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Competing Interests: None declared

Objective: Intracranial complications of sinusitis and acute otitis media (AOM) are rare but life-threatening events. In children with suppurative intracranial complications, concurrent neurosurgical and otolaryngological (ORL) intervention has been recommended to optimize outcomes. The aim of this study was to investigate outcomes following concurrent neurosurgical and ORL intervention., Methods: A retrospective cohort study of children undergoing neurosurgical intervention for intracranial complications of sinusitis or AOM in two neurosurgical centres in Ireland was conducted., Results: 65 children were identified. Mean age was 11.9 years. The most prevalent symptoms were headache, pyrexia, altered level of consciousness, facial swelling, and vomiting. Subdural empyema (n = 24, 36.9%) and extradural abscess (n = 17, 26.2%) were the most common complications. 54 underwent same admission ORL intervention; 47 (87%) were performed concurrently or earlier. For rhinogenic infections, 35 (64.8%) underwent endoscopic sinus surgery (ESS), 13 (24.1%) underwent frontal sinus trephine, and 5 (9.3%) underwent maxillary sinus washout alone. For otogenic infections, 10 (90.9%) underwent mastoidectomy and 7 (63.6%) underwent tympanostomy tube placement. 19 (29.2%) had post-operative neurological deficits, of which 2 (3.1%) were permanent. Streptococcus intermedius was the most common pathogen (n = 30, 46.2%). Concurrent intervention reduced the prevalence of residual collection (p = 0.018) and the need for revision neurosurgical intervention (p = 0.039) for sinogenic complications. The same trends did not achieve statistical significance for the otogenic group. Mortality was 0%., Conclusion: Intracranial complications of sinusitis and AOM are best managed in a specialist centre with multidisciplinary input. Concurrent ORL and neurosurgical intervention reduces abscess recurrence and requirement for revision neurosurgery in sinogenic complications and should represent the standard of care. ESS is the ORL modality of choice in experienced hands., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

A 56-year-old woman was admitted due to new ulceration and acute digital ischaemia on a background of chronic leg ulcers bilaterally. Vasculitis screening returned strongly positive lupus anticoagulant levels and elevated anticardiolipin antibodies; these remained elevated at repeat testing. A diagnosis of antiphospholipid syndrome was made. Transthoracic echocardiogram identified a mitral valve lesion suggestive of vegetation and mild mitral valve regurgitation. Blood cultures taken throughout her inpatient admission were negative. Mechanical mitral valve replacement was performed 3 months later, and subsequent culture of the excised tissue returned as sterile. Histological examination showed no morphological signs of infective endocarditis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Solitary fibrous tumours (SFTs) are rare neoplasms derived from mesenchymal cell lines. They are often asymptomatic, follow an indolent growth pattern and are more often benign than malignant. Here, we present a case of a very large, asymptomatic mediastinal SFT in an otherwise healthy man. A 67-year-old Irish man was referred for workup of an asymptomatic murmur. Auscultation of the lung fields revealed diminished breath sounds on the right side. Chest X-ray identified a 20 cm mass localised within the thorax. CT of the thorax confirmed a pleural based, solid lesion with no local invasion. CT-guided core biopsies were reported as consistent with SFT. Primary excision of the lesion was undertaken via median sternotomy. Histological examination confirmed a diagnosis of SFT. The patient remains well at this time. Primary excisive surgery is a safe and effective treatment modality for SFTs., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Moyamoya disease is a rare pathological disorder characterized by progressive intracranial artery stenosis and collateral vessel formation. Posterior cerebral artery involvement is rare with a predilection towards infarction. Herein we present a case of a young female with moyamoya disease treated with bilateral encephalomyosynangiosis which subsequently progressed to posterior cerebral artery involvement, requiring encephalomyosynangiosis to prevent further infarction., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Sexton et al.)

Osteomyelitis is an inflammatory bone disease that is caused by an infecting microorganism and leads to progressive bone destruction and loss. The most common causative species are the usually commensal staphylococci, with Staphylococcus aureus and Staphylococcus epidermidis responsible for the majority of cases. Staphylococcal infections are becoming an increasing global concern, partially due to the resistance mechanisms developed by staphylococci to evade the host immune system and antibiotic treatment. In addition to the ability of staphylococci to withstand treatment, surgical intervention in an effort to remove necrotic and infected bone further exacerbates patient impairment. Despite the advances in current health care, osteomyelitis is now a major clinical challenge, with recurrent and persistent infections occurring in approximately 40% of patients. This review aims to provide information about staphylococcus-induced bone infection, covering the clinical presentation and diagnosis of osteomyelitis, pathophysiology and complications of osteomyelitis, and future avenues that are being explored to treat osteomyelitis., (Copyright © 2018 American Society for Microbiology.)

Background and Aims: Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohn's disease (CD) and IBD activity., Methods: DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls., Results: A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients., Conclusions: Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Influenza D virus (FLUDV) was isolated from diseased pigs with respiratory disease symptoms in 2011, and since then the new virus has also been spread to cattle. Little is known about the susceptibility of other agricultural animals and poultry to FLUDV. This study was designed to determine if other farm animals such as goats, sheep, chickens, and turkey are possible hosts to this newly emerging influenza virus. 648 goat and sheep serum samples and 250 chicken and turkey serum samples were collected from 141 small ruminant and 25 poultry farms from different geographical locations in the United States and Canada. Serum samples were examined using the hemagglutination inhibition (HI) assay and the sheep and goat samples were further analyzed using the serum neutralization assay. Results of this study showed FLUDV antibodies were detected in 13.5% (17/126) of the sampled sheep farms, and 5.2% (29/557) of tested sheep serum samples were positive for FLUDV antibodies. For the goat results, the FLUDV antibodies were detected in 13.3% (2/15) of the sampled farms, and 8.8% (8/91) of the tested goat serum samples were positive for FLUDV antibodies. Furthermore, all tested poultry serum samples were negative for FLUDV antibodies. Our data demonstrated that sheep and goat are susceptible to FLUDV virus and multiple states in U.S. have this virus infection already in these two species. This new finding highlights a need for future surveillance of FLUDV virus in small ruminants toward better understanding both the origin and natural reservoir of this new virus., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Unlabelled: Influenza B virus (IBV) causes seasonal epidemics in humans. Although IBV has been isolated from seals, humans are considered the primary host and reservoir of this important pathogen. It is unclear whether other animal species can support the replication of IBV and serve as a reservoir. Swine are naturally infected with both influenza A and C viruses. To determine the susceptibility of pigs to IBV infection, we conducted a serological survey for U.S. Midwest domestic swine herds from 2010 to 2012. Results of this study showed that antibodies to IBVs were detected in 38.5% (20/52) of sampled farms, and 7.3% (41/560) of tested swine serum samples were positive for IBV antibodies. Furthermore, swine herds infected with porcine reproductive and respiratory syndrome virus (PRRSV) showed a higher prevalence of IBV antibodies in our 2014 survey. In addition, IBV was detected in 3 nasal swabs collected from PRRSV-seropositive pigs by real-time RT-PCR and sequencing. Finally, an experimental infection in pigs, via intranasal and intratracheal routes, was performed using one representative virus from each of the two genetically and antigenically distinct lineages of IBVs: B/Brisbane/60/2008 (Victoria lineage) and B/Yamagata/16/1988 (Yamagata lineage). Pigs developed influenza-like symptoms and lung lesions, and they seroconverted after virus inoculation. Pigs infected with B/Brisbane/60/2008 virus successfully transmitted the virus to sentinel animals. Taken together, our data demonstrate that pigs are susceptible to IBV infection; therefore, they warrant further surveillance and investigation of swine as a potential host for human IBV., Importance: IBV is an important human pathogen, but its ability to infect other species, for example, pigs, is not well understood. We showed serological evidence that antibodies to two genetically and antigenically distinct lineages of IBVs were present among domestic pigs, especially in swine herds previously infected with PRRSV, an immunosuppressive virus. IBV was detected in 3 nasal swabs from PRRSV-seropositive pigs by real-time reverse transcription-PCR and sequencing. Moreover, both lineages of IBV were able to infect pigs under experimental conditions, with transmissibility of influenza B/Victoria lineage virus among pigs being observed. Our results demonstrate that pigs are susceptible to IBV infections, indicating that IBV is a swine pathogen, and swine may serve as a natural reservoir of IBVs. In addition, pigs may serve as a model to study the mechanisms of transmission and pathogenesis of IBVs., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

