Software Architecture Patterns for Extending Sensing Capabilities and Data Formatting in Mobile Sensing.
Mobile sensing—that is, the ability to unobtrusively collect sensor data from built-in phone and attached wearable sensors—have proven to be a powerful approach to understanding the behavior, well-being, and health of people in their everyday life. Different platforms for mobile sensing have been presented and significant knowledge on how to facilitate mobile sensing has been accumulated. However, most existing mobile sensing platforms only support a fixed set of mobile phone and wearable sensors which are `built into' the platform's generic `study app'. This creates some fundamental challenges for the creation and approval of application-specific mobile sensing studies, since there is little support for adapting the sensing capabilities to what is needed for a specific study. Moreover, most existing platforms use their own proprietary data formats and there is no standardization in how data are collected and in what formats. This poses some fundamental challenges to realizing the vision of using mobile sensing in health applications, since mobile sensing data collected across different phones and studies cannot be compared, thus hampering generalizability and reproducibility across studies. This paper presents two software architecture patterns enabling (i) dynamic extension of mobile sensing to incorporate new sensing capabilities, such as collecting data from a wearable sensor, and (ii) handling real-time transformation of data into standardized data formats. These software patterns are derived from our work on CARP Mobile Sensing (CAMS), which is a cross-platform (Android/iOS) software architecture providing a reactive and unified programming model that emphasizes extensibility. This paper shows how the framework uses the two software architecture patterns to add sampling support for an electrocardiography (ECG) device and support data transformation into the new Open mHealth (OMH) data format. The paper also presents data from a small study, demonstrating the robustness and feasibility of using CAMS for data collection and transformation in mobile sensing.


A Parental Report of Youth Transition Readiness: The Parent STARx Questionnaire (STARx-P) and Re-evaluation of the STARx Child Report.
The STARx Questionnaire is a self-report measure of health care transition (HCT) readiness in youth with chronic diseases. We aimed to improve reliability and generalizability of the STARx and report initial reliability data on the STARx-P Questionnaire, a self-report measure of parent perspective on their child's HCT readiness. Participants were recruited in several clinics from a large academic hospital in the southeastern USA and via the therapeutic summer camp for children with chronic disease. Children with chronic conditions responded to the 18-question STARx Questionnaire and their parents responded to the parent version, the STARx-P Questionnaire. IRB-approved consents were obtained from 341 parents (89.4% mothers) and 455 children (Mean age 12.28±2.53; 36.9% Males; 68.6% Caucasian; 22.6% African-American). The most common diagnoses were kidney disease, inflammatory bowel disease, diabetes, cerebral palsy, sickle cell, and cystic fibrosis. Principal component analysis of the STARx-P Questionnaire identified three major subscales in both the child and parent-report: Disease Knowledge, Self-management and Provider Communication. Internal reliability was moderate to good (α=0.545-0.759). The STARx-P Questionnaire and STARx Version 4 Questionnaire have demonstrated initial reliability in this multi-institution study. It is the first HCT readiness questionnaire that includes a parent-proxy report which is needed in studies of non-verbal and/or developmentally delayed children. Parent-report can also give unique insights not obtained from self-reports.


Should the diagnosis of coronary artery disease be based on the evaluation of myocardial function or perfusion?
The aim of this review was to define the place of stress (exercise, dobutamine, and vasodilator) echocardiography in the context of perfusion scintigraphic techniques for the detection of coronary artery disease. Echocardiography and nuclear imaging have their strong and weak points. Echocardiography has the benefit of widespread availability, relatively low cost, portability, absence of radiation, safety, and determination of ischaemic threshold. However, echocardiographic imaging cannot be performed during treadmill exercise, the echocardiographic windows are variable with sometimes poor echogenicity, and interpretation is subjective and requires an important learning curve. Diagnostic comparisons were focused on studies involving echocardiographic and nuclear imaging in the same patients. These direct comparisons show that exercise or dobutamine echocardiography and perfusion imaging have similar accuracies for the detection and localization of coronary artery disease. Perfusion imaging may be more sensitive in the detection of mild coronary artery disease; echocardiography, however, has a better specificity. Vasodilator perfusion imaging is superior to vasodilator echocardiography, although the new dipyridamole-atropine echocardiography test will make future reassessment necessary. Once the condition of adequate echocardiographic training is fulfilled, we believe that the selection of one or other test should be tailored to clinical circumstances rather than be a uniform decision.


