Substituent Effect Transmission Power of Alkyl, Alkenyl, Alkynyl, Phenyl, Thiophenyl, and Polyacene Spacers.
The transmission of substituent effect through a variety of spacers, that is to say, alkyl, alkenyl, alkynyl, phenyl, thiophenyl, and polyacene has been studied by modeling Y-G-X type molecular systems (Y: reaction center; G: spacer moiety; X: substituent) using B3LYP/6-31G(d,p) density functional theory calculations. The reaction center is always kept as a C=C double bond and the molecular electrostatic potential (MESP) minimum (Vmin ) observed for this bond showed subtle variation with respect to the changes in the spacer unit and the nature of substituent. Strong linear correlations are observed between Hammett substituent constants (σI and σp ) and Vmin , which recommend the aptness of Vmin as an electronic descriptor to quantify the substituent effect. Since Vmin offers an alternative measure of substituent effect, the correlation between Vmin and σp has been used for assessing the transmission of substituent effect through a variety of spacer moieties. The highest transmission coefficient (γ) is always observed for smaller spacer length. Among all the spacers, alkenyl showed the highest and alkyl showed the lowest transmission power. The study recommends the use of short chains of C=C double, C≡C triple or a combination of both as spacers for the effective transmission of substituent effect to the reaction center.


Detection of the infant with congenital/early acquired hearing disability.
The age at identification and intervention in different samples of children with congenital/early acquired hearing disability is described. The prevalence of congenital/early acquired hearing disability was 1.3/1,000. Among hearing disabled children born 1970-1975 only 16% were identified at the age of one year, whereas among children born 1980-1985, 37% were identified at this age. Children at-risk are not identified earlier than children not-at-risk. In 50-60% the parents are the first to suspect their child's hearing disability, and it is emphasized that non-professional screening resources are present in the general population and should be taken into account. Better information to both professionals and non-professionals about high-risk criteria and about the signs of hearing disability in combination with easy access to a professional audiological unit could improve the early detection and intervention of hearing disabled children.


Properties of a modified cross-linked silicone for maxillofacial prostheses.
A dimethyl siloxane-triacetoxy terminated silane, Type A adhesive, can be modified with the base component of a medium grade polydimethyl siloxane with vinyl groups, MDX 4-4210, to produce more pliable maxillofacial prostheses. The mechanical properties of samples with various Type A adhesive/MDX 4-4210 ratios were determined. Addition of the MDX 4-4210 base decreased the hardness, modulus, and ultimate tensile strength, while the percentage elongation increased. The initial tear strength was relatively constant for the various ratios except for the 50/50 mix, where a 50% decrease was observed. The ability to obtain different mechanical properties by using various ratios of Type A adhesive and MDX 4-4210 could result in the production of maxillofacial prostheses which will more closely stimulate the properties of facial tissues.


Putative receptor binding sites on alphaviruses as visualized by cryoelectron microscopy.
The structures of Sindbis virus and Ross River virus complexed with Fab fragments from monoclonal antibodies have been determined from cryoelectron micrographs. Both antibodies chosen for this study bind to regions of the virions that have been implicated in cell-receptor recognition and recognize epitopes on the E2 glycoprotein. The two structures show that the Fab fragments bind to the outermost tip of the trimeric envelope spike protein. Hence, the same region of both the Sindbis virus and Ross River virus envelope spike is composed of E2 and is involved in recognition of the cellular receptor.


The association between caregiver burden and sleep disturbances in partners of patients with Parkinson's disease.
Caregivers of patients with various diseases frequently report sleep disturbances and depressive symptoms. Care intensity for individuals with Parkinson's disease is mainly influenced by the severity of their motor impairment. The latter is associated with sleep fragmentation, nocturnal pain and cramps. These disease-specific characteristics contribute to sleep-related problems in patients. However, little is known about prevalence and causes of sleep disturbances in caregivers of Parkinson's disease patients. Cross-sectional analysis, nested within the FAQT-Study, a prospective German cohort study evaluating determinants of quality of life in Parkinson's disease patients. We assessed 106 Parkinson's disease patients and their caregiving partners. Patients and partners were asked to fill in the Center for Epidemiologic Studies Depression Scale, the caregiver burden inventory, and the Giessener Beschwerdebogen of psychosomatic complaints. All instruments include questions about sleep related problems. Patients were examined by neurologists and classified according to established scales (UPDRS and Hoehn and Yahr scales). Frequent sleep disturbances were reported by 27% of all spouses. Relevant depressive symptoms were shown in 30% of spouses and 45% of Parkinson's disease patients (P<0.001). Depression scores in partners correlated with those in patients. Self-perceived bad night-time sleep in spouses was related to symptom severity, male gender, bad sleep in patients, and to the frequency of caregiving. Caregiver burden was identified as a mediator of the association between care intensity and bad sleep, while psychosomatic complaints were related to sleep problems independently. Sleep disturbances are prevalent in partners of Parkinson's disease patients and influenced by their engagement in the caregiving process. Treatment optimization for motor symptoms in patients may not only contribute to improved patient sleep but also to a lower prevalence of sleep disturbances in caregivers.


[Pancreatic enzyme activity in early phases of acute experimental pancreatitis in rats].
Experiments were performed on laboratory rats with acute pancreatitis caused by local freezing the pancreas with chlorethyl. An active action of enzymes alpha-amilase, lipase, phospholipase A2, was revealed. During the first hours, an increase in action of all three enzymes, particularly that of phospholipase A2, was found. It was established that the lipid spectrum of pancreas had changed. It shows that cell membranes were destroyed. Experiments revealed an activating role of Ca2+ ions for all the enzymes and a correcting action of chlorpromasine.


Pleural mesothelial sequestration of iron in the rat.
Examination of morphology and iron deposition in pulmonary tissue from rats loaded with parenteral iron demonstrated a significant increase (compared to controls) of iron in pleural lining cells. No significant differences were noted in iron deposition in macrophages or in lung parenchyma. These results suggest that the pleural surface may represent an unrecognized target tissue in hemochromatosis.


Selective palladium(ii)-mediated oxidation of homoallylic N-tert-butanesulfinyl amine derivatives.
The palladium(ii)-catalyzed oxidation of homoallylic amine derivatives resulting from the allylation of N-tert-butanesulfinyl imines with allyl bromide led to the formation of the corresponding terminal allylic acetates in a regioselective fashion in moderate yields. In the case of the homoallylic amine derivatives obtained using cyclohexenyl bromide as the allylating reagent, the allylic oxidation took place with high regio- and diastereoselectivity and yields ranging from 40 to 85%.


LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions.
LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%-26% lower than expected from Hardy-Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism. LAY SUMMARY: LRFN5 is involved with communication between brain cells. The gene sits alone in a huge genomic niche, called the LRFN5 locus, of complex structure and high mammalian conservation. We have found that a specific locus structure increases autism susceptibility in males, but we do not yet know how common this epigenetic cause of autism is. It is, however, a cause that potentially could explain why higher-functioning autism is more common in males than females.


Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 2002: a report of the Australian Mycobacterium Reference Laboratory Network.
The Australian Mycobacterium Reference Laboratory Network collected and analysed laboratory data on new cases of disease caused by Mycobacterium tuberculosis complex in the year 2002. A total of 712 cases were identified by bacteriology, representing an annual reporting rate of 3.6 cases of laboratory-confirmed tuberculosis per 100,000 population. The most commonly encountered culture-positive specimens were sputum (n=325), lymph node (n=142) and bronchoscopy (n=100). Smears containing acid fast bacilli were present in sputum (53.2%), bronchoscopy (37.9%) and lymph node (21.2%). Eight children (male n=3, female n=5) under 10 years of age had bacteriologically-confirmed tuberculosis. A total of 55 isolates (7.7%) of M. tuberculosis were resistant to at least one of the standard anti-tuberculosis agents. Resistance to at least isoniazid and/or rifampicin was noted for 53 isolates (7.4%), with multidrug-resistance (MDRTB) observed in 12 (1.9%) isolates. Of the 12 MDRTB isolates, eight were from the respiratory tract and five were from smear positive specimens. Of the patients with drug resistant M. tuberculosis isolates, 51/55 (92.7%) were classified as having initial resistance, none had acquired resistance during treatment in Australia. The country of birth was known for 54 of 55 such patients; four were Australian-born, and 50 (90.9%) had migrated from a total of 17 countries. Nucleic acid amplification testing (NAAT) was performed on 139 (19.5%) of the 712 culture-positive specimens. Of smear positive respiratory specimens, 74/80 (92.5%) were NAAT positive. For smear negative respiratory specimens, 12/17 (70.6%) reported a NAAT positive result. Importantly, false-negative NAAT results were obtained from 1/16 and 5/64 of smear positive bronchoscopy and sputum specimens respectively.


Chlorotoxin-A Multimodal Imaging Platform for Targeting Glioma Tumors.
Chlorotoxin (CTX) is a 36-amino-acid disulfide-containing peptide derived from the venom of the scorpion Leiurus quinquestriatus. CTX alters physiology in numerous ways. It interacts with voltage gated chloride channels, Annexin-2, and matrix metalloproteinase-2 (MMP-2). CTX-based bioconjugates have been widely subjected to phase I/II clinical trials and have shown substantial promise. Many studies have demonstrated that CTX preferentially binds to neuroectodermal tumors, such as glioblastoma, without cross-reactivity to normal brain cells. With its ability to penetrate the blood-brain-barrier (BBB) and its tyrosine residue allows covalent conjugation with functional moieties, CTX is an attractive platform to explore development of diagnostic and therapeutic agents for gliomas. In this review, we outline CTX structure and its molecular targets, summarize molecular variations of CTX developed for glioma imaging, and discuss future trends and perspectives for CTX conjugates as a theranostic agent.


[Scanning electron microscopy of blood monocytes after long-term effects of ethanol].
The surface architectonics of the blood monocytes from noninbred female rats after permanent oral administration of ethanol within 2, 5 and 10 months at concentration of 100 mg/l was studied. The earliest monocyte's reaction to ethanol exposure was the intensification of their interaction with lymphocytes. Cyclic changes in adhesive activity of monocytes from these rats were found, while the unfavourable alterations of cell surface structure increased with the amplifying of ethanol effect.


