Modulation of the liver export protein synthetic response to feeding by an n-3 fatty-acid-enriched nutritional supplement is associated with anabolism in cachectic cancer patients.
The acute-phase protein response is associated with accelerated weight loss and shortened survival in cancer. This may be due to hepatic protein synthesis increasing demand for amino acids. An n -3 fatty-acid-enriched nutritional supplement will moderate aspects of cachexia in cancer patients. The present study examined the effect of such a supplement on hepatic synthesis of albumin and fibrinogen. Albumin and fibrinogen synthesis were measured in the fed and fasting state in eight weight-losing patients with pancreatic cancer by an intravenous flooding dose technique. Tracer incorporation into proteins was measured by GC/MS. Patients were restudied after 3 weeks of oral supplement enriched with fish oil (providing 2510 kJ/day and 2 g of eicosapentaenoic acid/day). At baseline, all patients were losing weight (median, 2.4 kg/month). After 3 weeks of consumption of the fish-oil-enriched nutritional supplement, patients' weight stabilized (median change, +1 kg; P = 0.01). At baseline, albumin and fibrinogen synthesis rates were stimulated in the fed compared with the fasting state [14.2 compared with 11.3 g/day (29% rise; P = 0.01) and 4.5 compared with 3.3 g/day (38% rise; P = 0.01) respectively]. After 3 weeks of the supplement, this stimulation in the fed state was no longer observed for albumin and was reduced for fibrinogen [11.2 compared with 10.5 g/day (3% rise; P = 0.21) and 3.7 compared with 2.9 g/day (17% rise; P = 0.01) respectively]. After 3 weeks, the combined albumin plus fibrinogen synthetic rate tended to fall in the fasting state (14.7 compared with 12.3 g/day; P = 0.09) and was significantly reduced in the fed state (18.7 compared with 14.6 g/day; P = 0.01). Modulation of hepatic export protein synthesis with feeding may have contributed to the net whole-body anabolism observed with administration of the n -3 fatty-acid-enriched oral supplement.


[Converting enzyme inhibitors and coronary failure].
Nearly 15 years ago, it has been shown that myocardial infarction is accompanied by left ventricular dilatation. In the following years more details were obtained on morphological changes consecutive to myocardial infarction, now grouped together under the term left ventricular remodelling. These changes enable the patients to survive despite reduction of the contractile ventricular mass, but they expose the ventricles to constraints resulting in excessive work load. It has been shown that these changes can be reduced by early myocardial reperfusion and by administration of angiotensin-converting enzyme (ACE) inhibitors. These findings were established first in animals, then in man. Administering ACE inhibitors to patients with symptomatic heart failure consecutive to advanced ischaemic cardiopathy prolongs the patients' survival. When ACE inhibitors are given to patients with severe asymptomatic left ventricular dysfunction which started soon or long after a myocardial infarction, they reduce the frequency of ischaemic events, passage to symptomatic heart failure and, at least in one study, mortality. ACE inhibitors have also been shown to reduce the size of myocardial necrosis when administered in the acute phase of experimental myocardial infarction. Preliminary data have demonstrated that ACE inhibitors given in the acute phase of myocardial infarction reduce the left ventricular dilatation which follows infarction. However, a study of ACE inhibitors administered to a large number of patients in the acute phase of myocardial infarction had to be interrupted because of the over-mortality in the treated group. These facts are reviewed in this article, and attempts have been made at deducing from them the current indications of ACE inhibitors in patients with coronary heart disease.


Dynamics of bacterial microbiota during lignocellulosic waste composting: Studies upon its structure, functionality and biodiversity.
An intensive isolation program carried out in three replicated composting piles allowed the identification of the resident and transient components of the composting microbiome. More than 4000 bacterial strains were isolated, enzymatically characterized and identified by partial sequencing of their 16S rRNA gene. While microorganisms isolated under mesophilic conditions were prominent throughout the process, thermophilic stages gathered the highest total counts and spore-forming bacteria prevailed at the bio-oxidative phase of composting. Enzymatic capabilities related to the degradation of polymeric materials were exhibited by most of the isolates and as a result of these activities, more soluble compounds could be made available to the entire composting microbiota. A high proportion of isolates showed to be thermotolerant as they were detected at mesophilic and thermophilic phases. Isolated strains belonged to 187 bacterial species. Biodiversity was greater at the central stages of composting and mesophilic, thermophilic and cooling phases shared 50% of species.


The glory of guidelines and the twilight of reality: controversies and challenges in the prevention and treatment of HIV in children.
Since the discovery of HIV 30 years ago, we have learned much about HIV in children and adolescents. Dramatic declines have occurred in mother-to-child transmission of HIV in resource-rich countries. Resource-poor countries struggle with improving prevention of mother-to-child transmission due to the lack of universal antiretroviral treatment for pregnant and nursing mothers. In children infected with HIV, pharmacokinetic, safety and efficacy data have been determined for many of the older drugs. Data are lacking for the newer, safer and more effective currently available drugs, resulting in the pediatric guidelines lagging behind adult recommendations. Although guidelines for prevention and treatment are helpful, the way they are created causes them to lag behind new scientific evidence, and in some situations they will be confusing or only based on expert opinion. Improving prevention of HIV infection in adolescents and young adults and in treating those who become HIV infected is crucially important. The next 10 years hold tremendous opportunities for improvements in prevention and treatment of HIV in children, adolescents and young adults.


Carvedilol or propranolol in portal hypertension? A randomized comparison.
Carvedilol is a non-selective β-blocker with intrinsic anti-α(1)-adrenergic activity, potentially more effective than propranolol in reducing hepatic venous pressure gradient (HVPG). We compared the long-term effect of carvedilol and propranolol on HVPG and assessed whether the acute response to oral propranolol predicted the long-term HVPG response on either drug. HVPG was measured in 38 patients with cirrhosis and HVPG ≥ 12 mm Hg at baseline and then again 90 min after an oral dose of 80 mg propranolol. Patients were double-blinded randomized to either carvedilol (21 patients) or propranolol (17 patients) and after 90 days of treatment HVPG measurements were repeated. HVPG decreased by 19.3 ± 16.1% (p < 0.01) and by 12.5 ± 16.7% (p < 0.01) in the carvedilol and propranolol groups, respectively, with no significant difference between treatment regimens (p = 0.21). Although insignificant, an acute decrease in HVPG of ≥12% was the best cut-off value to predict long-term HVPG response to propranolol when using ROC curve analysis. This randomized study showed that carvedilol is at least as effective as propranolol on HVPG after long-term administration. Furthermore, a predictive value of an acute propranolol test on HVPG could not be confirmed.


[Chronic spondylogenic pain syndrome--tb-spondylitis?].
The incidence of tuberculosis is increasing in many of the industrialized countries, mainly due to the spreading of HIV infections, the migration from countries with high prevalence of tuberculosis and possibly through the increase of the aged population. In 10 to 25% of the cases, tuberculosis manifests itself in extrapulmonary organs. One of the most frequent locations is the spine. The symptoms of the TB spondylitis are unspecific, and the course is creeping, which makes an early diagnosis difficult. Because of the frequent, severe complications, this must be attempted. In patients belonging to a risk group or with known exposition to tuberculosis and vertebral pain, the TB spondylitis must be included in the differential diagnosis. Combined chemotherapy is the key to successful therapy and can make surgical interventions or immobilization unnecessary. Two cases are presented, and the disease of the TB spondylitis is discussed.


Metabolism of oltipraz and glutathione reductase inhibition.
A decrease in glutathione reductase (GR) activity was observed in Schistosoma mansoni isolated from oltipraz(OPZ)-treated mice. Yeast and Schistosoma mansoni GR-activity was inhibited by OPZ derivatives only. These OPZ-derivatives showed in vitro schistosomicidal activity. Using yeast GR and dithiolium salts of OPZ, time-dependent inactivation and gel chromatography experiments revealed irreversible inhibition dependent on the redox state of the enzyme. Binding of radiolabelled ([3H]7-methyl-8-methylthio-pyrrolo[1,2-a]pyrazine disulphide 1b) obtained from OPZ was observed using exclusion chromatography and equilibrium dialysis. These results indicate that GR can be considered as the target of schistosomicidal activity of OPZ. The lack of inhibitory activity of OPZ and dithiole-thione analogues, and the potent activity of the corresponding pyrrolo-pyrazine derivatives, is consistent with the hypothesis that OPZ is a pro-drug.


Identification of Breast Cancer Inhibitors Specific for G Protein-Coupled Estrogen Receptor (GPER)-Expressing Cells.
Together with estrogen receptors ERα and ERβ, the G protein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a few selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtual screening and cell-based studies for the identification of new chemical scaffolds with a specific antiproliferative effect against GPER-expressing breast cancer cell lines. Out of the four different scaffolds identified, 8-chloro-4-(4-chlorophenyl)pyrrolo[1,2-a]quinoxaline 14 c was found to be the most promising compound able to induce: 1) antiproliferative activity in GPER-expressing cell lines (MCF7 and SKBR3), similarly to G15; 2) no effect on cells that do not express GPER (HEK293); 3) a decrease in cyclin D1 expression; and 4) a sustained induction of cell-cycle negative regulators p53 and p21.


Replication, recombination and packaging of amplicon DNA in cells infected with the herpes simplex virus type 1 alkaline nuclease null mutant ambUL12.
The alkaline nuclease (AN) encoded by gene UL12 of herpes simplex virus type 1 (HSV-1) is essential for efficient virus replication but its role during the lytic cycle remains incompletely understood. Inactivation of the UL12 gene results in reductions in viral DNA synthesis, DNA packaging, egress of DNA-containing capsids from the nucleus and ability of progeny virions to initiate new cycles of infection. Mechanistically, AN has been implicated in resolving branched structures in HSV-1 replicative intermediates prior to encapsidation, and promoting DNA strand-exchange. In this study, amplicons (bacterial plasmids containing functional copies of a virus replication origin and packaging signal) were used to analyse further the defects of the UL12 null mutant ambUL12. When ambUL12 was used as a helper virus both replication and packaging of the transfected amplicon were reduced in comparison with cells infected with wild-type (wt) HSV-1, and to extents similar to those previously observed for genomic ambUL12 DNA. By using amplicons differing at a specific restriction endonuclease site it was demonstrated that replicating molecules exhibit high frequency intermolecular recombination in both wt- and mutant-infected cells. Surprisingly, in the absence of the UL12 product, amplicons lacking a functional encapsidation signal were packaged. Moreover, these packaged molecules could be serially propagated indicating that they had been incorporated into functional virions. This difference in packaging specificity between wt HSV-1 and ambUL12 might indicate that replicative intermediates accumulating in the absence of AN contain an increased incidence of structures that can serve for the initiation of DNA packaging.


