Likelihood analysis of ongoing gene flow and historical association.
We develop a Monte Carlo-based likelihood method for estimating migration rates and population divergence times from data at unlinked loci at which mutation rates are sufficiently low that, in the recent past, the effects of mutation can be ignored. The method is applicable to restriction fragment length polymorphisms (RFLPs) and single nucleotide polymorphisms (SNPs) sampled from a subdivided population. The method produces joint maximum-likelihood estimates of the migration rate and the time of population divergence, both scaled by population size, and provides a framework in which to test either for no ongoing gene flow or for population divergence in the distant past. We show the method performs well and provides reasonably accurate estimates of parameters even when the assumptions under which those estimates are obtained are not completely satisfied. Furthermore, we show that, provided that the number of polymorphic loci is sufficiently large, there is some power to distinguish between ongoing gene flow and historical association as causes of genetic similarity between pairs of populations.


Structure, stereochemistry and synthesis of enantiopure cyclohexenone cis-diol bacterial metabolites derived from phenols.
Biotransformation of 3-substituted and 2,5-disubstituted phenols, using whole cells of P. putida UV4, yielded cyclohexenone cis-diols as single enantiomers; their structures and absolute configurations have been determined by NMR and ECD spectroscopy, X-ray crystallography, and stereochemical correlation involving a four step chemoenzymatic synthesis from the corresponding cis-dihydrodiol metabolites. An active site model has been proposed, to account for the formation of enantiopure cyclohexenone cis-diols with opposite absolute configurations.


A double-blind study to establish the residual effects of zopiclone on performance in healthy volunteers.
A double-blind study was designed to establish the residual effects of zopiclone on performance in healthy volunteers. 10 healthy male volunteers aged 22-45 years (mean age 27.4 years) were included in this study. 6 of the volunteers were cigar/cigarette smokers and were asked to smoke as little as possible on the study days. The subjects were randomly allocated to a balanced design in which each subject received single oral doses of placebo, 2.5-, 5-, 7.5- and 10-mg tablets of zopiclone under double-blind conditions. A battery of tests were performed 10 and 13 h after overnight ingestion of the drug. The tests comprised: EEG, auditory reaction time, tapping rate, digit symbol substitution test, symbol copying test, mood rating scales, side effects rating scales, and subjective assessments of sleep and performance. Zopiclone is shown to have useful hypnotic properties but residual effects are detectable using EEG and psychological tests both 10 and 13 h after ingestion. The 10-mg dose significantly impairs performance the next day; the 5-mg dose is almost devoid of residual psychomotor effects but is only marginally effective in hastening onset of sleep and does not improve sleep quality. The 7.5-mg dose has definite effects on sleep and limited residual effects the next day. No significant side effects were reported. In this study, using single doses in healthy subjects, the best balance between wanted hypnotic effects and unwanted residual effects the next day was provided by the 7.5-mg dose of zopiclone. It is recommended that further studies with repeated doses in healthy volunteer subjects and in insomniac patients use the 7.5-mg dose as the reference point.


Niacin attenuates bleomycin-induced lung fibrosis in the hamster.
Bleomycin (BLM)-induced lung fibrosis has been shown to be accompanied by the activation of poly(ADP-ribose) polymerase and depletion of nicotinamide adenine dinucleotide (NAD) in the lung. Niacin, a precursor of NAD, was used in the present study to investigate its possible ameliorating effect on BLM-induced pulmonary fibrosis in hamsters. Niacin (500 mg/kg IP) or saline (IP) was injected daily for 16 or 23 days. On day 3, hamsters were treated with BLM (7.5 U/5 mL/kg) or an equivalent volume of saline intratracheally. BLM alone significantly increased lung hydroxyproline levels, bronchoalveolar lavage fluid protein concentration, and various inflammatory cell counts in the lavage in both experiments. In addition, BLM alone elevated prolyl hydroxylase and poly(adenosine-5'-diphosphate [ADP]-ribose) polymerase activities in the 3-week study. Niacin treatment significantly decreased BLM-elevated lung hydroxyproline, prolyl hydroxylase, and poly(ADP-ribose) polymerase activities. Histopathology revealed that niacin treatment attenuated BLM-induced thickened alveolar septa, foci of fibrotic consolidation, and accumulations of inflammatory cells in the parenchyma and air spaces. The ability of niacin to attenuate BLM-induced lung fibrosis in hamsters suggests that it may have potential as an antifibrotic agent in humans.


Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney.
An electroneutral thiazide-sensitive Na-Cl cotransport pathway (TSC) has been localized functionally to the distal convoluted tubule (DCT), although the TSC has also been detected in the connecting tubule (CNT), the cortical collecting duct, and the medullary collecting tubule as well. The present experiments were designed to localize expression of message for the TSC in rat and human kidney. A riboprobe, generated from the mouse TSC, was used for in situ hybridization. Simultaneous immunocytochemistry, using antibodies to Tamm-Horsfall protein, band 3, and the Na+/Ca2+ exchanger, permitted delineation of specific nephron segments. In rat, message for the TSC was highly expressed in DCT cells but not elsewhere. The transition from thick ascending limb to DCT was abrupt, whereas the transition to CNT was gradual. In the more distal region of rat DCT (DCT-2), which contained few intercalated cells, both TSC message and Na+/Ca2+ exchanger immunoreactivity were present. Treatment of rats with furosemide for 5 days increased expression of TSC message within the DCT but did not induce its expression elsewhere. In humans, expression of TSC message was also highest in cells of the DCT. In humans, however, expression extended well into the CNT. These experiments indicate that the TSC is expressed predominantly by DCT cells in both rat and humans, although expression extends into the CNT cells in humans. They also show that the TSC and Na+/Ca2+ exchanger are coexpressed by a subpopulation of DCT cells near the junction with the CNT.


Treatment of chronic pain with tricyclic antidepressants.
Tricyclic antidepressants are increasingly being used to treat chronic pain. A review of the literature supports their use in a variety of conditions and sheds some light on the question as to whether they exert a direct analgesic effect or act indirectly, by first alleviating an intercurrent depression. Their use is recommended for chronic pain before resorting to narcotics or neurosurgery.


Sympathoexcitatory CVLM neurons mediate responses to caudal pressor area stimulation.
Neurons in the caudal pressor area (CPA) are a source of tonic sympathoexcitation that is dependent on activation of cardiovascular sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM). In the present study, we sought to clarify the mechanism through which CPA neurons elicit increases in RVLM neuronal discharge, vasoconstrictor sympathetic tone, and arterial pressure. In urethan-chloralose-anesthetized, paralyzed, and artificially ventilated rats, bilateral disinhibition of CPA with bicuculline (Bic) after bilateral disinhibition of caudal ventrolateral medulla (CVLM) caused increases in splanchnic sympathetic nerve activity (+277% control) and arterial pressure (+54 mmHg). Inhibition of CVLM neurons with muscimol abolished the pressor response to activation of CPA neurons, suggesting that neurons within CVLM mediate the excitatory responses from CPA. Disinhibition of CVLM and CPA with Bic enhanced the sympathoexcitatory responses to stimulation of CPA with DL-homocysteic acid, which were blocked by microinjections of kynurenic acid into CVLM. We conclude that the pathway from CPA to RVLM involves an obligatory glutamatergic activation of sympathoexcitatory neurons in the vicinity of CVLM.


GATA-3 function in innate and adaptive immunity.
The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells, and promotes the CD4(+) T cell lineage after positive selection. GATA-3 also functions outside the thymus in hematopoietic stem cells, regulatory T cells, CD8(+) T cells, thymic natural killer cells, and ILC precursors. Here we discuss the varied functions of GATA-3 in innate and adaptive immune cells, with emphasis on its activity in T cells and ILCs, and examine the mechanistic basis for the dose-dependent, developmental-stage- and cell-lineage-specific activity of this transcription factor.


Nucleoside reverse transcriptase inhibitor backbones and pregnancy outcomes.
The aim of this study was to investigate whether specific nucleoside reverse transcriptase inhibitor (NRTI) backbones are associated with risk of adverse pregnancy outcomes among pregnant women starting antiretroviral therapy (ART). Seven observational studies across eight European countries of pregnancies in HIV-positive women. Individual-level data were pooled on singleton pregnancies conceived off-ART in which a single combination ART regimen was initiated at least 2 weeks before delivery, and ending in a live birth in 2008-2014. Preterm delivery (PTD) was defined as less than 37 gestational weeks and small-for-gestational-age (SGA) as less than 10th percentile according to INTERGROWTH standards. Poisson regression models were fitted to investigate associations between NRTI backbones and PTD/SGA. Out of 7193 pregnancies, 45% (3207) were in UK/Ireland, 44% (3134) in Ukraine. 10% (722/7193) of deliveries were preterm and 11.1% (785/7089) of newborns SGA. The most common NRTI backbones were zidovudine (ZDV)-lamivudine (3TC) (71%), tenofovir (TDF)-XTC (16%) and abacavir (ABC)-3TC (10%) with TDF-containing backbone use increasing over time. Overall, 77% of regimens contained ritonavir-boosted lopinavir (LPV/r). There was no association between NRTI backbone and PTD in main adjusted analyses [adjusted prevalence ratios (aPRs) 0.97 (95% confidence interval, 95% CI 0.73-1.28] for ABC-3TC and aPR 1.06 (95% CI 0.83-1.35) for TDF-XTC, both vs. ZDV-3TC) or in 4720 pregnancies on LPV/r [aPR 1.03 (95% CI 0.74-1.43) for ABC-3TC and aPR 1.16 [0.85-1.57] for TDF-XTC, both vs. ZDV-3TC]. Infants exposed to ABC-3TC or TDF-XTC in utero were less likely to be SGA than those exposed to ZDV-3TC [aPR 0.72 (95% CI 0.53-0.97) and aPR 0.70 (95% CI 0.53-0.93), respectively]. Results support the safety of TDF-XTC backbones initiated in pregnancy with respect to gestation length and birthweight.