[Postural activity--especially awaking from REM sleep].
The author previously examined functions of equilibrium of subjects using the statograph which records a movement of the center of gravity in a two dimensional trajectory. Results indicated that area enveloped by the trajectory and the total length of trajectory increased when subjects were awakened from NREM sleep. The analysis of frequency of the trajectory describing the body sway, which was performed using a signal processor connected to the statograph, showed that the high frequency components of the trajectory also increased. The author had often observed that some subjects exhibited rhythmic body sway immediately after awakened from stage-REM. The present report focuses the description of the rhythmic phenomena. The subjects were nine healthy male volunteers with a mean age of 20 years. They were awakened by a buzzer at stages of rest, stage-4, stage-REM and stage-2, and were made to stand on the platform of the statograph for 60 seconds, with their eyes closing and their soles of feet opening at the angle of 30 degrees. Then, their body sway were recorded. Anterior-posterior and lateral components of their trajectories were simultaneously examined by analyzing the trajectory by means of Fast Fourier Transformation method equipped in the signal processor. The total length of the trajectory of body sway in nine cases awakened from respective stages were: rest (control), 690 +/- 133; stage-4, 1311 +/- 220; stage-REM, 911 +/- 188; and stage-2, 863 +/- 212 mm (mean +/- SD). Power spectrum of the frequency of the trajectory was obtained with respect to the resolution of 0.0195 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)


Plasmonic nanoshell synthesis in microfluidic composite foams.
The availability of robust, scalable, and automated nanoparticle manufacturing processes is crucial for the viability of emerging nanotechnologies. Metallic nanoparticles of diverse shape and composition are commonly manufactured by solution-phase colloidal chemistry methods, where rapid reaction kinetics and physical processes such as mixing are inextricably coupled, and scale-up often poses insurmountable problems. Here we present the first continuous flow process to synthesize thin gold "nanoshells" and "nanoislands" on colloidal silica surfaces, which are nanoparticle motifs of considerable interest in plasmonics-based applications. We assemble an ordered, flowing composite foam lattice in a simple microfluidic device, where the lattice cells are alternately aqueous drops containing reagents for nanoparticle synthesis or gas bubbles. Microfluidic foam generation enables precisely controlled reagent dispensing and mixing, and the ordered foam structure facilitates compartmentalized nanoparticle growth. This is a general method for aqueous colloidal synthesis, enabling continuous, inherently digital, scalable, and automated production processes for plasmonic nanomaterials.


Repeatability of Scheimpflug based corneal tomography parameters in advanced keratoconus with thin corneas.
To determine the repeatability limits of corneal tomography parameters in patients with advanced and moderately thin keratoconic corneas to assist in planning thickness-based procedural interventions. Prospective, single-centre, repeatability study. Three tomography scans using the Pentacam AXL were obtained from patients with keratoconus with thinnest corneal thickness (TCT) ≦400 µm (sub-400 group) and compared to those with TCT = 450-500 µm (450-plus group). Eyes with previous crosslinking, intraocular surgery, or acute corneal hydrops were excluded. Eyes were age and gender-matched. The within-subject standard deviations for flat keratometry (K1), steep keratometry (K2), maximal keratometry (Kmax), astigmatism and TCT were used to calculate respective repeatability limits (r). Intra-class correlation coefficients (ICC) were also analysed. The sub-400 group comprised 114 eyes from 114 participants, and the 450-plus group comprised 114 eyes from 114 participants. In the sub-400 group, TCT was amongst the least repeatable parameters (33.92 µm; ICC 0.96), compared with the 450-plus group (14.32 µm; ICC 0.99, p < 0.01). In the sub-400 group, K1 and K2 of the anterior surface were the most repeatable parameters (r 3.79 and 3.22 respectively; ICC 0.97 and 0.98 respectively) compared with the 450-plus group (r 1.17 and 0.92 respectively; and ICC 0.98 and 0.99 respectively, p < 0.01). The repeatability of corneal tomography measurements is significantly reduced in sub-400 keratoconic corneas when compared to 450-plus corneas. Repeatability limits should be carefully considered when surgical interventions are planned for such patients.


TGF-β Effects on Prostate Cancer Cell Migration and Invasion Require FosB.
Activator Protein-1 (AP-1) family (cJun, JunB, JunD, cFos, FosB, Fra1, and Fra2) plays a central role in the transcriptional regulation of many genes that are associated with cell proliferation, differentiation, migration, metastasis, and survival. Many oncogenic signaling pathways converge at the AP-1 transcription complex. Transforming growth factor beta (TGF-β) is a multifunctional regulatory cytokine that regulates many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. This study investigated, the role of FOS proteins in TGF-β signaling in prostate cancer cell proliferation, migration, and invasion. Steady state expression levels of FOS mRNA and proteins were determined using RT-PCR and western blotting analyses. DU145 and PC3 prostate cancer cells were exposed to TGF-β1 at varying time and dosage, RT-PCR, western blot, and immunofluorescence analyses were used to determine TGF-β1 effect on FOS mRNA and protein expression levels as well as FosB subcellular localization. Transient silencing of FosB protein was used to determine its role in cell proliferation, migration, and invasion. Our data show that FOS mRNA and proteins were differentially expressed in human prostate epithelial (RWPE-1) and prostate cancer cell lines (LNCaP, DU145, and PC3). TGF-β1 induced the expression of FosB at both the mRNA and protein levels in DU145 and PC3 cells, whereas cFos and Fra1 were unaffected. Immunofluorescence analysis showed an increase in the accumulation of FosB protein in the nucleus of PC3 cells after treatment with exogenous TGF-β1. Selective knockdown of endogenous FosB by specific siRNA did not have any effect on cell proliferation in PC3 and DU145 cells. However, basal and TGF-β1- and EGF-induced cell migration was significantly reduced in DU145 and PC3 cells lacking endogenous FosB. TGF-β1- and EGF-induced cell invasion were also significantly decreased after FosB knockdown in PC3 cells. Our data suggest that FosB is required for migration and invasion in prostate cancer cells. We also conclude that TGF-β1 effect on prostate cancer cell migration and invasion may be mediated through the induction of FosB. Prostate 77:72-81, 2017. © 2016 Wiley Periodicals, Inc.


Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A.
(R)-Trichostatin A (TSA) is a Streptomyces product which causes the induction of Friend cell differentiation and specific inhibition of the cell cycle of normal rat fibroblasts in the G1 and G2 phases at the very low concentrations. We found that TSA caused an accumulation of acetylated histone species in a variety of mammalian cell lines. Pulse-labeling experiments indicated that TSA markedly prolonged the in vivo half-life of the labile acetyl groups on histones in mouse mammary gland tumor cells, FM3A. The partially purified histone deacetylase from wild-type FM3A cells was effectively inhibited by TSA in a noncompetitive manner with Ki = 3.4 nM. A newly isolated mutant cell line of FM3A resistant to TSA did not show the accumulation of the acetylated histones in the presence of a higher concentration of TSA. The histone deacetylase preparation from the mutant showed decreased sensitivity to TSA (Ki = 31 nM, noncompetitive). These results clearly indicate that TSA is a potent and specific inhibitor of the histone deacetylase and that the in vivo effect of TSA on cell proliferation and differentiation can be attributed to the inhibition of the enzyme.


Extracardiac 'hot' and 'cold' areas on thallium-201 myocardial SPECT imaging.
A 72-year-old man underwent Persantine 201Tl myocardial SPECT imaging that showed a transient area of extracardiac radiotracer accumulation inferior to the inferior wall of the left cardiac ventricle, and a persistent, rounded, cold area in the liver. CT of the abdomen confirmed a cystic lesion in the liver corresponding to the cold area, and the transient extracardiac tracer accumulation area corresponded to a large aneurysm of the distal descending thoracic aorta. An extracardiac abnormal area of 201Tl localization, 'hot' or 'cold', should be included for scan interpretation to depict thoracic and/or upper abdominal lesions(s).


New wearable walking-type continuous passive motion device for postsurgery walking rehabilitation.
While total knee arthroplasty is useful for treating osteoarthritis of the knee, the success of this treatment depends on effective rehabilitation. The goal of this study was to develop an assistive device for post-total knee arthroplasty patients for walking rehabilitation and for shortening the hospitalization period. We developed a brace electronic assist system termed the knee assistive instrument for walking rehabilitation (KAI-R) to illustrate the need for training during postoperative rehabilitation. Sixteen osteoarthritis patients (1 male and 15 females; average age 68.9 years) who underwent total knee arthroplasty were analyzed before operation and 2-4 weeks after operation, and 25 healthy individuals (14 males and 11 females; average age 26.2 years) formed the control group. Based on the pre- and postoperative data on peak knee flexion angle, foot height, and walking velocity, we developed the KAI-R, which consists of an assistive mechanism for the knee joint, a hip joint support system, and a foot pressure sensor system and is driven by a CPU board that generates the walking pattern. We then tested the walking gait in seven healthy volunteers with and without KAI-R assistance. KAI-R increased the peak flexion angle of the knee and foot height in all seven volunteers; their range of motion of the knee joint was increased. However, KAI-R also decreased the walking velocity of subjects, which was explained by reaction delay and slightly compromised physical balance, which was caused by wearing the KAI-R. KAI-R is useful for gait improvement. In future studies, KAI-R will be investigated in a clinical trial for its ability for walking rehabilitation in post-total knee arthroplasty patients.


The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling.
Our previous work showed that loss of the KIAA2022 gene protein results in intellectual disability with language impairment and autistic behavior (KIDLIA, also referred to as XPN). However, the cellular and molecular alterations resulting from a loss of function of KIDLIA and its role in autism with severe intellectual disability remain unknown. Here, we show that KIDLIA plays a key role in neuron migration and morphogenesis. We found that KIDLIA is distributed exclusively in the nucleus. In the developing rat brain, it is expressed only in the cortical plate and subplate region but not in the intermediate or ventricular zone. Using in utero electroporation, we found that short hairpin RNA (shRNA)-mediated knockdown of KIDLIA leads to altered neuron migration and a reduction in dendritic growth and disorganized apical dendrite projections in layer II/III mouse cortical neurons. Consistent with this, in cultured rat neurons, a loss of KIDLIA expression also leads to suppression of dendritic growth and branching. At the molecular level, we found that KIDLIA suppression leads to an increase in cell-surface N-cadherin and an elevated association of N-cadherin with δ-catenin, resulting in depletion of free δ-catenin in the cytosolic compartment. The reduced availability of cytosolic δ-catenin leads to elevated RhoA activity and reduced actin dynamics at the dendritic growth cone. Furthermore, in neurons with KIDLIA knockdown, overexpression of δ-catenin or inhibition of RhoA rescues actin dynamics, dendritic growth, and branching. These findings provide the first evidence on the role of the novel protein KIDLIA in neurodevelopment and autism with severe intellectual disability.