Safety, tolerability and immunogenicity of a Haemophilus influenzae type b vaccine containing aluminum phosphate adjuvant administered at 2, 3 and 4 months of age.
The primary aim of this study was to assess the tolerability and immunogenicity of a new Haemophilus influenzae type b (Hib)/AlPO4 (CHIRON, SpA) vaccine, in two-month-old healthy infants. Twenty-three subjects were enrolled and administered the new Hib vaccine containing AlPO4 adjuvant at two, three and four months of age concomitantly with diphtheria-pertussis-tetanus (DPT) and hepatitis B vaccines according to the local program. Children were observed for 30 minutes after each immunization for any immediate local and systemic reactions. An active surveillance for side effects was performed on the 2nd and 7th days following each immunization by telephone. Families also filled out diaries for the first seven days. From the 2nd day to the next immunization only data about adverse events necessitating a physician's visit or about serious adverse events were collected. Blood samples were obtained before the first immunization and one month after the third dose for evaluation of anti-polyribosylribitol phosphate (PRP) antibody response. Local reactions at the Hib site were mild and less frequent compared to those observed at the DPT site. Systemic reactions noted after the three immunizations were fever in 70 percent, irritability in 48 percent, persistent crying in 26 percent, change in eating habits in 22 percent, diarrhea in 17 percent, sleepiness in 17 percent, vomiting in 9 percent, and unusual crying in 4 percent of the cases. There was no serious adverse event. One hundred percent and 95 percent of children achieved an anti-PRP antibody response over 0.15 microg/ml and 1.0 microg/ml, respectively. The geometric mean titer was 15 microg/ml and the geometric mean ratio 84. It was concluded that the new (Hib)/AlPO4 vaccine is safe and well tolerated, and induced a good PRP antibody response in healthy two-month-old infants.


Minimum description length synthetic aperture radar image segmentation.
We present a new minimum description length (MDL) approach based on a deformable partition--a polygonal grid--for automatic segmentation of a speckled image composed of several homogeneous regions. The image segmentation thus consists in the estimation of the polygonal grid, or, more precisely, its number of regions, its number of nodes and the location of its nodes. These estimations are performed by minimizing a unique MDL criterion which takes into account the probabilistic properties of speckle fluctuations and a measure of the stochastic complexity of the polygonal grid. This approach then leads to a global MDL criterion without an undetermined parameter since no other regularization term than the stochastic complexity of the polygonal grid is necessary and noise parameters can be estimated with maximum likelihood-like approaches. The performance of this technique is illustrated on synthetic and real synthetic aperture radar images of agricultural regions and the influence of different terms of the model is analyzed.


Negative symptoms in depressed and schizophrenic patients: how do they differ?
The present study evaluated differences in negative symptoms between schizophrenic and depressive patients and investigated whether a consideration of the nature of negative symptoms (enduring vs. nonenduring) can help to improve their specificity for schizophrenia. Patients enrolled in the study were consecutively hospitalized with an acute exacerbation of schizophrenia (N = 33) or major depressive disorder (N = 43) (DSM-IV). Negative and depressive symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and the Montgomery-Asberg Depression Rating Scale, respectively. Duration of negative symptoms was assessed through a semistructured interview with the patients and their closest relatives. On the basis of the assessed duration of symptoms, negative symptoms were categorized as enduring or nonenduring. Analyses revealed high SANS ratings for both diagnostic groups. Negative symptoms in depressive patients (p =.01), but not in schizophrenic patients, were significantly associated with the presence or the emergence of depressive symptoms. The prevalence of enduring negative symptoms was significantly higher in schizophrenic patients than in depressive patients (p <.01). A consideration of enduring negative symptoms significantly increased the discriminative power of negative symptoms for schizophrenia (p =.02). The present findings suggest that negative symptoms in most depressive patients are just an epiphenomenon of depressive symptoms and can be distinguished from schizophrenic negative symptoms.


Drosophila ribosomal protein mutants control tissue growth non-autonomously via effects on the prothoracic gland and ecdysone.
The ribosome is critical for all aspects of cell growth due to its essential role in protein synthesis. Paradoxically, many Ribosomal proteins (Rps) act as tumour suppressors in Drosophila and vertebrates. To examine how reductions in Rps could lead to tissue overgrowth, we took advantage of the observation that an RpS6 mutant dominantly suppresses the small rough eye phenotype in a cyclin E hypomorphic mutant (cycE(JP)). We demonstrated that the suppression of cycE(JP) by the RpS6 mutant is not a consequence of restoring CycE protein levels or activity in the eye imaginal tissue. Rather, the use of UAS-RpS6 RNAi transgenics revealed that the suppression of cycE(JP) is exerted via a mechanism extrinsic to the eye, whereby reduced Rp levels in the prothoracic gland decreases the activity of ecdysone, the steroid hormone, delaying developmental timing and hence allowing time for tissue and organ overgrowth. These data provide for the first time a rationale to explain the counter-intuitive organ overgrowth phenotypes observed for certain members of the Minute class of Drosophila Rp mutants. They also demonstrate how Rp mutants can affect growth and development cell non-autonomously.


Perceptions of parental communication orientation, perfectionism, and disordered eating behaviors of sons and daughters.
This study investigated the influence of perceived parental communication orientation and individual perfectionism on late adolescent offspring's maladaptive eating behaviors using a nonclinical sample ( N=424). College students' perceptions of their communication patterns with parents, self- and parentally prescribed perfectionism, and perceptions of personal control were measured to explore possible associations among these variables and whether they, in combination, predicted maladaptive eating. Results revealed that 23% of the sample participated in maladaptive eating behaviors; in addition, a father-child conformity communication pattern and paternally prescribed perfectionism predicted maladaptive eating within this sample when controlling for individual factors such as offspring's perfectionism and perceived loss of personal control. These findings suggest that father-child communicative interaction that emphasizes conformity to high paternal standards may increase offspring's risk of developing maladaptive eating behaviors.