The transfer of electrons and protons between membrane-bound respiratory complexes is facilitated by lipid-soluble redox-active quinone molecules (Q). This work presents a structural analysis of the quinone-binding site (Q-site) identified in succinate:ubiquinone oxidoreductase (SQR) from Escherichia coli. SQR, often referred to as Complex II or succinate dehydrogenase, is a functional member of the Krebs cycle and the aerobic respiratory chain and couples the oxidation of succinate to fumarate with the reduction of quinone to quinol (QH(2)). The interaction between ubiquinone and the Q-site of the protein appears to be mediated solely by hydrogen bonding between the O1 carbonyl group of the quinone and the side chain of a conserved tyrosine residue. In this work, SQR was co-crystallized with the ubiquinone binding-site inhibitor Atpenin A5 (AA5) to confirm the binding position of the inhibitor and reveal additional structural details of the Q-site. The electron density for AA5 was located within the same hydrophobic pocket as ubiquinone at, however, a different position within the pocket. AA5 was bound deeper into the site prompting further assessment using protein-ligand docking experiments in silico. The initial interpretation of the Q-site was re-evaluated in the light of the new SQR-AA5 structure and protein-ligand docking data. Two binding positions, the Q(1)-site and Q(2)-site, are proposed for the E. coli SQR quinone-binding site to explain these data. At the Q(2)-site, the side chains of a serine and histidine residue are suitably positioned to provide hydrogen bonding partners to the O4 carbonyl and methoxy groups of ubiquinone, respectively. This allows us to propose a mechanism for the reduction of ubiquinone during the catalytic turnover of the enzyme.

Objective: To test our hypothesis that lower intakes of previously identified cardioprotective nutrients would be associated with the coronary epidemic in Central and Eastern Europe., Design: We conducted a survey of coronary mortality in 16 countries and diet in 19 countries., Subjects/setting: Countries were placed in four groups with different cultural patterns (Central and Eastern Europe, including Russia; Western Europe and the United States; Mediterranean; and Asian)., Main Outcome Measures: Independent predictors of coronary mortality., Statistical Analyses Performed: Means and standard deviations were calculated, and analysis of variance with Bonferroni post hoc tests and backward elimination regression analysis was conducted., Results: Coronary mortality was highest in Central and Eastern Europe followed by Western Europe and the United States, the Mediterranean countries, and Asia (Japan). The model with folate, fiber, and n-6/n-3 fatty acids explained the majority of variation in coronary mortality (men 86%, women 90%). Most of the variation was explained by folate (men 61%, women 62%). The picture is complicated by the fact that folate, lutein/zeaxanthin, and beta-carotene were highly intercorrelated ( r =0.87 to 0.99)., Conclusions: A diet low in foods containing folate and carotenoids (beta-carotene and lutein/zeaxanthin) may be a major contributing factor to increased coronary risk observed in the countries of Central and Eastern Europe.

Saccharomyces cerevisiae has been used as a model system to characterize the effect of cytochrome b mutations found in fungal and oomycete plant pathogens resistant to Q(o) inhibitors (QoIs), including the strobilurins, now widely employed in agriculture to control such diseases. Specific residues in the Q(o) site of yeast cytochrome b were modified to obtain four new forms mimicking the Q(o) binding site of Erysiphe graminis, Venturia inaequalis, Sphaerotheca fuliginea and Phytophthora megasperma. These modified versions of cytochrome b were then used to study the impact of the introduction of the G143A mutation on bc(1) complex activity. In addition, the effects of two other mutations F129L and L275F, which also confer levels of QoI insensitivity, were also studied. The G143A mutation caused a high level of resistance to QoI compounds such as myxothiazol, axoxystrobin and pyraclostrobin, but not to stigmatellin. The pattern of resistance conferred by F129L and L275F was different. Interestingly G143A had a slightly deleterious effect on the bc(1) function in V. inaequalis, S. fuliginea and P. megasperma Q(o) site mimics but not in that for E. graminis. Thus small variations in the Q(o) site seem to affect the impact of the G143A mutation on bc(1) activity. Based on this observation in the yeast model, it might be anticipated that the G143A mutation might affect the fitness of pathogens differentially. If so, this could contribute to observed differences in the rates of evolution of QoI resistance in fungal and oomycete pathogens.

Objective: Multidisciplinary vascular centers (VCs) have been proposed to integrate vascular patient care. No studies, however, have assessed referring physician interest or which services should be provided. A statewide survey of primary care physicians (PCPs) was performed to answer these questions., Methods: Questionnaires were mailed to 3711 PCPs, asking about familiarity with vascular disease, potential VC usage, and services VCs should provide. Univariate and multivariate analysis was used to determine which PCPs would refer patients, the services desired, and which patients would be referred., Results: Of 1006 PCPs who responded, 66% would refer patients to a VC, especially patients younger than 50 years (P<.001) and those with lower extremity disease (P<.001) or abdominal aortic aneurysm (P<.001). PCPs practicing within 50 miles of a VC (P<.001), those in practice less than 5 years (P<.001), and those without specific training in vascular disease during residency (P=.004) were most likely to refer patients. Vascular surgery (97%), interventional radiology (90%), and a noninvasive vascular laboratory (82%) were considered the most important services, and physician educational services (62%) were also desirable. PCPs did not think cardiology, cardiac surgery, smoking cessation programs, or diabetes or lipid management are needed. Reasons for VC nonuse included travel distance (23%), sufficient local services (21%), and insurance issues (12%). Only 16% of PCPs believe that their patients with vascular disease currently receive optimal care., Conclusion: There is considerable interest in VCs among PCPs. In contrast to recently described models, VCs need not incorporate cardiology, cardiac surgery, smoking cessation programs, or diabetes or lipid management. VCs should include vascular surgery, interventional radiology, a noninvasive vascular laboratory, and physician educational services.

We quantitatively investigated the effect of carbidopa/levodopa (25/100) on physical fatigue during finger tapping and force generation in a double-blind, placebo-controlled crossover study. Parkinson's disease (PD) subjects were randomly assigned to carbidopa/levodopa or placebo for Visit 1 or 2 and participated in the following two studies: (1) Finger tapping. Twenty-five PD patients used their index fingers to strike two keys 20 cm apart on a musical instrument digital interface (MIDI) keyboard. The slopes of the regression line of dwell time and movement time were used to assess the rate of fatigue development. (2) Force generation. Twelve PD patients contracted the wrist extensors maximally to obtain a baseline maximum voluntary contraction (BMVC) force. Then they repetitively contracted the wrist extensors at 50% of the BMVC for 7 seconds and rested for 3 seconds. An interval maximum voluntary contraction (IMVC) was measured every three repetitions. Fatigue was defined as an IMVC of less than 60% of the BMVC. The slope of the regression line of IMVC was used to assess the rate of force decline. These two studies were repeated 1 hour after carbidopa/levodopa (25/100) or placebo. Subjects filled out the Multidimensional Fatigue Inventory (MFI) at the beginning of the first visit. Results showed that the slope of dwell time decreased with levodopa but not with placebo (P = 0.004). The rate of force decline also decreased with levodopa but not with placebo (P = 0.01). The subscores in the dimension of physical fatigue in the MFI did not correlate with the rate changes in dwell time or the rate changes in force decline. We concluded that (1) levodopa improves physical fatigue in finger tapping and force generation, (2) physical fatigue in Parkinson's disease is at least partially related to dopamine deficiency, and (3) the MFI measures different aspects of physical fatigue compared with those measured by finger tapping and force generation., (Copyright 2003 Movement Disorder Society)