Decreased monocarboxylate transporter 1 in rat soleus and EDL muscles exposed to clenbuterol.
We hypothesized that a shift in muscle fiber type induced by clenbuterol would change monocarboxylate transporter 1 (MCT1) content and activity of lactate dehydrogenase (LDH) and isoform pattern and shift myosin heavy chain (MHC) pattern in soleus (Sol) and extensor digitorum longus (EDL) of male rats. In the clenbuterol-administered rats (2.0 mg x kg(-1) x day(-1) subcutaneously for 4 wk), the ratio of muscle weight to body weight increased in the Sol (P < 0.05) and the EDL (P < 0.01). Clenbuterol induced the appearance of fast MHC(2D) and decreased slow MHC(1) in Sol (13%) but had no effect on EDL. The MHC pattern of Sol changed from slow to fast type. Clenbuterol increased LDH-specific activity (P < 0.01) and the ratio of the muscle-type isozyme of LDH to the heart type (P < 0.05) in Sol. The LDH total activity of the EDL muscle was also increased (P < 0.05). Furthermore, MCT1 content significantly (P < 0.05) decreased in both Sol and EDL (27 and 52%, respectively). This study suggests that clenbuterol might mediate the shift of MHC from slow to fast type and the changes in the regulation of lactate metabolism. Novel to this study is the observation that clenbuterol decreases MCT1 content in the hindlimb muscles and that the decrease in MCT1 is not muscle-type specific. It may suggest that the genetic expressions of individual factors involving slow-type MHC, heart-type isozyme of LDH, and MCT1 are associated with one another but are regulated independently.


Improving biocatalyst performance by integrating statistical methods into protein engineering.
Directed evolution and rational design were used to generate active variants of toluene-4-monooxygenase (T4MO) on 2-phenylethanol (PEA), with the aim of producing hydroxytyrosol, a potent antioxidant. Due to the complexity of the enzymatic system-four proteins encoded by six genes-mutagenesis is labor-intensive and time-consuming. Therefore, the statistical model of Nov and Wein (J. Comput. Biol. 12:247-282) was used to reduce the number of variants produced and evaluated in a lab. From an initial data set of 24 variants, with mutations at nine positions, seven double or triple mutants were identified through statistical analysis. The average activity of these mutants was 4.6-fold higher than the average activity of the initial data set. In an attempt to further improve the enzyme activity to obtain PEA hydroxylation, a second round of statistical analysis was performed. Nine variants were considered, with 3, 4, and 5 point mutations. The average activity of the variants obtained in the second statistical round was 1.6-fold higher than in the first round and 7.3-fold higher than that of the initial data set. The best variant discovered, TmoA I100A E214G D285Q, exhibited an initial oxidation rate of 4.4 ± 0.3 nmol/min/mg protein, which is 190-fold higher than the rate obtained by the wild type. This rate was also 2.6-fold higher than the activity of the wild type on the natural substrate toluene. By considering only 16 preselected mutants (out of ∼13,000 possible combinations), a highly active variant was discovered with minimum time and effort.


Transforming growth factor-β1-induced epithelial to mesenchymal transition increases mitochondrial content in the A549 non-small cell lung cancer cell line.
The mitochondrial genome DNA copy number is critical for the functional maintenance of the mitochondria and energy acquisition for cell metabolism. Epithelial to mesenchymal transition (EMT) is an important process during embryonic development and has also been hypothesized to exhibit a significant role in cancer cell invasion and metastasis. In the present study, EMT was induced in the A549 non-small cell lung cancer (NSCLC) cell line, using transforming growth factor-β1 (TGF-β1) and changes in mitochondrial content, mitochondrial DNA (mtDNA) copy number and protein cytochrome c (Cyt c) were determined by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. mtDNA copy number and Cyt c protein levels were observed to increase following the induction of EMT in NSCLC cells. Results of the current study indicate that energy metabolism is adapted to facilitate EMT in NSCLC cells.


Big Brain Data Initiative in Universiti Sains Malaysia: Challenges in Brain Mapping for Malaysia.
Universiti Sains Malaysia has started the Big Brain Data Initiative project since the last two years as brain mapping techniques have proven to be important in understanding the molecular, cellular and functional mechanisms of the brain. This Big Brain Data Initiative can be a platform for neurophysicians and neurosurgeons, psychiatrists, psychologists, cognitive neuroscientists, neurotechnologists and other researchers to improve brain mapping techniques. Data collection from a cohort of multiracial population in Malaysia is important for present and future research and finding cure for neurological and mental illness. Malaysia is one of the participant of the Global Brain Consortium (GBC) supported by the World Health Organization. This project is a part of its contribution via the third GBC goal which is influencing the policy process within and between high-income countries and low- and middle-income countries, such as pathways for fair data-sharing of multi-modal imaging data, starting with electroencephalographic data.


The influence of N-acetylcysteine on cardiac function and rhythm disorders during ischemia and reperfusion.
To assess the ability of N-acetylcysteine to reduce the vulnerability of the heart to arrhythmias and improve its mechanical function during ischemia and reperfusion, groups of Langendorff-perfused rat hearts (15 per group) were subjected to 20 minutes of aerobic perfusion, 10 minutes of regional ischemia and 10 minutes of reperfusion. The hearts were perfused with N-acetylcysteine throughout the study. The incidences of ventricular premature beats and ventricular tachycardia induced by ischemia fell from 93% and 67%, in the N-acetylcysteine-free control group, to 40% and 27% with 8 microM N-acetylcysteine, to 33% and 27% with 80 microM N-acetylcysteine, and to 40% and 13% with 2000 microM N-acetylcysteine. The incidence of ventricular fibrillation induced by reperfusion was reduced from 93% to 60%, 67% and 47%, respectively. N-acetylcysteine had no significant effect upon the coronary flow and heart rate. When the ischemic period was prolonged to 30 minutes, N-acetylcysteine (8 microM) was shown to delay the time of onset of arrhythmias during ischemia and reperfusion. Thus, the incidences of ventricular premature beats and ventricular tachycardia were greatest after 15 minutes of ischemia in controls but were maximal after 18 minutes in hearts treated with N-acetylcysteine. N-acetylcysteine (8 microM) also improved the recovery of mechanical function after ischemia both in Langendorff preparations and in working preparations. In the working heart the post-ischemic recovery of aortic flow, coronary flow, cardiac output and aortic developed pressure after ischemia was improved from their control values of 30 +/- 5%, 82 +/- 2%, 43 +/- 2% and 63 +/- 4% to 59 +/- 7%, 98 +/- 5%, 71 +/- 3% and 80 +/- 6% respectively. Our results support the concept that agents which can alter redox state may exert protective effects against myocardial injury during both ischemia and reperfusion.


The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a haematological stress syndrome.
Systemic sclerosis (SSc) is a disease characterized by progressive microvascular occlusion and fibrosis resulting in irreversible organ damage, the pathogenesis of which is felt to be of vascular origin. To gain a comprehensive view of the coagulation/fibrinolytic balance in SSc, a number of haemostatic and fibrinolytic variables were measured in 26 SSc patients (11 limited, 15 diffuse) and in 22 control subjects. Of the coagulation activation markers, the mean plasma level of prothrombin fragment 1 + 2 (F1 + 2), but not of thrombin-antithrombin complexes (TAT), was higher in SSc patients than in controls (P < 0.001). Plasma levels of fibrin split product D-dimer (DD), fibrinogen (FNG) and von Willebrand factor (vWF) were higher amongst patients than controls (P < 0.001). vWF and FNG levels were positively correlated (P < 0.001). Mean levels of DD and vWF were more elevated in patients with diffuse than limited disease (P = 0.001 and P = 0.04, respectively). On the fibrinolytic side, defective tissue plasminogen activator (tPA) release (venous occlusion test, stimulated level < basal level) was noted in 46% (12/26) of SSc patients, but only in 4% (1/22) of controls. Patients had higher mean levels of tPA inhibitor (PAI) than controls (P < 0.001), levels being more elevated amongst patients with diffuse than limited disease (P = 0.01). An abnormally high lipoprotein (a) [Lp(a)] level was found in 9% (2/20) of control subjects, but in 30% (8/26) of SSc patients (P = 0.04) where it clustered with fibrinolytic defects. Altogether, these data suggest that patients with SSc are in a hypercoagulable state characterized by elevated plasma levels of FNG and vWF, by a dual hypofibrinolytic pattern (defective tPA release and elevated PAI), and by increased thrombin generation with enhanced fibrin formation. Higher levels of vWF, DD and PAI in patients with diffuse disease are consistent with more extensive (micro)vascular involvement, although no causal relationship can be inferred. The lack of a parallel increase of TAT with F1 + 2, in the presence of normal levels of antithrombin III (ATIII), indirectly suggests an impairment of the heparan sulphate-ATIII system which would favour thrombin generation. Since thrombin may act as a mitogen for fibroblasts, may upregulate vWF, PAI and endothelin production by endothelial cells, and may promote fibrin deposition on the vessel wall leading to worsening of microvascular occlusions, limitation of thrombin generation, besides fibrinolytic enhancement, could represent a possible coadjuvant interventional strategy.


Heat-induced drug resistance is associated with increased expression of Bcl-2 in HL60.
HL60 cells underwent apoptosis with heat treatment, i.e. exposure to 42 degrees C for 120 minutes. Cells exposed to the same temperature for 30 minutes became resistant to subsequent, otherwise lethal, heat shock. These thermotolerant cells also acquired resistance to anti-cancer drugs including daunorubicin and VP16. We found that mild heat shock upregulates not only HSP70 but also BCL-2, though BCL-2 has not previously been recognized as a heat-inducible protein. Expression of BCL-2 closely paralleled resistance to subsequent exposure to anticancer drugs. The present results suggest that BCL-2 may play a role in heat-induced drug resistance.