Endoscopic ultrasound-guided drainage of pancreatic collections with dedicated metal stents: A nationwide, multicenter, propensity score-matched comparison.
The new dedicated stents for endoscopic ultrasound (EUS)-guided transluminal drainage of peri‑pancreatic fluid collections (PFCs) demonstrated optimal efficacy and safety profiles. This study aimed to evaluate the safety, technical and clinical success, and recurrence rate of PFCs drained with Lumen Apposing Metal Stent (LAMS) or Bi-Flanged Metal Stent (BFMS). Data from a multicenter series of PFCs treated with LAMS or BFMS at 30 Italian centers during a 5-year period were retrieved. The rate of adverse events (AEs), technical success, clinical success, PFC recurrence were evaluated. To overcome biases, a 1-to-1 match was created using propensity score analysis. Out of 476 patients, 386 were treated with LAMS and 90 with BFMS, with a median follow-up of 290 days (95% CI 244 to 361). Using propensity score matching, 84 patients were assigned to each group. The incidence of AEs did not differ between the two stents (13.1% versus 15.5%, p = 0.29), mainly bleeding or recurrence rate (4.7% versus 3.5%, p = 1). Technical and clinical success in the BFMS and LAMS groups were 92% versus 95% (p = 0.36) and 91% versus 94% (p = 0.64), respectively. Our study demonstrates that LAMS and BFMS have comparable safety profiles with similar technical and clinical success rates for EUS-guided PFC drainage.


[Prenatal diagnosis of hemophilia B].
The authors are reporting on the prenatal diagnosis of the X-linked haemophilia B for the first time in Hungary applying the polymerase chain reaction. DNA sequence containing a HhaI restriction endonuclease site close to the factor IX gene was amplified using polymerase chain reaction. The products from polymerase chain reaction were detected on polyacrylamide gel with ethidium bromide staining after the digestion with HhaI restriction enzyme. In the first step of the diagnosis DNA specimen was prepared from chorion derived from a 11th week gestation of haemophilia B carrier mother. The investigation of fetal DNA proved a male fetus. The detection of HhaI polymorphism of the fetus demonstrated the inheritance of the disease causing allele. The parents asked for the termination of pregnancy based on the result.


Hepatic albumin and urea synthesis: The mathematical modelling of the dynamics of [14C]carbonate-derived guanidine-labelled arginine in the isolated perfused rat liver.
A mathematical model was constructed to define the dynamics of incorporation of radioactivity into urea carbon and the guanidine carbon of arginine in plasma albumin after the rapid intraportal-venous administration of Na214CO3 in the isolated perfused rat liver. 2. The model was formulated in terms of compartmental analysis and additional experiments were designed to provide further information on subsystem dynamics and to discriminate between alternative model structures. 3. Evidence for the rapid-time-constant of labelling of intracellular arginine was provided by precursor-product analysis of precursor [14C]carboante and product [14C]urea in the perfusate. 4. Compartmental analysis of the dynamics of newly synthesized urea was based on the fate of exogenous [13C]urea, endogenous [14C]urea and the accumulation of [12C]urea in perfusate water, confirming the early completion of urea carbon labelling, the absence of continuing synthesis of labelled urea, and the presence of a small intrahepatic urea-delay pool. 5. Analysis of the perfusate dynamics of endogenously synthesized and exogenously administered [6-14C]arginine indicated that although the capacity for extrahepatic formation of [14C]-urea exists, little or no arginine formed within the intrahepatic urea cycle was transported out of the liver. However, the presence of a rapidly turning-over intrahepatic arginine pool was confirmed. 6. On the basis of these subsystem analyses it was possible to offer feasible estimations for the parameters of the mathematical model. However, it was not possible to stimulate the form and magnitude of the dynamics of newly synthesized labelled urea and albumin which were simultaneously observed after administration of [14C]carbonate on the basis of a preliminary model which postulated that both products were derived from a single hepatic pool of [16-14C]arginine. On the other hand these observed dynamics could be satisfied to a two-compartment arginine model, which also provided an explanation for discrepancies observed between albumin synthesis measured radioisotopically and immunologically. This was based on a relative overestimation of [14C]urea specific radioactivity resulting from the rapid dynamics of [14C]carbonate and the [14C]urea subsystem relative to the labelled albumin subsystem. The effects of arginine compartmentalization could be minimized in the model by minor slowing of the rate of [14C]carbonate turnover or by constant infusion of [14C]carbonate, both of which permitted valid determination of albumin-synthesis rates.