Objectives: To measure exercise induced changes in cortico-motoneuron excitability in Parkinson's disease (PD) before and after levodopa., Methods: Transcranial magnetic stimulation was delivered at 10% above resting motor threshold in 9 PD and 8 control subjects. Each subject performed repetitive isometric wrist extension at 50% of the baseline maximal voluntary contraction (MVC) for 30s with 3s rest between extensions until fatigued, defined as the inability to generate force at more than 25% of the baseline MVC. We recorded motor evoked potentials (MEPs) from the resting extensor carpi radialis muscle before (baseline), during, and after fatiguing exercise. Baseline electromyographic activity was closely monitored. We compared absolute MEP amplitudes between PD and controls, before and after levodopa, during baseline, exercise, and recovery periods. We correlated absolute MEP amplitudes with an objective measure of fatigability., Results: PD subjects in the "off" state had increased absolute MEP amplitudes compared with controls. The effect was present in all 3 exercise periods. These differences disappeared after levodopa. Post-exercise facilitation was clear for PD subjects before and after levodopa, but post-exercise depression was not significant. Absolute MEP amplitude showed negative correlation with objective fatigability for PD subjects before levodopa., Conclusions: Levodopa normalized the increased cortico-motoneuron excitability in PD patients before, during, and after fatiguing exercise., Significance: This study demonstrated the abnormal cortico-motoneuron excitability associated with motor fatigue in PD.

A simple chloroalkane or chlorocycloalkane has a very small hydrogen bond basicity, B = 0.1 units. Since B is often an additive function, it is possible that polychloro-alkanes or -cycloalkanes could have quite large hydrogen bond basicities. Literature data on the 1,2,3,4,5,6-hexachlorocyclohexanes (HCHs) have been analyzed by Abraham's linear free energy relationships to obtain solvation descriptors. These are not extraordinary except for the hydrogen bond basicity, B, which is indeed very large. Values of B for the HCHs are larger than many functionally substituted aliphatic compounds and as large as that of aliphatic amines. We find that B is 0.62-0.72 for the HCHs compared to 0.45 for propanone and 0.70 for ethylamine, the first time that such large hydrogen bond basicities have been identified in compounds with no functional groups. Hydrogen bond basicities are analyzed in order to examine what types of polychlorocompounds give rise to these elevated B values.

Background: Several studies have shown that individually memory, hippocampal volume, and motor measures presage the onset of dementia. It is unclear if these independently contribute to the prediction of mild cognitive impairment., Objective: To determine the ability of memory, hippocampal volume, and a gait speed to independently predict cognitive decline in healthy elderly persons., Design: A prospective, longitudinal, observational cohort study with a mean follow-up of 6 years., Participants: One hundred eight optimally healthy elderly cognitively intact subjects., Main Outcome Measures: Any cognitive impairment noted on the Clinical Dementia Rating Scale (score = 0.5) or persistent or progressive cognitive impairment. Cox modeling determined if time to onset of cognitive impairment was associated with baseline logical memory II test score (a measure of delayed recall), hippocampal volume (magnetic resonance imaging), or gait speed (time to walk 30 ft [9 m]) independent of age, sex, depression, or the allele producing the epsilon4 type of apolipoprotein E (APOE epsilon4)., Results: Questionable dementia occurred in 48 participants in a mean (SD) of 3.7 (2.4) years. This progressed to persistent cognitive impairment in 38 of these participants in a mean (SD) of 4.4 (2.4) years. Logical memory II test performance and hippocampal volume each predicted onset of questionable dementia, independent of age and sex. Time to walk 30 ft additionally contributed independently to the prediction of time to onset of persistent cognitive impairment. Possessing the APOE epsilon4 allele and depression did not enter either model significantly., Conclusions: Models combining multiple risk factors should refine the prediction of questionable dementia and persistent cognitive impairment, harbingers of dementia. Individuals at risk for cognitive impairment may represent a high-risk group for intervention.

Several lines of evidence suggest that the variable age at onset of Parkinson disease (PD) is likely influenced by genes. The apolipoprotein E (APOE) gene is associated with onset of Alzheimer disease, and possibly other neurodegenerative disorders. APOE has been investigated in relation to onset of PD, but results have been inconsistent. The aim of the present study was to determine if APOE genotypes are associated with onset age of PD, using a patient population large enough to assure sufficient power. We studied 521 unrelated Caucasian patients with idiopathic PD from movement disorder clinics in Oregon and Washington. Genotyping and statistical analyses were carried out using standard methods. Age at onset of PD was significantly earlier in patients with the varepsilon3varepsilon4/varepsilon4varepsilon4 genotype than in patients with the varepsilon3varepsilon3 genotype (56.1 +/- 10.9 vs. 59.6 +/- 11.0, P = 0.003). The significantly earlier onset of PD was not influenced by the possible effects of recruitment site, family history and gender. The effect of the varepsilon2varepsilon3 genotype on onset of PD differed between the two recruitment sites. There was a trend for earlier onset of PD in varepsilon2varepsilon3 patients than in varepsilon3varepsilon3 patients only in the Oregon sample. In conclusion, APOE is associated with age at onset of PD., (Copyright 2001 Wiley-Liss, Inc.)

The tegument is an integral and essential structural component of the herpes simplex virus type 1 (HSV-1) virion. The UL37 open reading frame of HSV-1 encodes a 120-kDa virion polypeptide which is a resident of the tegument. To analyze the function of the UL37-encoded polypeptide a null mutation was generated in the gene encoding this protein. In order to propagate this mutant virus, transformed cell lines that express the UL37 gene product in trans were produced. The null mutation was transferred into the virus genome using these complementing cell lines. A mutant virus designated KDeltaUL37 was isolated based on its ability to form plaques on the complementing cell line but not on nonpermissive (noncomplementing) Vero cells. This virus was unable to grow in Vero cells; therefore, UL37 encodes an essential function of the virus. The mutant virus KDeltaUL37 produced capsids containing DNA as judged by sedimentation analysis of extracts derived from infected Vero cells. Therefore, the UL37 gene product is not required for DNA cleavage or packaging. The UL37 mutant capsids were tagged with the smallest capsid protein, VP26, fused to green fluorescent protein. This fusion protein decorates the capsid shell and consequently the location of the capsid and the virus particle can be visualized in living cells. Late in infection, KDeltaUL37 capsids were observed to accumulate at the periphery of the nucleus as judged by the concentration of fluorescence around this organelle. Fluorescence was also observed in the cytoplasm in large puncta. Fluorescence at the plasma membrane, which indicated maturation and egress of virions, was observed in wild-type-infected cells but was absent in KDeltaUL37-infected cells. Ultrastructural analysis of thin sections of infected cells revealed clusters of DNA-containing capsids in the proximity of the inner nuclear membrane. Occasionally enveloped capsids were observed between the inner and outer nuclear membranes. Clusters of unenveloped capsids were also observed in the cytoplasm of KDeltaUL37-infected cells. Enveloped virions, which were observed in the cytoplasm of wild-type-infected cells, were never detected in the cytoplasm of KDeltaUL37-infected cells. Crude cell fractionation of infected cells using detergent lysis demonstrated that two-thirds of the UL37 mutant particles were associated with the nuclear fraction, unlike wild-type particles, which were predominantly in the cytoplasmic fraction. These data suggest that in the absence of UL37, the exit of capsids from the nucleus is slowed. UL37 mutant particles can participate in the initial envelopment at the nuclear membrane, although this process may be impaired in the absence of UL37. Furthermore, the naked capsids deposited in the cytoplasm are unable to progress further in the morphogenesis pathway, which suggests that UL37 is also required for egress and reenvelopment. Therefore, the UL37 gene product plays a key role in the early stages of the maturation pathway that give rise to an infectious virion.