[Fatal anaphylaxis after eating wild boar meat in a patient with pork-cat syndrome].
Crossed allergy between pork and cat epithelia was described by us in 1994. It is due to serum albumin. Nowadays, other bio-chemical observations allow "completion" of the syndrome by extension of the crossed reactivity between other mammal meats and other epithelia of dog and horse. The authors report an observation of the pork-cat syndrome (developing in the form of anaphylaxis, and then ending in the death of the patient), following consumption of wild boar meat. Co-factors, such as effort, taking alcohol or hormonal condition may complicate the picture to make diagnosis more difficult.


Mesoblastic nephroma: a report of the United Kingdom Children's Cancer and Leukaemia Group (CCLG).
Mesoblastic nephroma (MN) is a rare tumour which occurs mainly in early infancy and for which primary nephrectomy is the treatment of choice. This study aimed to assess surgical complications and outcomes in this patient group and to re-evaluate the age threshold of 6 months for recommending primary nephrectomy. A retrospective file review of all cases of MN registered in UK Children's Cancer and Leukaemia Group renal tumour trials between October 1991 and March 2008. Data from the trials were compared with data held by the National Registry of Childhood Tumours, Oxford. Forty-seven (3.5%) confirmed cases of MN were found among 1346 registered renal tumours. Median age at diagnosis was 30 days (range birth-3.8 years). MN was significantly more common in the first 3 months of life compared to between 3 and 6 months (33 vs. 2 cases). Seven cases occurred between 6 months and 1 year and only five cases occurred beyond 1 year of age. There was a significant difference in the age of diagnosis by histological subtype. There were 11 complications in the series; no registered patient developed a recurrent tumour; and all were alive at last follow-up. Outcome for children with MN is excellent at all ages, with little indication for adjuvant chemotherapy. Children presenting at <3 months of age, should be treated by primary nephrectomy. In those presenting aged >3 months, alternative diagnoses should be considered, especially in the presence of surgical risk factors.


Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy.
Autophagy is a tightly-regulated catabolic process of cellular self-digestion by which cellular components are targeted to lysosomes for their degradation. Key functions of autophagy are to provide energy and metabolic precursors under conditions of starvation and to alleviate stress by removal of damaged proteins and organelles, which are deleterious for cell survival. Therefore, autophagy appears to serve as a pro-survival stress response in most settings. However, the role of autophagy in modulating cell death is highly dependent on the cellular context and its extent. There is an increasing evidence for cell death by autophagy, in particular in developmental cell death in lower organisms and in autophagic cancer cell death induced by novel cancer drugs. The death-promoting and -executing mechanisms involved in the different paradigms of autophagic cell death (ACD) are very diverse and complex, but a draft scenario of the key molecular targets involved in ACD is beginning to emerge. This review provides an up-to-date and comprehensive report on the molecular mechanisms of drug-induced autophagy-dependent cell death and highlights recent key findings in this exciting field of research.


Obesity in single gene disorders.
In the 1980s, the heritability of obesity has been calculated to be around 0.80, implying a significant genetic origin and sparking a worldwide "gold-rush" for causative genes. Since the discovery of leptin and the body weight homeostasis pathway it regulates, we have come to a greater understanding of the factors that now control it. Nevertheless, we are still some way off reaching the goal of effectively managing the consequences of dysregulation: obesity, a disease-related state that threatens the well-being of mankind. An unprecedented plethora of data has informed our understanding of obesogenic processes; this chapter examines the evidence, focusing on the substantial role of monogenic diseases.


Decreased Performance of Skilled Laparoscopic Surgeons at Microlaparoscopy versus Traditional Laparoscopy
The skill requirements for microlaparoscopy are significantly higher than those for the traditional technique. This program was designed to meet the demands of compensated two-dimensional depth perception, instrument accuracy, and ambidexterity. Three specialized drills were constructed and 60 experienced laparoscopists with advanced operative skills were evaluated. The three skill-assessment tasks were first performed using traditional laparoscopic instrumentation (10-mm laparoscopes, 5-mm accessory instruments). The performance of the study group was compared with an extensive database of over 1000 laparoscopic surgeons from around the world and did not reveal any significant deficits with traditional-size equipment. Next, the tasks were performed using miniature 2-mm laparoscopes and accessory instruments. Performance levels for all tasks were significantly lower than with traditional-size equipment. These results demonstrate the increased difficulty of performing laparoscopy with 2-mm instruments and underscore the importance of formal training and objective skill assessment. The relationship of skill to credentialing must be considered.


Rifaximin for preventing acute graft-versus-host disease: impact on plasma markers of inflammation and T-cell activation.
In murine allogeneic hematopoietic cell transplantation models, inhibiting bacterial translocation stemming from conditioning-induced damage to the gut mucosa abrogates inflammatory stimulation of donor T cells, preventing acute graft-versus-host disease (AGVHD). We conducted a phase I trial to begin testing the hypothesis that rifaximin, a broadly acting oral antibiotic, would reduce systemic inflammation and T-cell activation. We administered rifaximin to 20 adolescents and younger adults (day -10 through day +30) receiving intensive conditioning. We measured the plasma level of interleukin-6, as a marker of conditioning-induced inflammation, and the levels of soluble tumor necrosis factor receptor-1 and soluble interleukin-2 receptor, as surrogate markers of AGVHD. We formed a historical control group (n=24), from a previous study of biomarkers in AGVHD. The increase in the treatment group's mean interleukin-6 level from baseline to day 0 was 73% less than that in the control group (P=0.006). The increase from baseline to day 15 in the treatment group's mean soluble tumor necrosis factor-1 and soluble interleukin-2 receptor levels was similar to the control group. Incidences of grade 2 to 4 AGVHD also did not differ. This suggests that rifaximin may abrogate bacterial translocation and resultant inflammation, but in alternative donor transplants this does not prevent downstream activation of donor T cells.


Impact of breast cancer patients' awareness on attendance at screening.
The purpose of this study is to investigate the impact of breast cancer awareness on the attendance for screening among women with breast cancer prior to diagnoses of breast cancer. Breast cancer is the most commonly diagnosed cancer for women in Taiwan and its incidence rate continues to increase. However, screening for breast cancer is still not common even if the incidence rate has topped the list from 2003 to 2010. A cross-sectional study was conducted among women diagnosed with breast cancer. Subjects (535 women) were recruited from two medical centres in central Taiwan. Information on attendance for breast cancer screening was collected by self-report. Chi-square test and logistic regression were utilized to analyse the relationships between awareness of breast cancer and attendance at screening. The results indicated that pre-diagnostic awareness of 'the concept of early treatment relating to higher cure rate'[odds ratio (OR): 4.09; 95% confidence interval (CI): 1.12-14.9], 'various breast cancer screening methods' (OR:3.00; 95% CI: 1.23-7.30), 'the coverage of breast cancer screening programme in the National Health Insurance' (OR:1.76; 95% CI: 1.03-3.02) and 'breast self-examination after each menstrual cycle' (OR:3.42; 95% CI: 1.99-5.87) were all significantly associated with the screening procedures performed. Findings of this study indicated that particular attention should be paid towards enhancement of women's knowledge for prevention and early detection of breast cancer through educational efforts by nurse professionals, medical institutions and/or civil organizations.


Methylation of H3K27 and H3K4 in key gene promoter regions of thymus in RA mice is involved in the abnormal development and differentiation of iNKT cells.
Epigenetic modifications have been shown to be important for immune cell differentiation by regulating gene transcription. However, the role and mechanism of histone methylation in the development and differentiation of iNKT cells in rheumatoid arthritis (RA) mice have yet to be deciphered. The DBA/1 mouse RA model was established by using a modified GPI mixed peptide. We demonstrated that total peripheral blood, thymus, and spleen iNKT cells in RA mice decreased significantly, while iNKT1 in the thymus and spleen was increased significantly. PLZF protein and PLZF mRNA levels were significantly decreased in thymus DP T cells, while T-bet protein and mRNA were significantly increased in thymus iNKT cells. We found a marked accumulation in H3K27me3 around the promoter regions of the signature gene Zbtb16 in RA mice thymus DP T cells, and an accumulation of H3K4me3 around the promoters of the Tbx21 gene in iNKT cells. The expression levels of UTX in the thymus of RA mice were significantly reduced. The changes in the above indicators were particularly significant in the progressive phase of inflammation (11 days after modeling) and the peak phase of inflammation (14 days after modeling) in RA mice. Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels (H3K27me3 and H3K4me3) in the promoters of key genes Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet). Decreased UTX of thymus histone demethylase levels resulted in the accumulation of H3K27me3 modification.


A pharmacokinetic crossover study to compare the absorption characteristics of three transdermal nicotine patches.
We compared the pharmacokinetic profiles of the highest marketed doses of three different patch systems using a crossover study design. Specifically, each of the 25 subjects was assigned to receive the Pharmacia-Upjohn (McNeil) 15-mg, 16-h patch, the Novartis 21-mg, 24-h patch, and the Alza (SmithKline Beecham) 21-mg, 24-h patch. Subjects used each patch for 3 consecutive days, applying a new patch each morning. Plasma nicotine concentrations were measured 15 times during the first 24-h period and at 48, 48.5, 49.5, and 51 h following initial patch application. Measures of total nicotine absorbed (AUC), maximum plasma nicotine concentration (C(max)) and minimum plasma nicotine concentration (C(min)), were higher for the 21-mg, 24-h patches than for the 15-mg, 16-h patch during both the first day of dosing and during the modeled steady-state period (48-72 h after initial application). Within the 21-mg, 24-h patch systems, the Alza patch produced significantly higher AUC and C(max) values during acute dosing and during steady state, but there was no difference between C(min) values. The time to reach C(max) (T(max)) was fastest for the Alza patch system; the Pharmacia-Upjohn patch produced a faster T(max) than the Novartis patch. These results indicate that there are significant differences between the pharmacokinetics of the currently marketed patch systems, which may be important for effective relief of withdrawal symptoms and cigarette craving.


