03 ± 0·03, P < 0·001). A significant drop in the glutamate : creatine ratio could only be found in CON during hypoglycaemia (CON 1·36 ± 0·08 vs. 1·26 ± 0·11; P < 0·01; T1DM 1·32 ± 0·13 vs. 1·28 ± 0·15; P = NS). The ratios of glutamine, N‐acetylaspartate, choline and myo‐inositol : creatine were not different between both groups and did not change throughout the experiment.

Conclusions  Only in CON does moderate hypoglycaemia reduce intracerebral glutamate concentrations, possibly owing to a slower substrate flux through the tricarboxylic acid cycle in neurones. The maintenance of normal energy metabolism in T1DM during hypoglycaemia might effect glucose sensing in the brain and contribute to hypoglycaemia‐associated autonomic failure.
Visual impairments in people with severe and profound multiple disabilities: an inventory of visual functioning
Authors: Van Den Broek E. G. C. , Janssen C. G. C. , Van Ramshorst T. , Deen L.
Published: February 2006

Background The prevalence of visual impairments in people with severe and profound multiple disabilities (SPMD) is the subject of considerable debate and is difficult to assess.

Methods In a typical Dutch care organization, all clients with SPMD (n = 76) participated in the study and specific instruments adapted to these clients (requiring a minimum of cooperation) were used to measure visual acuity, the visual field, binocular vision, contrast sensitivity, refractive errors and visual functioning behaviour.

Results We found an unexpected 92% of clients with SPMD to have visual impairments. Previously, only 30% were known to have visual problems. None of the persons observed had normal visual acuity. Subnormal visual acuity was the best result. The severity of the visual impairment was related to the severity of the intellectual disability. In addition to the problem of acuity, impairments in the visual field, impaired contrast sensibility and impaired binocular functioning were found, as well as impaired visual attention, fixation and following. In 22% of the _clients observed, refractive errors were found and glasses were advised.

Conclusions Consequences for caregiving and for modifications of the environment were discussed.
Mechanotransduction and the homeostatic significance of maintaining blood viscosity in hypotension, hypertension and haemorrhage
Authors: MARTINI J. , CABRALES P. , TSAI A. G. , INTAGLIETTA M.
Published: February 2006

The increase of plasma and blood viscosity is usually associated with pathological conditions; however, elevation of both parameters often results in increased perfusion and the lowering of peripheral vascular resistance. In extreme haemodilution, blood viscosity is too low and insufficient to maintain functional capillary density, a problem that in experimental studies is shown to be corrected by increasing plasma viscosity up to 2.2 cP. This effect is mediated by mechanotransduction‐induced nitric oxide (NO) production via shear stress in the endothelium as shown by microelectrode perivascular measurements of NO concentration. Moderate elevations of blood viscosity by increasing haematocrit (∼10%) result in comparable reductions of blood pressure and peripheral vascular resistance, an effect also NO‐mediated as it is absent after Nω‐nitro‐L‐arginine methyl ester treatment and in endothelial nitric oxide synthase‐deficient mice. These findings show that the rheological properties of plasma affect vessel diameter in the microcirculation leading to counterintuitive responses to the changes in blood and plasma viscosity. Application of these findings to haemorrhagic shock resuscitation leads to the concept of hyperosmotic‐hyperviscous resuscitation as a modality for maintaining the recovery of microvascular function.
Rising incidence and persistently high mortality of hospitalized pneumonia: a 10‐year population‐based study in Denmark
Authors: THOMSEN R. W. , RIIS A. , NØRGAARD M. , JACOBSEN J. , CHRISTENSEN S. , MCDONALD C. J. , SØRENSEN H. T.
Published: February 2006

Background.  Little is known about temporal trends in the incidence and mortality of pneumonia in the general population.

Methods.  We conducted a population‐based cohort study in three Danish counties (population 1.4 million) to examine changes in the incidence and 30‐ and 90‐day mortality associated with hospitalized pneumonia between 1994 and 2004. All adults hospitalized with a first‐time diagnosis of pneumonia (n = 41 793) were identified in hospital discharge registries and followed for mortality through the Danish Civil Registry System. We determined age‐standardized incidence rates and adjusted mortality rates associated with calendar year, gender, age and comorbidity.

