Immunohistochemical PSMA expression patterns of primary prostate cancer tissue are associated with the detection rate of biochemical recurrence with 68Ga-PSMA-11-PET.
Prostate-specific membrane antigen (PSMA) targeted PET has a high detection rate for biochemical recurrence (BCR) of prostate cancer (PCa). Nevertheless, even at high prostate-specific antigen (PSA) levels (> 3 ng/ml), a relevant number of PSMA-PET scans are negative, mainly due to PSMA-negative PCa. Our objective was to investigate whether PSMA-expression patterns of the primary tumour on immunohistochemistry (IHC) are associated with PSMA-PET detection rate of recurrent PCa. Methods: Retrospective institutional review board approved single-centre analysis of patients who had undergone 68Ga-PSMA-11-PET for BCR after radical prostatectomy (RPE) between 04/2016 and 07/2019, with tumour specimens available for PSMA-IHC. Clinical information (age, PSA-level, ongoing androgen deprivation therapy (ADT), Gleason score) and PSMA-IHC of the primary tumour were collected and their relationship to results from PSMA-PET (positive/negative) was investigated using a multiple logistic regression analysis. Results: 120 PSMA-PET scans in 74 patients were available for this analysis. Overall detection rate was 62% (74/120 scans), with a mean PSA value at scan time of 0.99 ng/ml (IQR 0.32-4.27). Of the clinical factors, only PSA-level and ADT were associated with PSMA-PET positivity. The percentage of PSMA-negative tumour area on IHC (PSMA%neg) had a significant association to PSMA-PET negativity (OR = 2.88, p < 0.001), while membranous PSMA-expression showed no association (p = 0.73). The positive predictive value of PSMA%neg ≥ 50% for a negative PSMA-PET was 85% (13/11) and for a PSMA%neg of 80% or more, 100% (9/9). Conclusions: PSMA-negative tumour area on IHC exhibited the strongest association with negative PSMA-PET scans, beside PSA-level and ADT. Even at very high PSA levels, PSMA-PET scans were negative in most of the patients with PSMA%neg ≥ 50%.


Dose-response slope of forced oscillation and forced expiratory parameters in bronchial challenge testing.
In population studies, the provocative dose (PD) of bronchoconstrictor causing a significant decrement in lung function cannot be calculated for most subjects. Dose-response curves for carbachol were examined to determine whether this relationship can be summarized by means of a continuous index likely to be calculable for all subjects, namely the two-point dose response slope (DRS) of mean resistance (Rm) and resistance at 10 Hz (R10) measured by the forced oscillation technique (FOT). Five doses of carbachol (320 microg each) were inhaled by 71 patients referred for investigation of asthma (n=16), chronic cough (n=15), nasal polyposis (n=8), chronic rhinitis (n=8), dyspnoea (n=8), urticaria (n=5), post-anaphylactic shock (n=4) and miscellaneous conditions (n=7). FOT resistance and forced expiratory volume in one second (FEV1) were measured in close succession. The PD of carbachol leading to a fall in FEV1 > or = 20% (PD20) or a rise in Rm or R10 > or = 47% (PD47,Rm and PD47,R10) were calculated by interpolation. DRS for FEV1 (DRSFEV1), Rm (DRSRm) and R10 (DRSR10) were obtained as the percentage change at last dose divided by the total dose of carbachol. The sensitivity (Se) and specificity (Sp) of DRSRm, DRS10 delta%Rm and delta%R10 in detecting spirometric bronchial hyperresponsiveness (BHR, fall in FEV1 > or = 20%) were assessed by receiver operating characteristic (ROC) curves. There were 23 (32%) "spirometric" reactors. PD20 correlated strongly with DRSFEV1 (r=-0.962; p=0.0001); PD47,Rm correlated significantly with DRSRm (r=-0.648; p=0.0001) and PD47,R10 with DRSR10 (r=-0.552; p=0.0001). DRSFEV1 correlated significantly with both DRSRm (r=0.700; p=0.0001) and DRSR10 (r=0.784; p=0.0001). The Se and Sp of the various FOT indices to correctly detect spirometric BHR were as follows: DRSRm: Se=91.3%, Sp=81.2%; DRSR10: Se=91.3%, Sp=95.8%; delta%Rm: Se=86.9%, Sp=52.1%; and delta%R10: Se=91.3%, Sp=58.3%. Dose-response slopes of indices of forced oscillation technique resistance, especially the dose-response slope of resistance at 10Hz are proposed as simple quantitative indices of bronchial responsiveness which can be calculated for all subjects and that may be useful in occupational epidemiology.


Treatment of Uncomplicated Recurrent Urinary Tract Infection with Chinese Medicine Formula: A Randomized Controlled Trial.
To evaluate Chinese medicine (CM) formula Bazheng Powder () as an alternative therapeutic option for female patients with recurrent urinary tract infection (RUTI). A randomized double-blinded trial was performed. Eligible female patients with RUTI were recruited from one hospital and two community health centers. By using a blocked randomization scheme, participants were randomized to receive a CM formula (10 herbs) for 4 weeks or antibiotics for 1 week, followed by 3 weeks of placebo. Clinical cure rate and microbiological cure and recurrence after treatment were evaluated. A total 122 eligible patients were enrolled, with 61 cases in each group. The clinical cure rate by the intentto- treatment approach was 90.2% for the CM group and 82.0% for the antibiotics group (P>0.05). Bacteria were cleared from 88.5% (54/61) of patients in the CM group and 82.0% (50/61) in the antibiotics group. The recurrence rate in recovered patients at the 6-month follow-up was 9.1% (5/61) and 14.0 (7/61) in the CM and antibiotics groups, respectively (P>0.05). CM formula Bazheng Powder is a good alternative option for RUTI treatment. (Registration No. NCT01745328).


Animal models of obsessive-compulsive spectrum disorders.
Obsessive-compulsive disorder (OCD) and related conditions (trichotillomania, pathological skin-picking, pathological nail-biting) are common and disabling. Current treatment approaches fail to help a significant proportion of patients. Multiple tiers of evidence link these conditions with underlying dysregulation of particular cortico-subcortical circuitry and monoamine systems, which represent targets for treatment. Animal models designed to capture aspects of these conditions are critical for several reasons. First, they help in furthering our understanding of neuroanatomical and neurochemical underpinnings of the obsessive-compulsive (OC) spectrum. Second, they help to account for the brain mechanisms by which existing treatments (pharmacotherapy, psychotherapy, deep brain stimulation) exert their beneficial effects on patients. Third, they inform the search for novel treatments. This article provides a critique of key animal models for selected OC spectrum disorders, beginning with initial work relating to anxiety, but moving on to recent developments in domains of genetic, pharmacological, cognitive, and ethological models. We find that there is a burgeoning literature in these areas with important ramifications, which are considered, along with salient future lines of research.


Iron-catalyzed homocoupling of bromide compounds.
The homocoupling of bromide compounds was successfully performed in one pot by a combination of metallic magnesium and a catalytic amount of iron salts. The binary catalytic system differentiates itself from other homocoupling reactions catalyzed by iron salts in that it requires neither the in situ preparation of Grignard reagent nor the addition of a 1,2-dihalogen compound as an oxidant. Various aromatic and alkyl bromides underwent the homocoupling smoothly affording the corresponding symmetrical hydrocarbon compounds in moderate to excellent yields.


Effects of nanofibrillated cellulose hydrogels on adipose tissue extract and hepatocellular carcinoma cell spheroids in freeze-drying.
The aim of this study was to evaluate the effects of two nanofibrillated cellulose (NFC) hydrogels on two human derivatives during freeze-drying. Native NFC hydrogel is a suitable platform to culture 3D cell spheroids and a hydrogel processed further, called anionic NFC (ANFC) hydrogel, is an excellent platform for controlled release of proteins. Moreover, it has been shown to be compatible with freeze-drying when correct lyoprotectants are implemented. Freeze-drying is a method, where substance is first frozen, and then vacuum dried trough sublimation of water in order to achieve dry matter without the loss of the original three-dimensional structures. The first chosen human derivative was adipose tissue extract (ATE) which is a cell-free growth factor-rich preparation capable of promoting growth of regenerative cells. The release of growth factors from the freeze-dried mixture of ATE and ANFC was compared to that of non-freeze-dried control mixtures. The release profiles remained at the same level after freeze-drying. The second derivative was hepatocellular carcinoma (HepG2) cell spheroids which were evaluated before and after freeze-drying. The 3D structure of the HepG2 cell spheroids was preserved and the spheroids retained 18% of their metabolic activity after rehydration. However, the freeze-dried and rehydrated HepG2 cell spheroids did not proliferate and the cell membrane was damaged by fusion and formation of crystals.


A two-state analysis of co-operative oxygen binding in the three human embryonic haemoglobins.
The binding of oxygen to the three human embryonic haemoglobins, at pH 7.4, has been shown to occur as a co-operative process. Analysis of oxygen-binding curves obtained in the absence of organic phosphate allosteric effectors shows that the process can be described quite accurately by the two-state model of allosteric action. In the presence of organic phosphates, the binding affinity for oxygen to the T-state of the alpha 2 epsilon 2 and zeta 2 epsilon 2 haemoglobins is significantly lowered. The values of the best-fit two-state parameters determined for each of the embryonic haemoglobins together with the temperature-dependence of the overall equilibrium binding process are discussed in terms of oxygen transfer from the maternal blood supply. Fast-reaction studies have been used to determine the rate constants of the oxygen association and dissociation processes occurring in the R-state and the rate of the allosteric R > T conformational transition. Analysis of these data suggests a likely reason for the high affinity and low co-operativity of the embryonic proteins and identifies the origins of the inability of equilibrium measurements to identify chain non-equivalence in the R-state.


[Central venous catheter related infections: comparison of polyurethane film and gauze/tape dressing].
Central venous catheters (CVCs) are widely used in clinical practice; catheter related infection is the most important cause of sepsis in surgical patients . In the present study, we compared the effect of two different dressings in CVCs related infections and evaluated microorganisms involved. We studied 124 CVCs inserted patients. CVC was inserted under strict aseptic technique according to guidelines via percutaneous puncture of internal jugular or femoral vein. CVC dressing was made with gauze/tape in 60 patients (group A) and with polyurethane film in 64 patients (group B). Duration of catheterization was 5,27 SD 1,76 days in group A and 11,30 SD 5,84 days in group B. Statistical analysis showed a significant lower infection rate in tape/gauze dressings while polyurethane film dressings seemed to predispose to infections. For the statistic analysis we have used z statistic test and the contingency analysis charts.