Application of the SCC-DFTB method to H+(H2O)6, H+(H2O)21, and H+(H2O)22.
The low-lying potential energy minima of the H(+)(H(2)O)(n), n = 6, 21, and 22, protonated water clusters have been investigated using two versions of the self-consistent-charge density-functional tight-binding plus dispersion (SCC-DFTB+D) electronic structure methods. The relative energies of different isomers calculated using the SCC-DFTB+D methods are compared with the results of DFT and MP2 calculations. This comparison reveals that for H(+)(H(2)O)(6) the SCC-DFTB+D method with H-bonding and third-order corrections more closely reproduces the results of the MP2 calculations, whereas for the n = 21 and 22 clusters, the uncorrected SCC-DFTB+D method performs better. Both versions of the SCC-DFTB+D method are found to be biased toward Zundel structures.


Proposal for a quantitative index of flood disasters.
Drawing on calculations of wind scale and earthquake magnitude, this paper develops a new quantitative method for measuring flood magnitude and disaster intensity. Flood magnitude is the quantitative index that describes the scale of a flood; the flood's disaster intensity is the quantitative index describing the losses caused. Both indices have numerous theoretical and practical advantages with definable concepts and simple applications, which lend them key practical significance.


Myelolipoma of the adrenal gland associated with contralateral renal cell carcinoma: case report and review of the literature.
Adrenal myelolipoma is a rare benign hormonally inactive tumor. It is frequently detected incidentally on new imaging procedures, such as sonography and computerized tomography and, thus, the question of treatment arises. The association of myelolipomas with obesity, hypertension and malignant tumors has been described previously. We report the second case of myelolipoma associated with renal cell carcinoma. Pathogenesis, differential diagnosis and therapy are discussed.


The interplay between Araçatuba virus and host signaling pathways: role of PI3K/Akt in viral replication.
In this study, we describe the interaction between Araçatuba virus (ARAV), a naturally occurring Brazilian vaccinia virus isolated from an outbreak at a dairy farm, and the host cell's signal transduction pathways. Even though ARAV infection led to phosphorylation of MAPKs MEK/ERK, JNK, and p38MAPK, genetic or pharmacological inhibition of these pathways had no impact on viral replication. We also provide evidence that ARAV stimulated the phosphorylation of Akt (PKB) at serine 473 (S473-P), a signaling event that is required for full activation of Akt during the infectious cycle. Furthermore, pharmacological inhibition of PI3K (LY294002) abrogated ARAV-induced Akt activation (S473-P) and affected early and late viral gene expression, which was followed by a decrease in virus yield (~1 log). Taken together, our data shed some light onto the biological differences between ARAV and vaccinia virus strain WR (VACV-WR), which could contribute, at least in part, to the low-virulence phenotype displayed by ARAV. Thus, while the requirement for the PI3K/Akt pathway for successful ARAV replication is also shared with VACV-WR and cowpox virus strain BR (CPXV-BR), ARAV showed a lower replicative capacity, as well as a smaller plaque-size phenotype after infection of A31 cells when compared to VACV-WR.


Pharmacodynamics and clinical efficacy of fentanyl iontophoretic transdermal system for post-operative pain in hospitalized patients.
The fentanyl iontophoretic transdermal system (ITS) is a patient-controlled transdermal system allowing needle-free administration of on-demand doses of Fentanyl of 40 µg over a 10-min period up to 80 doses or over a 24-h period. It is indicated in opioid naïve patients for the treatment of acute postoperative pain in the hospitalized patients for up to 72 h. It has been demonstrated to be effective and safe in randomized trials and to provide comparable analgesia versus morphine intravenous (i.v.) patient-controlled analgesia (PCA) with adverse events similar between groups. Fentanyl ITS has shown high patient satisfaction rates, and was described by patients and investigators as easy and convenient to use. These properties make this technology interesting when considering perioperative pain management. In the present health care environment additional data are required to establish the cost-benefit ratio of this technology in optimizing patient's recovery from surgery.


Selectins, T-cell rolling and inflammation.
The selectins, a family of Ca(2+)-dependent lectins, are expressed on inflamed vascular endothelium and some leukocyte subsets, and mediate adhesive contacts between blood cells and vessel walls. These interactions are loose and reversible, operate under conditions of shear flow, and result in leukocyte rolling along the vessel wall. The structure of the selectins and their ligands makes them uniquely suited for supporting the type of bond formation and dissociation that must prevail in order for a cell to be able to roll under conditions of flow. Because rolling precedes (and appears to be essential for) the integrin-mediated firm arrest before extravasation in response to inflammatory or infectious stimuli, inhibition of selectin function has potential for anti-inflammatory therapy, but also presents some significant challenges because of the complexity of the processes involved.


Potentiometric immunoassay with quantum dot labels.
Potentiometric sensors based on polymer membrane electrodes, if properly optimized, are useful for measurements at trace levels. The expected independence of the electrochemical signal of the sample size makes them extremely attractive for measurements in small volumes. Here, we report on electrodes for the potentiometric detection of cadmium ions that reach a detection limit of 6 nM and utilize a Na(+)-selective electrode as pseudoreference in order to facilitate measurements in 150-microL samples. A potentiometric immunoassay of mouse IgG is performed via CdSe quantum dot labels on a secondary antibody according to a sandwich immunoassay protocol in a microtiter plate format. The CdSe quantum dots are found to be easily dissolved/oxidized in a matter of minutes with hydrogen peroxide, allowing us to maintain the pH at a near-neutral value. The potentiometric protein immunoassay exhibits a log-linear response ranging from 0.15 to 4.0 pmol of IgG, with a detection limit of <10 fmol in 150-microL sample wells.


The effect of dietary sodium and protein on urine volume and water intake.
To test the notion that water intake and urine volume are related to dietary sodium or protein intake in free-living persons, we studied normal men at three levels of sodium intake and two levels of protein intake. Twenty-four men received 10, 200, and 400 mEq/day sodium intake for 7 days while protein and caloric intake were maintained constant. Eight men received 80 or 180 gm/day protein intake for 7 days while caloric and sodium intake were maintained constant. Although sodium, solute, and urea nitrogen excretion changed appropriately according to the regimens, there was no demonstrable influence of sodium or protein intake on water intake and urine volume. We conclude that in normal free-living American man, water consumption is independent of either sodium or protein intake.


The role of paramedics in resuscitation of patients with prehospital cardiac arrest from coronary artery disease.
Columbus, Ohio added prehospital coronary care to its Emergency Medical Services System (EMS) in 1969. The EMS System, which is citizen activated and tax supported (+5 per citizen per year), currently sees 32,000 patients a year in a city with a population of 650,000. Ninety-six per cent of the population is aware of the system. Over two thirds of patients with ischemic sudden death or myocardial infarction are seen by advanced life support paramedic (EMT-P) units. The EMT-Ps operate by protocol without telemetry and carry all standard resuscitative drugs and devices. Serial evaluations have shown that within the limits of the protocol, the EMT-Ps perform as effectively as physicians in diagnosis and care of acute cardiovascular emergencies, including endotracheal intubation. One third of ischemic cardiac arrest patients in whom resuscitation is possible (60% of such patients seen) are discharged from the hospital alive (14.2/100,000 lives saved per year). Lives are also saved by treatment of other life-threatening prehospital complications. In Columbus, the estimated annual mortality from ischemic heart disease is only 19%. The EMS System contributes significantly to this low figure.


Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph(+) metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P =.0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P =.057 and P =.034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. The prognostic significance of deletion status should now be studied prospectively and, if confirmed, should be incorporated into management decisions and the analysis of clinical trials.


Effects of interferon alpha therapy on the catalytic domains of the polymerase gene and basal core promoter, precore and core regions of hepatitis B virus.
The aim of the present study was to examine the catalytic domains of the polymerase gene, the basal core promoter and the precore and core regions of the hepatitis B virus (HBV) genome for specific mutations. These may account for the response to interferon alpha (IFN-alpha) treatment, which may have prognostic value. Multiple serum samples were collected prospectively from 30 patients with chronic active hepatitis B who were treated with IFN-alpha. Patients were assigned to one of three groups: group A (n = 11) and group B (n = 10) individuals were hepatitis B e antigen (HBeAg)-positive prior to treatment. Group A patients underwent HBeAg seroconversion after treatment while group B patients did not. Group C (n = 9) patients were HBeAg-negative prior to treatment. The HBV DNA was extracted from the sera collected before, during and after treatment and the various genomic regions were amplified, sequenced and examined for mutations. During IFN-alpha therapy, multiple changes were found in the catalytic domains of the HBV polymerase gene in all groups. The frequency of mutations and associated amino acid changes were highest in virus from group C patients and lowest in group A patients. The interdomain regions of the viral polymerase were the most affected. Multiple mutations were also found in the precore, core and core promoter regions. However, no specific mutations were associated with clinical response or outcome. During IFN-alpha treatment, multiple mutations occurred in the HBV genome, including the catalytic domains of the polymerase gene. Changes that did occur could not be correlated to the clinical response or treatment outcome. However, no mutations were found that have been linked to lamivudine escape, indicating that lamivudine therapy would be effective in IFN-alpha non-responder patients.


Bioactive toxins from stinging jellyfish.
Jellyfish blooms occur throughout the world. Human contact with a jellyfish induces a local reaction of the skin, which can be painful and leave scaring. Systemic symptoms are also observed and contact with some species is lethal. A number of studies have evaluated the in vitro biological activity of whole jellyfish venom or of purified fractions. Hemolytic, cytotoxic, neurotoxic or enzymatic activities are commonly observed. Some toxins have been purified and characterized. A family of pore forming toxins specific to Medusozoans has been identified. There remains a need for detailed characterization of jellyfish toxins to fully understand the symptoms observed in vivo.


Demonstration and characterization of virus released by murine B cell leukemia cells (BCL1).
LPS-stimulated leukemia cells derived from BALB/c mice bearing transplantable B-lymphocytic leukemia (BCL1) which arose spontaneously in a female BALB/c mouse, contained viral particles as suggested by electron microscopy as well as by tissue cultures using the XC assay. Some cell free extracts prepared from BCL1 cells were capable of transforming normal B-lymphocytes when inoculated into untreated syngeneic recipients. Cytogenetic analysis of spleen cells obtained from a splenomegalic male mouse neonatally inoculated with cell-free extract indicated that the tumor cells had a male karyotype with 42 chromosomes as compared to 37 chromosomes and a female karyotype in original BCL1 cells, thus excluding the possibility of tumor propagation by transplantation of intact BCL1 cells. These findings suggest viral involvement in the etiology of BCL1.