Results.  Between 1994 and 2003, the incidence of hospitalized pneumonia amongst adults increased from 288 per 100 000 person‐years to 442 per 100 000 person‐years, equivalent to an age‐standardized incidence rate ratio of 1.50. The cumulative mortality within 30 and 90 days of admission was 15.2% and 21.9%, respectively, ranging from a 90‐day mortality of 2.5% in patients aged 15–39 years to 34.7% in those aged 80 and over. Advanced age was the most important poor prognostic factor, followed by a high comorbidity score and male gender. The adjusted mortality rate ratios amongst patients with hospitalized pneumonia in 1999–2004, when compared with 1994–1998, were 0.89 (95% CI 0.85–0.94) after 30 days and 0.91 (95% CI 0.88–0.95) after 90 days.

Conclusions.  The incidence of hospitalized pneumonia in Denmark has increased considerably during the last 10 years and, combined with persistently high mortality rates, is of clinical and public health concern.
Expression and Regulation of Human CD275 on Endothelial Cells in Healthy and Inflamed Mucosal Tissues
Authors: Youngnak‐Piboonratanakit P. , Tsushima F. , Otsuki N. , Igarashi H. , Omura K. , Azuma M.
Published: February 2006

The CD275‐CD278 costimulatory pathway is a new pathway for CD28‐B7 family molecules involved in the effector phase of T‐cell‐mediated immune responses. Expression of CD275 in oral mucosa at healthy and disease states has not been examined. We generated monoclonal antibodies against human CD275 and investigated its expression and regulation in cultured tissue cell lines and oral mucosal tissues. CD275 on monocytes was efficiently upregulated by interleukin‐4, while interferon‐γ abrogated this effect. CD275 on cultured endothelial cells (EC) was rapidly enhanced by tumour necrosis factor‐α. In healthy oral mucosa, CD275 was not detected on keratinocytes, Langerhans cells or intraepithelial lymphocytes within the epithelium or on interstitial dendritic cells or lymphocytes in the subepithelium. Constitutive expression of CD275 on EC in the connective tissues was observed in healthy mucosa, but CD275 expression on EC in oral lichen planus was either upregulated or downregulated. Approximately 20% of the T cells found within infiltrating mononuclear cells in the subepithelium expressed high levels of the CD278 receptor. CD275 on lymphoid and nonlymphoid cells is positively or negatively regulated by various cytokines. Our results suggest that CD275 on EC is involved in the recruitment or extravasation of receptor‐positive effector T cells into inflamed tissues.
Characterization of Monocyte‐Derived Dendritic Cells Maturated With IFN‐α
Authors: Svane I. M. , Nikolajsen K. , Walter M. R. , Buus S. , Gad M. , Claesson M. H. , Pedersen A. E.
Published: February 2006

Dendritic cells (DC) are promising candidates for cancer immunotherapy. These cells can be generated from peripheral blood monocytes cultured with granulocyte macrophage‐colony stimulating factor (GM‐CSF) and interleukin‐4 (IL‐4). In order to obtain full functional capacity, maturation is required, but the most potent reagents such as LPS or polyriboinosinic polyribocytidylic acid (Poly I:C) are not approved for clinical use. We tested the ability of type I interferon (IFN) to induce such maturation. We found that 24‐h IFN‐α co‐culture of day 7 monocyte‐derived DC generated with GM‐CSF and IL‐4 induces increased numbers of DC positive for CD54 and CD40 together with the co‐stimulatory molecule CD80 but not the activation marker CD83. Also, IFN‐α maturation leads to an increase in IP‐10 and MCP‐1 chemokine secretion, but only a minor increase in IL‐12p40 secretion. In line with this, maturation with IFN‐α has only a small effect on induction of autologous T‐cell stimulatory capacity of the DC. However, an increase in DC allogeneic T‐cell stimulatory capacity was observed. These data suggest that IFN‐α has a potential as a maturation agent used in DC‐based cancer vaccine trials, but not as a single reagent.
Clinical Aspects and Molecular Basis of Primary Deficiencies of Complement Component C3 and its Regulatory Proteins Factor I and Factor H
Authors: S. Reis E. , Falcão D. A. , Isaac L.
Published: February 2006

The complement system participates in both innate and acquired immune responses. Deficiencies in any of the protein components of this system are generally uncommon and require specialized services for diagnosis. Consequently, complement deficiencies are clinically underscored and may be more common than is normally estimated. As C3 is the major complement component and participates in all three pathways of activation, it is fundamental to understand all the clinical consequences observed in patients for which this protein is below normal concentration or absent in the serum. C3 deficiencies are generally associated with higher susceptibility to severe infections and in some cases with autoimmune diseases such as systemic lupus erythematosus. Here, we review the main clinical aspects and the molecular basis of primary C3 deficiency as well as the mutations in the regulatory proteins factor I and factor H that result in secondary C3 deficiencies. We also discuss the use of animal models to study these deficiencies.
Elevated Serum CCL2 Concomitant with a Reduced Mycobacterium‐Induced Response Leads to Disease Dissemination in Leprosy
Authors: Hasan Z. , Jamil B. , Zaidi I. , Zafar S. , Khan A. A. , Hussain R.
Published: February 2006