Phenome-wide examination of comorbidity burden and multiple sclerosis disease severity.
We assessed the comorbidity burden associated with multiple sclerosis (MS) severity by performing a phenome-wide association study (PheWAS). We conducted a PheWAS in 2 independent cohorts: a discovery (Boston, United States; 1993-2014) and extension cohort (British Columbia, Canada; 1991-2008). We included adults with MS, ≥1 Expanded Disability Status Scale (EDSS) score, and ≥1 International Classification of Diseases (ICD) code other than MS. We calculated the Multiple Sclerosis Severity Score (MSSS) using the EDSS. We mapped ICD codes into PheCodes (phenotypes), using a published system with each PheCode representing a unique medical condition. Association between the MSSS and the presence of each condition was assessed using logistic regression adjusted for covariates. The discovery and extension cohorts included 3,439 and 4,876 participants, respectively. After Bonferroni correction and covariate adjustments, a higher MSSS was associated with 37 coexisting conditions in the discovery cohort. Subsequently, 16 conditions, including genitourinary, infectious, metabolic, epilepsy, and movement disorders, met the reporting criteria, reaching the Bonferroni threshold of significance with the same direction of effect in the discovery and extension cohort. Notably, benign neoplasm of the skin was inversely associated with the MSSS. The phenome-wide approach enabled a systematic interrogation of the comorbidity burden and highlighted clinically relevant medical conditions associated with MS severity (beyond MS-specific consequences) and defines a roadmap for comprehensive investigation of comorbidities in chronic neurologic diseases. Further prospective investigation of the bidirectional relationship between disability and comorbidities could inform the individualized patient management.


Immunosuppressive therapy, 1987.
The use of cyclosporine in transplant practice has at least doubled graft survival in renal transplantation, and has improved patient survival as well. In cardiac transplants, cyclosporine was first used in combination with prednisone to achieve immunosuppression by inhibition of the synthesis of lymphokines. When stimulated in vitro, lymphocytes from cyclosporine-treated patients display an impaired ability to produce the critical lymphokine interleukin-2. When there is in vitro inhibition, the patient shows poor immunosuppression in vivo. Unfortunately, cyclosporine is toxic: given in high enough doses to weaken the immune response, it can have neuroectodermal, and (of greater concern) mesenchymal side effects, including hepato- and nephrotoxicity. Patients who display renal impairment before cardiac transplantation are at a greater risk of postoperative renal dysfunction with cyclosporine therapy. The most important adverse actions of cyclosporine upon the nephron are events that arise from reduced renal blood flow caused either by vasoconstriction or by platelet adhesion associated with reduced prostacyclin production. The accepted technique for control of cyclosporine nephrotoxicity has been to reduce the cyclosporine dose, while simultaneously initiating azathioprine therapy. In the presence of an abnormal serum creatinine level, cyclosporine trough values appear to correlate with rejection or toxicity, thereby providing an indicator of drug-induced complications. Preoperative pharmacokinetic profiling to test cyclosporine clearance can help optimize the regimen in both renal and cardiac transplant patients.


Postcolonoscopy appendicitis in a patient with active ulcerative colitis.
Complications due to diagnostic colonoscopy are uncommon and acute appendicitis is a very rare complication of colonoscopy. This poses a diagnostic challenge as the presentation of appendicitis is similar to that of other complications of colonoscopy such as perforation or postpolypectomy syndrome. It is hypothesized that postcolonoscopy appendicitis might be associated with obstruction of the appendiceal lumen with fecal matter during colonoscopy. None of the previous reports in the literature have described findings of appendicitis after colonoscopy in a patient with active ulcerative colitis. We present a case of a 28 year-old man with active ulcerative colitis who underwent colonoscopy and subsequently developed acute appendicitis.


Clinical Performance of Human Papillomavirus (HPV) Testing versus Cytology for Cervical Cancer Screening: Results of a Large Danish Implementation Study.
Human papillomavirus (HPV) testing is increasingly used as the primary cervical cancer screening test. In a large pilot implementation, we compared participation, referrals and detection of high-grade cervical intraepithelial neoplasia (CIN) in HPV- versus cytology-based cervical cancer screening. The implementation was embedded into the routine screening program at Lillebaelt Hospital, Department of Pathology, Vejle, Denmark. Based on the area of residence, women aged 30-59 years were screened by either HPV testing (with HPV16/18 genotyping and cytology triage) or cytology (with HPV triage for minor abnormalities). Our analysis includes women invited or screened during May 2017-May 2018 (invited: n=35,081; screened: n=28,352) with 6 months of follow-up. Information on screening results and sociodemographic characteristics were obtained from registers. Using logistic regression, we estimated odds ratios (ORs) with 95% confidence intervals (CIs) of participation, referral and CIN3+-detection in HPV- versus cytology-based screening, adjusting for sociodemographic characteristics. Participation was virtually identical in the HPV- and cytology group (58.4% vs 58.8%; ORadjusted=0.97, 95% CI, 0.93-1.01). Referral to colposcopy was more common in the HPV- than cytology group (3.8% vs 2.1%; ORadjusted=1.88, 95% CI, 1.63-2.17). More cases of CIN3+ were detected in the HPV- than cytology group (1.0% vs 0.7%, ORadjusted=1.47; 95% CI, 1.13-1.91). Participation did not differ between HPV- and cytology-based screening. HPV-based screening detected more cases of CIN3+, but in this initial screening round also led to more colposcopies than cytology-based screening.


Nociceptin augments K(+) currents in hippocampal CA1 neurons by both ORL-1 and opiate receptor mechanisms.
We previously reported (see also the accompanying paper) that dynorphin A significantly enhanced the voltage-dependent K(+) M-current (I(M)) in CA3 and CA1 hippocampal pyramidal neurons (HPNs). Because the opioid-receptor-like-1 (ORL-1) receptor shares a high sequence homology with opioid receptors and is expressed in rat hippocampus, we examined the effects of orphanin FQ or nociceptin, the endogenous ligand for the ORL-1 receptor, using the rat hippocampal slice preparation and intracellular voltage-clamp recording. Current-voltage (I-V) relationships from CA1 HPNs revealed that nociceptin superfusion induced an outward current reversing near the equilibrium potential for K(+) ions. Ba(2+) (2 mM) blocked this effect. The nociceptin-induced current was largest at depolarized membrane potentials, where I(M) is largely activated. Nociceptin concentrations of 0.5-1 microM (but not 0.1 microM) significantly increased I(M) relaxation amplitudes with recovery on washout. Interestingly, both the general opiate antagonist naloxone and the kappa receptor antagonist nor-binaltorphimine (nBNI) inhibited the nociceptin-induced I(M) increases and outward currents in the depolarized range but not the inward current induced at hyperpolarized potentials. The putative ORL-1 receptor antagonist, [Phe(1)Psi(CH(2)-NH)Gly(2)]NC(1-13)NH(2) (hereafter ORLAn), blocked most of the nociceptin current near rest but not the I(M) increase. However, ORLAn alone had direct effects similar to those of nociceptin, indicating that ORLAn might be a partial agonist. Our results suggest that nociceptin postsynaptically modulates the excitability of HPNs through ORL-1 and kappa-like opiate receptors linked to different K(+) channels.


Spinal cord stimulation with implanted epidural paddle lead relieves chronic axial low back pain.
Spinal cord stimulation (SCS) provides significant relief for lumbosacral radiculopathy refractory to both medical and surgical treatment, but historically only offers limited relief for axial low back pain (LBP). We aim to evaluate the response of chronic axial LBP treated with SCS using a surgically implanted epidural paddle lead. This is a retrospective review of a consecutive series of patients with exclusive LBP or predominant LBP associated with lower extremity (LE) pain evaluated and treated with SCS using an implanted paddle lead within the dorsal thoracic epidural space. Baseline LBP, and if present LE pain, were recorded using the visual analogue scale (VAS) at an initial evaluation. At a follow-up visit (a minimum of 12 months later), LBP and LE pain after a spinal cord stimulator implantation were again recorded using the VAS. Patients were also asked to estimate total LBP pain relief achieved. Patients with either exclusive (n=7) or predominant (n=2) axial LBP were treated with SCS by implantation of a paddle lead at an average spine level of T9. The baseline VAS score for LBP was 7.2; after a follow-up of 20 months, the score decreased to 2.3 (P=0.003). The LE pain VAS score decreased from 7.5 to 0.0 (P=0.103). Patients also reported a subjective 66.4% decrease of their LBP at follow-up. There were no surgical complications. Axial LBP is refractory to many treatments, including SCS. SCS using a surgically implanted paddle electrode provides significant pain relief for chronic axial LPB, and is a safe treatment modality.


Distinguishing the ultrafast dynamics of spin and orbital moments in solids.
For an isolated quantum particle, such as an electron, the orbital (L) and spin (S) magnetic moments can change provided that the total angular momentum of the particle is conserved. In condensed matter, an efficient transfer between L and S can occur owing to the spin-orbit interaction, which originates in the relativistic motion of electrons. Disentangling the absolute contributions of the orbital and spin angular momenta is challenging, however, as any transfer between the two occurs on femtosecond timescales. Here we investigate such phenomena by using ultrashort optical laser pulses to change the magnetization of a ferromagnetic film and then probe its dynamics with circularly polarized femtosecond X-ray pulses. Our measurements enable us to disentangle the spin and orbital components of the magnetic moment, revealing different dynamics for L and S. We highlight the important role played by the spin-orbit interaction in the ultrafast laser-induced demagnetization of ferromagnetic films, and show also that the magneto-crystalline anisotropy energy is an important quantity to consider in such processes. Our study provides insights into the dynamics in magnetic systems as well as perspectives for the ultrafast control of information in magnetic recording media.