Background: Few studies exist on the prognostic value of demographic, clinical, or psychosocial factors on long-term outcomes for patients with chronic low back pain., Objective: This study reports on long-term pain and disability outcomes for patients with chronic low back pain, evaluates predictors of long-term outcomes, and assesses the influence of doctor type on clinical outcome., Methods: Sixty chiropractic (DC) and 111 general practice (MD) physicians participated in data collection for a prospective, longitudinal, practice-based, observational study of ambulatory low back pain of mechanical origin. The primary outcomes, measured at 6 months and 12 months, were pain (by using the Visual Analog Scale), and functional disability (by using the Revised Oswestry Disability Questionnaire). Satisfaction was a secondary outcome., Results: Overall, long-term pain and disability outcomes were generally equivalent for patients seeking care from medical or chiropractic physicians. Medical and chiropractic care were comparable for patients without leg pain and for patients with leg pain above the knee. However, an advantage was noted for chronic chiropractic patients with radiating pain below the knee after adjusting for baseline differences in patient and complaint characteristics between MD and DC cohorts (adjusted differences = 8.0 to 15.2; P <.002). A greater proportion of chiropractic patients were satisfied with all aspects of their care (P =.0000). The strongest predictors of primary outcomes included an interaction of radiating pain below the knee with provider type and baseline values of the outcomes. Income, smoking, comorbidity, and chronic depression were also identified as predictors of outcomes in this study., Conclusion: Chiropractic care compared favorably to medical care with respect to long-term pain and disability outcomes. Further study is required to explore the advantage seen for chiropractic care in patients with leg pain below the knee and in the area of patient satisfaction. Identification of patient and treatment characteristics associated with better or worse outcomes may foster changes in physicians' practice activities that better serve these patients' needs.

We determined whether methylphenidate, a dopamine transporter blocker, modifies motor, cognitive, or affective responses to L-Dopa in Parkinson's disease (PD). Five patients who reported benefit from L-Dopa/carbidopa and motor fluctuations were admitted and withdrawn from their usual antiparkinsonian medications. On 3 consecutive days in a randomized double-blinded fashion, they took 0.2 mg/kg oral methylphenidate or placebo followed 30 minutes later by a 1-hour intravenous L-Dopa (2 mg/kg per h) or placebo infusion. Vital signs, tapping, walking, dyskinesias, mood, anxiety, concentration, and arousal were monitored every 30 minutes. Cognitive testing was performed before and following the infusion. Methylphenidate combined with L-Dopa led to greater peak right-hand tapping speed than either alone. Dyskinesia severity increased most when methylphenidate and L-Dopa were co-administered. There were no differences between conditions on the Stroop test, digit ordering, simple reaction time, or covert orienting of attention validity effect. Methylphenidate alone led to improvement in choice reaction time. Change in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ between conditions. Methylphenidate increased the motor effects of L-Dopa with minimal effects on cognitive or affective functions, suggesting a physiologic role for the dopamine transporter in patients with PD with motor fluctuations.

Objective: To characterize fatigue in Parkinson's disease (PD)., Background: Fatigue is a recognized problem in PD. Fatigue can be in the physical realm or in the mental realm. Fatigue has not been characterized in PD., Methods: We characterized fatigue in 39 PD patients and 32 age-matched normal controls using five questionnaires: A. The Multidimensional Fatigue Inventory (MFI), which measures five dimensions of fatigue independently including general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. B. The Fatigue Severity Inventory (FSI), which quantifies fatigue in general. C. The Profile of Mood States (POMS), which assesses six subjective subscales: tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia, vigor-activity, and confusion-bewilderment. D. Center for Epidemiological Studies-Depression Scale (CES-D). E. Visual Analog linear scale of energy (VA-E)., Results: PD patients scored higher in all of the five dimensions of fatigue in the MFI including general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue (P < 0.001 except for mental fatigue P = 0.005). The severity of physical fatigue did not correlate with that of mental fatigue. PD patients scored higher on the FSI, POMS, CES-D, and scored lower on the VA-E. The scores in the FSI correlated with general fatigue, physical fatigue, reduced activity, and reduced motivation but not with mental fatigue in the MFI. Depression correlated with all dimensions of fatigue except physical fatigue in the MFI. Disease severity, as measured by Modified Hoehn and Yahr staging, did not correlate with any of the measures., Conclusions: PD patients have increased physical fatigue and mental fatigue compared to normals. Physical fatigue and mental fatigue are independent symptoms in PD that need to be assessed and treated separately., (Copyright 2001 Movement Disorder Society.)

Background: Chronic low back pain sufferers are among those who account for the greatest usage of health care resources. Primary care medical (MD) physicians and chiropractic (DC) physicians treat most of these patients., Objectives: To study patient characteristics and physician practice activities for patients with chronic low back pain treated by DC physicians and MD physicians., Methods: A longitudinal, practice-based observational study was undertaken in 14 general practice and 51 DC community-based clinics. A total of 2945 consecutive patients with ambulatory low back pain of mechanical origin were enrolled; 835 patients were in the chronic subgroup. Patients were followed for 12 months. Data were obtained on all of the following: patient demographics, health status, and psychosocial characteristics; history, duration, and severity of low back pain and disability; physicians' practice activities; and low back complaint status at 1 year., Results: Patients treated by MD physicians were younger and had lower incomes; their care was more often paid for by a third party; their baseline pain and disability were slightly greater. In addition, patients treated by MD physicians had one fourth as many visits as patients treated by DC physicians. Utilization of imaging procedures by enrolling physicians was equivalent for the two provider groups. Medications were prescribed for 80% of the patients enrolled by MD physicians; spinal manipulation was administered to 84% of patients enrolled by DC physicians. Physical modalities, self-care education, exercise, and postural advice characterized low back pain management in both provider groups. Patients' care-seeking was not exclusive to one provider type. Most patients experienced recurrences (patients treated by MD physicians, 59.3%; patients treated by DC physicians, 76.4%); 34.1% of patients treated by MD physicians and 12.7% of patients treated by DC physicians reported 12 months of continuous pain. Only 6.7% of patients treated by MD physicians and 10.9% of patients treated by DC physicians reported 1 resolved episode during the year., Conclusions: Differences in sociodemographics, present pain intensity, and functional disability may distinguish patients with chronic low back pain seeking care from primary care medical physicians from those seeking care from DC physicians. Although the primary treatment modality differs, the practice activities of MD physicians and DC physicians have much in common. Long-term evaluation suggests that chronic back pain is persistent and difficult to treat for both provider types.

Premenopausal black women have a two to threefold greater rate of coronary heart disease than premenopausal white women. This study was designed to provide greater insight into the reasons for this difference which is currently unclear. Coronary heart disease risk factors were compared in 100 black and 100 white, healthy premenopausal women, ages 18-45 years, and of relatively advantaged socioeconomic status. Compared to white women, black women had a higher body mass index (32.0±9.2 vs. 29.0±9.4 kg/m2, p=0.021), and higher systolic (124±17 vs. 115±14 mm Hg, p<0.0001) and diastolic (79±14 vs. 75±11 mm Hg, p=0.048) blood pressures. The mean plasma lipoprotein(a) concentration was markedly higher in the black women (40.2±31.3 mg/dL) than in the white women (19.2±23.7 mg/dL, p<0.0001). The plasma total homocysteine level was also higher in the black women (8.80±3.38 vs. 7.81±2.58 mmol/L, p=0.013). The black women, however, had lower plasma triglyceride levels (0.91±0.46 vs. 1.22±0.60 mmol/L, p<0.0001) and a trend toward higher high-density lipoprotein cholesterol levels (1.37±0.34 vs. 1.29±0.31 mmol/L, p=0.064) than the white women. Plasma total and low-density lipoprotein cholesterol levels were similar. Black women consumed more saturated fat and cholesterol. Rates of cigarette smoking and alcohol intake were low and similar between the races. In summary, compared to white women, black women had a higher mean body mass index, higher blood pressures, higher lipoprotein(a) and plasma total homocysteine levels, and greater consumption of saturated fat and cholesterol. The differences in coronary risk factors between these two premenopausal groups may explain the higher incidence of coronary heart disease in black women. (c) 2000 by CHF, Inc.