[Placentofetal relations as a basis for development and differentiation of definitive organs and tissues].
On the basis of the analysis of clinical and experimental data a conclusion is made about existence of the regulatory-metabolic relations between different elements of the placenta and organs and tissues of the fetus which determine adaptive and pathological reactions in developing fetus. Regulation of metabolic relationships is a necessary part of systemogenesis and after development of the definitive cells and functional systems blocks the correlative systems. This mechanism is very important for development of the regulatory systems of the fetus forming postnatal homeostasis.


Ultrasonography, computed tomography and arteriography in the evaluation of the local spreading of malignant renal neoplasm.
In a series of 32 operated renal carcinoma patients, the ability of ultrasonography (US), computed tomography (CT) and arteriography to demonstrate the local spreading of renal carcinoma was investigated. Operation showed that 23 of the renal carcinomas were local. Nine carcinomas had spread locally. CT was the most sensitive indicator of local spreading (particularly perirenal extension). CT examinations, however, also gave most of the false positive findings. The number of false negative findings was highest in the US group.


[The role of histopathology in the assessment of incidence and etiology of cancer].
Histopathological examination of tumours is of vital importance in clinical oncology as well as for epidemiological registration of cancer. Evaluation of malignancy is basic, but the reporting of tumour type is also necessary for studies of etiology. In addition to adequate epidemiological and statistical methods, quality assurance of histological diagnoses is of great value in such work. This paper contains brief comments on histological examination, epidemiological registration and epidemiological research, with special reference to cancer etiology, and giving some examples.


Chronic urticaria and Helicobacter pylori.
Helicobacter pylori (HP) have recently emerged as a novel eliciting factor for chronic urticaria (CU). The possible association between HP and CU has enormous potential, as eradicating HP could cure CU. We conducted a study to assess the prevalence of HP infection and effect of bacterium eradication on skin lesions in patients of chronic idiopathic urticaria (CIU). Four hundred sixty patients of CU attending the allergy clinic, SMS hospital, Jaipur during the period February 6, 2004, to February 6, 2006, were screened for possible eliciting factors. Patients with CIU were enrolled and others were excluded. Sixty-eight patients of CIU and similar number of age and sex matched controls, attending the allergy clinic, SMS Hospital, Jaipur were enrolled in the study. All patients underwent endoscopy with antral biopsy for urease and histopathology to identify HP-associated gastritis. Infected patients were given HP eradication therapy. Eradication of bacterium was confirmed by fecal antigen assay. Subjective response to treatment was judged using chronic urticaria quality-of-life questionnaire (CU-Q 2 oL) while objective response to treatment was judged by need for 'rescue medication' (antihistaminics). Data were analyzed using Chi square and paired 't' test for their level of significance. HP associated gastritis was present in 48 (70.58%) patients, out of which 39 (81.25%) patients responded to eradication therapy. Ten (50.00%) patients without HP associated gastritis showed response to symptomatic therapy. Overall 49 (72.05%) patients responded and 19 (27.94%) showed no response. The value of chi2 was 28.571 (P = 0.003), which showed significant association between presence of HP and response to eradication regimen. The response of HP eradication therapy in infected patients of CIU is significant. HP should be included in diagnostic workup of patients with CIU.


A recommender system for medical imaging diagnostic.
The large volume of data captured daily in healthcare institutions is opening new and great perspectives about the best ways to use it towards improving clinical practice. In this paper we present a context-based recommender system to support medical imaging diagnostic. The system relies on data mining and context-based retrieval techniques to automatically lookup for relevant information that may help physicians in the diagnostic decision.


Retrospective analysis of S-1 monotherapy in patients with metastatic colorectal cancer after failure to fluoropyrimidine and irinotecan or to fluoropyrimidine, irinotecan and oxaliplatin.
Chemotherapy with irinotecan (CPT-11) or oxaliplatin (l-OHP) in combination with infusional 5-fluorouracil (5-FU) and their cross-over as second-line therapies are standard treatments for metastatic colorectal cancer (MCRC). Molecular target agents, which are used as third-line therapies in Western countries after failure of these three drugs, have not been available in Japan. Monotherapy with S-1 [Tegafur, Oteracil potassium and 5-chloro-2,4-dihydroxypyrimidine (CDHP)] showed activity against colorectal cancer with a response rate of 35% as a first-line therapy. It is not clear whether inhibition of dihydropyrimidine dehydrogenase by CDHP can modulate the activity of 5-FU even after patients initially fail with 5-FU. This retrospective study evaluated the efficacy and safety of monotherapy with S-1 for MCRC after the failure of standard chemotherapy. The subjects of this study comprised two cohorts; the first was 27 patients with MCRC who had failed with 5-FU and CPT-11 before approval of l-OHP in Japan (cohort 1), and the second was 23 patients who had failed with 5-FU, CPT-11 and l-OHP (cohort 2). S-1 was given orally twice daily (80 mg m(2)/day) for 28 days followed by a 14-day rest. In cohorts 1 and 2, the response rates were 7% and 0%, and the median progression-free survivals were 2.8 and 2.7 months, and overall survivals after initiation of S-1 were 10.5 and 4.7 months, respectively. The common grade 3 and 4 adverse events in cohorts 1 and 2 were diarrhea 15% and 13%, anorexia 11% and 17% and anemia 26% and 30%, respectively. S-1 monotherapy did not show promising activity against MCRC after the failures with 5-FU, CPT-11 and l-OHP.


Bone formation at a rabbit skull defect by autologous bone marrow cells combined with gelatin microspheres containing TGF-beta1.
The objective of the present study is to investigate the addition effect of transforming growth factor (TGF)-beta1 on the bone formation at a rabbit skull defect induced by autologous bone marrow (BM). Following application of gelatin microspheres containing TGF-beta1, with or without BM cells to skull bone defects, bone formation at the defect was assessed by soft X-ray, dual energy X-ray absorptometry (DEXA), and histological examinations. After implantation for 6 weeks, gelatin microspheres containing 0.05 microg of TGF-beta1 plus 10(6) of BM cells induced bone formation at the 6 mm diameter bone defect. The defect was histologically closed by newly formed bone tissue, whilst both gelatin microspheres containing 0.05 microg of TGF-beta1, and 10(6) and 10(7) of BM cells were ineffective. A DEXA experiment revealed that combination of gelatin microspheres containing TGF-beta1 with BM cells enhanced the bone mineral density at the skull defect to a significantly greater extent than other agents. These findings indicate that a combination of gelatin microspheres containing TGF-beta1 enabled BM cells to enhance the osteoinductive ability, resulting in bone formation even at the cell number at which BM cells alone were ineffective.


Succinylacetone inhibits delta-aminolevulinate dehydratase and potentiates the drug and steroid induction of delta-aminolevulinate synthase in liver.
Succinylacetone, an abnormal metabolite of the tyrosine metabolic pathway, is produced in patients with hereditary tyrosinemia because of a genetic deficiency of fumarylacetoacetase. This metabolite greatly inhibits the activity of ALA dehydratase and accounts for the elevated excretion of ALA in urine in this disease. We have studied the effects of succinylacetone on heme synthesis in cultured avian hepatocytes and on the activity of purified ALA dehydratase from normal human erythrocytes and from mouse liver. Succinylacetone markedly inhibited ALA dehydratase in a competitive manner. The compound also decreased cellular heme and cytochrome P-450 content, and greatly potentiated the drug and steroid induction of ALA synthase in primary cultures of liver cells. Four patients with hereditary tyrosinemia were found to have markedly low erythrocyte ALA dehydratase activity and elevated concentrations of an inhibitor of the enzyme in urine. The concentration of the inhibitor, i.e., succinylacetone, was reduced and the erythrocyte ALA dehydratase activity was restored toward normal in one patient treated with a diet formula low in tyrosine and phenylalanine. Hereditary tyrosinemia is a genetic disease of unique interest since an abnormal metabolite, succinylacetone, produced by the primary enzymatic deficiency in this disorder, profoundly inhibits an enzyme, ALA dehydratase, involved in heme biosynthesis. This enzyme inhibition results in a clinical and biochemical mimicry of AIP in some patients.


Metabolic rate monitoring and energy expenditure prediction using a novel actigraphy method.
A novel actigraphy method, the proportional integral mode, was used for monitoring metabolic rate and energy expenditure during different levels of exercise intensity. 13 young (24+/-3 yrs) male subjects, clothed in T-shirts, shorts and athletic shoes, ran/walked for 30 min on a level treadmill at different speeds (3, 5, 2, 6, 4, and 7 mph), 5 min at each speed. The following variables were continuously measured: Actigraphy (PCD, USA) data at three different modes (proportional integral mode, zero crossing, and time above threshold) from the wrist; oxygen consumption (Sensor Medics, USA), and heart rate (Polar, Finland). Analysis of the measured data revealed with low correlation between oxygen consumption and zero crossing or time above threshold (R=0.364 and 0.384, respectively), but with high correlation between oxygen consumption and proportional integral mode (R=0.843). The proportional integral mode, which is unlike the other modes, followed the oxygen consumption and the heart rate curves, showing a potential unique method to predict oxygen consumption and energy expenditure.


Radiographic contrast media and release of neutrophil specific proteins in vitro and after intravenous injection.
The neutrophil granulocytes contain granules in which different proteins are present. When activated the neutrophils degranulate and thereby release some of these proteins to the surroundings. Some of these proteins are specific for this type of cell, e.g., lactoferrin and elastase. To investigate the influence of contrast media (CM) on this release, blood was incubated with diatrizoate, ioxaglate, iohexol, iodixanol, hyperosmolar saline, and hyperosmolar mannitol at different concentrations, and the amount of the neutrophil specific proteins lactoferrin and elastase were measured. Decreasing protein concentrations were observed for increased medium concentrations, suggesting that the degranulation process of the neutrophils was inhibited by the CM. The protein concentrations were lowest after incubation with the two ionic media diatrizoate and ioxaglate. Significantly decreased values of plasma lactoferrin were observed one min after i.v. injection of iohexol or ioxaglate in 82 patients undergoing urography. There was no significant difference between the two CM.