BRAF, a target in melanoma: implications for solid tumor drug development.
The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy, and the identification of mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF), a serine/threonine kinase, has turned the attention of the melanoma field toward this concept. The current review indicated that BRAF represents an important target in cancer, in part because it is present in 7% of all cancers and also because it represents the first intracellular signaling molecule that is activated by point mutations for which single-agent therapy appears to have efficacy. Therapy for advanced melanoma has progressed slowly over the past 3 decades, although significant advances have been made in other cancers with the application of cytotoxic chemotherapy and targeted therapies. However, in melanoma, cytotoxic chemotherapies have severe limits, chemotherapy does not convincingly improve on the natural history of metastatic disease and has no role in the adjuvant setting, and cytokine therapy may have a niche in both the adjuvant and metastatic settings but confers only a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. Understanding network of signal-transduction pathways and how that network may adapt to BRAF inhibition or mitogen-activated protein kinase kinase inhibition will point to the next generation of clinical trials investigating rational combination regimens. The current investigations in melanoma will create a set of hypotheses to be tested in each cancer that harbors BRAF mutations.


Reversal of human multi-drug resistance leukaemic cells by stemofoline derivatives via inhibition of P-glycoprotein function.
Our previous study reported multi-drug resistance (MDR) reversing properties of synthetic stemofoline derivatives (STFD), OH-A1, NH-B6 and NH-D6 on P-glycoprotein (P-gp) overexpressing leukaemic cells (K562/Adr); however, the mechanism was unclear. In this study, we further investigated whether the STFD reverse MDR through either the inhibition of P-gp function or expression in K562/Adr cells, or both. The P-gp functional studies showed that the STFD increased the accumulation of calcein-AM, rhodamine 123 and [(14) C]-doxorubicin in K562/Adr cells, while the effects have not been seen in their parental sensitive cancer cell line (K562). Further, the STFD did not alter the P-gp expression as determined by Western blotting. This study concludes that the STFD reverse MDR via the inhibition of P-gp function. The efficacy of the STFD to inhibit P-gp function followed the order: NH-B6 > OH-A1 > NH-D6. These compounds could be introduced as candidate molecules for treating cancers exhibiting P-gp-mediated MDR.


Analgesic Response to Morphine in Children with Sickle Cell Disease: A Pilot Study.
Morphine given by Patient Controlled Analgesia (PCA) is widely used in hospital settings to manage severe pain during acute painful episodes. Wide variations in prescription patterns occur and some patients are often self-administering sub- or low- therapeutic doses. In this preliminary study, a descriptive design with repeated measures was used to examine the effects of different PCA morphine regimens on the intensity, location and quality of pain as well as on the perceived amount of relief and side effects in patients with sickle cell disease (N=13; mean age 13.7 years; eight males; five females). The preliminary data showed that a regimen with a high background infusion rate and low intermittent push dose (Regimen B) may provide better response to PCA morphine. The difference in trends between the worst and least pain intensity ratings were narrower in this regimen, suggesting that pain peaks and troughs were not occurring as in a regimen with an around the clock nurse administered dosing schedule (Regimen C). The amount of morphine that was administered per day was not significantly different (p > 0.05) among the three morphine regimens. The combination of a high background infusion rate and low intermittent push dose (as in Regimen B) within the first 24 hours of admission, may provide improved response and possibly shorter recovery from the painful episode than the regimen that would routinely be prescribed with lower background infusion rate and high intermittent push dose (as in regimen A).


Contribution of arteriogenesis and angiogenesis to postocclusive hindlimb perfusion in mice.
The goal of this study was to examine the mechanisms of vascular growth that lead to the restoration of perfusion in a peripheral vascular disease model in mice. We monitored blood flow recovery and measured vascular growth in inbred strains of mice following femoral artery occlusion. Acute collateral blood flow to the hindlimb was lowest in Balb/C mice, causing intense ischemia, and showed a slower recovery (more than 21 days to 50% normal) than C57Bl/6 which had a 7-fold higher acute collateral flow and a fast recovery (3 days). Collateral vessels were enlarged by proliferation of ECs and SMCs. Capillary density increased in the lower limbs of Balb/Cs (1.7-fold) and of sv129s. Tissue oxygen saturation recovered faster than flow in all strains. Morphometry of mature collaterals showed a diameter increase of 2.1-2.4 fold. The increase in total vessel wall area exceeded that of the femoral artery by 1.4-fold and the common lumenal area by 1.6-fold. Infusion of the growth factor peptide FGF-2 by osmotic minipump accelerated arteriogenesis but inhibited the angiogenic response probably because it prevented ischemia. the speed of arteriogenesis is inversely related to the intensity of ischemia, and arteriogenesis is by far the most efficient mechanism to increase blood flow after femoral artery occlusion. De novo arteriogenesis was not observed.