Mycobacterium leprae and Mycobacterium tuberculosis are successful intracellular pathogens which downregulate host immune responses. T‐cell interferon‐γ (IFNγ) and macrophage tumour necrosis factor‐α (TNFα) activate chemokines such as, C‐C chemokine ligand‐2 (CCL2) and CCL5, which play a role in granuloma formation. Lepromatous leprosy is characterized by defective granulomas with lowered T‐cell‐ and macrophage‐mediated responses. Tuberculosis (TB) can be localized to the lung, whereby discreet granulomas are formed. The role of chemokines in leprosy infections is as yet unclear. We compared chemokine responses in lepromatous leprosy and pulmonary tuberculosis patients. Circulating serum CCL2 was raised while CCL5 was lowered in leprosy, as compared with TB patients and healthy controls. However, both Mycobacterium bovis BCG‐ (P = 0.08) and M. leprae‐induced (P = 0.05) CCL2 secretion was reduced in leprosy. In leprosy, BCG induced greater CCL2 (P = 0.01), TNFα (P = 0.02) and somewhat greater CCL5 (P = 0.08) than M. leprae, while CXCL8 induction was comparable. Overall levels of Mycobacterium‐induced CCL2, TNFα and CXCL8 were two to threefold lower, and CCL5 was 10‐fold lower in leprosy as compared with TB. Reduced inducible CCL2 combined with a lowered TNFα response in lepromatous leprosy may contribute to the unrestricted growth and dissemination of mycobacteria found in the disease.
Coexisting subacute and systemic lupus erythematosus after terbinafine administration: successful treatment with mycophenolate mofetil
Authors: Cetkovská Petra , Pizinger Karel
Published: February 2006

A 39‐year‐old female patient with systemic lupus erythematosus was treated with terbinafine for onychomycosis. After only 7 days of treatment with 250 mg terbinafine, a widespread severe erythematous eruption developed. The results of clinical, histological and immunofluorescent examinations confirmed the diagnosis of coexisting subacute and systemic lupus erythematosus. The patient was treated with drug withdrawal and administration of cyclosporine and methylprednisolone. One year later, mycophenolate mofetil was successfully used. Exacerbation or induction of lupus erythematosus is an extremely rare cutaneous side‐effect of terbinafine. Patients with lupus erythematosus should be advised about the risk of some drugs that might exacerbate their disease.
Helminths can protect themselves against rejection inhibiting hostile respiratory allergy symptoms
Authors: Mingomataj E. Ç. , Xhixha F. , Gjata E.
Published: February 2006

The ability of common environmental allergens to stimulate IgE responses and thus to produce allergic diseases has tended to overshadow the fact that helminthic parasites are possibly the most potent inducers of this immunoglobulin that exists in nature. Although it has been well established that during these infections there is a stimulation of IgE against their own antigens as well as a strong induction of nonspecific TH2/IL‐4 polyclonal IgE, similarly to the allergic processes, many authors debate if the presence of these infections correlates inversely or not with the rate prevalence of atopy or respiratory allergy. Interpreting this relationship, we suggest that sometimes the intensive infections of hosts, especially with soil helminths which migrate in the respiratory ways or use there as entrance, can induce the production of some mediators (‘helminth(k)ines’), to reduce the possibility of their reactive expulsion from the host. The ability to suppress hostile allergic symptoms despite the simultaneous induction of IgE response and local inflammation maybe is established due to the selective evolution, to assure for the parasites better chances for an effective life and reproduction within their mammalian hosts.
A new recombinant mosquito salivary allergen, rAed a 2: allergenicity, clinical relevance, and cross‐reactivity
Authors: Peng Z. , Xu W. , Lam H. , Cheng L. , James A. A. , Simons F. E. R.
Published: February 2006

Background:  Mosquito salivary proteins cause allergic reactions in humans. The allergenicity, clinical relevance, and species cross‐reactivity of a new 37‐kDa recombinant mosquito (Aedes aegypti) salivary allergen, rAed a 2, were evaluated.

Methods:  rAed a 2 was expressed using a baculovirus/insect cell system and purified. Its allergenicity was examined using an enzyme‐linked immunosorbent assay (ELISA), ELISA inhibition tests, immunoblots, and skin tests. Epicutaneous tests with the allergen, mosquito whole body extracts, and mosquito bite tests were performed on 48 volunteers. Serum rAed a 2‐specific immunoglobulin E (IgE) was measured in individuals with positive mosquito saliva‐specific IgE and negative controls.