Running patterns for male and female competitive and recreational runners based on accelerometer data.
The purpose of this study was to classify runners in sex-specific groups as either competitive or recreational based on center of mass (CoM) accelerations. Forty-one runners participated in the study (25 male and 16 female), and were labeled as competitive or recreational based on age, sex, and race performance. Three-dimensional acceleration data were collected during a 5-minute treadmill run, and 24 features were extracted. Support vector machine classification models were used to examine the utility of the features in discriminating between competitive and recreational runners within each sex-specific subgroup. Competitive and recreational runners could be classified with 82.63 % and 80.4 % in the male and female models, respectively. Dominant features in both models were related to regularity and variability, with competitive runners exhibiting more consistent running gait patterns, but the specific features were slightly different in each sex-specific model. Therefore, it is important to separate runners into sex-specific competitive and recreational subgroups for future running biomechanical studies. In conclusion, we have demonstrated the ability to analyze running biomechanics in competitive and recreational runners using only CoM acceleration patterns. A runner, clinician, or coach may use this information to monitor how running patterns change as a result of training.


Null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2 impairs calcium transport into milk.
The means by which calcium is transported into the milk produced by mammary glands is a poorly understood process. One hypothesis is that it occurs during exocytosis of secretory products via the Golgi pathway, consistent with the observation that the SPCA1 Ca2+-ATPase, which is expressed in the Golgi, is induced in lactating mammary tissue. However, massive up-regulation of the PMCA2bw plasma membrane Ca2+-ATPase also occurs during lactation and is more strongly correlated with increases in milk calcium, suggesting that calcium may be secreted directly via this pump. To examine the physiological role of PMCA2bw in lactation we compared lactating PMCA2-null mice to heterozygous and wild-type mice. Relative expression levels of individual milk proteins were unaffected by genotype. However, milk from PMCA2-null mice had 60% less calcium than milk from heterozygous and wild-type mice, the total milk protein concentration was lower, and an indirect measure of milk production (litter weights) suggested that the PMCA2-null mice produce significantly less milk. In contrast, lactose was higher in milk from PMCA2-null mice during early lactation, but by day 12 of lactation there were no differences in milk lactose between the three genotypes. These data demonstrate that the activity of PMCA2bw is required for secretion of much of the calcium in milk. This major secretory function represents a novel biological role for the plasma membrane Ca2+-ATPases, which are generally regarded as premier regulators of intracellular Ca2+.


Does integrated academic and health education prevent substance use? Systematic review and meta-analyses.
Prevention of substance (alcohol, tobacco, illegal/legal drug) use in adolescents is a public health priority. As the scope for school-based health education is constrained in school timetables, interventions integrating academic and health education have gained traction in the UK and elsewhere, though evidence for their effectiveness remains unclear. We sought to synthesize the effectiveness of interventions integrating academic and health education for the prevention of substance use. We searched 19 databases between November and December 2015, among other methods. We included randomized trials of interventions integrating academic and health education targeting school students aged 4-18 and reporting substance use outcomes. We excluded interventions for specific health-related subpopulations (e.g., children with behavioural difficulties). Data were extracted independently in duplicate. Outcomes were synthesized by school key stage (KS) using multilevel meta-analyses, for substance use, overall and by type. We identified 7 trials reporting substance use. Interventions reduced substance use generally in years 7-9 (KS3) based on 5 evaluations (d = -0.09, 95% CI [-0.17, -0.01], I2 = 35%), as well as in years 10-11 (KS4) based on 3 evaluations (-0.06, [-0.09, -0.02]; I2 = 0%). Interventions were broadly effective for reducing specific alcohol, tobacco, and drug use in both KS groups. Evidence quality was highly variable. Findings for years 3-6 and 12-13 could not be meta-analysed, and we could not assess publication bias. Interventions appear to have a small but significant effect reducing substance use. Specific methods of integrating academic and health education remain poorly understood.


Population-specific short-form mini nutritional assessment with body mass index or calf circumference can predict risk of malnutrition in community-living or institutionalized elderly people in taiwan.
A simple, reliable, noninvasive, and easy-to-use instrument is important for successful monitoring of emerging nutrition problems in elderly people. The objectives of this study were to determine whether adoption of population-specific body mass index (BMI) cutpoints would improve the predictive ability of the short-form Mini Nutritional Assessment (MNA) and whether calf circumference could be an acceptable alternative to BMI in the short-form MNA without compromising its predictive ability. Using convenience sampling, the study recruited 301 community-living, 109 care center-living, and 68 nursing home-living elderly people, 65 years or older, as subjects. Subjects were evaluated with the short-form MNA in three versions: (a) the original, (b) Taiwan version 1 (T1), that adopted population-specific BMI cutpoints, and (c) Taiwan version 2 (T2), which substituted calf circumference for BMI, and with the long-form MNA-T2 as a reference. The ability of the short forms to predict the long-form MNA-T2 was evaluated with binary classification and analysis of receiver operating characteristic curves. Results were analyzed with an SPSS for Windows 12.0 software package (version 12.0.1C, 2000, SPSS Inc, Chicago, IL). Results showed that adoption of population-specific anthropometric BMI cutpoints improved the predictive ability of the short-form MNA, whereas replacement of BMI with calf circumference further improved the predictive ability of the scale (kappa values of the binary classification tests were 0.596, 0.742, and 0.843 for community-living; 0.560, 0.683, and 0.839 for care center-living; and 0.346, 0.454, and 0.522 for nursing home-living elderly for the original, T1, and T2 MNA short-form versions, respectively). These results suggest that modification of a measurement tool according to cultural or anthropometric features of the target population is necessary. The study also shows that calf circumference can be an acceptable alternative to BMI in the short-form MNA. Because measuring calf circumference is easier and less time-consuming then measuring BMI, the modified tool can make periodic nutritional screening an easier job and routine nutritional screening a more realistic goal in geriatric care.


Current status and optimal use of radiosurgery.
The field of stereotactic radiosurgery is rapidly advancing as a result of both improvements in radiosurgical equipment and better physician understanding of the clinical applications of stereotactic radiosurgery. This article will review recent developments in the field of radiosurgery, including advances in our understanding of the treatment of brain metastases and arteriovenous malformations, as well as the use of stereotactic radiosurgery as a boost following conventional radiation for nasopharyngeal carcinoma to minimize the rate of local recurrence. In addition, improved understanding of the radiobiology of normal neurologic structures adjacent to tumors undergoing radiosurgery has led to the use of fractionated stereotactic radiosurgery for the treatment of acoustic neuromas and tumors bordering the anterior visual pathways. Finally, a breakthrough in radiosurgery involving the development and use of frameless, image-guided stereotactic radiosurgery has allowed for both dose homogeneity and treatment of intracranial lesions based on nonisocentric treatment algorithms that result in improved target conformality. This same frameless radiosurgical system has also expanded the scope of radiosurgery to include the treatment of extracranial lesions throughout the body.


Two di-leucine-based motifs account for the different subcellular localizations of the human endothelin-converting enzyme (ECE-1) isoforms.
Endothelin-converting enzyme (ECE-1) is a type II integral membrane protein which plays a key role in the biosynthetic pathway of the vasoconstricting endothelins. Three ECE-1 isoforms, differing by their N-terminal cytoplasmic tails, are generated from a single gene. When expressed in CHO cells, they display comparable enzymatic activity but whereas ECE-1a is strongly expressed at the cell surface, ECE-1b is exclusively intracellular and ECE-1c presents an intermediate distribution. In the present study these different localizations were further described at the ultrastructural level, by electron microscope immunocytochemistry. To characterize the motifs responsible for the intracellular localization of ECE-1b we constructed chimeric proteins and point mutants. Two di-leucine-based motifs, contained in the N-terminal part of ECE-1b, were thus identified. One of these motifs (LV), displayed by both ECE-1b and ECE-1c, accounts for the reduced surface expression of ECE-1c as compared to ECE-1a. Mutation of both motifs (LL and LV) induces a very strong appearance of ECE-1b at the cell surface indicating that their presence in the N-terminal extremity of ECE-1b is critical for its exclusively intracellular localization.


Crusted Scabies Infection in the Setting of Chronic Steroid and Omalizumab Use.
Scabies infection is a very common skin disease that occurs due to infestation with the Sarcoptes scabei mite. Typically, it results in intensely pruritic papules and excoriations in the webs of the hand, groin, or axilla, and remains limited in its spread. In rare cases, the disease can become diffuse and progress to crusted or nodular subtypes. Here, we report the case of crusted scabies infestation in a 69-year-old male who presented with a diffuse pruritic, erythematous, and petechial rash. His medical history was significant for severe idiopathic urticaria treated with omalizumab. Before starting omalizumab, the patient was self-medicating for several months with corticosteroids obtained through his veterinary practice to alleviate symptoms. His presentation was complicated by immune thrombocytopenic purpura and muscle weakness, likely secondary to omalizumab and corticosteroid use, respectively. The patient underwent an extensive rheumatologic workup until skin biopsy confirmed the underlying etiology as crusted scabies infestation. He was treated with ivermectin and weekly 5% permethrin skin cream with great improvement of his rash; however, unfortunately, he succumbed to bacterial sepsis. Scabies infestation can masquerade as a manifestation of other systemic diseases and is often misdiagnosed. As this case illustrates, initial misdiagnosis and subsequent treatment with immunosuppressive drug regimens can cause preventable, but potentially fatal, concomitant superinfections.


Regulation of mitochondrial pyruvate carboxylation in isolated hepatocytes by acute insulin treatment.
The effect of acute insulin treatment of hepatocytes on pyruvate carboxylation in both isolated mitochondria and cells rendered permeable by filipin was examined. Challenging the cells with insulin alone had no effect on either the basal rate of pyruvate carboxylation or gluconeogenesis, although it did suppress the responses to both glucagon and catecholamines. Insulin treatment was unable to antagonize the enhanced rate of pyruvate carboxylation caused by stimulation of the cells with either angiotensin or vasopressin. Neither insulin nor the gluconeogenic hormones altered the total extractable pyruvate carboxylase activity in the isolated mitochondria, suggesting that the effect of hormones at the level of the isolated intact organelle was mediated via alterations in the intramitochondrial concentrations of effector molecules, notably ATP and the [ATP]/[ADP] ratio and substrate availability. The alterations in pyruvate carboxylation correlate well with glucose synthesis in terms of sensitivity to effector molecules, putative second messengers and time of onset of the response, indicating that alterations in the flux through this enzyme are compatible with it being an important site in the control of gluconeogenesis from C3 precursors.