A sample of 33 young-old (ages 65 to 74) and 20 oldest-old (ages 84 to 93) healthy elderly without dementia were assessed with neuropsychological tests annually over a 4-year period to examine longitudinal changes in cognitive functioning. Significant age-group differences existed at baseline in participants' performances on tests of immediate memory and visuospatial skills. There were no age-group differences in the rate of change over the 4-year interval on any neuropsychological tests. Within each age-group, the amount of change over time was minimal for most tests though some practice effects were apparent, and on some tests mild decline was observed. Results suggest that healthy old adults, including the oldest-old, do not experience measurable declines in cognitive functioning over a 4-year period.

Unlabelled: Increasing the delivery of therapeutic drugs to the brain improves outcome for patients with brain tumors. Osmotic opening of the blood-brain barrier (BBB) can markedly increase drug delivery, but achieving consistent, good quality BBB disruption (BBBD) is essential. We evaluated four experiments compared with our standard isoflurane/O2 protocol to improve the quality and consistency of BBBD and drug delivery to brain tumor and normal brain in a rat model. Success of BBBD was assessed qualitatively with the large molecular weight marker Evans blue albumin and quantitatively by measuring delivery of the low molecular weight marker [3H]-methotrexate. With isoflurane/O2 anesthesia, the effects of two BBBD drugs of different osmolalities were evaluated at two different infusion rates and infusion durations. Arabinose was superior to saline (P = 0.006) in obtaining consistent Evans blue staining in 16 of 24 animals, and it significantly increased [3H]-methotrexate delivery compared with saline in the tumor (0.388 +/- 0.03 vs 0.135 +/-0.04; P = 0.0001), brain around the tumor (0.269 +/- 0.03 vs 0.035 +/- 0.03; P = 0.0001), brain distant to the tumor (0.445 +/- 0.05 vs 0.034 +/- 0.07; P = 0.001), and opposite hemisphere (0.024 +/- 0.00 vs 0.016 +/- 0.00; P = 0.0452). Forty seconds was better than 30 s (P = 0.0372) for drug delivery to the tumor. Under isoflurane/O2 anesthesia (n = 30), maintaining hypocarbia was better than hypercarbia (P = 0.025) for attaining good BBBD. A propofol/ N2O regimen was compared with the isoflurane/O2 regimen, altering blood pressure, heart rate, and PaCO2 as covariates (n = 48). Propofol/N2O was superior to isoflurane/O2 by both qualitative and quantitative measures (P < 0.0001). Neurotoxicity and neuropathology with the propofol/N2O regimen was evaluated, and none was found. These data support the use of propofol/N2O along with maintaining hypocarbia to optimize BBBD in animals with tumors., Implications: Propofol/N2O anesthesia may be better than isoflurane/O2 for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumor and normal brain.

More than 40 million American adults snore. Habitual snoring afflicts 44% of adult males and 28% of females.(1) Uncomplicated snoring is generally due to vibration of the palatal soft tissues or the tongue base, causing intermittent airway obstruction. Loudness is correlated with the degree of vibration and/or obstruction. The tendency, frequency, duration, intensity, and sequelae of snoring are influenced by myriad structural, physiological, environmental and pharmacological factors. Uncomplicated, nonapneic snoring is treated in a wide variety of ways, ranging from self-help methods, such as positional therapy, to laser surgery. The purpose of this report is to evaluate the safety and efficacy of a natural medication for snoring in a randomized double-blind placebo-controlled trial. The treatment is significantly more effective than placebo. Neither side effects nor intolerance to the product was reported.

Purpose: An elevated plasma homocysteine level is an established risk factor for atherosclerotic coronary heart disease (CHD), cerebrovascular disease (CVD), and lower extremity occlusive disease (LED). An elevated plasma homocysteine level can be reduced by therapy with folate and vitamins B6 and B12. An accurate evaluation of the role of vitamin therapy requires knowledge of the influence of plasma homocysteine levels on the progression of CHD, CVD, and LED., Methods: The Homocysteine and Progression of Atherosclerosis Study is a blinded prospective study of the influence of homocysteine and of other atherosclerotic risk factors on the progression of disease in patients with symptomatic CVD, LED, or both. This study is set in a university hospital vascular surgery clinic and the General Clinical Research Center. Consecutive patients with stable symptomatic CVD or LED underwent baseline clinical, laboratory, and vascular laboratory testing for homocysteine and other risk factors and were examined every 6 months. The primary endpoints were ankle brachial pressure index, duplex scan-determined carotid stenosis, and death. The secondary endpoints were the clinical progressions of CHD, LED, and CVD. The hypothesis that was tested was whether the progression of symptomatic CVD or LED was more frequent or more rapid in patients with elevated plasma homocysteine levels. plasma homocysteine levels., Results: After a mean follow-up period of 37 months (range, 1 to 78 months) for deaths from all causes (>14 micromol/L; elevated, 18.6%; normal, 9.4%; P = .022), deaths from cardiovascular disease (elevated, 12.5%; normal, 6.3%; P = .05) and the clinical progression of CHD (highest 20% of homocysteine levels, 80%; lowest 20% of homocysteine levels, 39%; P = .007) were significantly more frequent or more rapid by life-table analysis when the homocysteine levels were elevated. Multivariate Cox proportional hazards regression model showed a significant independent and increasing relationship between the plasma homocysteine levels and the time to death (relative risk for highest one third of homocysteine values, 1.6; 95% confidence interval [CI], 1.04 to 2.56; P = 029; and relative risk for highest one fifth of homocysteine values, 3.13; 95% CI, 1.69 to 6.64; P = .0001). After an adjustment for age, smoking, hypertension, diabetes, cholesterol, and the vascular laboratory progression of CVD or LED, each 1.0 micromol/L increase in the plasma homocysteine levels resulted in a 3.6% increase (95% CI, 0.0% to 6.6%; P = .06) in the risk of death (all causes) at 3 years and a 5.6% increase (95% CI, 2.2% to 8.5%; P = .003) in the risk of death from cardiovascular disease., Conclusion: We conclude that elevated plasma homocysteine levels are associated significantly with death, with death from cardiovascular disease, and with the progression of CHD in patients with symptomatic CVD or LED. These results strongly mandate clinical trials of homocysteine-lowering vitamin therapy in such patients.

We examined the effects of a simultaneous verbal fluency task on walking in Parkinson's disease (PD) patients with freezing of gait (PD-F) compared to nonfreezing patients (PD-NF) or control subjects (C). Effects of antiparkinsonian medications on gait in PD-F were examined. PD-F patients exhibited a greater increase in the number of steps to complete the walk with verbal fluency, even when the effect of medication was taken into account (mean increase +/- SD): PD-F = 4.2 +/- 4.6, n = 10; PD-NF = 0.1 +/- 1.6, n = 9; C = 1.5 +/- 1.5, n = 19; P = .007. Medications improved walking in PD-F patients by decreasing the number of steps, the time to walk, and freezing. PD-F patients may be more dependent on attention for walking.