[miR-199b-5p inhibits proliferation and invasion of head and neck cancer cells].
This study identified the differentially expressed miR-199b-5p in the progressing of head and neck squamous cell carcinoma(HNSCC) and investigated its biological characters. The expression of miR-199b-5p in 128 HNSCC tissues samples was evaluated. The association between clinicopathological parameters and the expression levels of the candidated miRNAs was analyzed by using Kaplan-Meier survival analysis. Cell growth, invasion and migration potential, and clone formation were observed to detect the functions of the miRNAs in HNSCC cells. Statistical analysis was performed using SPSS 19.0 software package. In 79 HNSCC tissues with cervical lymph node metastasis, the expression level of miR-199b-5p was 1.68±0.21; while the expression level was 2.64±0.24 in 28 tissues without lymph node metastasis (P=0.001). In patients with HNSCC, lower level of miR-199b-5p expression significantly correlated with worse overall survival rate (P=0.01). Overexpression of miR-199b-5p inhibited HNSCC cell proliferation and invasion. miR-199b-5p plays a key role in cell invasion and metastasis and its expression correlated with overall survival in patients with HNSCC.


Priming or executive control? Associative priming of cue encoding increases "switch costs" in the explicit task-cuing procedure.
The explicit task-cuing procedure involves presenting a cue that indicates which task to perform on a target. Responses are typically faster when tasks repeat than when they alternate, and this difference is often interpreted as a measure of the time required for executive control processes to change task set. This article suggests that the difference reflects priming of cue encoding when successive cues are identical or associatively related. Subjects responded to task repetitions more quickly when the cue on the current trial was associatively related to the cue on the previous trial (e.g., day --> night) than when the cues were unrelated (e.g., verb --> night). Models applied to the time course function--generated by manipulating the interval between the onsets of the cue and the target--showed that the facilitation was due to cue encoding, a process that does not require online executive control.


Predicting the Feasibility of Correcting Mechanical Axis in Large Varus Deformities With Unicompartmental Knee Arthroplasty.
Due to disappointing historical outcomes of unicompartmental knee arthroplasty (UKA), Kozinn and Scott proposed strict selection criteria, including preoperative varus alignment of ≤15°, to improve the outcomes of UKA. No studies to date, however, have assessed the feasibility of correcting large preoperative varus deformities with UKA surgery. The study goals were therefore to (1) assess to what extent patients with large varus deformities could be corrected and (2) determine radiographic parameters to predict sufficient correction. In 200 consecutive robotic-arm assisted medial UKA patients with large preoperative varus deformities (≥7°), the mechanical axis angle (MAA) and joint line convergence angle (JLCA) were measured on hip-knee-ankle radiographs. It was assessed what number of patients were corrected to optimal (≤4°) and acceptable (5°-7°) alignment, and whether the feasibility of this correction could be predicted using an estimated MAA (eMAA, preoperative MAA-JLCA) using regression analyses. Mean preoperative MAA was 10° of varus (range, 7°-18°), JLCA was 5° (1°-12°), postoperative MAA was 4° of varus (-3° to 8°), and correction was 6° (1°-14°). Postoperative optimal alignment was achieved in 62% and acceptable alignment in 36%. The eMAA was a significant predictor for optimal postoperative alignment, when corrected for age and gender (P < .001). Patients with large preoperative varus deformities (7°-18°) could be considered candidates for medial UKA, as 98% was corrected to optimal or acceptable alignment, although cautious approach is needed in deformities >15°. Furthermore, it was noted that the feasibility of achieving optimal alignment could be predicted using the preoperative MAA, JLCA, and age.


Synthesis, characterization, and reactivity of dinuclear organo-rare-earth-metal alkyl complexes supported by 2-amidate-functionalized indolyl ligands: substituent effects on coordination and reactivity.
Two series of new dinuclear organo-rare-earth-metal alkyl complexes supported by 2-amidate-functionalized indolyl ligands with different haptic modes were synthesized and characterized. The treatment of [RE(CH2SiMe3)3(THF)2] with 1 equiv. of 2-(2,6-iPr2C6H3NHC[double bond, length as m-dash]O)C8H5NH (H2L1) and 2-(2-tBuC6H4NHC[double bond, length as m-dash]O)C8H5NH (H2L2) in toluene yielded the dinuclear organo-rare-earth-metal alkyl complexes {[η1:(μ2-η1:η1)-L1]RE(CH2SiMe3)(THF)2}2 [RE = Gd (1a), Dy (1b), Y (1c), Er (1d), and Yb (1e)] and {[η1:(μ2-η1:η1):η1-L2]RE(CH2SiMe3)(THF)2}2 [RE = Gd (2a), Dy (2b), Y (2c), Er (2d), and Yb (2e)] in good yields. When [RE(CH2SiMe3)3(THF)2] were treated with 2 equiv. of H2L1 or H2L2 in THF, the dinuclear organo-rare-earth-metal complexes {(η1:η1-HL)[η1:(μ2-η1:η1):η1-L]RE(THF)}2 (1ca: RE = Y, L = L1; 2ea: RE = Yb, L = L2) were obtained. The complexes could react with small organic molecules such as N,N'-diisopropylcarbodiimide (DIC), phenyl isocyanate, N-methylallylamine, phenylacetylene, pyridine, N-phenylimidazole, or 4-dimethylaminopyridine (DMAP) to yield a series of new complexes with different reactivity patterns along with the reported rare-earth-metal alkyl complexes. In the presence of cocatalysts, these dinuclear organo-rare-earth-metal alkyl complexes could initiate isoprene polymerization with high activity (100% conversion of 2000 equiv. of isoprene in 12 h), yielding polymers with high regioselectivity (1,4 polymers up to 96.1%).


How do scientists respond to anomalies? Different strategies used in basic and applied science.
We conducted two in vivo studies to explore how scientists respond to anomalies. Based on prior research, we identify three candidate strategies: mental simulation, mental manipulation of an image, and comparison between images. In Study 1, we compared experts in basic and applied domains (physics and meteorology). We found that the basic scientists used mental simulation to resolve an anomaly, whereas applied science practitioners mentally manipulated the image. In Study 2, we compared novice and expert meteorologists. We found that unlike experts, novices used comparison to address anomalies. We discuss the nature of expertise in the two kinds of science, the relationship between the type of science and the task performed, and the relationship of the strategies investigated to scientific creativity.


ReSure Sealant for Pars Plana Vitrectomy Wound Closure.
ReSure Sealant (Ocular Therapeutix, Bedford, MA) is an ocular sealant that demonstrated both safety and effectiveness in a prospective, randomized clinical trial for sealing clear corneal incisions following cataract surgery and intraocular lens placement in adults.1 PATIENTS AND METHODS: This is the first literature report of ReSure Sealant used for the closure of 23-gauge (G) pars plana vitrectomy (PPV) sclerotomies. A 70-year-old pseudophakic female with a history of epiretinal membrane and branch retinal vein occlusion of the right eye underwent 23-G PPV, membrane peel, and air-fluid exchange and was found to have leaking subconjunctival air at the end of the case. A linear conjunctival incision was performed to access the sclerotomy site. The incisions were then carefully dried before the sealant was applied to seal both the sclera and conjunctiva. After polymerization, the sealant formed a polyethylene glycol (PEG) hydrogel that was 89% water and 9.44% PEG. PEG is a synthetic material that is non-toxic and inert and, thus, suitable for use in medical products. ReSure Sealant may be a safe, quick method to close sclerotomy wounds in select cases. [


Bioenergetics and neuromuscular determinants of the time to exhaustion at velocity corresponding to VO2max in recreational long-distance runners.
The purpose of this study was to investigate the main bioenergetics and neuromuscular determinants of the time to exhaustion (T(lim)) at the velocity corresponding to maximal oxygen uptake in recreational long-distance runners. Twenty runners performed the following tests on 5 different days: (a) maximal incremental treadmill test, (b) 2 submaximal tests to determine running economy and vertical stiffness, (c) exhaustive test to measured the T(lim), (d) maximum dynamic strength test, and (e) muscle power production test. Aerobic and anaerobic energy contributions during the T(lim) test were also estimated. The stepwise multiple regression method selected 3 independent variables to explain T(lim) variance. Total energy production explained 84.1% of the shared variance (p = 0.001), whereas peak oxygen uptake (V(O2)peak) measured during T(lim)and lower limb muscle power ability accounted for the additional 10% of the shared variance (p = 0.014). These data suggest that the total energy production, V(O2)peak, and lower limb muscle power ability are the main physiological and neuromuscular determinants of T(lim)in recreational long-distance runners.


Peptide sequences that target proteins for enhanced degradation during serum withdrawal.
Fibroblasts increase the catabolism of certain intracellular proteins in response to serum withdrawal, and these proteins contain specific peptide regions that may be required for their increased degradation. We show that the increased degradation of microinjected ribonuclease A during serum withdrawal can be blocked by co-injection of a pentapeptide corresponding to residues 7-11 of ribonuclease A, Lys-Phe-Glu-Arg-Gln. Furthermore, similar peptide sequences appear to play a widespread role in targeting proteins for enhanced degradation. Affinity-purified antibodies raised against the pentapeptide are able to precipitate 20-35% of radiolabeled cytosolic proteins from fibroblasts. Such proteins are preferentially degraded when cells are deprived of serum while nonimmunoprecipitable proteins are degraded at the same rate in the presence and absence of serum. Immunoreactive cytosolic proteins also exist in rat liver and kidney, and these proteins are depleted when protein degradation rates are enhanced due to starvation. Several types of evidence suggest that the peptides recognized in cellular proteins are similar to Lys-Phe-Glu-Arg-Gln but are not this exact sequence. Analyses of amino acid sequences for four proteins whose degradative rates are enhanced in response to serum withdrawal and for four proteins that are degraded in a serum-independent manner indicate two possible peptide motifs related to Lys-Phe-Glu-Arg-Gln that may target cellular proteins for enhanced degradation. These results, combined with previous studies (McElligott, M. A., Miao, P., and Dice, J. F. (1985) J. Biol. Chem. 260, 11986-11993), suggest that these peptide regions target specific proteins to a lysosomal pathway of degradation during serum withdrawal.


The Defense Mechanism Test in clinical and personality research.
Different research strategies are used for the application of the Defense Mechanism Test in clinical and personality research. It is argued that the harvest of useful information would be greater if the effort of different research groups could be coordinated.