The APOE epsilon4 allele is associated with decline on delayed recall performance in community-dwelling older adults.
This study investigated whether the Apolipoprotein (APOE) epsilon4 allele was associated with cognitive decline in community-dwelling older adults. Longitudinal cognitive performance of older adults with the epsilon3/epsilon4 genotype was compared with that of older adults with the epsilon3/epsilon3 genotype. Aging Clinical Research Center, Stanford University. One hundred community-dwelling older adults were recruited from a pool of 531 individuals who had participated in a memory training study 4 to 5 years earlier. These individuals were concerned about their memory functioning and were recruited through newspaper advertisements and contacts with local senior centers. The 100 individuals who agreed to participate in the follow-up investigation were between 59 and 95 years of age. At both baseline and follow-up, subjects were administered a battery of seven cognitive tests that examined verbal and spatial memory, attention, speed-of-processing, and language abilities. APOE genotype was determined at follow-up. Individuals with the epsilon3/epsilon4 APOE genotype were significantly younger than individuals with the APOE epsilon3/epsilon3 genotype. No significant differences were observed between the two groups on measures of attention, speed-of-processing, vocabulary, immediate verbal memory, and immediate spatial memory. However, those older adults with the epsilon3/epsilon4 genotype exhibited significantly greater decline in performance on delayed recall of verbal material than did those with the epsilon3/epsilon3 APOE genotype. These findings are consistent with previous studies, which suggest that the APOE epsilon4 allele predicts decline on measures of delayed recall.


Acetylation-Dependent Control of Global Poly(A) RNA Degradation by CBP/p300 and HDAC1/2.
Acetylation of histones and transcription-related factors is known to exert epigenetic and transcriptional control of gene expression. Here we report that histone acetyltransferases (HATs) and histone deacetylases (HDACs) also regulate gene expression at the posttranscriptional level by controlling poly(A) RNA stability. Inhibition of HDAC1 and HDAC2 induces massive and widespread degradation of normally stable poly(A) RNA in mammalian and Drosophila cells. Acetylation-induced RNA decay depends on the HATs p300 and CBP, which acetylate the exoribonuclease CAF1a, a catalytic subunit of the CCR4-CAF1-NOT deadenlyase complex and thereby contribute to accelerating poly(A) RNA degradation. Taking adipocyte differentiation as a model, we observe global stabilization of poly(A) RNA during differentiation, concomitant with loss of CBP/p300 expression. Our study uncovers reversible acetylation as a fundamental switch by which HATs and HDACs control the overall turnover of poly(A) RNA.


Seasonal and regional dynamics of M. ulcerans transmission in environmental context: deciphering the role of water bugs as hosts and vectors.
Buruli ulcer, the third mycobacterial disease after tuberculosis and leprosy, is caused by the environmental mycobacterium M. ulcerans. Various modes of transmission have been suspected for this disease, with no general consensus acceptance for any of them up to now. Since laboratory models demonstrated the ability of water bugs to transmit M. ulcerans, a particular attention is focused on the transmission of the bacilli by water bugs as hosts and vectors. However, it is only through detailed knowledge of the biodiversity and ecology of water bugs that the importance of this mode of transmission can be fully assessed. It is the objective of the work here to decipher the role of water bugs in M. ulcerans ecology and transmission, based on large-scale field studies. The distribution of M. ulcerans-hosting water bugs was monitored on previously unprecedented time and space scales: a total of 7,407 water bugs, belonging to large number of different families, were collected over one year, in Buruli ulcer endemic and non endemic areas in central Cameroon. This study demonstrated the presence of M. ulcerans in insect saliva. In addition, the field results provided a full picture of the ecology of transmission in terms of biodiversity and detailed specification of seasonal and regional dynamics, with large temporal heterogeneity in the insect tissue colonization rate and detection of M. ulcerans only in water bug tissues collected in Buruli ulcer endemic areas. The large-scale detection of bacilli in saliva of biting water bugs gives enhanced weight to their role in M. ulcerans transmission. On practical grounds, beyond the ecological interest, the results concerning seasonal and regional dynamics can provide an efficient tool in the hands of sanitary authorities to monitor environmental risks associated with Buruli ulcer.


Association between initial and pretransplant dialysis modality and graft and patient outcomes in live- and deceased-donor renal transplant recipients.
The association between pretransplant dialysis modality and transplant outcomes remains inconsistent. The aim of this study is to address the association between alteration in dialysis modality and post-transplant outcomes. Using Australia and New Zealand Dialysis and Transplant Registry, primary live- and deceased-donor renal transplant recipients (RTR) between 1997 and 2009 were examined. Pre-emptive and multiple-organ transplants were excluded. The association between initial and pretransplant dialysis modality and transplant outcomes were examined. Of the 6701 RTR, 18.6% were initiated-maintained on peritoneal dialysis pretransplant (PD-PD), 9.2% were initiated on PD, but maintained on haemodialysis (HD) pretransplant (PD-HD), 63.3% were HD-HD and 8.9% were HD-PD. PD-HD [odds ratio(OR)1.44, 95% CI 1.21,1.72] and HD-HD (OR1.25, 95% CI 1.12,1.41) were associated with a significantly greater risk of slow graft function compared with the overall mean of the groups, whereas a change in initial dialysis modality from HD to pretransplant PD was associated with higher risk of overall graft failure [hazard ratio(HR)1.19, 95% CI 1.04,1.36) and recipient death (HR1.34, 95% CI 1.13,1.59). Our registry analysis suggest that dialysis modality pretransplant may affect transplant outcomes and future studies evaluating patient selection, choice of modality and/or potential interventions in the pre and post-transplant period may have a beneficial effect on post-transplant outcomes.