4-Acetylantroquinonol B from antrodia cinnamomea enhances immune function of dendritic cells against liver cancer stem cells.
The functions of 4-acetylantroquinonol B (4-AAQB), a ubiquinone derivative isolated from the mycelium of Antrodia cinnamomea, in immunotherapy for liver cancer were investigated. We found that 4-AAQB could inhibit liver cancer stem cell related manifestations and activate the antitumor ability of dendritic cells. Specifically, 4-AAQB can inhibit EpCAM, AFP and related pathways of HepG2 cells. It also significantly decreases the expression of β-catenin, inhibits the tumorigenicity and decreases the secretion of immune escape related cytokines. Moreover, 4-AAQB can stimulate the proliferation of immune cells and promote the endocytosis of immature dendritic cells. When co-cultured immature dendritic cells with EpCAM+ HepG2 cells, 4-AAQB enhanced the expression of MHC class I and II on the surface of liver cancer stem cells and dendritic cells, increased the expression of costimulatory molecules CD80 of dendritic cells and cytokines related to immune activation. In conclusion, 4-AAQB from Antrodia cinnamomea can enhance immune function of dendritic cells against liver cancer stem cells, and may have the potential to be used for liver cancer prevention and immunotherapy.


Exploration of treatment options for the management of stage I testicular seminoma.
Seminoma is the epitome of a highly treatable neoplastic malignancy. Approximately 80% of patients presenting with seminomatous germ cell tumors are diagnosed with stage I disease. Men with clinical stage I seminomas have an excellent chance of achieving a cure irrespective of the treatment option selected. With such high disease-specific survival rates, attention has turned to reducing treatment-related morbidity. Adjuvant radiotherapy to the para-aortic retroperitoneal lymph nodes in conjunction with orchidectomy has been the standard treatment since the mid-1990s. There is some evidence, however, suggesting potential deleterious long-term sequelae from radiation treatment. Adjuvant chemotherapy has gained support as an acceptable adjuvant treatment strategy for stage I seminoma. While long-term studies are limited, short-term data regarding the therapeutic efficacy of single-agent carboplatin are promising. Finally, surveillance following orchidectomy is an attractive option for motivated patients interested in avoiding immediate adjuvant therapy. It may be the optimal choice for compliant men who are able to handle the mental burden of not receiving active treatment.


Factors affecting patient and nursing staff adherence to an integrated physical activity and nutritional intervention targeting functional decline on an acute medical ward: a qualitative study.
Medical patients are particularly at risk of developing complications during and after hospitalization, due to impaired nutritional intake, physical inactivity, or immobilization. Evaluations of implementation studies on health-promoting interventions for medical patients in hospitals are scarce. The aim of this study was to identify factors affecting the adherence of patients and staff to an integrated physical activity and nutritional intervention on a medical ward. Two focus group interviews were conducted: one with patients and another with staff. Three individual telephone interviews were conducted, as three patients were not available at the time of the group interview. An inductive thematic analysis was fundamental to the findings of the study. Nine themes describe factors affecting adherence to integrated physical activity and nutrition intervention. Positive factors described by the patients were new knowledge and insight, and that they felt seen and believed in, which made a significant difference to their motivation. The nursing staff felt that the intervention provided important knowledge related to daily practice, prevented bad consciences due to time issues, and that they experienced happier and more active patients. Both staff and patients found that the approaches of the physiotherapist and the dietician positively changed their behavior, however staff members experienced limited resources as a barrier, and a lack of knowledge seemed to hinder full integration of the intervention. Patients reported that their illness situation, "being on their own," and failure to negotiate a shared goal with the project staff were barriers to adherence. Both the nursing staff and patients described positive experiences with the integration of a multifaceted health promotion intervention on physical activity and nutrition, however the nursing staff did not fully participate in the intervention and patient adherence differed; particularly, it tended to diminish when the patients were expected to act on their own.


Adaptation to invisible motion results in low-level but not high-level aftereffects.
After prolonged exposure to moving stimuli, illusory motion is perceived in stimuli that do not contain consistent motion, a phenomenon termed the motion aftereffect (MAE). In this study, we tested MAEs under binocular suppression that renders the motion adaptor invisible for the entire adaptation period. We developed a variant of the continuous flash suppression method to reliably suppress target motion stimuli for durations longer than several tens of seconds. Here, we ask whether motion systems are functional in the absence of perception by measuring the MAE, a question difficult to address using binocular rivalry that accompanies a switch of percept between visible and invisible. Results show that both the MAEs with static and dynamic tests are attenuated with an invisible adaptor when the adaptor and the test stimulus are presented to the same eye. In contrast, when the test pattern was presented to the other eye, the dynamic MAE was observed in invisible adaptor conditions. These results indicate that low-level adaptation survives under total binocular suppression, a finding predicted by previous studies. In contrast, disappearance of interocular transfer in the dynamic MAE suggests that a high-level motion detector does not operate when the motion adaptor is rendered invisible.


Orbital complications of paranasal sinusitis in Taiwan, 1988 through 2015: Acute ophthalmological manifestations, diagnosis, and management.
Paranasal sinusitis is widespread and can lead to orbital complications, blindness, and death. However, the correlation between ophthalmological findings and disease staging remains unclear. This study aimed to investigate the staging, acute ophthalmological manifestations, diagnosis, management, and outcomes of orbital complications of paranasal sinusitis during a 27-year period. We retrospectively reviewed the medical records of all patients with orbital complications of paranasal sinusitis hospitalized at the National Cheng Kung University Hospital, a medical center in Taiwan during 1988-2015. Sex, age, symptoms, history, ophthalmological findings, laboratory and imaging findings, treatments, and outcomes were analyzed by staging. Eighty-three patients aged 9 days to 80 years had stage I (preseptal cellulitis, n = 39 patients), II (postseptal orbital cellulitis, n = 8), III (subperiosteal abscess, n = 16), IV (orbital abscess, n = 8), or V (intracranial involvement, n = 12) complications. Peak incidences occurred in patients aged 0-19 and 60-69 years. Chronic sinusitis and diabetes mellitus were common preexisting diseases. Extraocular movement limitation and proptosis predicted postseptal (stage II or more) involvement. The likelihood of elevated intraocular pressure increased with stage. Reduced visual acuity and presence of relative afferent pupillary defect indicated consideration of magnetic resonance imaging to investigate possible intracranial extension. Ipsilateral maxillary (81.7%) and ethmoidal (75.6%) sinuses were the most common sources of infection, and the most frequently implicated pathogens were coagulase-negative Staphylococcus spp. (25.3%) and Staphylococcus aureus (20.5%). All patients received intravenous antimicrobial therapy (multi-drug therapy in 88.0%), and 55.4% underwent surgery, most commonly endoscopic sinus surgery. One (1.2%) diabetic man with stage V complications died of fungal sinusitis with intracranial invasion. Five (6.0%) patients, all stage V, lost vision despite intensive treatment. The average length of hospital stay was 13.8 days (range 2-72 days), and significantly longer stays were associated with stages II-V as compared to stage I. Orbital infection originating from paranasal sinusitis can cause vision loss and death due to intracranial extension. Acute ophthalmological findings predict staging and prognosis. Cooperative consultation between ophthalmologists, otorhinolaryngologists, and neurologists is essential. Urgent diagnostic studies and aggressive antimicrobial therapy are indicated, and surgery should be considered.


Heritability of growth and leaf loss compensation in a long-lived tropical understorey palm.
Defoliation and light competition are ubiquitous stressors that can strongly limit plant performance. Tolerance to defoliation is often associated with compensatory growth, which could be positively or negatively related to plant growth. Genetic variation in growth, tolerance and compensation, in turn, plays an important role in the evolutionary adaptation of plants to changing disturbance regimes but this issue has been poorly investigated for long-lived woody species. We quantified genetic variation in plant growth and growth parameters, tolerance to defoliation and compensation for a population of the understorey palm Chamaedorea elegans. In addition, we evaluated genetic correlations between growth and tolerance/compensation. We performed a greenhouse experiment with 711 seedlings from 43 families with twelve or more individuals of C. elegans. Seeds were collected in southeast Mexico within a 0.7 ha natural forest area. A two-third defoliation treatment (repeated every two months) was applied to half of the individuals to simulate leaf loss. Compensatory responses in specific leaf area, biomass allocation to leaves and growth per unit leaf area were quantified using iterative growth models. We found that growth rate was highly heritable and that plants compensated strongly for leaf loss. However, genetic variation in tolerance, compensation, and the individual compensatory responses was low. We found strong correlations between family mean growth rates in control and defoliation treatments. We did not find indications for growth-tolerance/compensation trade-offs: genetic correlation between tolerance/compensation and growth rate were not significant. The high genetic variation in growth rate, but low genetic variation in tolerance and compensation observed here suggest high ability to adapt to changes in environment that require different growth rates, but a low potential for evolutionary adaptation to changes in damage or herbivory. The strong correlations between family mean growth rates in control and defoliation treatments suggest that performance differences among families are also maintained under stress of disturbance.


Cellular resistance mechanisms with impact on the therapy of multiple myeloma.
Multiple myeloma (MM) is characterized by bone marrow infiltration with abnormal plasma cells which synthesize monoclonal immunoglobulins (Ig) or Ig fragments. Regularly, MM cells exhibit a high intrinsic resistance to available chemotherapeutic strategies. A number of cellular alterations including the cellular membrane, such as mutations of the glucocorticoid receptor or expression of membrane transport proteins, detoxification mechanisms and altered expression of topoisomerases, have been described. In addition to anti-apoptotic survival mechanisms, involving abnormalities of several oncogenes and suppressor genes (ras, c-myc, p53, Rb and bcl-2), the broad resistance spectrum might be explained but clinical studies which include the evaluation of resistance factors are missing. On the other hand, risk factor evaluation would be important as a number of therapeutical strategies with different intensities from corticosteroid monotherapy up to high-dose chemotherapy with tandem autologous bone marrow transplantation exist.