Dense energetic nitraminofurazanes.
3,3'-Diamino-4,4'-bifurazane (1), 3,3'-diaminoazo-4,4'-furazane (2), and 3,3'-diaminoazoxy-4,4'-furazane (3) were nitrated in 100 % HNO3 to give corresponding 3,3'-dinitramino-4,4'-bifurazane (4), 3,3'-dinitramino-4,4'-azofurazane (5) and 3,3'-dinitramino-4,4'-azoxyfurazane (6), respectively. The neutral compounds show very imposing explosive performance but possess lower thermal stability and higher sensitivity than hexogen (RDX). More than 40 nitrogen-rich compounds and metal salts were prepared. Most compounds were characterized by low-temperature X-ray diffraction, all of them by infrared and Raman spectroscopy, multinuclear NMR spectroscopy, elemental analysis, and by differential scanning calorimetry (DSC). Calculated energetic performances using the EXPLO5 code based on calculated (CBS-4M) heats of formation and X-ray densities support the high energetic performances of the nitraminofurazanes as energetic materials. The sensitivities towards impact, friction, and electrostatic discharge were also explored. Additionally the general toxicity of the anions against vibrio fischeri, representative for an aquatic microorganism, was determined.


Stain removal effect of novel papain- and bromelain-containing gels applied to enamel.
The aims of the study are to prepare novel stain removal gel-based formulations containing papain or bromelain and to investigate their stain removal effect when applied to enamel. Experimental bromelain- and papain-based stain removal gels were prepared. Next, enamel/dentin tooth samples (6 × 6 mm2, 4 mm in thickness) were obtained from bovine teeth, stained in coffee solution for 1 week, and measured with a digital spectrophotometer (Easyshade, Vita Zahnfabrik) for color assessment (baseline). The samples were then randomly allocated into four groups (n = 7), according to the stain removal agent applied: ContrastPM+ (Discus Dental, LLC), which is based on 20 wt.% carbamide peroxide (positive control); bromelain-based; papain-based; and no agent (negative control). The materials were applied once a week, three times per day, during 4 weeks, and following the directions of use from positive control. The samples were measured again with the Easyshade and using the CIEL * a * b * color system. The color change (ΔE *) results were obtained by subtracting the baseline values from the final color values obtained at each time point. The data were statistically analyzed using two-way repeated-measures analysis of variance and Student Newman Keuls's test as a post hoc test (α = 5 %). All stain removal agents produced greater color change than the negative control (p < .001), with the positive control demonstrating greater ΔE * values when compared to the experimental gels (p ≤ .004). The second application of all gels resulted in greater ΔE * values compared to the first application (p ≤ .025), although no color change was observed after the third application (p ≥ .051), regardless of the material evaluated. The proposed gels containing proteolytic enzymes (bromelain or papain) of vegetal origin may hold significant clinical potential as active agents for the preparation of stain removal agents free of hydrogen/carbamide peroxide.


Protease cell wall degradation of Chlorella vulgaris: effect on methane production.
In order to optimize the enzymatic dosage and microalgae biomass loads subjected to enzymatic hydrolysis prior anaerobic digestion of Chlorella vulgaris, organic matter solubilisation and methane production were investigated. Experimental data using protease dosage of 0.585 AU g DW(-1) showed that increasing biomass loads up to 65 g L(-1) did not affect markedly the hydrolysis efficiency (51%). Enzymatically pretreated biomasses subjected to anaerobic digestion enhanced methane production by 50-70%. The attempt of decreasing the enzymatic dosages revealed diminished hydrolysis efficiency concomitantly with a decreased methane production enhancement. In agreement with the good results observed for organic matter conversion into biogas, total nitrogen mineralization was attained for enzymatically pretreated biomass. Despite the high protein content of the biomass and the biocatalyst used in the present study no ammonia inhibition was detected.


Prospective clinical assessment of tibial tuberosity advancement for the treatment of cranial cruciate ligament rupture in dogs.
To evaluate clinically dogs that underwent tibial tuberosity advancement (TTA) six months previously. Dogs of various breeds, gender, weight, and age that had CCL rupture and underwent TTA for treatment were included in this study. Parapatellar arthrotomy was performed in all patients to assess the joint for a ruptured ligament and meniscal injury before the TTA. The appropriate cage for the TTA was chosen with planning surgery. The surgical procedure was performed according to the literature, using a modified Maquet technique. Six months after surgery, lameness during walking; muscular atrophy; crepitation, cranial drawer and tibial compression tests and quality of life based on owner's evaluation were assessed. Postoperative complications were observed in only one knee (4.76%), with a surgical site seroma. The mean lameness score at walking was 0.29 (± 0.64). The mean score regarding muscular atrophy was 0.95 (± 1.56). The mean score of the cranial drawer test, in a range from 0 to 5, was 1.52 (± 1.54). The owners rated the dog's quality of life as excellent in 44%, good in 30%, and moderate in 17%. This clinical study supports the affirmation that patients who undergo TTA for treatment of CCL rupture have an acceptable response.


An analysis of congressional health policy voting in the 1970s.
This paper analyzes nine health policy votes in the U.S. House of Representatives. The votes all occurred between 1973 and 1980 and include such issues as health planning, health maintenance organizations, cost containment, and professional standards review organizations. The objective of this analysis is to examine the independent contribution of variables indigenous to health issues while controlling for party identification and ideology. The influence of health providers, measured by the effect of the number of state medical association members in each state, is significant in the findings. The state and local share of Medicaid expenses is also significant in explaining several votes. Contributions from political action committees were not important until 1979, when the rising costs of campaigns gave them more influence, and when our measures of their influence improved. By the time Congress voted in 1979 on hospital cost containment legislation, the PAC variable surpassed even the AMA variable in importance.


[Vestibular nystagmus in rats after hypokinesia and prolonged rotation].
Changes in the latent period, number of beats, duration and frequency of the nystagmus were investigated in rats exposed to angular acceleration of an increasing value (10, 20, 30, and 40 degree/cm2) after a 21-day exposure to hypokinesia per se or hypokinesia in a rotating device (with a radius of 141 cm, rate of rotation of 33.3 rpm, and acceleration value of 2 g). The hypokinetic rats showed nystagmic changes only with the lowest acceleration used (10 degrees/cm2). The hypokinetic animals rapidly adapted to a repeated exposure to angular acceleration during the recovery period. A 21-day exposure to hypokinesia in a rotating device disturbed adaptation to a repeated effect of angular acceleration during recovery. Mechanisms of these effects are discussed. It is concluded that hypokinesia cannot be an adequate model for studying weightlessness effects on the vestibular function.


Prophylaxis in adults with haemophilia.
The indications for and the efficacy of prophylaxis in adults with haemophilia remain controversial. It is unclear whether the benefits of secondary prophylaxis outweigh the costs, because adults with haemophilia usually already have established arthropathy. The objectives of secondary prophylaxis in this group are therefore more limited than the objectives of primary prophylaxis in children. It is also uncertain whether primary prophylaxis should stop or continue once adulthood is reached. Some individuals with near-normal joints may stop prophylaxis in early adulthood and then bleed infrequently. Others who stop prophylaxis begin to bleed frequently and suffer progressive arthropathy; these patients should probably have continued prophylaxis. There is no satisfactory method for selecting patients for continued prophylaxis. Adult prophylaxis is less well studied than prophylaxis in children. A few studies with a small number of patients suggest that adults treated with prophylaxis experienced fewer bleeding episodes, less pain and improved quality of life compared with those treated on demand. The mean annual cost of prophylaxis tends be substantially higher for adults than for children, largely owing to the high cost of clotting factor. Here we review the literature regarding the prophylactic treatment of adult patients with haemophilia A, including studies of the discontinuation of prophylaxis. These studies and others all show clinical benefit from prophylaxis in adulthood and suggest the possibility that optimized prophylaxis (e.g. tailoring an intermediate- or low-dose regimen in patients who bleed infrequently) may improve clinical outcome. The cost-effect argument is more difficult to sustain in adults compared with children; however, the cost of prophylaxis may be counterbalanced by indirect factors, such as days gained at work, reduced hospitalizations, reduced need for orthopaedic surgery and improved quality of life.


Endometrial histology, microvascular density and caliber, and matrix metalloproteinase-3 in users of the Nestorone-releasing contraceptive implant with and without endometrial breakthrough bleeding.
This descriptive study evaluated endometrial histology, microvascular density and caliber, and quantification of matrix metalloproteinase (MMP-3) expression in long-term users of the Nestorone (NES)-releasing implant who presented or not endometrial breakthrough bleeding (BTB). Endometrial biopsies were obtained from 32 healthy women with unpredictable BTB. The quantitative analysis was performed only in 20 samples. The mean duration of use of the implant among the 14 women with BTB was 19.6+/-1.0 months, and the other six women had used the implant for 17.7+/-2.3 months (mean+/-S.E.M.). Histological analysis of the endometrial tissue showed a predominance of progestogenic pattern followed by atrophic and proliferative endometrium in both groups. Mucosal breakdown and glandular pseudostratification were observed in half of the cases. Endometrial vascular density was 73.1+/-10.0 and 57.5+/-24.1 vessels/mm(2), and maximum vessel diameter was 923.3+/-86.0 and 1038.0+/-404 microm (mean+/-S.E.M.) in the group with and without BTB, respectively, without significance, and the rate of cells expressing MMP-3x1000 counted stromal cells was 155.8+/-24.8 and 127.0+/-19.0 (mean+/-S.E.M.) in both groups, respectively, without significance. This study provides information about some endometrial aspects of women using NES in contraceptive implants. In addition, the endometrium was similar during long-term use of NES-releasing contraceptive implants in women with and without endometrial bleeding.


Racial and ethnic differences in the mental health needs and access to care of older adults in california.
Little is known about the unmet mental health needs of minority older adults. Racial and ethnic differences in the prevalence rates of psychological distress and reported need and use of mental health services were examined in a population-based sample of older adults using the 2005 California Health Interview Survey. The sample comprised 16,974 people aged 55 and older, with 13,974 non-Hispanic whites, 719 African Americans, 1,215 Asians, and 1,066 Latinos. Respondents were compared in terms of prevalence of symptoms of mental distress and serious mental illness, reported need for help, and access to mental health services. African Americans, Asians, and Latinos were more likely to have mental distress than whites (21.2-24.2% vs 14.4%, P<.001) and a higher prevalence of serious mental illness (4.1-7.7% vs 2.5%, P<.001). After adjustment for age, sex, birthplace, marital status, education, limited English proficiency, chronic health conditions, and insurance status, older African-American (adjusted odds ratio (aOR)=1.37, 95% confidence interval (CI)=1.04-1.81) and Asian (aOR=1.50, CI=1.13-2.00) adults still had greater odds of mental distress than whites. Furthermore, all three groups had worse access to mental health services than whites (African American aOR=0.64, 95% CI=0.43-0.96; Asian aOR=0.32, CI=0.16-0.63; Latino aOR=0.35, CI=0.17-0.70). Clinicians caring for older individuals should be aware of their high risk for mental health needs. Given that minorities' access to mental health services is worse than whites', even after adjusting for health insurance status, providing insurance alone will not eliminate this disparity. Innovative clinical and systemic strategies are needed to better identify individuals at risk and to provide needed services.