To assess how to maximize drug delivery to intracerebral tumors and surrounding brain, this study examined the effects of route and method of administration and tumor size on the distribution of three agents in a nude rat intracerebral tumor xenograft model. Aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), and dextran 70 (M(r) 70,000) were administered i.v. or intra-arterially (i.a.) with or without osmotic blood-brain barrier disruption (BBBD) at 8, 12, or 16 days after tumor cell inoculation (n = 72). A 2.2- to 2.5-fold increase in delivery to tumor and surrounding brain was observed when i.a. was compared with i.v., and a 2.5- to 7.6-fold increase was observed when BBBD was compared with the saline control. The combined effect of i.a. administration and BBBD was to increase delivery 6.3-16.7-fold. The greatest benefit of BBBD was seen in animals with 8-day tumors, whereas BBBD had less benefit in improving delivery to intracerebral tumor and brain around tumor as the tumors grew larger. Regional delivery decreased as the molecular weight of the agent increased. Based on these results, we suggest that i.a. administration of antitumor agents may be adequate to obtain initial responses in large, very permeable, intracerebral tumors. However, in smaller, less permeable tumors or after an initial response to treatment, there may be a significant therapeutic advantage to i.a. agent administration and BBBD.

Objective: The goal was to evaluate, at 1 year, 75 Long-Evans rats for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery., Methods: Seventy-five Long-Evans rats were randomized into four groups and evaluated at 1 year for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. Radiation (2,000 cGy) was administered as a single fraction, by using parallel opposed portals, 30 days before chemotherapy (Group 1), 24 hours before chemotherapy (Group 2), 30 days after chemotherapy (Group 3), or without chemotherapy or without radiation (control group, Group 4). Five subgroups within each treatment group included rats receiving intra-arterially administered methotrexate (1 g/m2) or intravenously administered etoposide (200 mg/m2) combined with intra-arterially administered carboplatin (200 mg/m2), administered with or without osmotic blood-rain barrier disruption, and a group receiving normal saline solution after blood-brain barrier disruption., Results: There was a significant increase in total toxic effects when the three experimental groups were compared with the control group (P = 0.001, 0.006, and 0.013 for Groups 1, 2, and 3, respectively). All groups receiving radiation and chemotherapy (particularly carboplatin and etoposide) had an increased incidence of hind limb paralysis, resembling experimental allergic neuritis (P = 0.053). Statistical analysis showed a trend toward increased mortality rates in Group 1 (antecedent radiation), compared with the control group (P = 0.082), and an increased incidence of intracerebral calcification (P = 0.019). No differences in mortality rates were observed for Group 2 or 3, compared with the control group., Conclusion: Radiation before chemotherapy was a more toxic sequence and, surprisingly, carboplatin/etoposide administered in combination with radiotherapy was more detrimental than methotrexate. Additional studies are in progress to evaluate the toxicity and efficacy of sequences of cranial irradiation and enhanced chemotherapy in tumor-bearing rats.

Objective: To look for preclinical markers of Alzheimer's dementia in a sample of healthy, oldest old individuals., Design: Prospective, longitudinal study of individuals examined at yearly intervals with neuropsychological tests selected to be sensitive to the early detection of dementia., Participants: One hundred and thirty-nine community-dwelling, functionally independent, healthy individuals 65 to 106 years of age who met strict criteria for lack of dementia at entry. Incident dementia cases consisted of 16 volunteers all 80 years old or older who developed dementia of the Alzheimer's type and 31 volunteers 80 years old and older showing no evidence of dementia during a mean 2.8-year follow-up interval., Measurements: Scores on 10 neuropsychological measures were analyzed for the initial examination when none of the volunteers showed clinical evidence of dementia and for the two subsequent yearly examinations., Results: Individuals who subsequently developed dementia showed evidence of verbal memory impairment at their initial examination, which was a mean of 2.8 years before clinical evidence of dementia. The average yearly incidence rate for dementia in those 80 years of age and older was 12%. Performance of individuals who did not development dementia remained relatively stable during follow-up for up to 5 years., Conclusion: Alzheimer's disease has a preclinical stage in which verbal memory decline is the earliest sign. Dementia in the oldest old is distinguishable from age-related cognitive decline.

The oldest old are the fastest-growing segment of our population and have the highest prevalence of dementia. Little is known about the genetics of cognitive health in the very old. The aim of this study was to determine whether the genetic risk factors for Alzheimer disease (AD)--namely, apolipoprotein E (APOE) epsilon4 allele and a family history of dementia-continue to be important factors in the cognitive health of the very old. Case-control studies suggest that the effect of genetic factors diminishes at age >75 years. The present prospective study provided evidence to the contrary. We studied 114 Caucasian subjects who were physically healthy and cognitively intact at age 75 years and who were followed, for an average of 4 years, with neurological, psychometric, and neuroimaging examinations. Excellent health at entry did not protect against cognitive decline. Incidence of cognitive decline rose sharply with age. epsilon4 and a family history of dementia (independent of epsilon4) were associated with an earlier age at onset of dementia. Subjects who had epsilon4 or a family history of dementia had a ninefold-higher age-specific risk for dementia than did those who had neither epsilon4 nor a family history of dementia. These observations suggest that the rate of cognitive decline increases with age and that APOE and other familial/genetic factors influence the onset age throughout life.

Objective: Several small short-term intervention studies have suggested that beta-carotene supplementation in HIV-infected patients can increase the number of various immune cells including CD4 cells. This prospective double-blinded study was designed to investigate whether beta-carotene supplementation would result in this immuno-enhancement in a larger number of patients over a longer time period., Methods: HIV-positive patients were randomly assigned to receive either 60 mg beta-carotene orally three times daily or a matched placebo. In addition, all patients received a multivitamin supplement. Patients were evaluated at baseline, 1 month, and 3 months for T-cell quantitative subsets, natural killer cells, HIV p24 antigen, beta-carotene levels, complete blood counts and chemistry batteries. Body weights and Karnofsky scores were evaluated at each visit., Results: Seventy-two patients signed informed consent forms and entered the study. Except for serum beta-carotene concentration, there were no statistically significant differences (P < 0.05) between the treatment (60 mg beta-carotene three times daily and multivitamins) and placebo (placebo and multivitamins) groups at baseline or after either 1 or 3 months of treatment., Discussion: Earlier studies suggesting that beta-carotene supplementation increased levels of immune cells in HIV-infected patients were not replicated in this study. The addition of a multivitamin supplement to both arms of this study may have masked any difference between the two groups. However, on the basis of the results of this study, we would not recommend supplementation with high doses of beta-carotene for HIV-infected patients.

Late-onset Alzheimer disease (AD) is associated with the apolipoprotein E (APOE)-epsilon4 allele. In late-onset familial AD, women have a significantly higher risk of developing the disease than do men. The aim of this study was to determine whether the gender difference in familial AD is a function of APOE genotype. We studied 58 late-onset familial AD kindreds. Kaplan-Meier survival analysis was used to assess genotype-specific distributions of age at onset. Odds ratios were estimated by logistic regression with adjustment for age and by conditional logistic regression with stratification on families. All methods detected a significant gender difference for the epsilon4 heterozygous genotype. In women, epsilon4 heterozygotes had higher risk than those without epsilon4; there was no significant difference between epsilon4 heterozygotes and epsilon4 homozygotes. In men, epsilon4 heterozygotes had lower risk than epsilon4 homozygotes; there was not significant difference between epsilon4 heterozygotes and those without epsilon4. A direct comparison of epsilon4 heterozygous men and women revealed a significant twofold increased risk in women. We confirmed these results in 15 autopsy-confirmed AD kindreds from the National Cell Repository at Indiana University Alzheimer Disease Center. These observations are consistent with the increased incidence of familial AD in women and may be a critical clue to the role of gender in the pathogenesis of AD.