Autotransplantation of human carotid body cell aggregates for treatment of Parkinson's disease.
In this study, we assessed the feasibility of autotransplantation of carotid body (CB) cell aggregates into the striatum for the treatment of patients with Parkinson's disease (PD). Six patients with advanced PD underwent bilateral autotransplantation of CB cell aggregates into the striatum. They were evaluated clinically preoperatively and for 18 months after surgery according to the recommendations of the Core Assessment Program for Intracerebral Transplantation. No major complications or adverse events resulted from the cell implantation or surgical procedures. During the course of the study, there was no significant aggravation of dyskinesia or decline in cognitive function in any of the patients. Five of the six patients who underwent transplantation manifested a measurable degree of clinical improvement evidenced by standardized clinical rating scales for PD. A decrease in the blinded Unified Parkinson's Disease Rating Scale Part III in the "off" state, the main measure of transplant efficacy in our study, was found to be maximal (between 26 and 74%) at 6 months after surgery. At 1 year, clear reductions in the blinded Unified Parkinson's Disease Rating Scale Part III were maintained in three patients (24, 38, and 52%, respectively). Modest improvement was seen in two patients (13 and 17%), and the sole patient who showed no improvement had the most fibrosis in the CB. The age of the patient and the state of the CB tissue were adversely correlated with clinical improvement after CB autotransplantation. This pilot study indicates that CB autograft transplantation is a relatively simple, safe, and viable therapeutical approach for the treatment of patients with advanced PD. More studies are needed to optimize the procedure and to assess its general applicability for the treatment of patients with PD.


Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy.
Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC. This retrospective analysis describes 38 patients with FIGO Stage I UPSC who were treated with the combinations of radiation therapy, chemotherapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO), with or without a surgical staging procedure. Twenty of 38 patients were treated with a combination of low dose-rate (LDR) uterine/vaginal brachytherapy using 226Ra or 137Cs and conventional whole-abdomen radiation therapy (WART) or whole-pelvic radiation therapy (WPRT). Of 20 patients (10%) in this treatment group, 2 received cisplatin chemotherapy. Eighteen patients were treated with high dose-rate (HDR) vaginal apex brachytherapy using 192Ir with an afterloading device and cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy (5 of 18 patients). Only 6 of 20 UPSC patients treated with combination LDR uterine/vaginal brachytherapy and conventional external beam radiotherapy underwent complete surgical staging, consisting of TAH/BSO, pelvic/para-aortic lymph node sampling, omentectomy, and peritoneal fluid analysis, compared to 15 of 18 patients treated with HDR vaginal apex brachytherapy. The 5-year actuarial OS for patients with complete surgical staging and adjuvant radiation/chemotherapy treatment was 100% vs. 61% for patients without complete staging (p = 0.002). The 5-year actuarial OS for all Stage I UPSC patients treated with postoperative HDR vaginal apex brachytherapy and systemic chemotherapy was 94% (18 patients). The 5-year actuarial OS for Stage I UPSC patients treated with HDR vaginal apex brachytherapy and chemotherapy who underwent complete surgical staging was 100% (15 patients). The 5-year actuarial OS for the 20 Stage I UPSC patients treated with combinations of pre- and postoperative LDR brachytherapy and postop WART was 65%. None of the 6 surgically staged UPSC patients treated with LDR radiation and WART/WPRT developed recurrent disease. For patients with FIGO Stage IA, IB, and IC UPSC who underwent complete surgical staging, the 5-year actuarial DFS by depth of myometrial invasion was 100, 71, and 40%, respectively (p = 0.006). The overall salvage rate for local and distant recurrence was 0%. Complications following HDR vaginal apex brachytherapy included only Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicity in 16% of patients. However, complications from patients treated with WART/WPRT, and/or LDR brachytherapy, included RTOG grade 3 and 4 toxicity in 15% of patients. Patients with UPSC should undergo complete surgical staging, and completely surgically staged FIGO Stage I UPSC patients can be effectively and safely treated with HDR vaginal apex brachytherapy and chemotherapy. Both OS and DFS of patients with UPSC are dependent on depth of myometrial invasion. The salvage rate for both local and distant UPSC recurrences is extremely poor. Complications from HDR vaginal apex brachytherapy were minimal.


Insect-protected event DAS-81419-2 soybean (Glycine max L.) grown in the United States and Brazil is compositionally equivalent to nontransgenic soybean.
The transgenic soybean event DAS-81419-2 contains genes that encode the Cry1F, Cry1Ac, and PAT proteins. Cry1F and Cry1Ac provide protection against key lepidopteran insect pests, while PAT confers tolerance to the herbicide glufosinate. To satisfy regulatory requirements for the safety evaluation of transgenic crops, studies were conducted in the United States and Brazil to evaluate the nutrient and antinutrient composition of event DAS-81419-2 soybean. On the basis of the results of these studies, event DAS-81419-2 soybean is compositionally equivalent to nontransgenic soybean. This conclusion concurs with numerous other published studies in soybean and other crops where compositional equivalence between the transgenic crop and its nontransgenic comparator has been demonstrated.


Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.
This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.


A toxin antitoxin system promotes the maintenance of the IncA/C-mobilizable Salmonella Genomic Island 1.
The multidrug resistance Salmonella Genomic Island 1 (SGI1) is an integrative mobilizable element identified in several enterobacterial pathogens. This chromosomal island requires a conjugative IncA/C plasmid to be excised as a circular extrachromosomal form and conjugally mobilized in trans. Preliminary observations suggest stable maintenance of SGI1 in the host chromosome but paradoxically also incompatibility between SGI1 and IncA/C plasmids. Here, using a Salmonella enterica serovar Agona clonal bacterial population as model, we demonstrate that a Toxin-Antitoxin (TA) system encoded by SGI1 plays a critical role in its stable host maintenance when an IncA/C plasmid is concomitantly present. This system, designated sgiAT for Salmonella genomic island 1 Antitoxin and Toxin respectively, thus seems to play a stabilizing role in a situation where SGI1 is susceptible to be lost through plasmid IncA/C-mediated excision. Moreover and for the first time, the incompatibility between SGI1 and IncA/C plasmids was experimentally confirmed.


The role of innate immunity in the induction of autoimmunity.
The autoimmune diseases are a diverse group of conditions characterized by abnormal B and T cell reactivity in association with autoantibody production. Among these diseases, systemic lupus erythematosus (SLE) is notable for the expression of antibodies to DNA, with these antibodies representing diagnostic markers. While mammalian DNA is immunologically inert, DNA from bacteria can potently stimulate the innate immune system, activating both toll-like receptors (TLRs) as well as non-TLR internal receptors. Since the sera of normal humans contain antibodies specific for bacterial DNA, this molecule appears to be immunogenic during infection. In pre-autoimmune mice, immunization with bacterial DNA can induce anti-DNA autoantibody production, suggesting a role in initiating this response. The immune properties of DNA are mutable, however, since mammalian DNA can acquire immunological activity when bound to certain proteins or anti-DNA antibodies to form immune complexes. In SLE, these immune complexes can drive the production of interferon by plasmacytoid dendritic cells, thereby intensifying autoimmunity. Together, these observations suggest that DNA can induce innate as well as adaptive immune responses and promote the pathogenesis of SLE because of its intrinsic immunostimulatory activity.


Highly emissive phenylene-expanded [5]radialene.
A pentagonal macrocycle (MC5-PER) with radialene topology was facilely synthesized through a selective one-pot Suzuki-Miyaura cross-coupling reaction. The resulting product is endowed with a pentagonal architecture as revealed by its single crystal structure, which affords the smallest ring strain and the best conjugation. As tetraphenylethene subunits are embedded, MC5-PER is highly emissive in the solid state due to the aggregation-induced emission effect. Because of the flexible structure and preferable fibre-like self-assembly, the aggregate of MC5-PER displays interesting polymorphism-dependent emission and acts as a sensitive fluorescence sensor for explosives detection.


A comparative genomics approach revealed evolutionary dynamics of microsatellite imperfection and conservation in genus Gossypium.
Ongoing molecular processes in a cell could target microsatellites, a kind of repetitive DNA, owing to length variations and motif imperfection. Mutational mechanisms underlying such kind of genetic variations have been extensively investigated in diverse organisms. However, obscure impact of ploidization, an evolutionary process of genome content duplication prevails mostly in plants, on non-coding DNA is poorly understood. Genome sequences of diversely originated plant species were examined for genome-wide motif imperfection pattern, and various analytical tools were employed to canvass characteristic relationships among repeat density, imperfection and length of microsatellites. Moreover, comparative genomics approach aided in exploration of microsatellites conservation footprints in Gossypium evolution. Based on our results, motif imperfection in repeat length was found intricately related to genomic abundance of imperfect microsatellites among 13 genomes. Microsatellite decay estimation depicted slower decay of long motif repeats which led to predominant abundance of 5-nt repeat motif in Gossypium species. Short motif repeats exhibited rapid decay through the evolution of Gossypium lineage ensuing drastic decrease of 2-nt repeats, of which, "AT" motif type dilapidated in cultivated tetraploids of cotton. The outcome could be a directive to explore comparative evolutionary footprints of simple non-coding genetic elements i.e., repeat elements, through the evolution of genus-specific characteristics in cotton genomes.


Converting from d to r to z when the design uses extreme groups, dichotomization, or experimental control.
Meta-analyses of the relationship between 2 continuous variables sometimes involves conversions between different effect sizes, but methodological literature offers conflicting guidance about how to make such conversions. This article provides methods for converting from a standardized mean difference to a correlation coefficient (and from there to Fisher's z) under 3 types of study designs: extreme groups, dichotomization of a continuous variable, and controlled experiments. Also provided are formulas and recommendations regarding how the sampling variance of effect size statistics should be estimated in each of these cases. The conversion formula for extreme groups designs, originally due to Feldt (1961), can be viewed as a generalization of Hunter and Schmidt's (1990) method for dichotomization designs. A simulation study examines the finite-sample properties of the proposed methods. The conclusion highlights areas where current guidance in the literature should be amended or clarified.