Measurement and treatment of elevated blood pressure in the pediatric patient with chronic kidney disease.
Hypertension, as in adults, is a frequent complication found in children with chronic kidney disease (CKD). Indeed, hypertension has now become one of the most prevalent chronic diseases of childhood. The most recent data available (2003) indicate that at least 38% of children with CKD in the United States are receiving antihypertensive therapy. Only recently has it been shown in children that hypertension, traditionally considered a marker for disease severity in children, is additionally a significant and independent risk factor for accelerated deterioration of kidney function and progression of CKD and a significant risk factor for cardiovascular disease. The following review outlines the differences and similarities of childhood versus adult hypertension with respect to measurement, diagnosis, treatment, and consequence in CKD. The definition of hypertension changes continually as a child grows with or without CKD. Despite numerous guidelines, the diagnosis of childhood hypertension continues to be based on epidemiologic data rather than evidence. For children, the current definition includes 2 categories: high normal, which is blood pressure (BP) between the 90th and 95th percentile, and hypertensive, which is BP above the 95th percentile. The evaluation of all hypertensive children should include a complete assessment of end-organ damage, including eyes, cardiovascular system (including blood vessels), kidneys, and nervous system. For children with CKD and end-stage renal disease (ESRD), a high percentage have left ventricular hypertrophy (LVH). The finding of end-organ damage or comorbidity (CKD, diabetes) in any child is an absolute indication for immediate pharmacologic therapy, whereas the presence of hypertension above the 95th percentile in children without CKD warrants initial intervention such as life style modification. The guidelines for measurement of BP in children with CKD are similar to those in children without CKD and include casual BP measurement, self-measured BP, and ambulatory BP monitoring. The recommendation for BP measurement in children is, when permitted, by auscultative method with a well-calibrated mercury manometer. Most casual BP measurements are performed with an automated oscillometric device whose validation has not been confirmed in children with CKD. The ambulatory BP monitor (ABPM) has 2 advantages: it significantly correlates with the presence of end-organ damage, and it identifies abnormal BP patterns that are frequently present in CKD patients, such as hypertension during the sleep period. An abnormal ABPM pattern can also be predictive of the development of end-organ damage. Treatment of hypertension in children, with and without CKD, is based on 3 factors: degree of BP elevation, the presence of cardiovascular risk factors, and the presence of end-organ damage. Additionally, the initial antihypertensive agent may be selected on available and age-appropriate formulations (eg, suspension and dosage selection). A physician treating a hypertensive child with CKD faces multiple challenges. They include selecting the convenience of available automated devices and the ABPM versus traditional auscultatory techniques upon which all normative standards have been based. Current research initiatives propose to develop pharmacokinetic and pharmacodynamics properties of antihypertensive medications and to study the effect of early intervention on end-organ damage.


Bulk Genotyping of Biopsies Can Create Spurious Evidence for Hetereogeneity in Mutation Content.
When multiple samples are taken from the neoplastic tissues of a single patient, it is natural to compare their mutation content. This is often done by bulk genotyping of whole biopsies, but the chance that a mutation will be detected in bulk genotyping depends on its local frequency in the sample. When the underlying mutation count per cell is equal, homogenous biopsies will have more high-frequency mutations, and thus more detectable mutations, than heterogeneous ones. Using simulations, we show that bulk genotyping of data simulated under a neutral model of somatic evolution generates strong spurious evidence for non-neutrality, because the pattern of tissue growth systematically generates differences in biopsy heterogeneity. Any experiment which compares mutation content across bulk-genotyped biopsies may therefore suggest mutation rate or selection intensity variation even when these forces are absent. We discuss computational and experimental approaches for resolving this problem.


Inadequate antiasthma drug use in the north of Italy.
A multicentre survey of prevalence, determinants and management of asthma (the European Community Respiratory Health Survey (ECRHS)) has shown that the ratio of subjects declaring current use of antiasthmatic drugs to those reporting asthma attacks in the previous 12 months was particularly low (0.54) in the north of Italy. In this study, we used a standardized clinical interview to gather a more detailed insight into the issue of asthma undertreatment in the north of Italy. A total of 1,104 subjects were interviewed, 116 of whom had been defined as asthmatic by the family doctor. Fifty subjects had current asthma and 66 had a history of previous asthma. A considerable percentage (26%) of subjects with current asthma were not being treated with antiasthmatic therapy. Even when only patients with severe asthma were considered, the percentage of untreated patients was still high (21%). Forty two per cent of subjects used inhaled beta2-agonists alone, 28% inhaled steroids plus beta2-agonists, 2% inhaled steroids alone and 2% other drugs. Only 19% of the asthmatics on treatment, 85% of whom had more severe asthma, received daily treatment. Only 65% of the subjects who had received antiasthmatic drug prescriptions declared they had taken all the drugs prescribed; this percentage was 74% when respiratory symptoms were worsening. Of the patients with past asthma, 18% had taken antiasthmatic drugs. Most of these patients were those who had had more severe asthma. In conclusion, antiasthmatic drugs are underused in the north of Italy, at least in part due to low compliance.


Contribution of Multimodal Analgesia to Postoperative Pain Outcomes Immediately After Primary Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis of Level 1 Randomized Clinical Trials.
Anterior cruciate ligament reconstruction (ACLR) is associated with moderate to severe pain in the immediate postoperative period. The optimal individual preemptive or intraoperative anesthetic modality on postoperative pain control is not well-known. To systematically review and perform a meta-analysis comparing postoperative pain scores (visual analog scale [VAS]), opioid consumption, and incidence of complications during the first 24 hours after primary ACLR in patients receiving spinal anesthetic, adjunct regional nerve blocks, or local analgesics. Systematic review and meta-analysis. PubMed, Embase, MEDLINE, Biosis Previews, SPORTDiscus, Ovid, PEDRO, and the Cochrane Library databases were systematically searched from inception to March 2020 for human studies, using a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. Inclusion criteria consisted of (1) level 1 studies reporting on the use of spinal anesthesia, adjunct regional anesthesia (femoral nerve block [FNB] or adductor canal block [ACB]), or local analgesia in patients undergoing primary ACLR and (2) studies reporting on patient-reported VAS, opioid consumption, and incidence of complications related to anesthesia within the first 24 hours after surgery. Non-level 1 studies, studies utilizing a combination of anesthetic modalities, and those not reporting outcomes during the first 24 hours were excluded. Data were synthesized, and a random effects meta-analysis was performed to determine postoperative pain, opioid use, and complications based on anesthetic modality at multiple time points (0-4, 4-8, 8-12, 12-24 hours). A total of 263 studies were screened, of which 27 level 1 studies (n = 16 regional blocks; n = 12 local; n = 4 spinal) met the inclusion criteria and were included in the meta-analysis. VAS scores were significantly lower in patients receiving a regional block as compared with spinal anesthesia 8 to 12 hours after surgery (P < .01), patients receiving an FNB versus ACB at 12 to 24 hours (P < .01), and those treated with a continuous FNB rather than single-shot regional blocks (FNB, ACB) at 12 to 24 hours (P < .01). No significant difference in VAS was appreciated when spinal, regional, and local anesthesia groups were compared. Based on evidence from level 1 studies, pain control after primary ACLR based on VAS was significantly improved at 8 to 12 hours in patients receiving regional anesthesia as compared with spinal anesthesia. Pain scores were significantly lower at 12 to 24 hours in patients receiving FNB versus ACB and those treated with continuous FNB rather than single-shot regional anesthetic.


Comprehensive fitness maps of Hsp90 show widespread environmental dependence.
Gene-environment interactions have long been theorized to influence molecular evolution. However, the environmental dependence of most mutations remains unknown. Using deep mutational scanning, we engineered yeast with all 44,604 single codon changes encoding 14,160 amino acid variants in Hsp90 and quantified growth effects under standard conditions and under five stress conditions. To our knowledge, these are the largest determined comprehensive fitness maps of point mutants. The growth of many variants differed between conditions, indicating that environment can have a large impact on Hsp90 evolution. Multiple variants provided growth advantages under individual conditions; however, these variants tended to exhibit growth defects in other environments. The diversity of Hsp90 sequences observed in extant eukaryotes preferentially contains variants that supported robust growth under all tested conditions. Rather than favoring substitutions in individual conditions, the long-term selective pressure on Hsp90 may have been that of fluctuating environments, leading to robustness under a variety of conditions.


Performance evaluation of finite normal mixture model-based image segmentation techniques.
Finite Normal Mixture (FNM) model-based image segmentation techniques adopt the following detection-estimation-classification paradigm: 1) detect the number of image regions by using theoretical information criteria; 2) estimate model parameters by using expectation-maximization (EM)/classification-maximization (CM) algorithms; and 3) classify pixels into regions by using various classifiers. This paper presents a theoretical framework to evaluate the performance of this class of image segmentation techniques. For the detection performance, probabilities of over-detection and under-detection of the number of image regions are defined, and the associated formulae in terms of model parameters and image quality are derived. For the estimation performance, both EM and CM algorithms are showed to produce asymptotically unbiased ML estimates of model parameters in the case of no-overlap. Cramer-Rao bounds of variances of these estimates are derived. For the classification performance, misclassification probability for the Bayesian classifier is defined, and a simple formula based on parameter estimates and classified data is derived to evaluate segmentation errors. This evaluation method provides both theoretically approachable accuracy limits of the techniques and practically achievable performance of the given images. Theoretical and experimental results are in good agreement and indicate that, for images of moderate quality, the detection operation is robust, the parameter estimates are accurate, and the segmentation errors are small.


Genetic effects on carotid intima-media thickness: systematic assessment and meta-analyses of candidate gene polymorphisms studied in more than 5000 subjects.
Carotid intima-media thickness (CIMT) is highly heritable and associated with stroke and myocardial infarction, making it a promising quantitative intermediate phenotype for genetic studies of vascular disease. There have been many CIMT candidate gene association studies, but no systematic review to identify consistent, reliable findings. We comprehensively sought all published studies of association between CIMT and any genetic polymorphism. We obtained additional unpublished data and performed meta-analyses for the 5 most commonly studied genes (studied in at least 2 studies in a total of >5000 subjects). We used a 3-step meta-analysis method: meta-analysis of variance; genetic model selection; and random effects meta-analysis of the mean CIMT difference between genotypes. We performed subgroup analyses to investigate effects of ethnicity, vascular risk status, and study size. We accounted for potential reporting bias by assessing qualitatively the possible effects of including unavailable data. Polymorphisms in 3 of the 5 genes (apolipoprotein E, angiotensin I converting enzyme, and 5,10-methylenetetrahydrofolate reductase) had an apparent association with CIMT, but for all these, we found evidence of small study bias. Apolipoprotein E epsilon2/epsilon3/epsilon4 was the only polymorphism with a persistent, statistically significant but modest association when we restricted analysis to larger studies (>1000 subjects). Of the most extensively studied polymorphisms, apolipoprotein E epsilon2/epsilon3/epsilon4 is the only one so far with a convincing association with CIMT. Larger studies than have generally been performed so far may be needed to confirm the associations identified in future genome-wide association studies, and to investigate modification of effect according to characteristics such as ethnicity and vascular risk status.