Mesenchymal stem cell and gene therapies for spinal fusion.
THE IDEAL GRAFT material to promote spinal fusion should possess osteoconductive, osteoinductive, and osteogenic properties. Although autogenous bone graft has all three qualities and is the standard for comparison, research has focused on finding alternatives that have similar efficacy but not the morbidities associated with graft donor sites. Efforts have focused on various osteoconductive scaffolds and introduction of osteoinductive proteins, including bone morphogenetic protein. Recently, interest in using osteoprogenitor cells, or osteogenesis, for spinal fusion has increased. Bone marrow aspiration allows the introduction of mesenchymal stem cells and ultimately osteoblasts to promote fusion. Preclinical studies suggest that the addition of osteoprogenitor cells to various osteoconductive materials results in a fusion rate similar to that of autograft. There is growing recognition that local gene therapy has the benefit of delivering therapeutic genes that encode novel osteoinductive proteins. Gene delivery offers an alternative to local implantation of recombinant protein, which typically requires high doses of the protein to result in a sufficient osteoinductive response. The findings of animal studies demonstrate that gene therapy results in sustained and regulated production of desired osteoinductive proteins and is efficacious in promoting spinal fusion; however, before treatment in humans can be undertaken, obstacles such as the safety profile, host immune response, transfection rates with insufficient transgene expression, and imprecise control of the timing of transgene expression must be overcome. In this review, the authors summarize the latest research efforts under way to promote spinal fusion with osteoprogenitor cells and gene therapy and discuss the clinical implications of these treatments.


Acute calcific tendonitis of dorsal interosseous muscles of the hand: uncommon site of a frequent disease.
Acute calcific tendinopathy is one of the manifestations of hydroxyapatite crystal deposition disease. While it is more frequent in the shoulder, it has been described in virtually all areas of the body, but rarely in the muscles of the hand. Its etiopathogenesis is not yet fully understood and despite being a fairly frequent condition, it is commonly misdiagnosed. The onset of the disease is usually acute and resolves spontaneously. Acute calcific tendinitis of the interosseous tendons of the hand is an uncommon site of a frequent condition. The clinical presentation is similar to other entities, thus errors in diagnosis frequently occur, resulting in over-treatment or unnecessary tests. We describe a case of acute calcific tendinitis of the interosseous muscles of the hand with a brief review of the current literature with emphasis on diagnostic imaging methods.


Bile acids stimulate proliferative and secretory events in large but not small cholangiocytes.
Accumulation of bile acids (BA) and cholangiocyte proliferation occur in cholestasis, but BA effects on the proliferative and secretory capacity of cholangiocytes are undefined. Cholangiocyte proliferation coupled with increased expression of H3 histone and secretin receptor (SR) genes and secretin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) levels is limited to large cholangiocytes. We isolated pooled small and large cholangiocytes and studied the effect of taurocholic (TC) and taurolithocholic (TLC) acids on proliferation, by measurement of H3 histone gene expression, and secretion, by measurement of SR gene expression, cAMP levels, and Cl-/HCO3- exchanger activity. In pooled cholangiocytes, TC and TLC increased H3 histone (12-fold) and SR (3-fold) gene expression and both spontaneous (1.4-fold) and secretin-induced (4-fold) cAMP response. TC and TLC increased H3 histone (10-fold) and SR (2-fold) gene expression and secretin-induced cAMP response and Cl-/HCO3- exchanger activity (3-fold) only in large cholangiocytes. In large cholangiocytes, BA may have a signaling function in the modulation of ductal secretion.


Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study.
Currently approved Alzheimer's disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor. The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD. This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for > or =12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] A) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatment-emergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements. The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0-138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Delta in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Delta in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs -1.5 [0.88], respectively [P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]).Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication. In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation. ClinicalTrials.gov identifier: NCT00478205.


Retromandibular approach to condyle fractures: two case reports.
Retromandibular approach was first described in 1967 for vertical subcondylar osteotomy and later became popular for surgical treatment of temporomandibular joint dysfunction and low condyle fractures. The trajectory of the incision, parallel to the posterior border of the mandibular ramus, allows a good approach with easy separation of the buccal and marginal mandibular branches of the facial nerve, when they are present in the surgical field. When open reduction and internal rigid fixation with plates and screws are indicated for condylar fractures, retromandibular approach offers an excellent esthetic result with low morbidity. Two clinical cases are presented, in which the surgical treatment was carried out for condylar fractures, and clearly illustrate the proposed approach.


Headache characteristics in senior medical students in Turkey.
Headache is one of the most common neurological complaints of the young population and it affects the quality of life due to limitation of daily activities. In this study, our main goal was to appraise the general headache characteristics in senior medical students just before graduation and to determine the impact of headache on the quality of life, as well as the general attitude of students about their headaches. The study group consisted of 141 senior students. As the first step, the question about "having headache within the past one year period" was asked. Of the 141 students, 127 students answering "yes" were invited to a face-to-face interview. Of these, 67 students (52.8%) participated in the second evaluation. The second evaluation consisted of history taking and neurological and physical examination. All subjects were classified according to the International Classification of Headache Disorders (2nd edition) criteria. Validated Turkish version of Migraine Disability Assessment questionnaire was given to the subjects to evaluate the socio-economical impact of headache. Tension-type headache, which is the most common form of primary headaches, was identified in 34 students (50.7%) out of 67 students. Migraine was detected in 31 students (46.3%). This is the first study performed on a face-to-face interview basis with medical students using the new classification criteria in Turkey. Astonishingly, most of the students (n:65) ignored their headaches and did not seek medication, despite the negative impact of headache on daily functioning and overall quality of life.


Clinical and microbiologic study of periodontal surgery by means of apically positioned flaps with and without osseous recontouring.
In periodontitis lesions with interproximal craters, periodontal flap surgery with osseous recontouring allows more apical positioning of the soft periodontal tissue than flap surgery without osseous recontouring. The present study determined the clinical and microbiologic responses to periodontal surgery with and without osseous recontouring in adult periodontitis lesions with interproximal craters. In 7 osseous surgery patients, osteoplasty and ostectomy were performed from the lingual/palatal aspect to eliminate interproximal osseous defects and to partly mimic the original alveolar bony transition to neighboring teeth. In 7 nonosseous surgery patients, the surgical flap was adapted to the preexisting osseous level. Clinical monitoring included periodontal probing depth, Plaque Index, gingival bleeding index, and radiographic examination. Samples of the subgingival microbiota were examined. In sites treated with osseous surgery, mean pocket depth was 5.5 mm at baseline, 1.9 mm at 1 month, 2.0 mm at 3 months, and 2.1 mm at 6 months. In sites not receiving osseous recontouring surgery, the corresponding pocket depths were 5.9 mm, 3.1 mm, 3.8 mm, and 4.1 mm. At baseline in the osseous surgery group, Actinobacillus actinomycetemcomitans was recovered from one patient and Porphyromonas gingivalis from 5 patients; posttreatment, these microbiota were not detected in any patient. In the nonosseous surgery group, the presence of A actinomycetemcomitans increased posttreatment, and levels of P gingivalis remained essentially unchanged after therapy. This study suggests that in patients not receiving adjunctive antibiotic therapy, apically positioned flap surgery with osseous recontouring is more effective than apically positioned flap surgery without osseous recontouring in reducing periodontal pocket depth and levels of major periodontal pathogens.


Progress in high-power continuous-wave quantum cascade lasers [Invited].
Multi-watt continuous-wave room temperature operation with efficiency exceeding 10% has been demonstrated for quantum cascade lasers essentially in the entire mid-wave and long-wave infrared spectral regions. Along with interband cascade lasers, these devices are the only room-temperature lasers that directly convert electrical power into mid- and long-infrared optical power. In this paper, we review the progress in high-power quantum cascade lasers made over the last 10 years. Specifically, an overview of the most important active region, waveguide, and thermal design techniques is presented, and various aspects of die packaging for high-power applications are discussed. Prospects of power scaling with lateral device dimensions for reaching optical power level in the range from 10 W to 20 W are also analyzed. Finally, coherent and spectral beam-combining techniques for very high-power infrared platforms are discussed.


Chemoproteomics, A Broad Avenue to Target Deconvolution.
As a vital project of forward chemical genetic research, target deconvolution aims to identify the molecular targets of an active hit compound. Chemoproteomics, either with chemical probe-facilitated target enrichment or probe-free, provides a straightforward and effective approach to profile the target landscape and unravel the mechanisms of action. Canonical methods rely on chemical probes to enable target engagement, enrichment, and identification, whereas click chemistry and photoaffinity labeling techniques improve the efficiency, sensitivity, and spatial accuracy of target recognition. In comparison, recently developed probe-free methods detect protein-ligand interactions without the need to modify the ligand molecule. This review provides a comprehensive overview of different approaches and recent advancements for target identification and highlights the significance of chemoproteomics in investigating biological processes and advancing drug discovery processes.


Polyamine effects on cytochrome P-450- and flavin-containing monooxygenase-mediated oxidation of xenobiotics.
The effects of in vitro addition of polyamines on the female mouse hepatic microsomal cytochrome P-450- and flavin-containing monooxygenase-dependent oxidation of xenobiotics were examined. Putrescine, spermine, and spermidine all caused a different degree of stimulation of oxidative dearylation of parathion and O-ethyl-O-p-nitrophenylphosphonothioate, epoxidation of aldrin, and O-deethylation of 7-ethoxycoumarin. The degree of stimulation was greatest in the presence of spermidine. Enhancement of aldrin epoxidation by spermidine was higher in pregnant mice as compared to nonpregnant mice. Total phorate S-oxidation was stimulated by all the polyamines tested. Phorate S-oxidation, mediated by microsomal flavin-containing monooxygenase, was only slightly increased by spermine and spermidine while putrescine caused slight inhibition. Of the various steps involved in the monooxygenation cycle examined, only the rates of NADPH oxidation and cytochrome P-450 reduction were significantly increased. Efficient coupling of NADPH utilization with substrate oxidation appears to be the underlying mechanism responsible for the polyamine-stimulated xenobiotic oxidation.