Role of adipocyte lipid-binding protein (ALBP) and acyl-coA binding protein (ACBP) in PPAR-mediated transactivation.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by a number of fatty acids and fatty acid derivatives. By contrast, we have recently shown that acyl-CoA esters display PPAR antagonistic properties in vitro. We have also shown that the adipocyte lipid binding protein (ALBP), the keratinocyte lipid binding protein (KLBP) and the acyl-CoA binding protein (ACBP) exhibit a prominent nuclear localization in differentiating 3T3-L1 adipocytes. Similarly, ectopic expression of these proteins in CV-1 cells resulted in a primarily nuclear localization. We therefore speculated that FABPs and ACBP might regulate the availability of PPAR agonists and antagonists by affecting not only their esterification in the cytoplasm but also their transport to and availability in the nucleus. We show here that coexpression of ALBP or ACBP exerts a negative effect on ligand-dependent PPAR transactivation, when tetradecylthioacetic (TTA) is used as ligand but not when the thiazolidinedione BRL49653 is used as ligand. The results presented here do not support the hypothesis that ALBP facilitates the transport of the fatty acid-type ligands to the nucleus, rather ALBP appears to sequester or increase the turn-over of the agonist. Similarly, our results are in keeping with a model in which ACBP increase the metabolism of these ligands.


The mouse Thy-1.2 glycoprotein gene: complete sequence and identification of an unusual promoter.
Recombinant bacteriophage and cosmid clones containing the gene for the mouse Thy-1.2 glycoprotein were isolated and characterized. The complete sequence of the gene was determined, including a previously unidentified exon located 2.1 kb upstream of the portion of the gene encoding the Thy-1.2 glycoprotein. The transcriptional initiation site was located by S1 nuclease protection mapping in both T lymphocytes and neural cells and was found to be located immediately upstream of this exon. S1 nuclease protection mapping was also used to define the 3' end of the Thy-1.2 transcription unit, and no evidence for alternate mRNA processing was found. Thus, the mouse Thy-1.2 gene is 5447 base pairs in length, including promoter sequences, rather than 2094 as previously described. The mouse and rat Thy-1 genes are highly homologous in both introns and exons. However, the mouse Thy-1 cDNA and rat Thy-1 cDNA differ significantly in sequence in the 5' untranslated region. This suggests that the transcriptional initiation site of the mouse and rat genes may be located at different positions within the genomic sequence and may be related to the differing tissue distribution of Thy-1 in the two species.


[Treatment with electric stimulation].
The author presents various electrostimulation techniques that have been applied with good results for triggering and stimulation of parturition, preventing secondary adynamia of pharmacologic analgesia at birth, for analgesia and sedation during childbirth, for the treatment of hypertensive dysgravida, for postoperative analgesia, and the prophylaxis of dynamic ileus, for the treatment of postoperative dynamic ileus and for the therapy of chronic pain. The electrostimulation technique is applied with several devices that deliver pulse currents of various form with a frequency between 1 and 250 Hz and intensities between 1 and 40 mA, through 2, 3 or 4 transcutaneous electrodes. The electrostimulation techniques can be applied as current therapeutical methods, or can be used as reserve therapy in various specialties. They are economical, easy to perform, and protect the patient against toxic, allergic, and genetic side effects of pharmacologic therapy.


Characterisation of a glycine to valine substitution at amino acid position 910 of the triple helical region of type III collagen in a patient with Ehlers-Danlos syndrome type IV.
We have studied a patient with Ehlers-Danlos syndrome type IV. Protein mapping studies of her type III collagen had indicated that cyanogen bromide fragment 9 contained the site of the mutation. Here we describe the mapping of this region for a single base mutation using a chemical modification and cleavage technique. Sequence analysis of cDNA showed a G to T mutation resulting in the substitution of glycine 910 by valine. This was confirmed by allele specific oligonucleotide hybridisation to the proband's genomic DNA.


Reactivity of the NS2/3(907-1206)ASK(4) protein with beta-mercaptoethanol studied by electrospray ion trap mass spectrometry.
The present work reports a mass spectrometric investigation of the NS2/3 protein, a protease from hepatitis C virus (HCV). During routine protein manipulation, in the presence of 100 mM beta-mercaptoethanol and under denatured conditions, the protein was unexpectedly modified at its cysteine residues, and the increased molecular weight corresponded to one molecule of beta-mercaptoethanol bound. The modified protein, once refolded, was found to be less active than the unmodified one. The aim of this work was to investigate whether the reactivity of cysteines with beta-mercaptoethanol involves one specific, highly reactive residue of the sequence, or if the modification is a random process. Liquid chromatography (LC) coupled on-line with an electrospray ion trap mass spectrometer was used to identify the modification sites. It was found that five cysteines out of nine had reacted with beta-mercaptoethanol, none of them showing a significantly higher reactivity than the others. 95% of sequence coverage was obtained.


Medically unexplained symptoms: how often and why are they missed?
We assessed risk factors affecting the provisional diagnosis of medically unexplained symptoms made by physicians in new patients, in 526 clinical encounters. Comparisons were made between the doctor's initial assessments regarding the nature of symptoms, and the final diagnosis. Physicians were more likely to err on the side of diagnosing the symptoms as medically explained rather than unexplained. When physicians perceived the interaction with the patient to be positive, they were more likely to make a provisional diagnosis that the symptoms were explained. Conversely, a negative perception of the interaction was associated with an increased likelihood of viewing symptoms as medically unexplained. Physicians should be aware of the effect of their own perceptions on their diagnostic behaviour.


Equivalence theorem for light waves on scattering from particulate media.
The equivalence theorem of light waves on scattering from a collection of particles is discussed. It is shown that when light waves are scattered from two different particulate media, the spectral density or the spectral degree of coherence may present identical distribution, provided that some relationship between the two particulate media is satisfied. An example of light waves on scattering from a collection of particles with random distribution is discussed, and the conditions for producing identical normalized spectral density and that for producing identical spectral degree of coherence are investigated. This phenomenon is illustrated with some numerical results.


Chemotherapy in the Intensive Care Unit: An Evaluation of Context and Outcomes.
Administration of chemotherapy to highly vulnerable, critically ill patients in the intensive care unit (ICU) is becoming more common, but the process requires significantly more resources than chemotherapy administration in specialized oncology settings. To describe the context, complications, and outcomes of chemotherapy administration for cancer-related indications in ICU patients. For this retrospective observational study, consecutive patients receiving parenteral chemotherapy in the ICU at the General Campus of The Ottawa Hospital between January 1, 2014, and December 31, 2017, were identified using pharmacy records. The clinical characteristics of these patients, details of their chemotherapy regimens, and outcomes were analyzed. A total of 32 patients were included in the study. Of these, 27 patients (84%) had a hematological malignancy, 16 (50%) had a documented infection at the time of chemotherapy administration, and 29 (91%) received their first cycle of chemotherapy on an urgent basis during the ICU admission rather than as a scheduled or planned treatment. Severity of illness was high both at ICU admission and at the time of chemotherapy treatment; regimen modifications, drug interactions, and adverse events were common. Remission and survival data were available for 28 patients at 12 months. Eighteen (56%) of the 32 patients survived to hospital discharge, and 12 (38%) survived to 6 months; at 12 months, survival was 25% (7 of 28 patients with available data). About one-quarter of the patients were in remission at 6 and 12 months. Administering chemotherapy in the ICU is feasible, but the process is resource-intensive. Patients with aggressive hematological cancers who require treatment on an urgent basis represent the most commonly observed scenario. This study highlights the complexity of management and the importance of multidisciplinary care teams for this patient population.


Novel Preparation Method for Nano-Sized Gold Particles by Using NH2-Terminated Polyethyleneoxide.
Nano-sized gold particles dispersed in a composite were prepared by using NH2-terminated polyethyleneoxide (PEO-NH2) as a matrix. Gold was vapor-deposited onto a melt of PEO-NH2. Gold was smoothly dispersed into the interior of PEO-NH2 to form nano-sized gold particles. After cooling the melt to room temperature, a stable solid composite was obtained. The composite readily dissolved in water or various kinds of organic solvents to produce a stable colloidal solution. The mean size of the gold particles was 3.4 nm, and the content of gold was ca. 5 wt%. Copyright 1999 Academic Press.


Full-length core sequence dependent complex-type glycosylation of hepatitis C virus E2 glycoprotein.
To study HCV polyprotein processing is important for the understanding of the natural history of HCV and the design of vaccines against HCV. The purpose of this study is to investigate the affection of context sequences on hepatitis C virus (HCV) E2 processing. HCV genes of different lengths were expressed and compared in vaccinia virus/T7 system with homologous patient serum S94 and mouse anti-serum M( E2116) raised against E.coli -derived E2 peptide, respectively. Deglycosylation analysis and GNA ( Galanthus nivalus ) lectin binding assay were performed to study the post-translational processing of the expressed products. E2 glycoproteins with different molecular weights (-75 kDa and -60 kDa) were detected using S94 and M( E2116), respectively. Deglycosylation analysis showed that this difference was mainly due to different glycosylation. Endo H resistance and its failure to bind to GNA lectin demonstrated that the higher molecular weight form (75 kDa) of E2 was complex-type glycosylated, which was readily recognized by homologous patient serum S94. Expression of complex-type glycosylated E2 could not be detected in all of the core-truncated constructs tested, but readily detected in constructs encoding full-length core sequences. The upstream conserved full-length core coding sequence was required for the production of E2 glycoproteins carrying complex-type N-glycans which reacted strongly with homologous patient serum and therefore possibly represented more mature forms of E2. As complex-type N-glycans indicated modification by Golgi enzymes, the results suggest that the presence of full-length core might be critical for E1/E2 complex to leave ER. Our data may contribute to a better understanding of the processing of HCV structural proteins as well as HCV morphogenesis.


Phloem mobility of xenobiotics: I. Mathematical model unifying the weak Acid and intermediate permeability theories.
A passive diffusion model has been developed which simultaneously accounts for the dependence of phloem mobility on permeability and acid dissociation. The model is consistent with the observation that the addition of an acid moiety to an otherwise phloem immobile compound may enhance that compound's ability to move in the phloem. However, acid trapping in the basic phloem is not the only enhancement factor. Acid functionalization also lowers the effective permeability usually towards its optimum value. The unified theory predicts that for a given acid dissociation constant there is an optimum permeability and conversely for a given permeability there is an optimum dissociation constant.