Results:  Both immunoblots and ELISAs demonstrated that rAed a 2 bound to the IgE of mosquito‐allergic individuals. The binding could be inhibited by the addition of a natural mosquito preparation. Furthermore, rAed a 2 induced immediate and delayed skin reactions. Ten per cent of 31 participants with a positive mosquito bite test had positive skin reactions to rAed a 2, compared with 32% for mosquito whole body extract. None of the participants with a negative bite test showed positive reactions to either of the two extracts. Forty‐three per cent of individuals with positive saliva‐IgE had positive rAed a 2‐IgE. rAed a 2 was a species‐shared allergen, being present in the saliva of the 11 species studied.

Conclusions:  rAed a 2 has identical antigenicity and biologic activity to its native form. It can be used in the diagnosis of mosquito allergy, and is an important species‐shared antigen.
Transplantation of Normal Boar Testicular Cells Resulted in Complete Focal Spermatogenesis in a Boar Affected by the Immotile Short‐tail Sperm Defect
Authors: Mikkola M , Sironen A , Kopp C , Taponen J , Sukura A , Vilkki J , Katila T , Andersson M
Published: February 2006

Contents

Transplantation of testicular cells, also known as spermatogonial stem cell transplantation, is a relatively new approach in the field of male infertility. We used this technique to determine whether donor‐derived sperm production in unrelated porcine recipients is possible following ultrasound‐guided transfer of testicular cells. This study was undertaken because we had a strain of Finnish Yorkshire boars with a hereditary recessive gene defect rendering all spermatozoa immotile and anatomically abnormal in homozygous boars. Thus, monitoring of the focal success of colonization of donor spermatogonia with subsequent production of progressively motile spermatozoa was extremely sensitive. Testicular cells from young normal crossbred boars were transplanted into the testes of two boars affected with the immotile short‐tail sperm (ISTS) defect. Prior to the transplantations, busulfan was used to suppress recipients’ endogenous spermatogenesis. The ejaculates were collected and analysed for the presence of motile spermatozoa. In one of the two recipient boars transplanted with testicular cells from normal donors, motile spermatozoa appeared in the ejaculates 12 weeks after the transplantation. Spermatozoa manually selected under a microscope from a frozen aliquot of ejaculate collected 27 weeks after transplantation were genotyped. In two of the 20 vials the donor‐derived genotype was visible. The genotyping results substantiated the success – as indicated by the appearance of motile spermatozoa after the spermatogonial transfer. Thus, donor‐derived sperm production in unrelated recipients is possible. In addition, the production after transplantation of progressively motile spermatozoa with normal tail lengths shows that the ISTS defect in Finnish Yorkshire boars apparently results from defective transcription of an essential gene for sperm motility in germline cells. To conclude, the transplantation of donor testicular cells can, at least in boars with the ISTS defect, result in complete focal spermatogenesis.
Gene Expression and Developmental Competence of Bovine Embryos Produced In Vitro with Different Serum Concentrations
Authors: de Oliveira ATD , Lopes RFF , Rodrigues JL
Published: February 2006

Contents

The objective of this study was to determine the developmental rates and relative abundance of Hsp 70.1 and Glut‐1 transcripts in in vivo‐ and in vitro‐produced (IVP) bovine embryos in media supplemented with bovine serum albumin (BSA) or different oestrous cow serum concentrations. In experiment 1, in vitro maturation and culture media were supplemented with 0.4% BSA or 1, 5, 10 or 20% of oestrous cow serum (ECS). The analysis of the expression of Hsp 70.1 and Glut‐1 was carried out in individual days 7 and 8 embryos by a semi‐quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR) assay. In experiment 2, in vivo‐produced morulae were collected on day 7 of the oestrous cycle and employed for the comparison of the relative abundances of Hsp 70.1 and Glut‐1 transcripts with IVP morulae produced using two protein sources (10% ECS or 0.4% BSA). No differences were observed in cleavage rate among groups, but blastocyst formation (27%) and hatching rates (78%) were significantly higher in IVP embryos produced with 20% ECS than the other groups (p < 0.05). No significant differences were observed in the relative abundances of Hsp 70.1 and Glut‐1 mRNA in days 7 and 8 blastocysts expanded blastocysts between groups. The abundances of mRNA for those genes were similar between IVP and in vivo‐produced morulae. In spite of the alterations observed in embryonic development, the presence of serum at distinct concentrations did not appear to alter the relative abundance profiles of Hsp 70.1 and Glut‐1 compared with controls or the BSA supplementation to the IVP media.