Caveolin 2: a facultative marker of unfavourable prognosis in long-term patency rate of internal thoracic artery grafts used in coronary artery bypass grafting. Preliminary report.
Intimal hyperplasia leading to graft failure in patients undergoing coronary artery bypass grafting (CABG) is related to vascular smooth muscle cells (SMCs) proliferation. SMCs respond to a variety of mediators, the most important of which is platelet-derived growth factor (PDGF). The platelet-derived growth factor-induced cellular response has been shown to be mediated by caveolins. The aim of this study was to analyze CAV1-3 expression in internal thoracic artery (ITA) grafts used in CABG and correlate their expression with graft occlusion. Six hundred patients undergoing CABG with the use of ITA grafts between 2008 and 2014 were enrolled into this prospective study. CAV1-3 expression in the ITA grafts was analyzed prior to graft transplantation into the coronary circulation via immunohistochemistry. Estimated caveolins expression pattern was then correlated with the occurrence of ITA graft failure observed within 24-months of surgery. Thirty-four patients developed ITA graft failure (subgroup A) and 566 study participants presented no adverse events (subgroup B). CAV1 and CAV3 expression levels in SMCs of the tunica media of the ITA grafts did not differ between the study subgroups and were not associated with the risk of graft failure. CAV2 was expressed within SMCs of the ITA grafts in 94.1% of the patients from subgroup A and 2.5% from subgroup B, and its expression was associated with ITA graft occlusion observed within 24-months after CABG. CAV2 expression in SMCs of the tunica media in autologous ITA transplants might indicate the risk of graft failure.


Immunogenetics associated with severe coccidioidomycosis.
Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.


Investigation of argyrophilic nucleolar organizing region.
Ischemia/reperfusion (I/R) injury is a complex event frequently observed in vascular surgery and can cause functional and structural cell damage. Nucleolar-organizing regions (NORs) are sites of the ribosomal genes located on chromosomes and can be stained with silver when they are active. Thus these proteins are named as argyrophilic-NOR (AgNOR)-associated proteins. We aimed to investigate any possible effects of renal I/R injury on the NOR protein synthesis and association between the AgNOR proteins amount and histopathological injuring score. Nine female wistar-albino rats with weight of 200-250g were included into the study. The animals were randomly divided in two groups, a Control Group and an I/R Group. In I/R group, rats were subjected to 45 minutes of renal pedicle occlusion followed by 24 hours of reperfusion. In the control group no drug injections or ischemia reperfusion were performed in animals. Then histopathological injury score, mean AgNOR number and total AgNOR area/nuclear area (TAA/NA) were detected for each rat. The differences between control and I/R groups were significant for histopathological injury scores (p = 0.016). Also the differences between control group and I/R group were significant for mean AgNOR number (p = 0.000) and TAA/NA ratio (p = 0.000). Additionally, there was a positive correlation between TAA/NA ratio and histopathological injury score (r = 0.728; p = 0.026) and between mean AgNOR number and histopathological injury score (r = 0.670; p = 0.048). The detection of AgNOR proteins amount may be used as an indicator to obtain information about the cellular behaviour (self-protective mechanism of tubular epithelial cells) against I/R injury and cellular damage levels (Tab. 2, Fig. 4, Ref. 24).


Myeloablative cord blood transplantation in adults with acute leukemia: comparison of two different transplant platforms.
We compared the clinical outcomes of adults with acute leukemia that received single-unit umbilical cord blood transplantation (sUCBT) after conditioning with a busulfan/antithymocyte globulin (BU-ATG)-based regimen at University Hospital La Fe (n = 102) or double-unit UCBT (dUCBT) after conditioning with a total body irradiation (TBI)-based regimen at the University of Minnesota (n = 91). Nonrelapse mortality, relapse and disease-free survival were similar in the 2 groups. Multivariate analyses, showed more rapid neutrophil (hazard ratio [HR], .6; 95% confidence interval [CI], .45 to .80; P = .0006) and platelet recovery (HR, .59; 95% CI, .43 to.83; P = .002) after the BU-ATG-based conditioning and sUCBT. Although there was a lower risk of acute graft-versus-host disease (GVHD) grade II to IV (HR, 2.81; 95% CI, 1.75 to 4.35; P < .001) after BU-ATG and sUCBT, the incidences of grade III to IV acute and chronic GVHD were similar between the 2 groups. Regarding disease-specific outcomes, disease-free survival in both acute myeloid leukemia and acute lymphoblastic leukemia (ALL) patients were not significantly different; however, a significantly lower relapse rate was found in patients with ALL treated with TBI and dUCBT (HR, .3; 95% CI, .12 to .84; P = .02). In the context of these specific treatment platforms, our study demonstrates that sUCB and dUCBT offer similar outcomes.


[Subcutaneous mastectomy: the importance of the histopathological assessment technic].
Subcutaneous mastectomy was performed in 300 patients between 1974 and 1981 for various indications. Precancerosis or non-invasive carcinomas were established by previous biopsy in 106 patients. The comparison of pathologic anatomy data of conventional and serial assessment of specimens showed an increase of clinically occult non-invasive carcinomas from 5.4 to 18.3% and of preoperatively undiagnosed invasive carcinomas from 2.3 to 7.7% in serial assessment and unchanged indication. Whereas the therapeutic value of subcutaneous mastectomy cannot be judged with certainty due to the relatively short observation period, the diagnostic value seems, according to these findings, to be ascertained. However, a much more complex histologic assessment technique beyond the usual is required.


The effects of soy flour and N-nitrosobis (2-oxopropyl) amine on the pancreas of the hamster.
Syrian golden hamsters fed diets of raw or heated soy flour for 16 months had an incidence (4%) of pancreatic neoplasms in both groups. Animals injected with N-nitrosobis (2-oxopropyl) amine (BOP) and fed heated soy flour for 15 months developed a high incidence (88%) of microscopic benign and malignant neoplasms, primarily of ductal origin. This was in marked contrast to a similar group of BOP-injected animals which had been fed raw soy flour and in which the incidence of pancreatic neoplasms was less than 10%.


Primary Biliary Cholangitis Alters Functional Connections of the Brain's Deep Gray Matter.
Fatigue, itch, depressed mood, and cognitive impairment significantly impact the quality of life of many patients with primary biliary cholangitis (PBC). Previous neuroimaging studies of non-hepatic diseases suggest that these symptoms are often associated with dysfunction of deep gray matter brain regions. We used resting-state functional magnetic resonance imaging (rsfMRI) to determine whether PBC patients exhibit altered functional connections of deep gray matter. Twenty female non-cirrhotic PBC patients and 21 age/gender-matched controls underwent rsfMRI. Resting-state functional connectivity (rsFC) of deep gray matter brain structures (putamen, thalamus, amygdala, hippocampus) was compared between groups. Fatigue, itch, mood, cognitive performance, and clinical response to ursodeoxycholic acid (UDCA) were assessed, and their association with rsFC was determined. Relative to controls, PBC patients exhibited significantly increased rsFC between the putamen, thalamus, amygdala, and hippocampus, as well as with frontal and parietal regions. Reduced rsFC of the putamen and hippocampus with motor and sensory regions of the brain were also observed. Fatigue, itch, complete response to UDCA, and verbal working memory performance were also associated with altered rsFC of deep gray matter. These rsFC changes were independent of biochemical disease severity. PBC patients have objective evidence of altered rsFC of the brain's deep gray matter that is in part linked to fatigue severity, itch, response to UDCA therapy, and cognitive performance. These results may guide future approaches to define how PBC leads to altered brain connectivity and provide insight into novel targets for treating PBC-associated brain dysfunction and behavioral symptoms.


Cholesterol: A Prelate in Cell Nucleus and its Serendipity.
Cholesterol is a chameleon bio-molecule in cellular multiplex. It acts as a prelate in almost every cellular compartment with its site specific characteristics viz. regulation of structural veracity and scaffold fluidity of bio-membranes, insulation of electrical transmission in nerves, controlling of genes by making steroid endocrines, acting as precursors of metabolic regulators and many more with its emerging prophecy in the cell nucleus to drive new cell formation. Besides the crucial legacy in cellular functionality, cholesterol is ostracized as a member of LDL particle, which has been proved responsible to clog blood vessels. LDL particles get deposited in the blood vessels because of their poor clearance owing to the non-functioning LDL receptor on the vessel wall and surrounding tissues. Blocking of blood vessel promotes heart attack and stroke. On the other hand, cholesterol has been targeted as pro-cancerous molecule. At this phase again cholesterol is biphasic. Although cholesterol is essential to construct nuclear membrane and its lipid-rafts; in cancer tumour cells, cholesterol is not under the control of intracellular feedback regulation and gets accumulated within cell nucleus by crossing nuclear membrane and promoting cell proliferation. In precancerous stage, the immune cells also die because of the lack of requisite concentration of intracellular and intranuclear cholesterol pool. The existence of cholesterol within the cell nucleus has been found in the nuclear membrane, epichromosomal location and nucleoplasm. The existence of cholesterol in the microdomain of nuclear raft has been reported to be linked with gene transcription, cell proliferation and apoptosis. Hydrolysis of cholesterol esters in chromosomal domain is linked with new cell generation. Apparently, Cholesterol is now a prelate in cell nucleus too ------ A serendipity in cellular haven.


[The action of laser radiation on the phosphoinositide cycle and calcium absorption in the squid neural trunk].
The content of polyphosphoinositides and phosphatidic acid increases in the squid axon under the action of laser radiation and the content of monophosphoinsitide decreases. At the same time the absorption of calcium ions by axon decreases. It is suggested that the laser radiation intensifies the synthesis of polyphosphoinositides and inhibits the system responsible for their degradation as well causes the desorption of the surface-bound calcium.