Investigation of laser-induced plasma characteristics in bulk water under different focusing arrangements.
Laser-induced breakdown spectroscopy (LIBS) has drawn more attention as a new technique for in situ detection of seawater, especially for hydrothermal areas. In order to evaluate the focusing geometry effect on laser-induced plasma in bulk water, four focusing arrangements were tried out with a single lens as well as with a double-lens combination. We demonstrated that, for the same transmission distance in water, the double-lens combination with shorter effective focal length generated more condensed plasma, as shown by the spectroscopic and fast imaging results. Accordingly, the moving breakdown phenomenon significantly decreased with well-improved LIBS intensity, signal-to-noise ratio, and stability. The plasma emissions evidently attenuated along the laser transmission due to the strong absorption effect of the water medium. Based on the acquired results, the performance of a practical detection window was evaluated by combining the regular lens with a customized lens-shaped optical window, and a positive outcome was also reached. The obtained results suggested that improved LIBS detection could be easily achieved via settling another lens window to LIBS system, which is considered helpful for better in situ submarine application.


Patterns of Buprenorphine-Naloxone Treatment for Opioid Use Disorder in a Multistate Population.
Buprenorphine-naloxone treatment for opioid use disorder has rapidly expanded, yet little is known about treatment outcomes among patients in the general population. To examine predictors of treatment duration, dosage, and continuity in a diverse community setting. We examined QuintilesIMS Real World Data, an all-payer, pharmacy claims database, to conduct an analysis of individuals age 18 years and above initiating buprenorphine-naloxone treatment between January 2010 and July 2012 in 11 states. We used logistic regression to assess treatment duration longer than 6 months. We used accelerated failure time models to assess risk of treatment discontinuation. We used ordinary least squares regression to assess mean daily dosage. For patients with ≥3 fills, we also used logistic regression to assess whether ;an individual had a medication possession ratio of <80% and/or gaps in treatment >14 days. Models adjusted for individual demographics, prescribing physician specialty, state, and county-level variables. Overall, 41% of individuals were retained in treatment for at least 6 months and the mean treatment length was 266 days. Compared with individuals who paid primarily for treatment with cash, adjusted odds of 6 month retention were significantly lower for individuals with primary payment from Medicaid fee-for-service, Medicare part D, and third-party commercial. There were substantial differences in 6-month retention across states with the lowest in Arizona and highest in New York. Low-possession ratios occurred for 30% of individuals and 26% experienced treatment episodes with gaps >14 days. Odds of low-possession and treatment gaps were largely similar across demographic groups and geographic areas. Current initiatives to improve access and quality of buprenorphine-naloxone treatment should examine geographic barriers as well as the potential role of insurance benefit design in restricting treatment length.


Invariant Valpha14 natural killer T cell activation by edible mushroom acidic glycosphingolipids.
Invariant natural killer T (iNKT) cells regulate multi-immune response through Th1/Th2 cytokine release triggered by the recognition of CD1d-restricted glycosphingolipid antigens. Here we report that acidic glycosphingolipids (AGLs) of mushroom (Hypsizigus marmoreus and Pleurotus eryngii) presented by murine CD1d-transfected rat basophilic leukocytes induced interleukin-2 (IL-2) release from iNKT hybridoma cells. AGL-1, one of the AGLs, containing mannose at the non-reducing ends, induced CD1d-dependent IL-2 release. Al-though alpha-galactosylceramide (alpha-GalCer) presented by CD11c-positive cells induced both interferon-gamma (IFN-gamma) and IL-4 release, all of AGLs presented by CD11c-positive cells and AGL-1 presented by B cells induced IL-4 release from iNKT hybridoma cells. A single intravenous injection of AGLs into B6 mice induced only a little elevation of IL-4 in serum but repeated intravenous injection of AGLs induced prolonged retention of IL-4 in serum; therefore, these results suggested that edible mushroom AGLs might contribute to the retention of immunohomeostasis through the minimum induction of iNKT cell activation in vivo.


Mammary Microvessels are Sensitive to Menstrual Cycle Sex Hormones.
The mammary gland is a highly vascularized organ influenced by sex hormones including estrogen (E2) and progesterone (P4). Beyond whole-organism studies in rodents or cell monocultures, hormonal effects on the breast microvasculature remain largely understudied. Recent methods to generate 3D microvessels on-chip have enabled direct observation of complex vascular processes; however, these models often use non-tissue-specific cell types, such as human umbilical vein endothelial cells (HUVECs) and fibroblasts from various sources. Here, novel mammary-specific microvessels are generated by coculturing primary breast endothelial cells and fibroblasts under optimized culture conditions. These microvessels are mechanosensitive (to interstitial flow) and require endothelial-stromal interactions to develop fully perfusable vessels. These mammary-specific microvessels are also responsive to exogenous stimulation by sex hormones. When treated with combined E2 and P4, corresponding to the four phases of the menstrual cycle (period, follicular, ovular, and luteal), vascular remodeling and barrier function are altered in a phase-dependent manner. The presence of high E2 (ovulation) promotes vascular growth and remodeling, corresponding to high depletion of proangiogenic factors, whereas high P4 concentrations (luteal) promote vascular regression. The effects of combined E2 and P4 hormones are not only dose-dependent but also tissue-specific, as are shown by similarly treating non-tissue-specific HUVEC microvessels.


How effective is the Trail Making Test (Parts A and B) in identifying cognitively impaired drivers?
the medical community plays an important role in identifying drivers who may no longer be competent to drive due to illnesses such as dementia. Several office-based cognitive screening tools are currently used by the medical community, e.g. Mini-Mental State Examination, Trail Making Test (TMT), to assist in the identification of cognitively impaired (CI) at-risk drivers. However, the predictive validity of these tools is questionable. to examine the predictive power of the TMT for on-road driving performance. data from a prospective sample of CI and healthy older drivers were collected. TMT-A and -B (time and errors) served as predictor variables, with pass/fail on a scientifically based on-road assessment used as the criterion variable. Receiver operating characteristic (ROC) curve analysis was used to assess overall 'diagnostic' accuracy of TMT-A and -B for driving competency. Cut points from previous studies/guidelines were used to assess predictive power. a total of 134 older drivers (mean age = 75.30; SD = 7.83) participated: 87 healthy controls and 47 CI individuals. All predictor variables, with the exception of TMT-A errors, were significantly correlated with driving outcome. However, results from ROC curve analyses indicated that only TMT-A and -B total time had moderate discriminative abilities. Results also indicate that the power of the TMT is the lowest where physicians need it most (e.g. identifying CI patients whose driving skills have declined to an unsafe level). TMT-A and -B outcomes are most likely to be inaccurate in those whose driving competency has declined to an unsafe level, resulting in risks to both individual and public safety.


Perils of partialing redux: The case of the Dark Triad.
The Dark Triad (DT) is a collection of overlapping aversive personality profiles constituting psychopathy, narcissism, and Machiavellianism. Debates remain regarding the optimal way to examine the unique outcomes associated with each construct, with several scholars advocating partialing these profiles in multiple regression analyses (i.e., removing their shared variance). The present paper details the pitfalls inherent in this approach by comparing the convergence and divergence of relations derived from raw and residualized DT composite scores. In Sample 1 (N = 393), DT scores were examined to determine the extent to which their raw and residualized components manifested similar relationships with the Five-Factor Model and the DSM-5 Section III personality disorder traits. In Sample 2 (N = 542), the same approach was taken in relation to an array of associated behaviors (e.g., antisocial behavior, promiscuity). Findings from Samples 1 and 2 demonstrate that the use of residualized (vs. raw) coefficients presents important interpretative challenges for both narcissism and Machiavellianism. This study illustrates the substantial interpretive difficulties that can arise when using findings from residualized analyses (e.g., multiple regression) to build nomological networks around Dark Triad constructs. We argue that bivariate relations be given preferential treatment, given their more direct ties to the assessments, and that if multivariate approaches are to be used, they must be accompanied by strong theory about the components of DT constructs. (PsycINFO Database Record


Methotrexate Polyglutamation in a Myasthenia Gravis Clinical Trial.
Methotrexate (MTX) is an immunosuppressive and anti-inflammatory drug used to treat rheumatoid arthritis (RA) and other autoimmune conditions. MTX is transported into cells, where glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported that the degree of polyglutamation correlates with the anti-inflammatory effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome measures. The objective of this study was to assess the correlation between methotrexate (MTX) polyglutamates (MTXPGs) with Myasthenia Gravis (MG) outcome measures. An analysis was done of blood drawn from patients enrolled in the 12-month randomized, placebo-controlled study of MTX in MG study. Red blood cell MTXPGs were measured via ultra-performance liquid chromatography and tandem mass spectrometry. MTXPG was correlated to MG outcome measures using Spearman Correlation Coefficient. A two-group t-test was used to determine the difference in MTXPG based on clinical outcome responder definitions. Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects on placebo. Pentaglutamate had the strongest correlation with the MG-ADL (0.99), while tetraglutamate had the strongest correlation with the QMG (0.54). Triglutamate had the strongest correlation with MGC (0.76). There were variable correlations between MTXPG1-5 and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long chain methotrexate polyglutamates correlate better with MG outcomes.