Dapsone activation of CYP2C9-mediated metabolism: evidence for activation of multiple substrates and a two-site model.
Dapsone activates CYP2C9-mediated metabolism in various expression systems and is itself metabolized by CYP2C9 to its hydroxylamine metabolite. Studies were conducted with expressed CYP2C9 to characterize the kinetic effects of dapsone (0-100 microM) on (S)-flurbiprofen (2-300 microM), (S)-naproxen (10-1800 microM), and piroxicam (5-900 microM) metabolism in 6 x 6 matrix design experiments. The influence of (S)-flurbiprofen on dapsone hydroxylamine formation was also studied. Dapsone increased the Michaelis-Menten-derived V(max) of flurbiprofen 4'-hydroxylation from 12.6 to 20.6 pmol/min/pmol P450, and lowered its K(m) from 28.9 to 10.0 microM, suggesting that dapsone activates CYP2C9-mediated flurbiprofen metabolism without displacing flurbiprofen from the active site, supporting a two-site model describing activation. Similar results were observed with piroxicam 5'-hydroxylation, as V(max) was increased from 0.08 to 0.20 pmol/min/pmol P450 and K(m) was decreased from 183 to 50 microM in the presence of dapsone. In addition, the kinetic profile for naproxen was converted from biphasic to hyperbolic in the presence of dapsone, while exhibiting similar decreases in K(m) and increases in V(max). Kinetic parameters were also estimated using the two-site binding equation, with alpha values <1 and beta values >1, indicative of activation. Additionally, dapsone hydroxylamine formation was measured from incubations containing flurbiprofen, exhibiting a kinetic profile that was minimally affected by the presence of flurbiprofen. Overall, these results suggest that dapsone activates the metabolism of multiple substrates of CYP2C9 by binding within the active site and causing positive cooperativity, thus lending further support to a two-site binding model of P450-mediated metabolism.


Digital holography for coherent fiber beam combining with a co-propagative scheme.
We present a technique for passive coherent fiber beam combining based on digital holography. In this method, the phase errors between the fibers are compensated by the diffracted phase-conjugated -1 order of a digital hologram. Unlike previous digital holography technique, the probe beams measuring the phase errors between the fibers are co-propagating with the phase-locked signal beams. This architecture is compatible with the use of multi-stage isolated amplifying fibers. It does not require any phase calculation algorithm and its correction is collective. This concept is experimentally demonstrated with three fibers at 1.55 μm. A residual phase error of λ/20 is measured.


Producing small scale temperature fluctuations in an airstream.
A 4.5-microm ''hot'' wire is used to heat a low-speed airstream at frequencies from dc to 400 Hz. For dc excitation the thermal noise spectrum produced was white to a frequency of 2 kHz. ac heating of the wire up to a frequency of 400 Hz (800 Hz thermal fluctuation of the airstream) yielded a good thermal signal as far as 2 cm from the hot wire. Calculation shows excellent heat transfer between the wire and airstream. The technique is very useful for calibrating the frequency response of temperature sensors and for investigating turbulent heat transfer for various flow configurations.


Avian paramyxovirus type 1 infection in houbara bustards (Chlamydotis undulata macqueenii): clinical and pathologic findings.
Clinical and pathologic findings of avian paramyxovirus type 1 (PMV-1) in 19 houbara bustards (Chlamydotis undulata macqueenii) imported from Pakistan into the United Arab Emirates and one captive-bred bird are reported. Clinical signs included circling, walking backward, ataxia, opisthotonos, torticollis, recumbency, head tilt, head shaking, head tremor, tucking of head under keel, nasal discharge, conjunctivitis, and diarrhea. The length of time imported birds exhibited clinical signs varied from 4 days to 18 mo after importation. Hemagglutinating antibodies against PMV-1 were detected in the sera of all 17 birds from which blood samples were collected, and PMV-1 was isolated from pooled brain, spleen, and lung tissues from two birds with acute clinical signs. There were no distinctive gross lesions at necropsy, and histologic findings were consistent with but not pathognomonic for PMV-1. All houbara bustards managed in a captive breeding and restoration program established by the National Avian Research Center have been vaccinated against PMV-1 since October 1992, and no case of PMV-1 has been reported in this collection since that time.


α-Diazo-β-ketonitriles: uniquely reactive substrates for arene and alkene cyclopropanation.
An investigation of the intramolecular cyclopropanation reactions of α-diazo-β-ketonitriles is reported. These studies reveal that α-diazo-β-ketonitriles exhibit unique reactivity in their ability to undergo arene cyclopropanation reactions; other similar acceptor-acceptor-substituted diazo substrates instead produce mixtures of C-H insertion and dimerization products. α-Diazo-β-ketonitriles also undergo highly efficient intramolecular cyclopropanation of tri- and tetrasubstituted alkenes. In addition, the α-cyano-α-ketocyclopropane products are demonstrated to serve as substrates for SN2, SN2', and aldehyde cycloaddition reactions.


Alternative splicing isoforms of synaptotagmin VII in the mouse, rat and human.
Synaptotagmin VII (Syt VII) has been proposed to regulate several different types of Ca2+-dependent exocytosis, but its subcellular localization (lysosome or plasma membrane) and the number of alternative splicing isoforms of Syt VII (single or multiple forms) are matters of controversy. In the present study, we show by reverse transcriptase-PCR analysis that mouse Syt VII has one major isoform (Syt VIIalpha), the original Syt VII, and two minor isoforms (Syt VIIbeta and Syt VIIgamma), which contain unique insertions (of 44 and 116 amino acids respectively) in the spacer domain between the transmembrane and C2 domains of Syt VIIalpha. Similar results were obtained with respect to rat and human Syt VII mRNA expression. An antibody against the N-terminal domain of mouse Syt VII [anti-(Syt VII-N)], which specifically recognized recombinant Syt VII but not other Syt isoforms expressed in COS-7 cells, recognized two major, closely co-migrating bands (p58 and p60) and minor bands of approx. 65 kDa in mouse brain. Immunoaffinity purification of proteins that bind the anti-(Syt VII-N) antibody, and peptide sequence analysis revealed that: (i) the major p58 and p60 bands are identified as adenylate cyclase-associated protein 2; (ii) actin-binding protein is localized at the plasma membrane; and (iii) Syt VIIalpha (65 kDa) is the major Syt VII isoform, but with a much lower expression level than previously thought. It was also shown that FLAG-Syt VII-green-fluorescence-protein fusion protein stably expressed in PC12 cells is localized in the perinuclear region (co-localization with TGN38 protein, even after brefeldin A treatment) and in the tips of neurites (co-localization with Syt I), and not in the plasma membrane.


Detraining-related changes in left ventricular wall thickness and longitudinal strain in a young athlete likely to have hypertrophic cardiomyopathy.
One of the diagnostic criteria in order to differentiate between physiological and pathological left ventricular hypertrophy is the wall thickness reduction after at least 3-month detraining period, which is considered a marker of the athlete's heart. This report describes detraining-related regression of LV hypertrophy and improvement in myocardial deformation in a junior athlete likely to have hypertrophic cardiomyopathy. Key pointsHypertrophic cardiomyopathy in adolescent athletes can be discovered by 12-lead ECGPhysical training is an important trigger for the clinical presentation of hypertrophic cardiomyopathyReverse LV remodeling (wall thickness reduction) with detraining is a common echocardiographic finding in athletes with physiological hypertrophyThis report demonstrates that reverse remodeling can also be found in adolescent athletes likely to have hypertrophic cardiomyopathy.


Long-term effects of supervised exercise training on walking capacity and quality of life in patients with intermittent claudication.
Supervised exercise training has been shown to improve walking capacity in several studies of patients with intermittent claudication. However, data on long-term outcome are quite limited. The aim of this prospective study was to evaluate long-term effects of supervised exercise training on walking capacity and quality of life in patients with intermittent claudication. Sixty-seven consecutive patients with intermittent claudication who completed a supervised 12-week exercise training program were asked for follow up evaluation 39 +/- 20 months after program completion. Pain-free walking distance (PWD) and maximum walking distances (MWD) were assessed by treadmill test and several questionnaires. Forty (60%) patients agreed to participate, 22 (33%) refused participation, and 5 (7%) died during follow-up. PWD and MWD significantly improved at completion of 12-weeks supervised exercise training as compared to baseline (PWD 114 +/- 100 vs. 235 +/- 248, p = 0.002; MWD 297 +/- 273 vs. 474 +/- 359, p = 0.001). Improvement of PWD and MWD could be maintained at follow up (197 +/- 254, p = 0.014; 390 +/- 324, p = 0.035, respectively) with non-smokers showing significantly better sustained PWD and MWD improvement as compared to baseline. Overall, walking capacity correlated with functional status of quality of life. Major findings of this investigation were that improvement in walking capacity is sustained after completion of supervised exercise training program with best results in patients who quitted or never smoked. Improved walking capacity is associated with increased functional status of quality of life.


The preliminary assessment of the Social Transition in the North dataset: a comparison of STN survey and enumeration data for selected Northwest Alaskan communities.
This study compared the results from STN survey data with a mailback health study of the same communities to assess the reliability of the STN data. STUDY DESIGN. Sample characteristics and respondes to health questions were compared through secondary data analysis. Data from the STN sample was compared to an enumeration study for the same or similar questions, including demographic characteristics and health status indicators, were compared. The STN study used the sample of 715 households in 18 Alaskan and Russian Far East communities to obtain data on the demographic transition, epidemiological transition and domestic transition of residents in northern communities. A study of the health and human service needs was conducted in Northwest Alaska using a mailback health questionnaire within a few years of the STN study. Both data sets appear to be taken from similar populations. Responses to health questions show marked similarities. The comparison strongly suggests that the STN data is representative of northern Alaska communities surveyed and can be a valuable source of reliable data on the health and welfare of northern communities. The data on the self-reported prevalence of health conditions may not be useful at the community level.


Wind-Driven Erosion and Exposure Potential at Mars 2020 Rover Candidate-Landing Sites.
Aeolian processes have likely been the predominant geomorphic agent for most of Mars' history and have the potential to produce relatively young exposure ages for geologic units. Thus, identifying local evidence for aeolian erosion is highly relevant to the selection of landing sites for future missions, such as the Mars 2020 Rover mission that aims to explore astrobiologically relevant ancient environments. Here we investigate wind-driven activity at eight Mars 2020 candidate-landing sites to constrain erosion potential at these locations. To demonstrate our methods, we found that contemporary dune-derived abrasion rates were in agreement with rover-derived exhumation rates at Gale crater and could be employed elsewhere. The Holden crater candidate site was interpreted to have low contemporary erosion rates, based on the presence of a thick sand coverage of static ripples. Active ripples at the Eberswalde and southwest Melas sites may account for local erosion and the dearth of small craters. Moderate-flux regional dunes near Mawrth Vallis were deemed unrepresentative of the candidate site, which is interpreted to currently be experiencing low levels of erosion. The Nili Fossae site displayed the most unambiguous evidence for local sand transport and erosion, likely yielding relatively young exposure ages. The downselected Jezero crater and northeast Syrtis sites had high-flux neighboring dunes and exhibited substantial evidence for sediment pathways across their ellipses. Both sites had relatively high estimated abrasion rates, which would yield young exposure ages. The downselected Columbia Hills site lacked evidence for sand movement, and contemporary local erosion rates are estimated to be relatively low.