Multifunctional Nanoplatform for NIR-II Imaging-Guided Synergistic Oncotherapy.
Tumors are a major public health issue of concern to humans, seriously threatening the safety of people's lives and property. With the increasing demand for early and accurate diagnosis and efficient treatment of tumors, noninvasive optical imaging (including fluorescence imaging and photoacoustic imaging) and tumor synergistic therapies (phototherapy synergistic with chemotherapy, phototherapy synergistic with immunotherapy, etc.) have received increasing attention. In particular, light in the near-infrared second region (NIR-II) has triggered great research interest due to its penetration depth, minimal tissue autofluorescence, and reduced tissue absorption and scattering. Nanomaterials with many advantages, such as high brightness, great photostability, tunable photophysical properties, and excellent biosafety offer unlimited possibilities and are being investigated for NIR-II tumor imaging-guided synergistic oncotherapy. In recent years, many researchers have tried various approaches to investigate nanomaterials, including gold nanomaterials, two-dimensional materials, metal sulfide oxides, polymers, carbon nanomaterials, NIR-II dyes, and other nanomaterials for tumor diagnostic and therapeutic integrated nanoplatform construction. In this paper, the application of multifunctional nanomaterials in tumor NIR-II imaging and collaborative therapy in the past three years is briefly reviewed, and the current research status is summarized and prospected, with a view to contributing to future tumor therapy.


Phosphatidylinositol 3-kinase inhibitor suppresses inducible nitric oxide synthase expression in bronchiole epithelial cells in asthmatic rats.
Inducible nitric oxide synthase (iNOS) is known to produce nitric oxide (NO), which is a main contributor to asthmatic airway inflammation. Recent studies have shown that phosphatidylinositol 3-kinase (PI3K) is ubiquitously expressed in airway epithelial cells and its inhibition could relieve airway inflammation and hyperresponsiveness. This study aimed to explore the interaction of PI3K and NO signaling in allergic asthma. We investigated the effects of PI3K inhibitor wortmannin on iNOS expression in bronchiole epithelial cells and NO, IL-4 and IFN-γ levels in lung tissues of asthmatic rat model, which was prepared by 10% OVA solution sensitization and 1% OVA aerosol challenge. Our results showed that the ratio of eosinophils to total cells in BALF, PI3K activity, NO and IL-4 levels in lung tissues was increased after OVA sensitization and challenge, but then was attenuated by the administration of wortmannin. In contrast, IFN-γ level in lung tissues was decreased after OVA sensitization and challenge and increased after the administration of wortmannin. The expression of iNOS protein in bronchiole epithelial cells, iNOS mRNA level and iNOS activity in lung tissues was markedly upregulated after OVA sensitization and challenge, but the upregulation was significantly antagonized by wortmannin. Taken together, these data provide evidence that PI3K functions upstream to modulate iNOS/NO signaling, which then promotes the development of airway inflammation in asthmatic animal model. PI3K inhibitor wortmannin could lead to reduced iNOS expression and NO production, therefore inhibiting airway inflammatory responses.


TMEM16A channels generate Ca²⁺-activated Cl⁻ currents in cerebral artery smooth muscle cells.
Transmembrane protein (TMEM)16A channels are recently discovered membrane proteins that display electrophysiological properties similar to classic Ca(2+)-activated Cl(-) (Cl(Ca)) channels in native cells. The molecular identity of proteins that generate Cl(Ca) currents in smooth muscle cells (SMCs) of resistance-size arteries is unclear. Similarly, whether cerebral artery SMCs generate Cl(Ca) currents is controversial. Here, using molecular biology and patch-clamp electrophysiology, we examined TMEM16A channel expression and characterized Cl(-) currents in arterial SMCs of resistance-size rat cerebral arteries. RT-PCR amplified transcripts for TMEM16A but not TMEM16B-TMEM16H, TMEM16J, or TMEM16K family members in isolated pure cerebral artery SMCs. Western blot analysis using an antibody that recognized recombinant (r)TMEM16A channels detected TMEM16A protein in cerebral artery lysates. Arterial surface biotinylation and immunofluorescence indicated that TMEM16A channels are located primarily within the arterial SMC plasma membrane. Whole cell Cl(Ca) currents in arterial SMCs displayed properties similar to those generated by rTMEM16A channels, including Ca(2+) dependence, current-voltage relationship linearization by an elevation in intracellular Ca(2+) concentration, a Nerstian shift in reversal potential induced by reducing the extracellular Cl(-) concentration, and a negative reversal potential shift when substituting extracellular I(-) for Cl(-). A pore-targeting TMEM16A antibody similarly inhibited both arterial SMC Cl(Ca) and rTMEM16A currents. TMEM16A knockdown using small interfering RNA also inhibited arterial SMC Cl(Ca) currents. In summary, these data indicate that TMEM16A channels are expressed, insert into the plasma membrane, and generate Cl(Ca) currents in cerebral artery SMCs.


Structural brain changes as biomarkers and outcome predictors in patients with late-life depression: a cross-sectional and prospective study.
The relationship between structural changes in grey matter and treatment response in patients with late-life depression remains an intriguing area of research. This magnetic resonance imaging (MRI) study compares the baseline grey matter volume of elderly people with and without major depression (according to the DSM-IV-TR criteria) and assesses its association with antidepressant treatment response. Brain MRI scans were processed using statistical parametric mapping and voxel-based morphometry. The sample consisted of 30 patients with depression and 22 healthy controls. We found a significant volumetric reduction in the orbitofrontal cortex bilaterally in patients in comparison with controls. According to their remission status after antidepressant treatment, patients were classified as remitted or not remitted. Compared with controls, remitted patients showed a volumetric reduction in the orbitofrontal cortex bilaterally and in another cluster in the right middle temporal pole. Non-remitted patients showed an even greater volumetric reduction in the orbitofrontal cortex bilaterally compared with controls. To investigate predictive factors of remission after antidepressant treatment, we used a logistic regression. Both baseline Mini Mental State Examination score and baseline left superior lateral orbitofrontal cortex volume (standardized to the total grey matter volume) were associated with remission status. Our findings support the use of regional brain atrophy as a potential biomarker for depression. In addition, baseline cognitive impairment and regional grey matter abnormalities predict antidepressant response in patients with late-life depression.


Co-capping of insulin, epidermal growth factor and concanavalin A surface receptors with each other and with cytoplasmic actin.
Concanavalin A (Con A), insulin and epidermal growth factor (EGF) surface membrane receptors on cultured bovine odontogenic epithelial cells, were demonstrated by immunofluorescent reactivity with fluorescein-isothiocyanate (FITC) conjugated Con A, FITC-insulin, or EGF and anti-EGF, traced with FITC goat anti-rabbit globulin. Con A, insulin and EGF receptors co-capped with each other and with cytoplasmic actin; the latter was demonstrated by anti-actin antibody (AAA) traced with fluorescein or rhodamine-labelled goat anti-human globulin. Capping of receptors was promoted by prior treatment of cells with cytochalasin B or colchicine, but inhibited by the presence of the drugs throughout the experimental procedure. Binding of a ligand to its receptor promoted capping of an unrelated ligand-bound receptor, a phenomenon that was inhibited by cytochalasin B or colchicine. These results suggest that surface receptors for insulin, EGF and Con A interact with each other and with cytoplasmic actin.


Sinonasal Anatomic Variants in Allergic Fungal Rhinosinusitis.
The pathophysiology of allergic fungal rhinosinusitis (AFRS) is not well understood. To study the incidence of sinonasal anatomic variants (AVs) in AFRS. Retrospective cohort study. Patients with AFRS presenting to our clinic from 2008 to 2018 were reviewed for laterality of the disease. Patients with unilateral involvement were further studied for AV presence by reviewing their preoperative sinus CT scan at original presentation. Each patient's uninvolved side served as its own control. AVs studied include agger nasi (AN), Haller's cells (HC), concha bullosa (CB) and supraorbital ethmoid cells (SOEC). A total of 155 patients with AFRS were identified. 30 patients (19.3%) had unilateral disease involvement. Of these, 16 patients had left sided and 14 patients had right sided disease. AV were present in 26 of the 30 AFRS sides (86.7%) and in 21 of the 30 healthy sides (70%), (chi squared = 2.45, p = 0.117). CB were present in 12 of 30 AFRS sides (40%) and only in 1 of 30 healthy sides (3%), (chi squared = 11.88, p = 0.0006). The presence of HC was more common in the AFRS vs healthy sides (7 of 30, 23.3% vs 2 of 30, 6.7%, respectively, p = 0.071). AN and SOEC presence was similar in both AFRS and healthy sides (p = 0.598 and p = 0.718 respectively). AV are more common on the sides with AFRS compared to healthy sides, with the presence of CB reaching unquestionable statistical significance. Further study is needed to determine the possible association of AV, especially concha bullosa, with the pathophysiology of AFRS.


Release of oxygen products from lung macrophages by N-formyl peptides.
Incubation of guinea pig pulmonary macrophages with N-formylmethionylphenylalanine (FMP) resulted in 1) a rapid increase in O2 consumption and 2) an accumulation of superoxide anion and hydrogen peroxide in the extracellular medium. The accumulation of superoxide anion and hydrogen peroxide was completely prevented in the presence of superoxide dismutase and catalase, respectively. FMP-stimulated O2 consumption and superoxide anion and hydrogen peroxide accumulation were proportional to the macrophage concentration, showed similar dependence on FMP concentration, had nearly identical kinetics, and were partially abolished by antimycin A, an inhibitor of mitochondrial respiration. FMP also stimulated a three- to fourfold increase in hexose monophosphate shunt (HMS) activity. Catalase had no effect on the amount of glucose oxidized by the HMS, indicating that removal of hydrogen peroxide was without effect on the observed HMS activity. Since FMP is similar in structure to the oligopeptides of bacterial metabolism, its ability to stimulate the release of these microbiocidal products of oxygen metabolism may be important in vivo.