Long-Term Oncologic and Reproductive Outcomes in Young Women With Early Endometrial Cancer Conservatively Treated: A Prospective Study and Literature Update.
This study aimed to analyze the long-term oncologic and reproductive outcomes in endometrial cancer (EC) in young patients conservatively treated by combined hysteroscopic resection (HR) and levonorgestrel intrauterine device (LNG-IUD). Twenty-one patients (age ≤ 40 years; Stage IA, G1-2 endometrioid EC), wishing to preserve their fertility, were enrolled into this prospective study. The HR was used to resect (1) the tumor lesion, (2) the endometrium adjacent to the tumor, and (3) the myometrium underlying the tumor. Hormonal therapy consisted of LNG-IUD (52 mg) for at least 6 months. The median follow-up time is 85 months (range, 30-114). After 3 months from the progestin start date, 18 patients (85.7%) showed a complete regression (CR), 2 (9.5%) showed persistent disease, whereas 1 patient (4.8%) presented with progressive disease and underwent definitive surgery (Stage IA, G3 endometrioid). At 6 months, 1 of the 2 persistences underwent definitive surgery (Stage IA, G1 endometrioid), whereas the other was successfully re-treated. Two recurrences (10.5%) were observed, both involving the endometrium and synchronous ovarian cancer (OC) (atypical hyperplasia and Stage IIB G1 endometrioid OC; Stage IA endometrioid G1 EC, and Stage IA G1 endometrioid OC). The median duration of complete response was 85 months (range, 8-117). Sixty-three percent of complete responders attempted to conceive with 92% and 83% pregnancy and live birth rates, respectively. To date, all patients are alive and have no evidence of disease. After a long follow-up, combined HR and LNG-IUD would seem to improve the efficacy of progestin alone. High pregnancy and live birth rates were observed in women attempting to conceive. This approach is still experimental and should be offered only in the framework of scientific protocols conducted in cancer centers.


[Treatment of depressed skull fractures].
On the basis of differentiated surgical management of 276 patients with depressed fractures of the skull the authors proved the efficacy of bone-preserving operations and accomplishing all surgical manipulations in a single stage with the conduction of primary cranioplasty. The justification of performing all stages of surgical treatment during the patient's first stay at the hospital with the conduction of cranioplasty in three stages is substantiated. It is shown that differentiated treatment of depressed fractures improves the results and shortens the period of social and working readaptation of the patients.


Inform: Efficient Information-Theoretic Analysis of Collective Behaviors.
The study of collective behavior has traditionally relied on a variety of different methodological tools ranging from more theoretical methods such as population or game-theoretic models to empirical ones like Monte Carlo or multi-agent simulations. An approach that is increasingly being explored is the use of information theory as a methodological framework to study the flow of information and the statistical properties of collectives of interacting agents. While a few general purpose toolkits exist, most of the existing software for information theoretic analysis of collective systems is limited in scope. We introduce Inform, an open-source framework for efficient information theoretic analysis that exploits the computational power of a C library while simplifying its use through a variety of wrappers for common higher-level scripting languages. We focus on two such wrappers here: PyInform (Python) and rinform (R). Inform and its wrappers are cross-platform and general-purpose. They include classical information-theoretic measures, measures of information dynamics and information-based methods to study the statistical behavior of collective systems, and expose a lower-level API that allow users to construct measures of their own. We describe the architecture of the Inform framework, study its computational efficiency and use it to analyze three different case studies of collective behavior: biochemical information storage in regenerating planaria, nest-site selection in the ant Temnothorax rugatulus, and collective decision making in multi-agent simulations.


Cerebellar-dependent eyeblink conditioning deficits in schizophrenia spectrum disorders.
Accumulating evidence suggests that abnormalities in neural circuitry and timing associated with the cerebellum may play a role in the pathophysiology of schizophrenia. Schizotypal personality disorder (SPD) may be genetically linked to schizophrenia, but individuals with SPD are freer from potential research confounds and may therefore offer insight into psychophysiological correlates of schizophrenia. The present study employed a delay eyeblink conditioning (EBC) procedure to examine cerebellar-dependent learning in schizophrenia, SPD, and healthy control subjects (n = 18 per group) who were matched for age and gender. The conditioned stimulus was a 400-ms tone that coterminated with a 50 ms unconditioned stimulus air puff. Cognitive performance on the Picture Completion, Digit Symbol Coding, Similarities, and Digit Span subscales of the Wechsler Adult Intelligence Scale--Third Edition was also investigated. The schizophrenia and SPD groups demonstrated robust EBC impairment relative to the control subjects; they had significantly fewer conditioned responses (CRs), as well as smaller CR amplitudes. Schizophrenia subjects showed cognitive impairment across subscales compared with SPD and control subjects; SPD subjects showed intermediate performance to schizophrenia and control subjects and performed significantly worse than controls on Picture Completion. Impaired EBC was significantly related to decreased processing speed in schizophrenia spectrum subjects. These findings support the role of altered cortico-cerebellar-thalamic-cortical circuitry in the pathophysiology of schizophrenia spectrum disorders.


Improving the coordination of care for low back pain patients by creating better links between acute and community services.
This paper reports on the development of a care-pathway to improve service linkages between the acute setting and community health services in the treatment of low back pain. The pathway was informed by two processes: (1) a literature review based on best-practice guidelines in the assessment, treatment and continuity of care for low back pain patients; and (2) consultation with staff and key stakeholders. Stakeholders from both the acute and community sectors comprised the Working Group, who identified central areas of concern to be addressed in the care-pathway, with the goal of preventing chronicity of low back pain and reducing emergency department presentations. The main outcomes achieved include: the development of a new care-coordinator role, which would support a greater focus on integration between acute and community sectors for low back pain patients; identifying the need to screen at-risk patients; implementation of the SCTT (Service Coordination Tool Templates) tool as a system of referral across the acute and community settings; and agreement on the need to develop an evidence-based self-management program to be offered to low back pain patients. The benefits and challenges of implementing this care pathway are discussed.


Anti-nutritional factors in the roots of a local cultivar of Moringa oleifera (Lam).
The evergreen plant, Moringa oleifera (Lam) has been known to have both medicinal and nutritional properties, thus its wide use in traditional medicine in Africa and Asia. The roots, in particular, have been reported to possess antibiotic, anti-tumour and anti-oxidative activities. This study therefore seeks to determine the levels of the anti-nutritional factors and other proximate analyses in the roots of a local cultivar of Moringa oleifera which might be responsible for such activities. The concentrations of oxalates and phytates in the roots were determined using the methods of Munro and Bassir and Griffith and Thomas, respectively. The methods of Association of Analytical Chemists (AOAC) were used to estimate the amount of tannins, saponins and cyanogenic glycosides while the Technicon sequential Multi-sample amino acid analyzer (TSM) was used determine the amino acid concentration in the roots. Tannins (45 mg 100 g(-1)) and oxalates (17.08 mg 100 g(-1)) were present in the roots at higher levels while saponins (4.20mg 100 g(-1)), cyanogenic glycosides (2.72 mg 100 g(-1)) and phytates (0.07 mg 100 g(-1)) occurred at much lower levels. The roots contained (Mean +/- Standard Error of mean) %crude lipid (6.33 +/- 1.64), %crude proteins (5.02 +/- 1.52), %carbohydrates (76.75), %ash (4.97 +/- 0.53) and %moisture (6.93 +/- 0.58). The roots lacked the water-soluble vitamins pyridoxine, riboflavin and thiamine but contained ascorbic acid (48.13 mg 100 g(-1)) and niacin (5.83 mg 100 g(-1)). This study has shown that Moringa oleifera roots are rich in anti-nutritional factors and that is why they are widely used in traditional medicine in Africa, Asia and Americas for its medicinal importance.


Aldosterone and the enhanced natriuresis of hypertonic infusions in the dog.
The purpose of this study was to determine whether small elevations in plasma sodium concentration (PNa) were effective in decreasing aldosterone secretion and, hence, in increasing sodium excretion in dogs fed normal sodium diets. Ten dogs fed a normal sodium diet, six DOCA-treated dogs, and four adrenalectomized dogs were given the same sodium load (2.5 mmol/kg) either as a hypertonic (1 M NaCl) or hypotonic (0.1 M NaCl) infusion. In all three groups of dogs, PNa was greater after the hypertonic than after the hypotonic infusion during most of the 22-h experiment. The dogs fed a normal sodium diet responded to the elevation in PNa (hypertonic infusion) with decreased aldosterone excretion and an exaggerated natriuresis. When aldosterone levels were maintained constant by either DOCA treatment or adrenalectomy, the exaggerated natriuresis that accompanied the hypertonic infusion was prevented. Therefore, elevation of PNa appears to be an important determinant of aldosterone secretion and, hence, of sodium excretion in conscious dogs fed normal sodium diets.


Mapping human brain capillary water lifetime: high-resolution metabolic neuroimaging.
Shutter-speed analysis of dynamic-contrast-agent (CA)-enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (τ(b)) and blood volume fraction (v(b); capillary density-volume product (ρ(†)V)) in a high-resolution (1)H2O MRI voxel (40 μL) or ROI. The equilibrium water extravasation rate constant, k(po) (τ(b)(-1)), averages 3.2 and 2.9 s(-1) in resting-state normal white matter (NWM) and gray matter (NGM), respectively (n = 6). The results (italicized) lead to three major conclusions. (A) k(po) differences are dominated by capillary water permeability (P(W)(†)), not size, differences. NWM and NGM voxel k(po) and v(b) values are independent. Quantitative analyses of concomitant population-averaged k(po), v(b) variations in normal and normal-appearing MS brain ROIs confirm P(W)(†) dominance. (B) P(W)(†) is dominated (>95%) by a trans(endothelial)cellular pathway, not the P(CA)(†) paracellular route. In MS lesions and GBM tumors, P(CA)(†) increases but P(W)(†) decreases. (C) k(po) tracks steady-state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional k(po) correlates with literature MRSI ATP (positively) and Na(+) (negatively) tissue concentrations. This suggests that the P(W)(†) pathway is metabolically active. Excellent agreement of the relative NGM/NWM k(po)v(b) product ratio with the literature (31)PMRSI-MT CMR(oxphos) ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (k(io)) is proportional to plasma membrane P-type ATPase turnover, likely due to active trans-membrane water cycling. With synaptic proximities and synergistic metabolic cooperativities, polar brain endothelial, neuroglial, and neuronal cells form "gliovascular units." We hypothesize that a chain of water cycling processes transmits brain metabolic activity to k(po), letting it report neurogliovascular unit Na(+),K(+)-ATPase activity. Cerebral k(po) maps represent metabolic (functional) neuroimages. The NGM 2.9 s(-1) k(po) means an equilibrium unidirectional water efflux of ~10(15) H2O molecules s(-1) per capillary (in 1 μL tissue): consistent with the known ATP consumption rate and water co-transporting membrane symporter stoichiometries.