The sequence of chemotherapy administered prior to cranial irradiation rather than the more traditional order of radiation followed by chemotherapy is currently being evaluated. This rodent study was designed to assess the sequencing of radiation therapy and chemotherapy administered with osmotic blood-brain barrier disruption (BBBD). Drug delivery and acute toxicity were evaluated. Two clinically relevant chemotherapy regimens were given with BBBD: intraarterial methotrexate (MTX, 1 g/m2), or a combination of intraarterial carboplatin (200 mg/m2) and i.v. etoposide (200 mg/m2). In a randomized protocol, the standard rodent model of 2000 cGy as a single fraction using parallel opposed portals was administered 30 days prior to, concurrent with (24 h prior), or 30 days after these two chemotherapeutic regimens. A total of 72 animals was evaluated in this study. The administration of external beam radiation therapy either prior to or concurrent with the administration of a high molecular weight marker 14C-labeled dextran 70 (Mr 70,000), or a low molecular weight marker 3H-labeled MTX (Mr 456) resulted in a statistically significant (P < 0.01) decrease in drug delivery when compared to animals not receiving cranial irradiation. Seizures were observed in 26% of the animals that received radiation prior to the administration of intraarterial MTX after BBBD. It did not matter whether the radiotherapy was administered 30 days prior to or concurrent with MTX. Seizures were not seen in any other group. The mortality in animals receiving radiotherapy 30 days prior to chemotherapy was significantly (P = 0.03) higher than the mortality in control animals receiving chemotherapy after osmotic BBBD, but no radiation. Drug delivery was significantly decreased when the animals received prior radiotherapy; the administration of radiation prior to MTX with BBBD resulted in an increased incidence of seizures, and there was a significant increase in mortality when cranial irradiation was given 30 days prior to chemotherapy administered with BBBD. With regard to delivery and toxicity, chemotherapy with BBBD administered prior to radiotherapy may have advantages over the other sequences utilizing chemotherapy and cranial irradiation.

This study characterized agent differential permeability, three-dimensional tumor volume, and survival in an LX-1 human small cell lung carcinoma intracerebral xenograft model in the nude rat. The percent accessible tissue space (distribution volume) and the permeability x capillary surface product for aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), dextran 10 (M(r) 10,000), and dextran 70 (M(r) 70,000) were measured between 8 and 16 days after inoculation of tumor. Magnetic resonance imaging and histology were used to quantitate intracerebral tumor volume (mm3). Accessible tissue space (ml/g) and permeability x capillary surface product in intracranial tumor, surrounding brain, and subcutaneous tumor decreased with increasing molecular weight of the agent, regardless of the number of days after inoculation. Accessible tissue space in intracranial tumor increased between 8 and 16 days for all agents except dextran 70. There was little change in the subcutaneous tumor or other tissues with time. Tumor volume calculations from imaging studies correlated with volumetric measurements from histological sections (r2 = 98.5%) and illustrated natural tumor progression (9 to 225 mm3). These results provide a basis for therapeutic design based on differential permeability of specific agents and the ability to quantitatively measure brain tumor volume for accessing tumor response.

The feasibility of utilizing the differential permeability of the blood-tumour barrier to low- vs. high-molecular-weight compounds is demonstrated in a brain tumour model. Nude rats (n = 27) with or without intracerebral tumours received intravenous [3H]methotrexate (M(r) 454), followed 60 min later by antimethotrexate antibody (M(r) 150,000) or nonspecific mouse antibody. Antimethotrexate antibody resulted in 93% binding of serum methotrexate. In contrast, the percentage of antibody-bound methotrexate in brain and intracerebral tumour was only slightly greater than preantibody protein binding. Methotrexate delivery to tumour was significantly greater than to brain adjacent to tumour and normal brain. The percentage delivery of [3H]methotrexate to all areas of brain was similar between animals receiving antimethotrexate antibody and nonspecific antibody. These findings support the theory that a drug rescue method may be developed that may permit the safe administration of increased dosages of chemotherapeutic drugs for the treatment of intracerebral tumours.

Background: Autoantibodies to phospholipid (aPL) have been associated with vascular thromboses in cerebral, coronary, and peripheral venous and arterial sites. To date, no large cross-sectional study has examined the incidence of occurrence of aPL in patients with peripheral arterial disease., Methods: A cross-sectional study was performed with patients admitted for vascular surgery procedures to treat peripheral arterial disease for 23 months between January 1, 1990 and November 1, 1991. Consecutive patients were evaluated for the presence of aPL. Medical records for each patient were reviewed in detail, and historic, operative, and postoperative parameters were tabulated for relationship to the presence of aPL., Results: Two hundred thirty-four patients underwent complete testing for aPL. All patients were receiving chronic aspirin therapy. This represented 86% of admissions. Antiphospholipid antibodies were detected in 60 patients (26%). No differences in age, sex, operation performed, or postoperative outcome were found between patients with and without aPL. However, patients with aPL were 1.8 times more likely to have undergone previous lower extremity (LE) vascular surgery than patients without aPL (95% confidence interval = 1.0 - 3.6, p = 0.047). Patients with aPL and previous LE vascular surgery were 5.6 times more likely to have had occlusion of that procedure than patients without aPL (95% confidence interval = 1.9 - 16.8, p = 0.03). The occluded previous LE procedures had a shorter duration of patency before occlusion in patients with aPL than in those without (mean duration of patency 17 months vs. 50 months, p < 0.003). Patients with occluded previous LE procedures and aPL were 4 times more likely to be female (95% C.I. = 1.4 - 11.3, p = 0.018)., Conclusions: The incidence of aPL in vascular surgery patients is substantial. Vascular surgery patients with aPL are more likely to have failure of previous LE bypass procedures and to be female and the bypass failure occurs significantly more rapidly than in patients without aPL. Based on these data, testing of vascular surgery patients for aPL and investigation of alternative antithrombotic treatment regimens in patients with aPL appears warranted.

A software system has been developed for facilitating modeling calculations on large numbers of molecules. Using the system, it is possible to subject one or more molecules to a series of calculations, each requiring use of a different computer program. No user intervention is required: where necessary, output from one program is used automatically as input to the next. Names are assigned to output files automatically and in a systematic manner. As an example, the system can be used to perform a succession of calculations aimed at identifying the major low-energy conformers of each of a set of molecules, starting only from their chemical connectivities. The reliability of the results has been tested by calculations on 40 molecules taken from the Cambridge Structural Database. The observed crystal structure geometry could be found for the majority of these molecules.

We have compared the effects of lovastatin and simvastatin on plasma lipoproteins, fibrinogen and urinary mevalonic acid excretion in twenty-three patients with heterozygous familial hypercholesterolemia. After a baseline period patients were randomly assigned to receive lovastatin or simvastatin at doses of 10, 20 and 40 mg twice daily, for a period of 2 months each, and then, after a 4-week wash-out period, all patients received the alternate drug for a similar period of therapy. Both drugs were well-tolerated and no patients were withdrawn due to side effects. Lipid values returned to baseline after discontinuation of therapy and no carry-over effect was observed. Treatment with lovastatin resulted in decreases in LDL cholesterol concentrations from 274 mg/dl at baseline to 211, 192 and 178 mg/dl, respectively, on doses of 20, 40 and 80 mg/day. Treatment with simvastatin reduced concentrations of LDL cholesterol to 194, 168 and 156 mg/dl, respectively, on doses of 20, 40 and 80 mg/day. Concentrations of HDL cholesterol increased on both drugs, but no dose response relationship was apparent. Both drugs reduced the 24-h urinary excretion of mevalonic acid, an intermediate in cholesterol biosynthesis, but the magnitude of decrease was similar with lovastatin and simvastatin. Small, but statistically non-significant decreases in fibrinogen occurred with both drugs. Patients who showed the greatest hypolipidemic effect during treatment with lovastatin also showed an excellent therapeutic response to simvastatin and vice versa. We conclude that, on a milligram per milligram basis, simvastatin is twice as potent as lovastatin in the treatment of familial hypercholesterolemia and that with both drugs, reductions in LDL cholesterol concentrations are accompanied by decreases in the urinary excretion of mevalonic acid.