Sudden cardiac death in young athletes: time for a Nordic approach in screening?
In 2005, the European Society of Cardiology published recommendations for cardiovascular screening in athletes. Discussion on whether screening is beneficial is ongoing. Recently, the first prospective results on effectiveness of screening in preventing sudden deaths were published from Italy. The results were supportive of screening, but did not provide conclusive evidence. Our suggestion for a Nordic approach on this issue is a directed cardiovascular examination initially involving elite athletes, because this is feasible with respect to the Nordic health care systems and the organization and logistics of elite competitive sports, but also because of the negative aspects of screening large populations. This directed cardiovascular examination would include personal and family history, clinical examination, and electrocardiography (ECG). Further examinations should thereafter be carried out in athletes with suggestive findings in the initial evaluation. The directed cardiovascular examination should be voluntary. It should be conducted at least once, with information on alarming symptoms (syncope, chest pain or dizziness during exercise) and heredity (sudden cardiac death or hereditary heart disease in near relatives) stressed to the athlete as indications for necessary check-ups in the future. The examination would also provide the athlete with an ECG recording, which is valuable as a reference at a later time.


Natural family-free genomic distance.
A classical problem in comparative genomics is to compute the rearrangement distance, that is the minimum number of large-scale rearrangements required to transform a given genome into another given genome. The traditional approaches in this area are family-based, i.e., require the classification of DNA fragments of both genomes into families. Furthermore, the most elementary family-based models, which are able to compute distances in polynomial time, restrict the families to occur at most once in each genome. In contrast, the distance computation in models that allow multifamilies (i.e., families with multiple occurrences) is NP-hard. Very recently, Bohnenkämper et al. (J Comput Biol 28:410-431, 2021) proposed an ILP formulation for computing the genomic distance of genomes with multifamilies, allowing structural rearrangements, represented by the generic double cut and join (DCJ) operation, and content-modifying insertions and deletions of DNA segments. This ILP is very efficient, but must maximize a matching of the genes in each multifamily, in order to prevent the free lunch artifact that would otherwise let empty or almost empty matchings give smaller distances. In this paper, we adopt the alternative family-free setting that, instead of family classification, simply uses the pairwise similarities between DNA fragments of both genomes to compute their rearrangement distance. We adapted the ILP mentioned above and developed a model in which pairwise similarities are used to assign weights to both matched and unmatched genes, so that an optimal solution does not necessarily maximize the matching. Our model then results in a natural family-free genomic distance, that takes into consideration all given genes, without prior classification into families, and has a search space composed of matchings of any size. In spite of its bigger search space, our ILP seems to be boosted by a reduction of the number of co-optimal solutions due to the weights. Indeed, it converged faster than the original one by Bohnenkämper et al. for instances with the same number of multiple connections. We can handle not only bacterial genomes, but also fungi and insects, or sets of chromosomes of mammals and plants. In a comparison study of six fruit fly genomes, we obtained accurate results.


Receipt of monitoring of diabetes mellitus in older adults with comorbid dementia.
To examine the extent to which receipt of recommended monitoring of diabetes mellitus (DM) differed for participants with and without comorbid dementia, as well as the effect of other comorbidities on monitoring of DM in individuals with comorbid dementia. Retrospective cohort study. Secondary analysis of 2005/2006 claims and enrollment data for a 5% national random sample of Medicare beneficiaries. Two hundred eighty-eight thousand eight hundred five Medicare fee-for-service beneficiaries with a diagnosis of DM before 2006, 44,717 (16%) of whom had evidence of comorbid dementia in claims. Established algorithms were used to determine whether patients received at least one glycosylated hemoglobin (HbA1c) test, one low-density lipoprotein cholesterol (LDL-C) test, and one annual eye examination in 2006 and to construct variables representing comorbidities common in DM, sociodemographic characteristics, and patterns of healthcare utilization. In unadjusted and fully adjusted models, the presence of dementia reduced the likelihood of receiving HbA1c tests, LDL-C tests, and eye examinations, with effects being smallest for HbA1c tests. The effects of other comorbidities on DM monitoring in participants with dementia varied according to the nature of the comorbidity and the specific test. Dementia reduces the likelihood that individuals with DM will receive recommended annual monitoring for DM. More research is needed to understand reasons for lower monitoring in this subgroup and how this affects functioning, adverse events, and quality of life.


Mesoscale laser 3D printing.
3D meso scale structures that can reach up to centimeters in overall size but retain micro- or nano-features, proved to be promising in various science fields ranging from micro-mechanical metamaterials to photonics and bio-medical scaffolds. In this work, we present synchronization of the linear and galvanometric scanners for efficient femtosecond 3D optical printing of objects at the meso-scale (from sub-μm to sub-cm spanning five orders of magnitude). In such configuration, the linear stages provide stitch-free structuring at nearly limitless (up to tens-of-cm) working area, while galvo-scanners allow to achieve translation velocities in the range of mm/s-cm/s without sacrificing nano-scale positioning accuracy and preserving the undistorted shape of the final print. The principle behind this approach is demonstrated, proving its inherent advantages in comparison to separate use of only linear stages or scanners. The printing rate is calculated in terms of voxels/s, showcasing the capability to maintain an optimal feature size while increasing throughput. Full capabilities of this approach are demonstrated by fabricating structures that reach millimeters in size but still retain sub-μm features: scaffolds for cell growth, microlenses, and photonic crystals. All this is combined into a benchmark structure: a meso-butterfly. Provided results show that synchronization of two scan modes is crucial for the end goal of industrial-scale implementation of this technology and makes the laser printing well aligned with similar approaches in nanofabrication by electron and ion beams.


Biochemical and structural insights into microtubule perturbation by CopN from Chlamydia pneumoniae.
Although the actin network is commonly hijacked by pathogens, there are few reports of parasites targeting microtubules. The proposed member of the LcrE protein family from some Chlamydia species (e.g. pCopN from C. pneumoniae) binds tubulin and inhibits microtubule assembly in vitro. From the pCopN structure and its similarity with that of MxiC from Shigella, we definitively confirm CopN as the Chlamydia homolog of the LcrE family of bacterial proteins involved in the regulation of type III secretion. We have also investigated the molecular basis for the pCopN effect on microtubules. We show that pCopN delays microtubule nucleation and acts as a pure tubulin-sequestering protein at steady state. It targets the β subunit interface involved in the tubulin longitudinal self-association in a way that inhibits nucleotide exchange. pCopN contains three repetitions of a helical motif flanked by disordered N- and C-terminal extensions. We have identified the pCopN minimal tubulin-binding region within the second and third repeats. Together with the intriguing observation that C. trachomatis CopN does not bind tubulin, our data support the notion that, in addition to the shared function of type III secretion regulation, these proteins have evolved different functions in the host cytosol. Our results provide a mechanistic framework for understanding the C. pneumoniae CopN-specific inhibition of microtubule assembly.


Enoyl coenzyme a hydratase domain-containing 2, a potential novel regulator of myocardial ischemia injury.
We reported previously that Brown Norway (BN) rats are more resistant to myocardial ischemia/reperfusion (I/R) injury than are Dahl S (SS) rats. To identify the unique genes differentially expressed in the hearts of these rats, we used DNA microarray analysis and observed that enoyl coenzyme A hydratase-containing domain 2 (ECHDC2) is highly expressed (≈18-fold) in the SS hearts compared with the BN hearts. RT-PCR, Western blot, and immunohistochemistry analyses verified that ECHDC2 was highly expressed in SS hearts compared with the BN hearts. ECHDC2 gene locates at chromosome 5 of rat and is expressed in mitochondria of the heart, mainly in cardiomyocytes but not in cardiofibroblasts. Overexpression of ECHDC2 in cells increased susceptibility to I/R injury while knockdown of ECHDC2 enhanced resistance to I/R injury. Furthermore, we observed that left anterior descending coronary artery ligation-induced myocardial infarction was more severe in the SS hearts than in the BN hearts or SSBN5 hearts, which was built on SS rats but had the substitution of chromosome 5 from BN rats. We also demonstrated that ECHDC2 did not alter mitochondrial O2 consumption, metabolic intermediates and ATP production. By gas chromatography-mass spectrometry, we found that ECHDC2 overexpression increased the levels of the cellular branched chain amino acids leucine and valine. ECHDC2, a mitochondrial protein, may be involved in regulating cell death and myocardial injury. Its deficiency in BN rats contributes to their increased resistance to myocardial I/R compared with SS rats. ECHDC2 increases branched chain amino acid metabolism and appears to be a novel regulator linking cell metabolism with cardiovascular disease.


Streptomyces sp. TEM 33 possesses high lipolytic activity in solid-state fermentation in comparison with submerged fermentation.
Solid-state fermentation (SSF) is a bioprocess that doesn't need an excess of free water, and it offers potential benefits for microbial cultivation for bioprocesses and product development. In comparing the antibiotic production, few detailed reports could be found with lipolytic enzyme production by Streptomycetes in SSF. Taking this knowledge into consideration, we prefer to purify Actinomycetes species as a new source for lipase production. The lipase-producing strain Streptomyces sp. TEM 33 was isolated from soil and lipase production was managed by solid-state fermentation (SSF) in comparison with submerged fermentation (SmF). Bioprocess-affecting factors like initial moisture content, incubation time, and various carbon and nitrogen additives and the other enzymes secreted into the media were optimized. Lipase activity was measured as 1.74 ± 0.0005 U/g dry substrate (gds) by the p-nitrophenylpalmitate (pNPP) method on day 6 of fermentation with 71.43% final substrate moisture content. In order to understand the metabolic priority in SSF, cellulase and xylanase activity of Streptomyces sp. TEM33 was also measured. The microorganism degrades the wheat bran to its usable form by excreting cellulases and xylanases; then it secretes the lipase that is necessary for degrading the oil in the medium.