In Vivo Efficacy, Toxicity Assessment, and Elemental Analysis of Traditionally Used Polyherbal Recipe for Diarrhea.
A polyherbal formulation consisting of Mentha piperita L., Camellia sinensis L. Kuntze, and Elettaria cardamomum (L.) Maton with a ratio of 10 : 5 : 2, respectively, was recommended for curing nausea, vomiting, and diarrhea. Experimental validation is crucial to affirm its therapeutic property leads toward the development of modified antidiarrheal agents. This research aimed to investigate the in vivo antidiarrheal efficacy of traditionally used polyherbal recipe in a castor oil-induced animal model. Moreover, the study also presents the elemental screening and in vivo toxicity of tested polyherbal recipe. Individual plant parts of the polyherbal recipe were mixed according to the traditional prescription ratio, and hydromethanolic extract was prepared by the cold maceration process. The antidiarrheal activity was assessed by castor oil induction method, charcoal meal test, and enteropooling procedure in Sprague-Dawley rats. Elemental analysis and in vivo subacute toxicity were carried out, followed by biochemical, hematological, and histopathological analyses. Polyherbal extract significantly delayed the diarrhea onset in a dose-dependent manner and showed marked inhibition at 200 and 400 mg/kg. Fecal weight was reduced significantly (p < 0.05) at 200 mg/kg (0.26 ± 0.25) in comparison with the control (1.63 ± 0.15). The diarrhea score was zero at a concentration of 200 and 400 mg/kg. Antienteropooling effect of the extract was greater than that of loperamide. Following subacute toxicity, all the treated rats were normal, survived, and showed no changes in behavior. There were no significant differences between values of blood parameters in both the control and extract-treated groups except a significant decrease in monocytes (control 8.4; polyherbal 2.2). Elemental analysis showed a slight increase in the amount of manganese (Mn, 8.076 ppm) as compared to the WHO recommended level (2 ppm). Traditionally used polyherbal recipe is effective and safe for combating diarrheal diseases. In vivo evidence supported the use, safety, and efficacy of the polyherbal recipe that has been used as an alternative medicine for diarrhea in the study area. Inhibition of castor oil-induced diarrhea and antisecretory effect of the studied polyherbal recipe makes it a potent antidiarrheal drug without no or limited toxic effects at the tested dose after further analysis.


Extraskeletal problems and amyloid.
The major clinical manifestations of dialysis-associated A beta 2M amyloidosis are chronic arthralgias, destructive arthropathy and the carpal tunnel syndrome. For dialysis patients who have been maintained on renal replacement therapy for more than 10-15 years, this complication may become a major physical handicap. It may even be life-threatening in some instances due to cervical cord compression. Amyloid deposits in joint areas precede clinical symptoms and signs by several years. Systemic deposits may also occur but their clinical manifestations are infrequent. The diagnosis of dialysis arthropathy associated with beta 2-microglobulin-associated (A beta 2M) amyloidosis mostly relies on indirect clinical and radiological evidence. Histologic proof is rarely obtained in vivo. The pathogenesis of the disease is complex. It includes reduced elimination of beta 2M and potentially also as impaired degradation of A beta 2M as well as enhanced production of A beta 2M amyloid fibrils. Non enzymatic modifications of beta 2M probably play a role, including beta 2M protein modification with advanced glycation end-products (AGE) and advanced oxidation protein products. Modified beta 2M, collagen and proteoglycans appear actively involved in the induction of a local inflammatory response and beta 2M amyloid formation. There is also evidence in favor of treatment-related factors such as the type of hemodialysis membrane and the purity of dialysis water. Hopefully, the translation of our improving knowledge of all the factors involved will lead to a better treatment and eventually to the prevention of this dramatic complication of dialysis.


Evaluating Random Forests for Survival Analysis using Prediction Error Curves.
Prediction error curves are increasingly used to assess and compare predictions in survival analysis. This article surveys the R package pec which provides a set of functions for efficient computation of prediction error curves. The software implements inverse probability of censoring weights to deal with right censored data and several variants of cross-validation to deal with the apparent error problem. In principle, all kinds of prediction models can be assessed, and the package readily supports most traditional regression modeling strategies, like Cox regression or additive hazard regression, as well as state of the art machine learning methods such as random forests, a nonparametric method which provides promising alternatives to traditional strategies in low and high-dimensional settings. We show how the functionality of pec can be extended to yet unsupported prediction models. As an example, we implement support for random forest prediction models based on the R-packages randomSurvivalForest and party. Using data of the Copenhagen Stroke Study we use pec to compare random forests to a Cox regression model derived from stepwise variable selection. Reproducible results on the user level are given for publicly available data from the German breast cancer study group.


N-docosahexaenoyl ethanolamine (synaptamide) has antinociceptive effects in male mice.
N-docosahexaenoyl ethanolamine (DHEA; also known as synaptamide) binds to both the cannabinoid-1 and 2 (CB1 and CB2) cannabinoid receptors and has anti-inflammatory properties in vitro. However, the in vivo effects of DHEA remain unknown. Therefore, this study was designed to understand the effects of DHEA in models of pain and inflammation in mice. The intraplantar formaldehyde assay, hot water tail withdrawal assay and hotplate model were used to assess the antinociceptive properties of DHEA in mice. The mechanism of action was studied by antagonising the cannabinoid receptors, transient receptor potential vanilloid 1 (TRPV1) ion channel, peroxisome proliferator-activated receptors (PPARs) and G-protein receptor 55 (GPR55). N-docosahexaenoyl ethanolamine (2-10 mg/kg) reduced the levels of nociceptive and inflammatory pain-related behaviour over 60 min in the intraplantar formaldehyde assay via both intraperitoneal and local intraplantar administration. The area under the curve analysis showed the overall antinociceptive effects of DHEA (10 mg/kg) were not modulated by pre-treatment with antagonists for the cannabinoid receptors, TRPV1ion channel, PPARα, PPARγ or GPR55. However, the time-course analysis showed that within the early inflammatory phase, antagonism of the CB2 receptor, PPARα and PPARγ led to a partial reversal of the antinociceptive effects of DHEA. In the hot water tail withdrawal and hotplate models of thermal nociception, DHEA (2-10 mg/kg) did not have any antinociceptive effects. N-docosahexaenoyl ethanolamine reduced the level of formaldehyde-induced nociceptive and inflammatory pain-related behaviour; however, was not active in thermal nociceptive models. This study highlights the potential of DHEA for the treatment of acute inflammatory pain. This study shows that both intraperitoneal and intraplantar administration of DHEA reduces the level of formaldehyde-induced nociceptive and inflammatory pain.


Differential susceptibility 2.0: Are the same children affected by different experiences and exposures?
Differential susceptibility theory stipulates that some children are more susceptible than others to both supportive and adverse developmental experiences/exposures. What remains unclear is whether the same individuals are most affected by different exposures (i.e., domain general vs. specific). We address this issue empirically for the first time using, for illustrative and proof-of-principle purposes, a novel influence-statistics' method with data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care. Results indicated that previously documented effects of greater quality of care on enhanced pre-academic skills and greater quantity of care on more behavior problems apply mostly to different children. Analyses validating the new method indicated, as predicted, that (a) the quantity-of-care effect applied principally to children from more socioeconomically advantaged families and that (b) being highly susceptible to both, one or neither childcare effect varied as a function of a three-gene, polygenic-plasticity score (serotonin transporter linked polymorphic region [5-HTTLPR], dopamine receptor D4 [DRD4], brain-derived neurotrophic factor [BDNF]) in a dose-response manner (i.e., 2>1>0). While domain-specific findings involving child-care effects cannot be generalized to other environmental influences, the influence-statistics' approach appears well suited for investigating the generality-specificity of environment effects, that is, of "differential, differential susceptibility."


Isolated congenital tuberculosis otitis in a preterm infant.
We report an unusual case of localized congenital tuberculosis otitis in a preterm infant. Unlike disseminated congenital cases, the manifestations of localized otitis are associated with a triad of signs: (i) regional lymphadenopathy in the absence of typical systemic features of tuberculosis; (ii) delayed onset of presentation; and (iii) refractory otitis unresponsive to conventional antimicrobial agents. The need for greater diligence in looking for neonatal tuberculosis is emphasized, especially in an ethnic or socioeconomic environment where the disease is prevalent.


Exclusive lower extremity mirror movements and diastematomyelia.
Mirror movements usually seen in the Klippel-Feil syndrome are most commonly appreciated in the upper extremities. Lower extremity involvement is seen rarely and when observed, is found in conjunction with upper extremity mirror movements. We report what we believe to be the first case of mirror movements found exclusively in the lower extremities in a female patient presenting with tethered cord syndrome. Our hopes are that this report will help elucidate mechanisms involved with these anomalous movements, as currently there is no commonly accepted etiology.


Novel use of laser to assist ICSI for patients with fragile oocytes: a case report.
An inadvertent consequence of intracytoplasmic sperm injection (ICSI) is the degeneration of some of the microinjected oocytes. Most patients may not suffer any disadvantage through losing oocyte(s) during micromanipulation; however, in some circumstances, this can result in a reduction of the chances for pregnancy. This study reports a clinical pregnancy obtained by a novel approach using laser-assisted micro-opening of the zona pellucida prior to ICSI to secure a non-traumatic microinjection that avoids degeneration of oocytes. A total of 12 oocytes were obtained from the 36 year old patient in her third IVF treatment cycle, following two previously failed attempts where very high degeneration rates of oocytes after ICSI were recorded, together with suboptimal embryo quality. Five of the 11 matured (MII) oocytes were submitted to conventional ICSI and the other six MII oocytes first underwent laser-assisted opening of the zona pellucida (5-7 microm hole size was created with a 1.48 microm diode laser) before microinjection (LA-ICSI). Three of the five conventionally microinjected oocytes degenerated while one oocyte fertilized normally and developed to a good quality embryo. After the LA-ICSI procedure, one of the six oocytes degenerated and four oocytes fertilized normally; of these, two developed to excellent quality embryos, one to a good quality embryo and one to a poor quality embryo. The three best embryos (LA-ICSI group) were transferred to the patient on day 3. Rising serum human chorionic gonadotrophin concentrations were measured 12 days after transfer and on week 7 two implantation sites were detected, together with regular heart activity. The results of the present report suggest that laser-assisted ICSI may provide a safer approach to non-traumatic microinjection of oocytes than conventional ICSI, thereby minimizing the risk of degeneration and possibly also improving embryo quality. Therefore, it is suggested that laser-assisted ICSI might be applied in all cases associated with difficult zona pellucida penetration or/and fragile oolemma, or where patients have very few oocytes available, to improve the chances for pregnancy.