Effects of potassium-channel opener HOE 234 in guinea-pig airways.
The mechanism of the bronchospasmolytic effect of HOE 234 ((3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl) 6-phenylsulphonylchromane hemihydrate), a novel opener of ATP-sensitive potassium channels, has been studied by in-vitro testing in ring preparations of trachea and different parts of the principle bronchus of guinea-pigs, using methacholine, histamine and KCl as preconstrictors. The contribution of prostanoids was estimated in the presence and absence of indomethacin. Regional differences in the bronchodilatory effect of HOE 234 were compared with that of salbutamol. HOE 234 had a concentration-dependent relaxing effect on the smooth muscle preparations. In the absence of indomethacin no regional differences were seen for the effect of HOE 234 against the metacholine or KCl preconstriction, whereas with histamine a particularly strong relaxation was detectable in trachea. In the presence of indomethacin, distal bronchus after methacholine and trachea after KCl preconstriction were relaxed significantly more strongly than the other parts. The relaxation of the histamine-constricted trachea rings was not increased in comparison with that without indomethacin pretreatment. Thus the bronchospasmolytic effect of HOE 234 varied depending on the pretreatment, method of preconstriction and part of the airways examined. It was strongest in trachea rings with histamine preconstriction but its potency was clearly less than that of salbutamol. The latter had regionally different effects, being stronger in trachea than in the bronchi for all methods of preconstriction. The results suggest that the formation of bronchoconstricting prostanoids can attenuate parts of the relaxing effect of HOE 234. The possible advantages of HOE 234 as an anti-asthma drug might be related to an effect on bronchial hyper-reactivity and mucus secretion, because as a direct bronchodilator it is inferior to salbutamol.


Correlates of psychological adjustment to pediatric physical disorders: a meta-analytic review and comparison with existing models.
Thirty-eight studies of correlates of children's adjustment to physical disorders were reviewed in a meta-analysis and compared with existing models. Results indicate (1) considered collectively, disease/disability risk factors, parent/family risk factors, and child characteristics are significantly correlated with child adjustment although stressors (including socioeconomic status) are not; (2) disease/disability risk factors show significantly lower correlations than do parent/family or child characteristics; (3) child characteristics show the strongest correlation to adjustment, but these measures may be contaminated because items on some of these scales (e.g., self-concept, temperament) sometimes overlap with those on measures of total adjustment. With the exception of studies of disease severity, the number of studies meeting criteria for inclusion, with quantifiable correlates and measures of adjustment, was quite small. Inclusion of child, family/parent, social and medical risk/protective factors in future models is most appropriate, but greater emphasis needs to be placed on the child and family/parent characteristics. Greater attention also must be devoted to examining the interaction of risk/protective factors, including those that may be general and those that may be specific to a particular disability.


Rôle of ear piercing in metal allergic contact dermatitis.
To evaluate the effect of ear piercing on sensitization to gold and other metals, diagnostic patch testing with 18 metals was performed. 377 patients (65 men and 312 women, ranging in age from 15 to 78 years; mean 34.2, S.D +/- 15.1 years) were patch tested; 107 had pierced earlobes. Metals were applied on the back for 2 days, and the results read with the ICDRG scoring system 3 days after application. Reactions of + to +3 were regarded as positive. There were significantly more patients reacting to gold chloride (p < 0.001), mercuric chloride and nickel sulfate (p < 0.05) in patients with pierced ears than in those without. Statistical issues included: (i) a significant number of patients with pierced ears referred because of earring dermatitis; (ii) those with pierced ears represented a different age group from those without; (iii) a significant number of patients without eczema in the non-pierced ear group. However, our data suggests that ear piercing is a risk factor not only for nickel but also for gold sensitization. Gold was the second most frequent metal allergen after nickel in the pierced group.


Sirtuin 2 enhances dopaminergic differentiation via the AKT/GSK-3β/β-catenin pathway.
Proper and efficient differentiation of dopaminergic (DA) neurons is essential for the cell-based dopamine replacement strategies that have become an attractive therapeutical option in Parkinson's disease, a disorder typically known for the degeneration of the nigral DA neurons. Here, we established that the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 2 (SIRT2) interacts with protein kinase B, and, via the glycogen synthase kinase 3β/β-catenin pathway, modulates the differentiation of DA neurons. Deletion of SIRT2 resulted in a decreased number of DA neurons in the substantia nigra and lower striatal fiber density in SIRT2 knock-out mice. Similarly, we found a decreased ratio of DA neurons in primary midbrain cultures treated with the SIRT2 inhibitor AK-7. Using protein kinase B and glycogen synthase kinase 3β inhibitors, we found that those molecules act downstream of SIRT2. Thus, SIRT2 acts as a novel regulator of the differentiation process of DA neurons, further supporting its potential as a therapeutic target in Parkinson's disease.


[Differential action of 7 beta-hydroxycholesterol on myocardial cells and fibroblasts. Obtaining primary cultures of pure myocardial cells].
Newborn rat myocardial cells, grown in primary cultures, beat synchronously. Addition of 7 beta-hydroxycholesterol, at a 2.5 microM concentration, impairs this synchrony and may even stop any contraction. The associated fibroblasts no longer adhere to the support, and can be washed away by fresh culture medium. This restores the synchronous beatings of the myocardial cells, the viability of which is then even improved while they grow in the absence of fibroblasts.


3D Engineering of Ocular Tissues for Disease Modeling and Drug Testing.
The success rate from investigational new drug filing to drug approval has remained low for decades despite major scientific and technological advances, and a steady increase of funding and investment. The failure to demonstrate drug efficacy has been the major reason that drug development does not progress beyond phase II and III clinical trials. The combination of two-dimensional (2D) cellular in vitro and animal models has been the gold standard for basic science research and preclinical drug development studies. However, most findings from these systems fail to translate into human trials because these models only partly recapitulate human physiology and pathology. The lack of a dynamic three-dimensional microenvironment in 2D cellular models reduces the physiological relevance, and for these reasons, 3D and microfluidic model systems are now being developed as more native-like biological assay platforms. 3D cellular in vitro systems, microfluidics, self-organized organoids, and 3D biofabrication are the most promising technologies to mimic human physiology because they provide mechanical cues and a 3D microenvironment to the multicellular components. With the advent of human-induced pluripotent stem cell (iPSC) technology, the 3D dynamic in vitro systems further enable extensive access to human-like tissue models. As increasingly complex 3D cellular systems are produced, the use of current visualization technologies is limited due to the thickness and opaqueness of 3D tissues. Tissue-clearing techniques improve light penetration deep into tissues by matching refractive indices among the 3D components. 3D segmentation enables quantitative measurements based on 3D tissue images. Using these state-of-the-art technologies, high-throughput screening (HTS) of thousands of drug compounds in 3D tissue models is slowly becoming a reality. In order to screen thousands of compounds, machine learning will need to be applied to help maximize outcomes from the use of cheminformatics and phenotypic approaches to drug screening. In this chapter, we discuss the current 3D ocular models recapitulating physiology and pathology of the back of the eye and further discuss visualization and quantification techniques that can be implemented for drug screening in ocular diseases.


Overexpression of LAPTM4B-35 is a negative prognostic factor in head and neck squamous cell carcinoma.
Overexpression of LAPTM4B-35 (lysosomal-associated transmembrane protein 4β-35) is associated with a poor prognosis in numerous malignant tumours. Expression patterns and effects of LAPTM4B-35 on head and neck squamous cell carcinomas (HNSCC) are unknown. The aim of this study was to investigate the prognostic relevance of LAPTM4B-35 in HNSCC. Tissue microarrays were constructed with primary tumours and associated lymph node metastases isolated from 127 patients. The expression of LAPTM4B-35 was investigated by immunohistochemistry and the results were correlated with survival data. LAPTM4B-35 in the primary tumour was highly expressed in 47.2% of the patients (60/127). LAPTM4B-35 expression was significantly associated with tumour stage. Moreover, overexpression of LAPTM4B-35 correlated with a significantly worse disease-free survival (10.23 years vs. not reached) and a higher recurrence rate (40.7% vs. 25%). High expression of LAPTM4B-35 in lymph node metastasis was found in 29.2% of cases. In 19.4% of cases, high LAPTM4B-35 expression was observed in both the primary tumour and corresponding lymph node metastases. In conclusion, our data indicates that overexpression of LAPTM4B-35 is associated with poor prognosis and may therefore serve as a new prognostic marker in HNSCC.


What Can Be Learned from Existing Investigations of Weight-Related Practices and Policies with the Potential to Impact Disparities in US Child-Care Settings? A Narrative Review and Call for Surveillance and Evaluation Efforts.
Child-care settings and the combination of policies and regulations under which they operate may reduce or perpetuate disparities in weight-related health, depending on the environmental supports they provide for healthy eating and activity. The objectives of this review are to summarize research on state and local policies germane to weight-related health equity among young children in the United States and on how federal policies and regulations may provide supports for child-care providers serving families with the most limited resources. In addition, a third objective is to comprehensively review studies of whether there are differences in practices and policies within US child-care facilities according to the location or demographics of providers and children. The review found there is growing evidence addressing disparities in the social and physical child-care environments provided for young children, but scientific gaps are present in the current understanding of how resources should best be allocated and policies designed to promote health equity. Additional research is needed to address limitations of prior studies relating to the measurement of supports for weight-related health; complexities of categorizing socioeconomic position, ethnicity/race, and urban and rural areas; exclusion of legally nonlicensed care settings from most research; and the cross-sectional nature of most study designs. There is a particularly great need for the development of strong surveillance systems to allow for better monitoring and evaluation of state policies that may impact weight-related aspects of child-care environments, implementation at the program level, and needed implementation supports.