Magnitude of flat foot and its associated factors among school-aged children in Southern Ethiopia: an institution-based cross-sectional study.
Flat foot, also known as pes planus, is a common condition among primary school children and is a leading cause of all clinical visits related to foot problems worldwide. It can cause skeletal problems and joint misalignment. This study aimed to assess the magnitude of flat foot and its associated factors among public primary school children. An institutional-based cross-sectional study was conducted on 1072 school children aged 11 to 18 years. A structured questionnaire was used for data collection and the footprints were used to calculate the plantar arch index. Data were entered into Epi data version 4.6, and analyzed by STATA version 15. Bivariable and multivariable binary logistic regressions were conducted. Adjusted odds ratios (AORs) with corresponding 95% confidence intervals (CIs) were calculated. Statistical significance was declared at a P-value < 0.05. Out of 1022 participants, 105(10.27%) 95%CI: 8.5-12) had a flat foot. Being male (AOR = 2; 95%CI:1.22-3.30), living in highland altitude (AOR = 8.83; 95% CI: 4.64-16.79), living in midland altitude (AOR = 3.32;95% CI:1.75-6.29), living in an urban area (AOR = 2.42;95% CI:1.15-5.09), insufficient physical activity (AOR = 8.78;95% CI: 4.42-12.3), wearing closed-toe shoes (AOR = 2.33;95%CI:1.27-4.28), obesity (AOR = 6.30;95% CI:3.31-11.9), and foot pain (AOR = 3.52;95%CI:2.08-6.27) had a higher likelihood of flat foot as compared to their counterparts. One in every ten children had a flat foot. Altitude, residence, sex, physical activity, foot pain, body mass index, and type of footwear were found to be factors statistically associated with flat foot. Integrated interventions for children to have sufficient physical activity, wearing sandals, maintaining a healthy body mass index, and flatfoot screening and monitoring are recommended.


Live cell imaging of phosphoinositide dynamics during Legionella infection.
The "accidental" pathogen Legionella pneumophila replicates intracellularly in a distinct compartment, the Legionella-containing vacuole (LCV). To form this specific pathogen vacuole, the bacteria translocate via the Icm/Dot type IV secretion system approximately 300 different effector proteins into the host cell. Several of these secreted effectors anchor to the cytoplasmic face of the LCV membrane by binding to phosphoinositide (PI) lipids. L. pneumophila thus largely controls the localization of secreted bacterial effectors and the recruitment of host factors to the LCV through the modulation of the vacuole membrane PI pattern. The LCV PI pattern and its dynamics can be studied in real-time using fluorescently labeled protein probes stably produced by the soil amoeba Dictyostelium discoideum. In this chapter, we describe a protocol to (1) construct and handle amoeba model systems as a tool for observing PIs in live cell imaging, (2) capture rapid changes in membrane PI patterning during uptake events, and (3) observe the dynamics of LCV PIs over the course of a Legionella infection.


Academic time during college: Associations with mood, tiredness, and binge drinking across days and semesters.
The current study examined the amount of time American college students spent on academics and explored whether functioning indicators (i.e., positive affect, negative affect, tiredness, and binge drinking) rose and fell with academic time across days and semesters. College students (N = 735) were followed longitudinally and completed 14 daily diaries within each of 7 semesters (N = 56,699 days). The results revealed that academic time decreased slightly during the middle semesters and then increased in later semesters. Furthermore, on days when students spent more time on academics, they reported less positive affect, more tiredness, and less binge drinking; however, the strength and direction of associations depended on the analysis level and whether it was a weekend. Positive affect, for instance, was inversely associated with academics across days, but the reverse was true across semesters. These results emphasize the importance of considering the temporal context in research on adolescent and young adult time use.


Relationship between abdominal obesity, platelet blood count and mean platelet volume in patients with metabolic syndrome.
There is evidence that patients with the metabolic syndrome have altered platelet indices including higher mean platelet volume. According to the 2009 International Diabetes Federation criteria of metabolic syndrome diagnosis, elevated waist circumference (≥94 cm in M, ≥80 cm in F), as a determinant of abdominal obesity, is not an obligatory component. The aim of this study was to evaluate the relationship between platelet indices, including mean platelet volume, and abdominal obesity in patients with metabolic syndrome. 382 consecutive patients were enrolled in the study and divided into three groups: group A, 218 patients with metabolic syndrome and abdominal obesity (132 M, mean age 65.3 ± 10.9 yrs); group B, 35 patients with metabolic syndrome without abdominal obesity (28 M, mean age 63.3 ± 11.2 yrs); and, group C, 129 patients without metabolic syndrome and without abdominal obesity (99 M, mean age 62.2 ± 13.8 yrs). In group A, mean platelet volume was significantly higher than in group C (10.70 ± 1.01 vs. 10.35 ± 0.94 fL, p = 0.007). However, there was no difference in mean platelet volume between group A and B (10.70 ± 1,01vs. 10.63 ± 1.03 fL, p >0.05). Furthermore, in group A, mean platelet volume was correlated with waist circumference (r = 0.14, p = 0.041) and body mass index (r = 0.14, p = 0.045). In all study groups, a significant association between mean platelet volume and platelet count (r = -0.33, p <0.001) was found. In individuals with metabolic syndrome and abdominal obesity mean platelet volume is positively correlated with waist circumference and significantly higher than in patients without these abnormalities.


Asymptomatic patients of chronic obstructive pulmonary disease in China.
Chronic obstructive pulmonary disease (COPD) has a variable natural history and not all individuals follow the same course. This study aimed to identify the prevalence and characteristics of asymptomatic COPD patients from a population-based survey in China. A multistage cluster sampling strategy was used in a population from seven different provinces/cities. All residents (over 40 years old) were interviewed with a standardized questionnaire and spirometry. Post-bronchodilator forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) of less than 70% was defined as the diagnostic criterion of COPD. All COPD patients screened were divided into symptomatic group and asymptomatic group according to the presence or absence of chronic respiratory symptoms. Socio-demographic, personal and exposure variables were collected and analyzed. Among the 1668 patients who were diagnosed with COPD from the 25 627 sampling subjects, 589 (35.3%) were asymptomatic. The age, sex, body mass index (BMI), rural and urban distributions, smoking habit and education levels were similar in the two groups. A total of 64.7% of the asymptomatic patients had no comorbidities. Cardiovascular diseases and lung cancer were more common among symptomatic COPD patients than asymptomatic group. Asymptomatic COPD group were less likely to present with poor ventilation in the kitchen, a family history of respiratory disease and recurrent childhood cough. Asymptomatic COPD patients had significantly higher FEV(1) (73.1% vs. 61.0%), FVC (91.9% vs. 82.0%), and a higher ratio of FEV(1)/FVC (62.9% vs. 58.7%) (all P < 0.001) than symptomatic group. More asymptomatic patients were underdiagnosed (91.9% vs. 54.3%, P < 0.001) than symptomatic patients. This large population-based survey confirmed a high prevalence of asymptomatic COPD patients in China. More use of spirometry screening test may be important to the early detection of COPD.


Helper component-proteinase enhances the activity of 1-deoxy-D-xylulose-5-phosphate synthase and promotes the biosynthesis of plastidic isoprenoids in Potato virus Y-infected tobacco.
Virus-infected plants show strong morphological and physiological alterations. Many physiological processes in chloroplast are affected, including the plastidic isoprenoid biosynthetic pathway [the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway]; indeed, isoprenoid contents have been demonstrated to be altered in virus-infected plants. In this study, we found that the levels of photosynthetic pigments and abscisic acid (ABA) were altered in Potato virus Y (PVY)-infected tobacco. Using yeast two-hybrid assays, we demonstrated an interaction between virus protein PVY helper component-proteinase (HC-Pro) and tobacco chloroplast protein 1-deoxy-D-xylulose-5-phosphate synthase (NtDXS). This interaction was confirmed using bimolecular fluorescence complementation (BiFC) assays and pull-down assays. The Transket_pyr domain (residues 394-561) of NtDXS was required for interaction with HC-Pro, while the N-terminal region of HC-Pro (residues 1-97) was necessary for interaction with NtDXS. Using in vitro enzyme activity assays, PVY HC-Pro was found to promote the synthase activity of NtDXS. We observed increases in photosynthetic pigment contents and ABA levels in transgenic plants with HC-Pro accumulating in the chloroplasts. During virus infection, the enhancement of plastidic isoprenoid biosynthesis was attributed to the enhancement of DXS activity by HC-Pro. Our study reveals a new role of HC-Pro in the host plant metabolic system and will contribute to the study of host-virus relationships.


Accommodation and related risk factors associated with myopia progression and their interaction with treatment in COMET children.
To examine baseline measurements of accommodative lag, phoria, reading distance, amount of near work, and level of myopia as risk factors for progression of myopia and their interaction with treatment over 3 years, in children enrolled in the Correction of Myopia Evaluation Trial (COMET). COMET enrolled 469 ethnically diverse children (ages, 6-11 years) with myopia between -1.25 and -4.50 D. They were randomly assigned to either progressive addition lenses (PALs) with a +2.00 addition (n = 235) or single vision lenses (SVLs; n = 234), the conventional spectacle treatment, and were observed for 3 years. The primary outcome measure was progression of myopia by autorefraction after cycloplegia with 2 drops of 1% tropicamide. Other measurements included accommodative response (by an open field of view autorefractor), phoria (by cover test), reading distance, and hours of near work. Independent and interaction analyses were based on the mean of the two eyes. Results were adjusted for important covariates with multiple linear regression. Children with larger accommodative lags (>0.43 D for a 33 cm target) wearing SVLs had the most progression at 3 years. PALs were effective in slowing progression in these children, with statistically significant 3-year treatment effects (mean +/- SE) for those with larger lags in combination with near esophoria (PAL - SVL progression = -1.08 D - [-1.72 D] = 0.64 +/- 0.21 D), shorter reading distances (0.44 +/- 0.20 D), or lower baseline myopia (0.48 +/- 0.15 D). The 3-year treatment effect for larger lags in combination with more hours of near work was 0.42 +/- 0.26 D, which did not reach statistical significance. Statistically significant treatment effects were observed in these four groups at 1 year and became larger from 1 to 3 years. The results support the COMET rationale (i.e., a role for retinal defocus in myopia progression). In clinical practice in the United States children with large lags of accommodation and near esophoria often are prescribed PALs or bifocals to improve visual performance. Results of this study suggest that such children, if myopic, may have an additional benefit of slowed progression of myopia.