Optimization and Control of Large Block Copolymer Self-Assembly via Precision Solvent Vapor Annealing.
The self-assembly of ultra-high molecular weight (UHMW) block copolymers (BCPs) remains a complex and time-consuming endeavor owing to the high kinetic penalties associated with long polymer chain entanglement. In this work, we report a unique strategy of overcoming these kinetic barriers through precision solvent annealing of an UHMW polystyrene-block-poly(2-vinylpyridine) BCP system (M w: ∼800 kg/mol) by fast swelling to very high levels of solvent concentration (ϕs). Phase separation on timescales of ∼10 min is demonstrated once a thickness-dependent threshold ϕs value of ∼0.80-0.86 is achieved, resulting in lamellar feature spacings of over 190 nm. The threshold ϕs value was found to be greater for films with higher dry thickness (D 0) values. Tunability of the domain morphology is achieved through controlled variation of both D 0 and ϕs, with the kinetically unstable hexagonal perforated lamellar (HPL) phase observed at ϕs values of ∼0.67 and D 0 values of 59-110 nm. This HPL phase can be controllably induced into an order-order transition to a lamellar morphology upon further increase of ϕs to 0.80 or above. As confirmed by grazing-incidence small-angle X-ray scattering, the lateral ordering of the lamellar domains is shown to improve with increasing ϕs up to a maximum value at which the films transition to a disordered state. Thicker films are shown to possess a higher maximum ϕs value before transitioning to a disordered state. The swelling rate is shown to moderately influence the lateral ordering of the phase-separated structures, while the amount of hold time at a particular value of ϕs does not notably enhance the phase separation process. These large period self-assembled lamellar domains are then employed to facilitate pattern transfer using a liquid-phase infiltration method, followed by plasma etching, generating ordered, high aspect ratio Si nanowall structures with spacings of ∼190 nm and heights of up to ∼500 nm. This work underpins the feasibility of a room-temperature, solvent-based annealing approach for the reliable and scalable fabrication of sub-wavelength nanostructures via BCP lithography.


Sympathetic neurotransmitters promote the process of recellularization in decellularized liver matrix via activating the IL-6/Stat3 pathway.
Recellularized liver, as an approach for hepatic tissue engineering, is an effective alternative to orthotopic liver transplantation for end-stage hepatic failure. When compared with normal liver, recellularized liver has a disparity in hepatocyte viability and function, owing to the difficulty of fully simulating the microenvironment of liver. Although the sympathetic nervous system (SNS) is considered an important constituent of liver function, few studies have examined the effect of the SNS on hepatic tissue engineering. It is imperative to explore the regulation of the SNS on a tissue-like configuration to obtain an intact recellularized liver with better hepatic function. We have observed that various subtypes of adrenergic receptors (ARs) are expressed on the hepatocyte membrane. Salbutamol, an agonist of β2-AR, promoted cell proliferation, albumin secretion and urea synthesis in the recellularized liver. Cytokines were screened in isoprenaline/salbutamol-treated recellularized liver, and the expression of IL-6 was significantly increased. Isoprenaline or salbutamol especially promoted the expression of Stat 3 and phosphorylated Stat 3, contributing to the activation of IL-6/Stat 3 signalling in promoting hepatocyte proliferation and recellularized liver function. This study suggests that activation of β2-AR accelerated hepatocyte proliferation and improved recellularized liver function by mediating the IL-6/Stat 3 signalling pathway, indicating that nervous system regulation may be an essential component contributing to the complexity of recellularized liver in tissue engineering.


Trajectories of e-cigarette advertising exposure, e-cigarette use and cigarette smoking in a sample of young adults from Hawaii.
To test whether intrapersonal growth in e-cigarette advertising exposure over time is associated with growth in e-cigarette use and/or cigarette smoking. Longitudinal study using four waves of data were collected in 6-month intervals between 2018 and 2020. Participants were 2327 young adults recruited from colleges in Hawaii, USA. Data were collected on demographics, e-cigarette advertising exposure measured using the cued- recall method and recent (past 30-day) cigarette and e-cigarette use. The average trajectory for e-cigarette advertising exposure over time was significant and upward [M slope = 0.18 (0.14-0.22), P < 0.0001]. However, average trajectories for e-cigarette [M slope = -0.08 (-0.18 to 0.02), P = 0.09] and cigarette [M slope = -0.14 (-0.30 to 0.02), P = 0.07] use were not. There were significant differences in individual level trajectories across participants for advertising exposure [σ2 = 0.12 (0.10-0.14), P < 0.0001], e-cigarette use [σ2 = 0.22 (0.14-0.30), and cigarette smoking (σ2 = 0.17 [0.09-0.25], P < 0.0001). Individuals with an increasing rate of advertising exposure showed an increasing rate of e-cigarette use [B = 0.63 (0.36-0.90), P < 0.0001). Neither initial level of, nor rate of change in, advertising exposure was significantly associated with cigarette smoking growth factors (P > 0.05). Higher initial level of e-cigarette use was associated with higher initial level of cigarette smoking [B = 0.89 (0.69-1.09), P < 0.0001] but decreased rate of cigarette smoking over time [B = -0.12 (-0.20 to -0.04) P = 0.003]. Rate of change in e-cigarette use was not associated with the rate of change in cigarette smoking (P > 0.05). Increased exposure to e-cigarette advertising appears to be associated with increased e-cigarette use but not with increased cigarette smoking. Higher initial level of e-cigarette use appears to be associated with higher initial level of cigarette smoking but may be associated with a decreasing rate of cigarette smoking over time.


The Meaning of 'Dining': The Social Organization of Food in Long-term Care.
To explore the social organization of food provision in publicly funded and regulated long-term care facilities. Observations were conducted, along with 90 interviews with residents, families, and health providers in two Southern Ontario sites using rapid site-switching ethnography within a feminist political economy framework as part of an international, interdisciplinary study investigating healthy ageing. Food is purchased within a daily $7.80/per resident allotment, limiting high quality choices, which is further problematized by privatization of food services. Funding restrictions also result in low staffing levels, creating tensions in aligning with other Ministry mandated tasks such as bathing, and documenting: competing demands often lead to rushed meals. Regulations, primarily set in response to scandals and to ensure appropriate measured nutrition, reinforce the problem. Further, regulations regarding set meal times result in lack of resident agency, which is compounded by fixed menu options and seating arrangements in one common dining room. Rather than being viewed as an important part of resident socialization, food is reduced to a medicalized task, organized within a climate of cost-containment. Findings warrant Ministry financial support for additional staff and for food provision. Policy changes are also required to give primacy to this population's quality of life.


Pharmacological Targeting of STING-Dependent IL-6 Production in Cancer Cells.
Activation of the STING pathway upon genotoxic treatment of cancer cells has been shown to lead to anti-tumoral effects, mediated through the acute production of interferon (IFN)-β. Conversely, the pathway also correlates with the expression of NF-κB-driven pro-tumorigenic genes, but these associations are only poorly defined in the context of genotoxic treatment, and are thought to correlate with a chronic engagement of the pathway. We demonstrate here that half of the STING-expressing cancer cells from the NCI60 panel rapidly increased expression of pro-tumorigenic IL-6 upon genotoxic DNA damage, often independent of type-I IFN responses. While preferentially dependent on canonical STING, we demonstrate that genotoxic DNA damage induced by camptothecin (CPT) also drove IL-6 production through non-canonical STING signaling in selected cancer cells. Consequently, pharmacological inhibition of canonical STING failed to broadly inhibit IL-6 production induced by CPT, although this could be achieved through downstream ERK1/2 inhibition. Finally, prolonged inhibition of canonical STING signaling was associated with increased colony formation of MG-63 cells, highlighting the duality of STING signaling in also restraining the growth of selected cancer cells. Collectively, our findings demonstrate that genotoxic-induced DNA damage frequently leads to the rapid production of pro-tumorigenic IL-6 in cancer cells, independent of an IFN signature, through canonical and non-canonical STING activation; this underlines the complexity of STING engagement in human cancer cells, with frequent acute pro-tumorigenic activities induced by DNA damage. We propose that inhibition of ERK1/2 may help curb such pro-tumorigenic responses to DNA-damage, while preserving the anti-proliferative effects of the STING-interferon axis.


Relativistic configuration interaction study of the electronic spectrum of SnTe and SnTe+.
Ab initio based relativistic configuration interaction calculations have been performed to study the electronic spectrum of the heaviest tin chalcogenide and its monopositive ion. Potential energy curves and spectroscopic constants of low-lying states of both species within 7 eV are reported. The ground-state dissociation energies of SnTe and SnTe+ are computed to be 3.48 and 2.50 eV, respectively. The spin-orbit splitting between the two components of the X 2Pi state of SnTe+ is about 3030 cm(-1). Effects of the strong spin-orbit coupling on the potential curves and spectroscopic properties of both the species are investigated in detail. The electric dipole moments of some of the low-lying states of SnTe and SnTe+ are reported. Transition moments of some important spin-allowed and spin-forbidden transitions are calculated from the configuration interaction wave functions. The radiative lifetime of the excited E 1sigma0+(+) state of SnTe is about 39 ns. The X2-X1 transition in SnTe+ is found to be more probable than the similar transition in the lighter ions. The vertical ionization energy of SnTe in the ground state is estimated to be 8.22 eV.