Depressive disorders and unprotected casual anal sex among Australian homosexually active men in primary care.
To examine the relationship between depressive disorders and unprotected anal intercourse with casual partners, among homosexually active men attending for primary care. The first 460 homosexually active men enrolling in an Australian integrated primary care programme were screened for current depressive disorders using the Primary Care Evaluation of Mental Disorders (PRIME-MD) and completed questionnaires on their sexual behaviour in the prior 6 months. One hundred and sixty-two (35%) were HIV positive, 283 (62%) were HIV negative and 15 (3%) were untested. The prevalence of major depressive episode (MDE), as measured by the PRIME-MD, on enrollment was 28% (129/460), while the prevalence of dysthymic disorder (DD) was 26% (121/460). These include 84 men (18%) who met the criteria for both disorders ('double depression'). Neither disorder was associated with HIV status. Men with MDE were less likely to have been sexually active than the remainder of the cohort (90/129 [70%] vs. 291/331 [88%]; OR: 0.32 [95% CI: 0.19-0.52]; P<0.0001). Men with DD alone, however, were significantly more likely than men with neither disorder to report having had unprotected anal intercourse with a casual partner (11/38 [29%] vs. 43/292 [15%]; OR: 2.36 [95%CI: 1.09-5.10]; P=0.035). Depressive disorders were highly prevalent in this cohort and independent of HIV status. MDE was associated with reduced sexual activity. Among men without MDE, the presence of DD was independently associated with an increased likelihood of reporting unsafe anal sex with a casual partner in the prior 6 months.


Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis.
Dendritic arborization patterns are consistent anatomical correlates of genetic disorders such as Down syndrome (DS) and autism spectrum disorders (ASDs). In a screen for abnormal dendrite development, we identified Minibrain (MNB)/DYRK1a, a kinase implicated in DS and ASDs, as a regulator of the microtubule cytoskeleton. We show that MNB is necessary to establish the length and cytoskeletal composition of terminal dendrites by controlling microtubule growth. Altering MNB levels disrupts dendrite morphology and perturbs neuronal electrophysiological activity, resulting in larval mechanosensation defects. Using in vivo and in vitro approaches, we uncover a molecular pathway whereby direct phosphorylation of β-tubulin by MNB inhibits tubulin polymerization, a function that is conserved for mammalian DYRK1a. Our results demonstrate that phosphoregulation of microtubule dynamics by MNB/DYRK1a is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of posttranslational microtubule regulation in neurons and uncovering a conserved pathway for a DS- and ASD-associated kinase.


A 3D musculoskeletal model of the western lowland gorilla hind limb: moment arms and torque of the hip, knee and ankle.
Three-dimensional musculoskeletal models have become increasingly common for investigating muscle moment arms in studies of vertebrate locomotion. In this study we present the first musculoskeletal model of a western lowland gorilla hind limb. Moment arms of individual muscles around the hip, knee and ankle were compared with previously published data derived from the experimental tendon travel method. Considerable differences were found which we attribute to the different methodologies in this specific case. In this instance, we argue that our 3D model provides more accurate and reliable moment arm data than previously published data on the gorilla because our model incorporates more detailed consideration of the 3D geometry of muscles and the geometric constraints that exist on their lines-of-action about limb joints. Our new data have led us to revaluate the previous conclusion that muscle moment arms in the gorilla hind limb are optimised for locomotion with crouched or flexed limb postures. Furthermore, we found that bipedalism and terrestrial quadrupedalism coincided more regularly with higher moment arms and torque around the hip, knee and ankle than did vertical climbing. This indicates that the ability of a gorilla to walk bipedally is not restricted by musculoskeletal adaptations for quadrupedalism and vertical climbing, at least in terms of moment arms and torque about hind limb joints.


Optimal pH strategy for selective cerebral perfusion.
Selective cerebral perfusion (SCP) affords brain protection superior to hypothermic circulatory arrest (HCA) for prolonged aortic arch procedures. Optimal pH strategy for HCA is controversial; for SCP it is unknown. We compared pH strategies during SCP in a survival pig model. Twenty juvenile pigs (26+/-2.4 kg), randomized to alpha-stat (n=10) or pH-stat (n=10) management, underwent cooling to 20 degrees C on cardiopulmonary bypass (CPB) followed by 90 min of SCP at 20 degrees C. SCP was conducted with a mean pressure of 50 mmHg and hematocrit of 22.5%. Using fluorescent microspheres and sagittal sinus blood sampling, cerebral blood flow (CBF) and oxygen metabolism (CMRO2) were assessed at the following time points: baseline, after 30 min cooling (20 degrees C), 30 min of SCP, 90 min of SCP, 15 min post-CPB and 2h post-CPB. Visual evoked potentials (VEP) were assessed at baseline and monitored for 2h during recovery. Neurobehavioral recovery (10=normal) was assessed in a blinded fashion for 7 postoperative days. There were no significant differences between the groups at baseline. CBF was significantly higher at the end of cooling, and after 30 and 90 min of SCP in the pH-stat group (P=0.02, 0.007, 0.03). CMRO2 was also higher with pH-stat (P=0.06, 0.04, 0.10). Both groups showed prompt return to values close to baseline after rewarming (P=ns). VEP suggested a trend towards improved recovery in the alpha-stat group at 2h post-CPB, P=0.15. However, there were no significant differences in neurobehavioral score: (alpha-stat versus pH-stat) median values 7 and 7.5 on day 1; 9 and 9 on day 4, and 10 and 10 on day 7. These data suggest that alpha-stat management for SCP provides more effective metabolic suppression than pH-stat, with lower CBF. Clinically, the better preservation of cerebral autoregulation during alpha-stat perfusion should reduce the risk of embolization.


Sympatry Predicts Spot Pigmentation Patterns and Female Association Behavior in the Livebearing Fish Poeciliopsis baenschi.
In this study, we explored the possibility that differences in pigmentation patterns among populations of the fish Poeciliopsis baenschi were associated with the presence or absence of the closely related species P. turneri. If reproductive character displacement is responsible, spotting patterns in these two species should diverge in sympatry, but not allopatry. We predicted that female P. baenschi from sympatric sites should show a preference for associating with conspecifics vs. heterospecific males, but females from allopatric sites should show no such preferences. To evaluate these predictions, we compared spotting patterns and female association behaviors in populations of P. baenschi from Central Mexico. We found that both of our predictions were supported. Poeciliopsis baenschi that co-occured with P. turneri had spotting patterns significantly different than their counterparts from allopatric sites. Using a simultaneous choice test of video presentations of males, we also found that female P. baenschi from populations that co-occured with P. turneri spent significantly more time with males of their own species than with P. turneri males. In contrast, females from allopatric populations of P. baenschi showed no differences in the amount of time they spent with either conspecific or heterospecific males. Together, our results are consistent with the hypothesis that reproductive character displacement may be responsible for behavioral and spotting pattern differences in these populations of P. baenschi.


Erythrocyte membrane inhibitor of reactive lysis: effects of phosphatidylinositol-specific phospholipase C on the isolated and cell-associated protein.
The erythrocyte membrane inhibitor of reactive lysis (MIRL) is an 18-Kd protein that controls complement-mediated hemolysis by restricting the activity of the membrane attack complex. MIRL expression on the erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) is abnormally low, and the greater susceptibility of PNH erythrocytes to complement is causally related to this deficiency. Inasmuch as other proteins that are deficient in PNH are anchored to the membrane through a glycosyl phosphatidylinositol moiety, studies were undertaken to determine if MIRL shares this structural feature. Normal human erythrocytes that had been radiolabeled with 125I were incubated with phosphatidylinositol-specific phospholipase C (PIPLC), and the supernate and the solubilized membrane proteins were immunoprecipitated using anti-MIRL antiserum. The MIRL that was specifically released into the supernate had an Mr of 19 Kd, while the MIRL that remained bound to the membrane had an Mr of 18 Kd. A quantitative assay showed that approximately 10% of erythrocyte MIRL was susceptible to PIPLC; however, treatment with PIPLC had no effect on either the electrophoretic mobility or the functional activity of purified MIRL. These studies show that the effects of PIPLC on MIRL are similar to those observed for other human erythrocyte membrane proteins that are anchored by a glycosyl phosphatidylinositol moiety.


[Evaluating the performance appraisal in daily nursing practice].
The objective of this study was determine the development of performance appraisal in daily nursing practice aiming to up-date and adequate the program of Nursing Management Post-graduation Courses. The sample was composed by 27 nurses students of the first and second post-graduation course in 1994 and 1995. The results showed that performance appraisal is not established in the nurses work reality (51%) and 70% of respondents assert that they did not receive any training in this field. The qualitative results added to quantitative data allow to point the necessity to invest in nursing education both in graduation and post-graduation levels, to carry out the performance appraisal like a process searching the development and improvement of human resources and working relations.


A comparison of palliative care outcome measures used to assess the quality of palliative care provided in long-term care facilities: a systematic review.
Provision of palliative care in long-term care (LTC) facilities is important, but limited research has been undertaken to investigate the most appropriate outcome measure for use in this setting. In this systematic review we aimed to measure the psychometric properties (reliability/validity) and feasibility of palliative outcome measures used to assess the quality of palliative care provided in LTC. For identification of outcome measures we undertook systematic searches of electronic databases from 1 January 2000 to 12 September 2008. Included studies were assessed by two independent reviewers for methodological quality prior to inclusion in the review using an appraisal checklist developed for the review to evaluate validity, reliability and feasibility. Ten articles were included in the final review and these provided specific information on the psychometric properties of 10 outcome measures. Four of these measures reported data specifically for residents in LTC facilities, while the remaining six measures reported a sub-set of data for residents in LTC facilities. The Family Perceptions of Care Scale is considered by the authors as the most suitable outcome measure for use in LTC facilities. Of the remaining nine measures, a further two were also considered suitable for measuring the quality of palliative care in residential aged care facilities. These are the Quality of Dying in Long-term Care scale and the Toolkit Interview.