Application of a viability-staining method for Mycobacterium leprae derived from the athymic (nu/nu) mouse foot pad.
Mycobacterium leprae cannot be cultured, so ascertaining viability of the organism remains a major obstacle, impeding many avenues of investigation. This study tested a two-colour, Syto9 and propidium iodide, fluorescence assay, which scores for membrane damage in individual bacilli, to determine if a rapid direct-count viability-staining technique can be reliably applied to M. leprae. A variety of experimental conditions were employed to validate this technique. This technique was also used to correlate the viability of M. leprae with the course of athymic mouse foot pad infection to optimize the provision of viable M. leprae as a research reagent. The data show that in untreated suspensions of M. leprae there is a good correlation between the metabolic activity of leprosy bacilli and their membrane damage. Fixation of M. leprae with ethanol, paraformaldehyde and gluteraldehyde completely suppressed their metabolic activity but showed little effect on their membrane integrity. The present study also showed that the metabolic activity of M. leprae declines more than the extent of membrane damage at 37 degrees C within 72 h, but that they are not significantly affected at 33 degrees C. Irradiation at 10(4) Gy showed high numbers of dead bacilli by the staining method. The results show that the reliability of metabolic-activity data as well as viability-staining data is dependent on the method by which M. leprae is killed. This staining method helped us predict reliably that the smaller M. leprae-infected athymic mouse foot pad seen early in infection, between 4 and 5 months, yields markedly better quality leprosy bacilli than older, larger foot pad infections, as defined by their metabolic activity and membrane integrity.


Use of photoplethysmography to determine the survival length of skin flaps.
Photoplethysmography was used to evaluate 14 skin flaps in the pig. Eight skin flaps were 4x12 cm and were based dorsally. Six skin flaps were 4x18 cm and were based ventrally. All flaps were designed to undergo necrosis of the distal end. After elevation of the flap, blood flow to the skin flaps was estimated immediately by means of intravenously administered fluorescein. Photoplethysmography was used to determine blood flow to the skin flaps at 3, 24, 72, and 144 hours after elevation. Surviving length of the skin flaps was measured at nine days. Fluorescein accurately predicted the surviving length of the skin flaps. Photoplethysmography did not show a decrease in blood flow at the level of fluorescein penetration 3 or 48 hours after elevation. However, 72 and 144 hours after elevation, an abrupt decrease in blood flow was noted by photoplethysmography at the level of eventual skin necrosis.


Recent highlights in electro-driven separations- selected applications of alkylthiol gold nanoparticles in capillary electrophoresis and capillary electro-chromatography.
To date, alkylthiol gold nanoparticles (AuNPs) have been widely used in electro-chromatographic separation techniques as a viable alternative to traditional stationary phases. This is mainly due to their stability, chemical inertness, ease of functionality, increased phase ratio, ability to form self-assembled monolayers. They also yield versatile stationary phases with highly specific targeted functionalities. At the nanoscale region, the chemical and physical properties of a molecule display different attributes to that of the parent molecules or material, hence these features can be harnessed in electro-driven chromatographic separations. Application areas illustrating the use of AuNPs in separation science continue to grow and expand to cover many different kinds of analysis. The last decade has witnessed a successful trend in miniaturisation of chemical separation systems toward the micro and nanoscale ranges. Nanoparticle-based stationary phases fit well with performing chemical separations on microfluidic and capillary platforms. In this review the theory of the use of alkylthiol gold nanoparticles in electro-chromatographic driven separation methods will be discussed. This will be followed by details of recent and selected applications showing alkylthiol gold nanoparticles in capillary electrophoretic and open-tubular electro-chromatographic separations. This review will focus solely on alkylthiol based gold nanoparticles, therefore other kinds of chemical moieties bonded to gold nanoparticles are outside the scope of this review. Finally the future outlook of this exciting technology will be outlined in some detail in the final section.


Defective splicing of the first nad4 intron is associated with lack of several complex I subunits in the Nicotiana sylvestris NMS1 nuclear mutant.
In this work, we provide evidence for the existence of a nuclear factor involved in the splicing of a specific mitochondrial intron in higher plants. In the Nicotiana sylvestris nuclear NMS1 mutant, defective in both vegetative and reproductive development, the first intron of the nad4 transcript encoding the complex I NAD4 subunit is not removed, whatever the tissue analysed. Transcript patterns of other standard mitochondrial genes are not affected in NMS1. However, numerous polypeptides are missing in two-dimensional in organelle mitochondrial protein synthesis patterns and several nuclear and mitochondrial complex I subunits are present in trace amounts. This indicates that translational or post-translational steps in the synthesis of other mitochondrial proteins are affected. All of these defects co-segregated with the abnormal phenotype in the offspring of a NMS1 x wild-type cross, showing that they are controlled by the same nuclear gene (MS1) or tightly linked loci. Such a complex situation has been described in chloroplasts and mitochondria of fungi, but never in higher plant mitochondria.


Preprocessing of NMR metabolomics data.
Metabolomics involves the large scale analysis of metabolites and thus, provides information regarding cellular processes in a biological sample. Independently of the analytical technique used, a vast amount of data is always acquired when carrying out metabolomics studies; this results in complex datasets with large amounts of variables. This type of data requires multivariate statistical analysis for its proper biological interpretation. Prior to multivariate analysis, preprocessing of the data must be carried out to remove unwanted variation such as instrumental or experimental artifacts. This review aims to outline the steps in the preprocessing of NMR metabolomics data and describe some of the methods to perform these. Since using different preprocessing methods may produce different results, it is important that an appropriate pipeline exists for the selection of the optimal combination of methods in the preprocessing workflow.


A paper triboelectric nanogenerator for self-powered electronic systems.
Paper, as one of the most important inventions of mankind, is still widely used in our daily life. In this study, the paper is explored as a platform for power sources based on the universally known triboelectric friction. A novel paper triboelectric nanogenerator (P-TENG) was successfully developed, which could harvest mechanical energy from ambient sources and generate considerable electrical energy. The maximum power density of the P-TENG reached 53 W m-2. In addition, the P-TENG possesses a natural advantage of being able to be integrated within a book, and thus can effectively convert mechanical energy from the action of turning book pages into electricity. When turning a book page, the output voltage and current of the P-TENG were obtained to be about 400 V and 0.17 mA, respectively. This generated electricity could directly light up 80 commercial white light-emitting diodes (LEDs) connected in series without any energy storage process. The white LEDs powered by the P-TENG can provide sufficient illumination for reading printed text in darkness. This research provides a promising solution for developing paper-based self-powered electronic systems.


Neuroanesthesiology update 2010.
We provide a summary of the 2010 literature pertinent to the care of neurosurgical patients and those requiring neurocritical care. In addition, we address topics in the basic neurosciences as they relate to neuroanesthesiology. This review incorporates studies not only from both neuroanesthesiology and general anesthesiology-focused journals, but also from neurology, neurosurgery, critical care, and internal medicine journals and includes articles published after January 1, 2010, through those available on-line by November 31, 2010. We will review the broad categories of general neuroanesthesiology, with particular emphasis on cerebral physiology and pharmacology, intracranial hemorrhage, carotid artery disease, spine surgery, traumatic brain injury, neuroprotection, and neurotoxicity. When selecting articles for inclusion in this review, we gave priority to those publications that had: (1) new or novel information, (2) clinical utility, (3) a study design possessing appropriate statistical power, and/or (4) meaningful, unambiguous conclusions.


Differential predictive validity of the Historical, Clinical and Risk Management Scales (HCR-20) for inpatient aggression.
The Historical, Clinical and Risk Management Scales (HCR-20) may be a better predictor of inpatient aggression for selected demographic and clinical groups but homogeneity of study samples has prevented definitive conclusions. The aim of this study, therefore, was to test the predictive validity of the HCR-20 as a function of gender, diagnosis, age, and ethnicity while controlling for potential covariates. A pseudo-prospective cohort study (n=505) was conducted in a UK secure/forensic mental health setting using routinely collected data. The HCR-20 predicted aggression better for women than men, and for people with schizophrenia and/or personality disorder than for other diagnostic groups. In women, the presence of the risk management items (R5) was important while men׳s aggression was best predicted solely by current clinical features from the C5 scale. R5 items were better than C5 items for predicting aggression in people with organic and developmental diagnoses. Our data provide additional information on which HCR-20 raters can formulate overall summary judgements about risk for inpatient aggression based on important demographic and clinical characteristics.


A flash-photolysis study of the reactions of a caa3-type cytochrome oxidase with dioxygen and carbon monoxide.
The time course of absorbance changes following flash photolysis of the fully-reduced carboxycytochrome oxidase from Bacillus PS3 in the presence of O2 has been followed at 445, 550, 605, and 830 nm, and the results have been compared with the corresponding changes in bovine cytochrome oxidase. The PS3 enzyme has a covalently bound cytochrome c subunit and the fully-reduced species therefore accommodates five electrons instead of four as in the bovine enzyme. In the bovine enzyme, following CO dissociation, four phases were observed with time constants of about 10 microseconds, 30 microseconds, 100 microseconds, and I ms at 445 nm. The initial, 10-microsecond absorbance change at 445 nm is similar in the two enzymes. The subsequent phases involving heme a and CuA are not seen in the PS3 enzyme at 445 nm, because these redox centers are re-reduced by the covalently bound cytochrome c, as indicated by absorbance changes at 550 nm. A reaction scheme consistent with the experimental observations is presented. In addition, internal electron-transfer reactions in the absence of O2 were studied following flash-induced CO dissociation from the mixed-valence enzyme. Comparisons of the CO recombination rates in the mixed-valence and fully-reduced oxidases indicate that more electrons were transferred from heme a3 to a in PS3 oxidase compared to the bovine enzyme.