Liver function tests in workers with occupational exposure to polychlorinated biphenyls (PCBs): comparison with yusho and yu-cheng.
The results of liver function tests in a population manufacturing capacitors and transformers are presented. Two clinical field examinations were performed, one in 1976 when PCBs were still used in the manufacturing of the electrical equipment and one at the end of 1979, 2.5 years after discontinuation of PCBs use. A low prevalence of abnormal liver function tests was found and mean values for all tests were within normal laboratory ranges. At the initial examination, weak, but statistically significant correlations were found between log LDH and plasma levels of log HPCB (higher chlorinated congeners of polychlorinated biphenyls) and log TPCB (total polychlorinated biphenyls) among the female workers, while log gamma-GTP correlated significantly only with log HPCB among the male workers. A significant increase to abnormal levels of gamma-GTP was noted at the follow-up examination in both male and female workers, and preliminary results indicate significant correlations between gamma-GTP and serum levels of PCBs among the male workers. These findings are in accordance with previously reported data on populations occupationally exposed to PCBs, but differ from hepatic biochemistry findings in accidental poisonings due to ingestion of cooking oil contaminated with PCBs and related compounds, i.e., polychlorinated dibenzofurans (PCDFs) and polychlorinated quaterphenyls (PCQs). Hence, the importance of considering the related compounds as etiologic factors in PCB poisoning is emphasized.


Surgical management of bisphosphonate induced osteonecrosis of the jaws.
Recent literature contains numerous articles on osteonecrosis of the jaws (ONJ) associated with bisphosphonate treatment (BPT), with most advocating a conservative approach to management. A prospective study was designed to review the surgical management of cases of ONJ that did not respond to conservative management. Forty patients, referred with ONJ that did not respond to conservative management, were treated surgically and followed up for 6 months to 4 years. Four patients were taking i.v. BPT as part of their bone cancer management and 16 were taking oral BPT for osteoporosis. The surgical management of ONJ involved antibiotic therapy, surgical debridement of all necrotic bone and tension-free primary closure. All 40 cases healed uneventfully with no wound breakdown during follow-up. Most of the literature supports the conservative management of ONJ, but the condition leaves the patient debilitated. Many cases do not respond to conservative management and the infection and bone destruction is progressive. The conservative management of ONJ is to be supported, but this prospective study has shown that those cases that do not respond may be managed surgically. It should be recognized that while the results of this paper are encouraging, some cases will be resistant to all treatments.


Factors influencing the development of melatonin rhythmicity in humans.
The emergence of melatonin rhythmicity was studied in 163 infants between 46-55 weeks postconception by monitoring the excretion of the urinary melatonin metabolite 6-sulfatoxymelatonin (aMT.6S). From this population, we examined the effects of gender, season, multiple birth, home birth, previous sudden infant death syndrome in the family, premature labor, spontaneous rupture of membranes, preeclampsia, intrauterine growth restriction, and nursery lighting on pineal rhythmicity. As previously reported, rhythmic excretion of aMT.6S appeared between 49-55 weeks postconception (9-15 weeks of age) in singleton babies born at term in the hospital. Full-term infants who had a sibling die of sudden infant death syndrome had a pattern of melatonin rhythm development no different from that of the control full-term infants. In contrast, full-term infants born at home and full-term twins born in the hospital had significantly lower aMT.6S excretion than hospital-born singleton infants at the same ages despite similar body weights (e.g. at 52 weeks postconception; 1.8 +/- 0.4, 1.1 +/- 0.3, and 3.6 +/ -0.5 nmol/day, respectively). In full-term infants, there was no difference in the development of melatonin rhythmicity between the sexes, with season or method of delivery (vaginal vs. caesarean). The premature infants were divided into 5 groups (babies born after premature labor, premature rupture of membranes, preeclampsia, intrauterine growth restriction, and fetal distress). All premature infants had a delay in the appearance of aMT.6S rhythms in the urine in relation to chronological age. When the infants were compared on the basis of weeks since conception, those infants born after spontaneous premature labor excreted amounts of aMT.6S no different from those of full-term singleton infants during the period of study. In contrast, the premature rupture of membranes, preeclampsia, and fetal distressed infants excreted 50% less aMT.6S, and intrauterine growth restricted infants excreted 67% less at the same postconceptional ages. These differences were due to reduced nocturnal excretion of the metabolite. In an attempt to accelerate the development of melatonin rhythmicity, premature labor and premature rupture of membranes infants were randomly assigned to be totally deprived of light (using phototherapy eye shields) or partially deprived of light by moving them to a dimly lit room each night for the last 3-8 weeks of their stay in the hospital nursery. Babies born after premature labor produced normal amounts of aMT.6S between 46-52 weeks postconception, and this pattern was not affected by the nocturnal light deprivation. Infants born after premature rupture of membranes and totally deprived of light at night had aMT.6S excretion rhythms at 52 weeks postconception no different from those of full-term hospital-born infants or premature labor infants, whereas those in infants placed in dim light were similar to those in untreated premature rupture of membranes infants. These results suggest that premature birth alone is not the sole cause of altered rhythm development; other factors, such as preeclampsia, growth restriction, and nursery lighting, play an important role. The consequences of the delayed appearance of melatonin in infants are not known, but deserve further study.


Solution densities and estimated total protein contents associated with inappropriate flotation of separator gel in different blood collection tubes.
Clinical samples that have densities greater than that of separator gel in specimen tubes may exhibit gel flotation to the top of the specimen upon centrifugation. Inappropriate separator gel flotation can occur in specimens with high protein content. In automated analytical systems, gel flotation can lead to mechanical disruption and potential inaccurate result reporting upon aspiration into instrument sampling probes. To determine the relative specimen densities and estimated total protein contents at which specimen gel flotation would occur upon centrifugation in commonly used commercial specimen tubes, a comparative study of separator gel density was initiated using prepared dextran solutions. Specific gravity of several dextran solutions was determined by direct hydrometry. The dextran solutions were introduced to serum and plasma lithium heparin BD Vacutainer specimen tubes manufactured by Becton, Dickinson and Company and into Vacuette specimen tubes manufactured by Greiner Bio-One containing separator gel. Following centrifugation the specimen tubes were examined for gel flotation. Flotation was observed at a lower dextran solution density for Greiner than for BD tubes in both serum and plasma separator gel specimen tubes. Additionally, some differences between specimen tube lots were observed for both BD and Greiner tubes. The total protein content in clinical samples that would result in gel flotation can be estimated for different specimen container types. Differences were observed for the gel separator specific gravity in different blood collection containers. Laboratories wishing to avoid problems with inappropriate gel flotation in high protein samples should consider these observations.


Robust temperature change rate actuated valving and switching for highly integrated centrifugal microfluidics.
We present new unit operations for valving and switching in centrifugal microfluidics that are actuated by a temperature change rate (TCR) and controlled by the rotational frequency. Implementation is realized simply by introducing a comparatively large fluidic resistance to an air vent of a fluidic structure downstream of a siphon channel. During temperature decrease at a given TCR, the air pressure inside the downstream structure decreases and the fluidic resistance of the air vent slows down air pressure compensation allowing a thermally induced underpressure to build up temporarily. Thereby the rate of temperature change determines the time course of the underpressure for a given geometry. The thermally induced underpressure pulls the liquid against a centrifugal counterpressure above a siphon crest, which triggers the valve or switch. The centrifugal counterpressure (adjusted by rotation) serves as an independent control parameter to allow or prevent valving or switching at any TCR. The unit operations are thus compatible with any temperature or centrifugation protocol prior to valving or switching. In contrast to existing methods, this compatibility is achieved at no additional costs: neither additional fabrication steps nor additional disk space or external means are required besides global temperature control, which is needed for the assay. For the layout, an analytical model is provided and verified. The TCR actuated unit operations are demonstrated, first, by a stand-alone switch that routes the liquid to either one of the two collection chambers (n = 6) and, second, by studying the robustness of TCR actuated valving within a microfluidic cartridge for highly integrated nucleic acid testing. Valving could safely be prevented during PCR by compensating the thermally induced underpressure of 3.52 kPa with a centrifugal counterpressure at a rotational frequency of 30 Hz with a minimum safety range to valving of 2.03 kPa. Subsequently, a thermally induced underpressure of 2.55 kPa was utilized for robust siphon valving at 3 Hz with a minimum safety range of 2.32 kPa.


The effects of varying fluid volume and rate of resuscitation during uncontrolled hemorrhage.
The role of rate and volume of infusion in survival from experimental uncontrolled hemorrhage was evaluated. Hemorrhage was initiated using tail resection in 43 female rats assigned to the following five groups: nonresuscitated; resuscitated with moderate volume, slower rate; resuscitated with moderate volume, faster rate; resuscitated with high volume, slower rate; and resuscitated with high volume, faster rate. A trend toward improved survival was noted with faster rate of infusion (60 vs. 33.3% survival rate with moderate volume and 28.6 vs. 12.5% with high volume, compared with 16.7% in the nonresuscitated animals). Rapid infusion of moderate volume of isotonic saline improved survival in uncontrolled hemorrhage. Extreme volumes, infused rapidly, also resulted in higher survival rates compared with those observed in nonresuscitated rats.


The assessment of biliary CA 125, CA 19-9 and CEA in diagnosing cholangiocarcinoma--the influence of sampling time and hepatolithiasis.
This study was conducted to assess the clinical value of biliary CA 19-9, CA 125 and CEA sampled in different situations for the diagnosis of cholangiocarcinoma. Bile was obtained from patients with bile duct obstruction on the day of biliary drainage and 3 days later separately. The etiology of biliary obstruction included choledocholithiasis (N = 51), hepatolithiasis (N = 19) and cholangiocarcinoma (N = 28). Patients of the former two conditions were all complicated with cholangitis. The sensitivity of biliary CEA, CA 19-9 and CA 125, whenever checked were all less than 70%. The biliary CEA and CA 19-9 were elevated in the presence of cholangitis. In addition, the biliary CEA was also increased in the patients with hepatolithiasis. The specificity of CA 125 was better than those of CEA and CA 19-9 (75.7% vs. 33.3% and 60%, respectively) on the day of biliary drainage. The diagnostic efficiency was slightly improved when combining biliary CA 125 and CEA. As the biliary CA 125 was less affected by inflammation and hepatolithiasis, it is more useful than CEA and CA 19-9 in the diagnosis of cholangiocarcinoma. The single tumor marker test of CA 125 or combined tumor marker test of CEA and CA 125 may be used as a useful complement to other investigative methods to differentiate benign from malignant causes of the bile duct obstruction.