Cutoff radius effect of the isotropic periodic sum and Wolf method in liquid-vapor interfaces of water.
As a more economical but similarly accurate computation method than the Ewald sum, the isotropic periodic sum (IPS) method for nonpolar molecules (IPSn) and polar molecules (IPSp), along with the Wolf method are of interest, but the cutoff radius dependence is an important issue. To evaluate the cutoff radius effect of the three methods, a water-vapor interfacial system has been studied by molecular dynamics. The Wolf method can produce adequate results for surface tension compared to that of the Ewald sum (within 2.9%) at a long enough cutoff radius, r(c). However, the estimation of the electrostatic potential profile and dipole orientational function is poor. The Wolf method cannot estimate electrostatic configuration at r(c) ≤ L(z)∕2 (L(z) is the longest lattice of the system). We have found that the convergence of the surface tension and the electrostatic configuration of the IPSn method is faster than that of the IPSp method. Moreover, the IPSn method is most accurate among the three methods for the same cutoff radius. Furthermore, the behavior of the surface tension against the cutoff radius shows a greater difference for the IPSn and IPSp method. The surface tension of the IPSp method fluctuates and presents a similar result to that of the Ewald sum, but the surface tension for the IPSn method greatly deviates near r(c) = L(z)∕3. The cause of this deviation is the difference between the interfacial configuration of the water surface and the cutoff treatment of the IPS method. The deviation becomes insignificant far from r(c) = L(z)∕3. In spite of this shortcoming, the IPSn method gives the most accurate result in estimating the surface tension at r(c) = L(z)∕2. From all the results in this work, the IPSn and IPSp method have been found to be more accurate than the Wolf method. In conclusion, the surface tension and structure of water-vapor interface can be calculated by the IPSn method when r(c) is greater than or equal to the longest lattice of the system. The IPSp method and the Wolf method require a longer cutoff radius than the longest lattice of the system to estimate interfacial properties.


Brachionus rotifers as a model for investigating dietary and metabolic regulators of aging.
Because every species has unique attributes relevant to understanding specific aspects of aging, using a diversity of study systems and a comparative biology approach for aging research has the potential to lead to novel discoveries applicable to human health. Monogonont rotifers, a standard model for studies of aquatic ecology, evolutionary biology, and ecotoxicology, have also been used to study lifespan and healthspan for nearly a century. However, because much of this work has been published in the ecology and evolutionary biology literature, it may not be known to the biomedical research community. In this review, we provide an overview of Brachionus rotifers as a model to investigate nutritional and metabolic regulators of aging, with a focus on recent studies of dietary and metabolic pathway manipulation. Rotifers are microscopic, aquatic invertebrates with many advantages as a system for studying aging, including a two-week lifespan, easy laboratory culture, direct development without a larval stage, sexual and asexual reproduction, easy delivery of pharmaceuticals in liquid culture, and transparency allowing imaging of cellular morphology and processes. Rotifers have greater gene homology with humans than do established invertebrate models for aging, and thus rotifers may be used to investigate novel genetic mechanisms relevant to human lifespan and healthspan. The research on caloric restriction; dietary, pharmaceutical, and genetic interventions; and transcriptomics of aging using rotifers provide insights into the metabolic regulators of lifespan and health and suggest future directions for aging research. Capitalizing on the unique biology of Brachionus rotifers, referencing the vast existing literature about the influence of diet and drugs on rotifer lifespan and health, continuing the development of genetic tools for rotifers, and growing the rotifer research community will lead to new discoveries a better understanding of the biology of aging.


A rapid gene-based genome-wide association test with multivariate traits.
A gene-based genome-wide association study (GWAS) provides a powerful alternative to the traditional single single nucleotide polymorphism (SNP) association analysis due to its substantial reduction in the multiple testing burden and possible gain in power due to modeling multiple SNPs within a gene. A gene-based association analysis on multivariate traits is often of interest, but it imposes substantial analytical as well as computational challenges to implement it at a genome-wide level. We propose a rapid implementation of the multivariate multiple linear regression (RMMLR) approach in unrelated individuals as well as in families. Our approach allows for covariates. Moreover, the asymptotic distribution of the test statistic is not heavily influenced by the linkage disequilibrium (LD) among the SNPs and hence can be used efficiently to perform a gene-based GWAS. We have developed a corresponding R package to implement such multivariate gene-based GWAS with this RMMLR approach. Through extensive simulation, we compared several approaches for both single and multivariate traits. Our RMMLR approach maintained a correct type I error level even for sets of SNPs in strong LD. It also demonstrated a substantial gain in power to detect a gene when it is associated with a subset of the traits. We also studied performances of the approaches on the Minnesota Center for Twin Family Research dataset. In our overall comparison, our RMMLR approach provides an efficient and powerful tool to perform a gene-based GWAS with single or multivariate traits and maintains the type I error appropriately.


Thin-layer and gas chromatographic determination of ketamine and its biotransformed products in biological fluids.
Ketamine, (2-(o-chlorophenyl)-2-methylamine cyclohexanone) and its in vivo metabolite I (2-(o-chlorophenyl)-2-aminocyclohexanone) and metabolite II (2-(o-chlorophenyl)-2-amino-5-cyclohexene-1-one) were determined by thin-layer (TLC) and gas chromatography (GC). In vivo studies include intraperitoneal injection of ketamine in rats. Urine and blood samples were collected at regular intervals. The unreacted ketamine and its biotransformed products were extracted from urine and blood and subjected to TLC and GC analysis. 1% Carbowax-20M on Gas Chrom G-AW-DMCS and precoated LQ6D TLC plates were used in this study. In conclusion a rapid, simple, accurate, and sensitive thin-layer and gas chromatographic method for the identification of ketamine and its metabolites from biological fluids have been developed.


Relationship between body mass index and anti-hypertensive efficacy of doxazosin according to a survey of Japanese patients.
In this cross-sectional study, we surveyed a population of 101 hypertensive patients in Japan to determine the efficacy of the blood pressure lowering effect of alpha 1-blockers in relation to their body mass index (BMI). We found that doxazosin was frequently administered to obese hypertensive patients; many patients treated with doxazosin were taking concomitant medication. We also demonstrated that the higher the dose of doxazosin, the lower the ambulatory blood pressure measured in the out-patient clinic. Doxazosin showed a more favourable blood pressure lowering effect in patients with a higher BMI. These results suggest that anti-hypertensive drugs are useful when used in obese patients receiving multiple concomitant medications. These patients would normally be considered to show a poor response to anti-hypertensive treatment. Furthermore, we expect the alpha 1-blocker doxazosin to demonstrate a dose-dependent effect in obese patients with hypertension.


Transfusion-related acute lung injury.
Transfusion-related acute lung injury (TRALI) is an uncommon complication of allogeneic blood transfusion manifested typically by shortness of breath, fever, and hypotension. It has been estimated to occur in 0.04% to 0.16% per patient transfused. TRALI has been identified as an important cause of transfusion-related morbidity and mortality. Despite the increasing recognition that TRALI represents an important clinical syndrome, much about the pathogenesis, treatment, and prevention of TRALI is poorly understood or is controversial. In this report, what is known about TRALI is summarized and some of the areas in which knowledge and/or consensus are currently lacking are identified.


Isolation of phenolic compounds from iceberg lettuce and impact on enzymatic browning.
Enzymatic browning is generally reported as the reaction between phenolic substances and enzymes. The quality of iceberg lettuce is directly linked to this discoloration. In particular, the color change of lettuce stems considerably reduces consumer acceptance and thus decreases sales revenue of iceberg lettuce. Ten phenolic compounds (caffeic acid, chlorogenic acid, phaseolic acid, chicoric acid, isochlorogenic acid, luteolin-7-O-glucuronide, quercetin-3-O-glucuronide, quercetin-3-O-galactoside, quercetin-3-O-glucoside, and quercetin-3-O-(6″-malonyl)-glucoside) were isolated from Lactuca sativa var. capitata by multilayer countercurrent chromatography (MLCCC) and preparative high-performance liquid chromatography (HPLC). In addition, syringin was identified for the first time in iceberg lettuce. This polyphenolic ingredient was previously not mentioned for the family of Cichorieae in general. The purity and identity of isolated compounds were confirmed by different NMR experiments, HPLC-DAD-MS, and HR-MS techniques. Furthermore, the relationship between discoloration of iceberg lettuce and enzymatic browning was thoroughly investigated. Unexpectedly, the total concentration of phenolic compounds and the activity of polyphenol oxidase were not directly related to the browning processes. Results of model incubation experiments of plant extract solutions led to the conclusion that in addition to the typical enzymatic browning induced by polyphenol oxidases, further mechanisms must be involved to explain total browning of lettuce.


Chiral colloidal clusters.
Chirality is an important element of biology, chemistry and physics. Once symmetry is broken and a handedness is established, biochemical pathways are set. In DNA, the double helix arises from the existence of two competing length scales, one set by the distance between monomers in the sugar backbone, and the other set by the stacking of the base pairs. Here we use a colloidal system to explore a simple forcing route to chiral structures. To do so we have designed magnetic colloids that, depending on both their shape and induced magnetization, self-assemble with controlled helicity. We model the two length scales with asymmetric colloidal dumbbells linked by a magnetic belt at their waist. In the presence of a magnetic field the belts assemble into a chain and the steric constraints imposed by the asymmetric spheres force the chain to coil. We show that if the size ratio between the spheres is large enough, a single helicity is adopted, right or left. The realization of chiral colloidal clusters opens up a new link between colloidal science and chemistry. These colloidal clusters may also find use as mesopolymers, as optical and light-activated structures, and as models for enantiomeric separation.


[Computed tomography of anterior dislocation of the temporomandibular articular disk].
In a prospective study, the findings on arthrography and CT in 51 TMJs with anterior meniscus dislocation were compared. The CT diagnosis of anterior dislocation was made by a standardised method which we have developed and which depends upon evaluating axial sections. Sensitivity of the CT methods was 87%. In the absence of arthrography, a negative diagnosis in the asymptomatic contralateral side was made in 81%. Ruptures and adhesions could not be demonstrated by CT. For these reasons, arthrography is to be preferred to CT for making the initial diagnosis. CT should be carried out for special indications, such as contrast sensitivity, the documentation of a clinically confirmed diagnosis and for follow-up of treatment. Currently an attempt is being made to stage the disease by computed tomography.