The Diet Habit Survey was designed to identify eating habits and measure dietary changes made over time by 442 adults in the Family Heart Study, a coronary heart disease prevention project. Reliability was determined by test-retest analysis. Validity was assessed by comparison with 24-hour dietary recalls and by comparing changes in diet with changes in plasma cholesterol levels. At baseline, 89% of the subjects were classified as eating the current American diet (37% fat), 10% reported eating Diet 1 (30% fat), and 1% reported eating Diet 2 (25% fat). After 5 years of dietary intervention, the population's eating habits had shifted; 48% reported eating the current American diet, 37% reported Diet 1, 14% reported Diet 2, and 1% reported Diet 3 (20% fat). Significant plasma cholesterol lowering was associated with changes in Diet Habit Survey scores reflecting lower cholesterol and saturated fat and higher complex carbohydrate intakes. This questionnaire is an inexpensive, reliable, and valid instrument for rapid assessment of eating habits and diet composition and, thus, is an important new tool for dietetics researchers and practitioners.

Objective: To determine the rate of bone loss in normal men, and to examine the effects of dietary calcium and cholecalciferol supplementation on bone loss in men., Design: Double-blinded, placebo-controlled 3-year trial of supplementation with calcium (1000 mg/d) and cholecalciferol (25 micrograms/d)., Setting: Clinical research center at a university medical facility., Subjects: Normal men 30 to 87 years old, recruited from the Portland community., Measurements and Main Results: Radial bone mineral content (assessed by single-photon absorptiometry) fell by 1.0%/y (95% CI, -1.3% to 0.7%) at a proximal radial site and 1.0%/y (95% CI, -1.4% to -0.6%) at a distal radial site. Vertebral bone mineral content (assessed by dual-energy quantitative computed tomography) declined by 2.3%/y (95% CI, -2.8% to -1.8%). In these healthy men with a high basal dietary calcium intake (1159 mg/d), calcium and cholecalciferol supplementation did not affect bone loss at any site., Conclusions: Normal men experience a substantial bone loss at both axial and appendicular sites that is not prevented by calcium and vitamin D supplementation in a well-nourished population.

To obtain further information about the effects of cessation of smoking on pulmonary function, we followed subjects who attended 2 smoking cessation clinics during a period of 30 months. This paper reports the results from 15 persons who succeeded in stopping smoking for the full 30-month period and from 42 who did not succeed for more than one month. Testing included a respiratory questionnaire, spirometry, and the single-breath N2 test. Standardized methods, the same equipment, and the same experienced personnel were used throughout the study. We found that forced vital capacity, one-second forced expiratory volume, closing volume as a percentage of vital capacity, closing capacity as a percentage of total lung capacity, and the slope of the alveolar plateau of the single-breath N2 test all improved significantly in the subjects who stopped smoking. This improvement continued for as long as 6 to 8 months, and then remained stable. There was no sex difference in the response to smoking cessation, nor could we find a threshold of function below which cessation did not result in improvement. On the contrary, those subjects with the greatest impairment initially showed the greatest improvement. Respiratory symptoms virtually disappeared in those who stopped smoking. Subjects who continued to smoke showed an initial improvement in some function tests, probably due to a marked decrease in consumption, but no significant improvement during the whole period. We concluded from this study that cessation of smoking results in definite improvement in pulmonary function, that there is greater improvement in persons who begin with impaired function than in those whose function is initially normal, that respiratory symptoms disappear rapidly.

In an effort to examine knowledge about heart disease and nutrition and attitudes toward dietary change, 754 women and 125 men were interviewed. The majority of respondents recognized the association between coronary heart disease and various risk factors, including dietary cholesterol. Although they acknowledged the value of dietary change in reducing risk, the majority denied that the food they now eat increases their risk for heart disease, which suggests a lack of perception about possible benefits to be derived from dietary change. The importance of addressing perceived barriers to change is discussed.

In this paper we present the initial cross-sectional data from a prospective study of lung aging in heterozygotes for alpha 1-antitrypsin deficiency. Using a case-control design, our cases included 37 heterozygotes for alpha 1-antitrypsin deficiency, protease inhibitor phenotypes MZ and MS, selected because they were parents of children with homozygous alpha 1-antitrypsin deficiency identified in a statewide newborn screening program between 1971 and 1974. All of the heterozygotes were less than 40 yr of age. Our control subjects were selected from a random sample of a working population participating in a longitudinal study of lung aging, using a 2:1 match of control subjects to cases, matching age, sex, ethnic origin, and smoking. Using a respiratory symptom questionnaire, spirometry, and the single-breath N2 test, we found no significant difference between heterozygotes and control subjects in terms of respiratory symptoms or pulmonary function data. We conclude that to 40 yr of age, the heterozygous phenotype (Pi MZ and MS) is not a risk factor for impairment of pulmonary function.

To determine the relation of functional residual capacity and maximal expiratory flow at functional residual capacity to sex, age, height, and weight in healthy young children living in Portland, Oregon, we tested 37 boys and 36 girls using a modified helium-dilution technique and partial expiratory flow-volume curves. Within the age, height, and weight ranges studied, exponential or multiple regression techniques offered no substantial advantage over simple linear regression using height, weight, or age. There were no sex differences for the relationship between either variable and age, height, or weight. These techniques can readily be used in children as young as 3 years of age and may provide a method for studying lung growth and development in early childhood and a way to observe the progression of disease or the effect of treatment in the young child.

A random sample of 501 eligible families was selected from a designated neighborhood in Portland, Oregon, and given the opportunity to join a 5-year intervention program promoting a low-fat and low-cholesterol eating pattern designed to reduce risk for coronary heart disease. Participation entailed three baseline assessments of clinical, dietary, and psychological indices, periodic follow-up measurements, and monthly small group meetings led by psychologists and nutritionists. A prior home health survey allowed comparisons of respondents from joining and nonjoining families in terms of reported health status, health beliefs, health locus of control, knowledge about health and nutrition, and demographic characteristics. Almost half (47%) of all invited families agreed to join this long-term nutrition intervention program and completed the necessary baseline assessments. Factors discriminating joiners and nonjoiners were not generally consistent with the health belief model of preventive health behavior. Joiners were similar to nonjoiners in terms of perceived susceptibility to disease, family health histories, and reports of elevated plasma cholesterol levels in the family. However, families with hypertensive members were less likely to join this heart disease prevention program. Positive predictors of participation included higher occupational status, greater knowledge about heart disease, a more internal health locus of control, and the belief that there are few barriers preventing the adoption of a healthier low-fat eating pattern. These findings indicate that there is widespread community interest in optimal nutrition, and they also provide suggestions as to what motivates the general public to take preventive health actions.

In this paper we report the initial cross-sectional data from a prospective study of pulmonary function in children with moderately severe and severe alpha 1-antitrypsin deficiency. Using a case-control design, our cases were 19 children 3 to 7 years of age with alpha 1-antitrypsin deficiency, Pi phenotype ZZ or SZ. Control subjects were selected from healthy children participating in a study to establish reference values for functional residual capacity and maximal expiratory flow at functional residual capacity, using a 1:1 match for sex, height, age, and weight. We found no significant difference between the cases and their matched control subjects with respect to functional residual capacity and maximal expiratory flow at functional residual capacity. We conclude that through 7 years of age there is no gross impairment in overall pulmonary function in children with moderately severe and severe alpha 1-antitrypsin deficiency, Pi phenotypes ZZ and SZ.

The purpose of this study was to obtain more information about the effect on lung function of stopping smoking or of modifying the smoking habit and to determine the time course of change. We followed a group of 75 cigarette smokers who attended a smoking cessation clinic in May 1973, using a respiratory symptom questionnaire, spirometry, closing volumes, and the slope of the alveolar plateau of the single-breath nitrogen test. Subjects were tested before stopping smoking and at 1, 3, 6, and 12 months after the initial testing. We found a significant (P less than 0.05) improvement in closing volume as a percentage of vital capacity and closing capacity as a percentage of total lung capacity at 6 and 12 months and in the slope of the alveolar plateau at 1, 6, and 12 months in those who stopped smoking. There was also a dramatic decrease in respiratory symptoms in those who stopped smoking, a moderate decrease in those who reduced their consumption by at least 25 per cent, and very little change in those who did not appreciably modify their smoking consumption.