Anterior cruciate ligament reconstruction in adolescent patients: limb asymmetry and functional knee bracing.
Anterior cruciate ligament (ACL) reinjury rates are high in adolescent patients. Knee braces are commonly used after ACL reconstruction to prevent reinjury during return to sports. Adolescent patients following ACL injury would demonstrate a decreased vertical ground-reaction force, knee extension moment, knee flexion angle, and knee flexion velocity on the surgical limb when compared with the nonsurgical limb during a side-cutting task. A functional knee extension-resistant brace would decrease the limb asymmetries. Controlled laboratory study. Twenty-three adolescent patients 6 months after ACL reconstruction were recruited for this study. Three-dimensional kinematic and kinetic data were collected bilaterally (surgical, nonsurgical) during a 35° side-cutting task while the patient was wearing and not wearing a functional knee extension-resistant brace (nonbraced, braced) on the surgical limb. The surgical limb demonstrated a significant decrease in peak impact vertical ground-reaction force (2.55 body weight [BW] vs 2.8 BW; P < .01), peak propulsion vertical ground-reaction force (2.15 BW vs 2.3 BW; P < .01), peak knee extension moment (0.13 BW × body height [BH] vs 0.17 BW × BH; P < .01), knee flexion angle at peak knee flexion velocity (27.8° vs 30.0°; P = .01), peak knee flexion angle (44.1° vs 48.5°; P < .01), and peak knee flexion velocity (571.3 deg/sec vs 640.1 deg/sec; P < .01) when compared with the nonsurgical limb during both nonbraced and braced conditions. Bracing increased the initial knee flexion velocity (42.4 deg/sec vs -40.2 deg/sec; P = .01) and decreased the initial knee flexion angle on the surgical limb (13.1° vs 15.7°; P < .01). Bracing also affected kinematics of the nonsurgical limb. Bracing did not decrease the asymmetry between surgical and nonsurgical limbs. Adolescent patients 6 months after ACL reconstruction demonstrated significant kinematic and kinetic asymmetries between the surgical and nonsurgical limbs. The limb asymmetries persisted when the patients were wearing a functional knee brace. There were changes in the surgical knee kinematics with and without bracing, especially near initial ground contact. The limb asymmetries are of concern with regard to injuring the graft or the contralateral limb when the patients return to sport.


Bone scintigraphy in the evaluation of ejection injuries.
The Royal Air Force (RAF) experience on local back injury with all ejection seats is that 50% have vertebral fractures on radiographic examination, with or without symptoms. These aviators are placed under the care of an orthopedic specialist and restricted from flying duties for 3 months or more. About half of the remainder demonstrate positive bone scans. Until recently, RAF policy was to treat these individuals the same as those with radiographically defined fractures. The author recommends this group of pilots be examined by orthopedic surgeons, and reviewed annually to assess long-term sequelae. Meanwhile, if asymptomatic, they are allowed to return to flying duties. The RAF recently incorporated most of these recommendations into a policy change.


Ricinine-elicited seizures. A novel chemical model of convulsive seizures.
The present investigation introduces ricinine-elicited seizures as a novel chemical model of convulsive seizure. Ricinine, a neutral alkaloid obtained from the plant Ricinus communis, induces seizures when administered to mice at doses higher than 20 mg/kg. Animals presenting seizures showed a marked preconvulsive phase followed by short duration hind limb myoclonus, respiratory spasms, and death. The lethal nature of ricinine seizures is also pointed out as a good model to study the events causing death in clonic seizures, particularly those related to respiratory spasms, which are also observed in some types of human epilepsy. The behavioral signs of ricinine-elicited seizures are accompanied by electrographic alterations more evident during the preconvulsive phase in the cerebral cortex and more intense during the ictal phase both in the cortex and in the hippocampus. The ricinine-elicited seizures may be inhibited by diazepam but not by phenobarbital, phenytoin, or ethosuximide. Micromolar concentrations of ricinine cause a small decrease in the binding of [3H]-flunitrazepam to cerebral cortex membranes, but do not alter the binding of other radioligands to AMPA, 5-HT(1A), muscarinic, and alpha(1)-adrenergic receptors. Although ricinine presents a cyanide radical, only higher doses of ricinine (4 mM) caused a small impairment of mitochondrial respiration. These results suggest that the mechanism of action of ricinine probably involves the benzodiazepine site in the GABA(A) receptor. This may represent a new mechanism of drug-elicited seizures that may contribute to a better understanding of epilepsy and to new therapeutic approaches to this disease.


Renal tubular Na(+)-K(+)-ATPase in diabetes mellitus: relationship to metabolic abnormality.
This study was undertaken to evaluate the effect of long-term diabetes on Na(+)-K(+)-ATPase in isolated nephron segments in five groups of rats: 1) controls of 7 wk duration (7 WD), 2) diabetes mellitus (DM) of 7 WD, 3) DM of 7 WD treated with insulin replacement, 4) DM rats of 25 WD, and 5) control rats of 25 WD. The blood glucose (BG) values in the first three groups were 123 +/- 9, 450 +/- 25, and 302 +/- 30 mg/dl; the glomerular filtration rate (GFR) was 1.34 +/- 0.08, 1.80 +/- 0.10, and 1.77 +/- 0.08 ml/min; and urinary sodium excretion was 0.94 +/- 0.05, 1.76 +/- 0.10, and 1.40 +/- 0.07 mu eq/min. Na(+)-K(+)-ATPase in group 2 increased in all segments studied (P < 0.001, group 1 vs. 2 for all). In group 3, Na(+)-K(+)-ATPase normalized in proximal convoluted (PC), proximal straight (PS), and distal convoluted (DC) tubules (P < 0.001, group 2 vs. group 3 for all), whereas in the outer medullary thick ascending limb (OMTAL) the correction was partial and in the CTAL and CCD there was no correction. In group 4 BG was 420 +/- 20 mg/100 ml compared with 123 +/- 9 in group 5 (P < 0.001), and GFR was 1.19 +/- 0.11 ml/min vs. 1.15 +/- 0.11 in group 5 (P = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)


Basic response characteristics of auditory nerve fibers in the grassfrog (Rana temporaria).
Responses to free-field sound of 401 fibers from the VIIIth nerve of the grassfrog, Rana temporaria, are described. The spontaneous activities of the fibers ranged from 0 to 75 spikes/s, showing only weak correlation with frequency or sensitivity of the fibers. The highest spontaneous activities were approximately twice as high as reported previously for frogs. Best frequencies ranged from 100 to 1600 Hz and thresholds ranged from 21 to 80 dB SPL. The median dynamic range was 20 dB and the slopes of the rate-level curves ranged from 5 to 20 spikes/(s-dB). Most of the units showed post-excitatory suppression (PS) of their spontaneous activity. The duration of PS increased with sound level, also in fibers showing a decrease in firing rate at high intensities. Most fibers showing one-tone suppression did not show PS at their best suppression frequencies. Strong suppression was observed also in very phasic cells giving one spike per stimulation. Therefore, the mechanism underlying PS is probably different from that underlying adaptation. The sharpening of the neural encoding of temporal parameters and the strong encoding of sound offset as well as onset caused by PS very likely is biologically important.


Identifying mechanisms of treatment effects and recovery in rehabilitation of schizophrenia: longitudinal analytic methods.
The longitudinal dimension of schizophrenia and related severe mental illness is a key component of theoretical models of recovery. However, empirical longitudinal investigations have been underrepresented in the psychopathology of schizophrenia. Similarly, traditional approaches to longitudinal analysis of psychopathological data have had serious limitations. The utilization of modern longitudinal methods is necessary to capture the complexity of biopsychosocial models of treatment and recovery in schizophrenia. The present paper summarizes empirical data from traditional longitudinal research investigating recovery in symptoms, neurocognition, and social functioning. Studies conducted under treatment as usual conditions are compared to psychosocial intervention studies and potential treatment mechanisms of psychosocial interventions are discussed. Investigations of rehabilitation for schizophrenia using the longitudinal analytic strategies of growth curve and time series analysis are demonstrated. The respective advantages and disadvantages of these modern methods are highlighted. Their potential use for future research of treatment effects and recovery in schizophrenia is also discussed.


Evidence of juxtacrine signaling for transforming growth factor alpha in human endometrium.
To determine the mechanism of signaling for transforming growth factor alpha (TGFalpha) in human endometrium, uterine luminal fluid proteins were retrieved by lavage followed by collection of the adjacent endometrium at hysterectomy. In the endometrium we observed the presence of the full-length transmembrane TGFalpha protein and the phosphorylation of its only known receptor, the epidermal growth factor receptor (EGFR), by immunoprecipitation-Western blot; TGFalpha mRNA via reverse transcription-polymerase chain reaction; and immunolocalization of TGFalpha to the surface endometrium adjacent to the uterine lumen. Despite this demonstration of TGFalpha in functional endometrium, we could not detect measurable amounts of TGFalpha in any of the 16 endometrial washings by either immunoprecipitation-Western blot or by ELISA. Recovery rate for intraluminal fluid spiked with TGFalpha control peptide was 93.4-97%. The inability to detect TGFalpha in intraluminal fluid despite its high concentration in cells directly adjacent to the uterine lumen, along with the absence of any cleaved TGFalpha species identified in the endometrium, suggests that TGFalpha signals its receptor as a transmembrane ligand. Since the EGFR is present in the endometrium and on the surface of embryos, these data are consistent with a juxtacrine mode of signaling for TGFalpha between endometrial cells, and between the luminal surface epithelium and preimplantation embryos.


Good enough: a primer on the analysis and interpretation of noninferiority trials.
Active-control noninferiority trials are being performed with increasing frequency when standard placebo-controlled trials are considered unethical. Three attributes are optimally required to establish noninferiority: 1) The treatment under consideration exhibits therapeutic noninferiority to the active control; 2) the treatment would exhibit therapeutic efficacy in a placebo-controlled trial if such a trial were to be performed; and 3) the treatment offers ancillary advantages in safety, tolerability, cost, or convenience. Trials designed to show noninferiority require an appropriate reference population, a proven active control and dose, a high level of adherence to treatment, and adequate statistical power. However, the formal analysis of such trials is founded on several assumptions that cannot be validated explicitly. These assumptions are evaluated in the context of 8 recently published noninferiority trials. The analyses in this paper confirm the establishment of noninferiority in only 4 of the 8 trials. The authors conclude that if noninferiority trials are to be applied to clinical and regulatory decisions about the marketing and use of new treatments, these assumptions must be made explicit and their influence on the resultant conclusions assessed rigorously.