Growth of the pectoralis muscle of the house sparrow (Passer domesticus).
The pectoralis muscle from growing house sparrows was investigated using linear, gravimetric, histological and ultrastructural techniques. The structure of the muscle at different stages of development was discussed in relation to known behavioural activities, such as the onset of regular wing exercising and thermogenic shivering in the nestlings. Fibres in the pectoralis muscle of birds about to fledge (15 day nestlings) were similar in composition to fibres in muscles from fully fledged juveniles, with two exceptions. Firstly, numerous lipid droplets had accumulated adjacent to mitochondria in fibres from the pectoralis muscle of the nestlings. This lipid could act as a readily available source of energy for the birds on fledging. Secondly, masses of ribosomes and irregularly shaped myofibrils were present, indicating the continued elaboration of the contractile apparatus in fibres from the pectoralis muscle of the 15 day nestlings. The inefficient flight of newly fledged house sparrows may be accounted for by the size of the pectoralis muscle relative to total body weight. The total contractile material in the muscle of the birds about to fledge was estimated to be 60% or less of that found in fully fledged juveniles, while the body weight was nearly that of an adult bird.


Optimization of Aspergillus versicolor Culture and Aerosolization in a Murine Model of Inhalational Fungal Exposure.
Aspergillus versicolor is ubiquitous in the environment and is particularly abundant in damp indoor spaces. Exposure to Aspergillus species, as well as other environmental fungi, has been linked to respiratory health outcomes, including asthma, allergy, and even local or disseminated infection. However, the pulmonary immunological mechanisms associated with repeated exposure to A. versicolor have remained relatively uncharacterized. Here, A. versicolor was cultured and desiccated on rice then placed in an acoustical generator system to achieve aerosolization. Mice were challenged with titrated doses of aerosolized conidia to examine deposition, lymphoproliferative properties, and immunotoxicological response to repeated inhalation exposures. The necessary dose to induce lymphoproliferation was identified, but not infection-like pathology. Further, it was determined that the dose was able to initiate localized immune responses. The data presented in this study demonstrate an optimized and reproducible method for delivering A. versicolor conidia to rodents via nose-only inhalation. Additionally, the feasibility of a long-term repeated exposure study was established. This experimental protocol can be used in future studies to investigate the physiological effects of repeated pulmonary exposure to fungal conidia utilizing a practical and relevant mode of delivery. In total, these data constitute an important foundation for subsequent research in the field.


Differences in nocturnal and daytime sleep between primary and psychiatric hypersomnia: diagnostic and treatment implications.
The differential diagnosis of primary (idiopathic) vs. psychiatric hypersomnia is challenging because of the lack of specific clinical or laboratory criteria differentiating these two disorders and the frequent comorbidity of mental disorders in patients with primary hypersomnia. The aim of this study was to assess whether polysomnography aids in the differential diagnosis of these two disorders. After excluding patients taking medication and those with an additional diagnosis of sleep-disordered breathing, we compared the nocturnal and daytime sleep of 82 consecutive patients with a diagnosis of either primary hypersomnia (N = 59) or psychiatric hypersomnia (N = 23) and normal control subjects (N = 50). During nocturnal sleep, patients with psychiatric hypersomnia showed significantly higher sleep latency, wake time after sleep onset, and total wake time and a significantly lower percentage of sleep time than patients with primary hypersomnia and control subjects (p < .05). In addition, the daytime sleep of patients with psychiatric hypersomnia was significantly higher in terms of sleep latency, total wake time, and percentage of light (stage 1) sleep and lower in terms of percentage of sleep time and stage 2 sleep than in patients with primary hypersomnia and control subjects (p < .05). The daytime sleep of patients with primary hypersomnia as compared with that of control subjects was characterized by lower sleep latency and total wake time and a higher percentage of sleep time (p < .05). Finally, a sleep latency of less than 10 minutes or a sleep time percentage greater than 70% in either of the two daytime naps was associated with a sensitivity of 78.0% and a specificity of 95.7%. Our findings indicate that psychiatric hypersomnia is a disorder of hyperarousal, whereas primary hypersomnia is a disorder of hypoarousal. Polysomnographic measures may provide useful information in the differential diagnosis and treatment of these two disorders.


The regulatory proteins of the myofibril. Separation and biological activity of the components of inhibitory-factor preparations.
1. Inhibitory-factor preparations isolated from myofibrils were shown to consist principally of proteins with molecular weights of 37000 and 23000. Under certain preparative procedures an additional component of molecular weight 14000 was present. 2. The 23000-dalton protein, the inhibitory factor, was the major active component. Its activity was enhanced by tropomyosin. 3. The 14000-dalton component also possessed inhibitory activity, although less than that of the 23000-dalton component when compared on a molar basis. Its activity was not always enhanced by tropomyosin. The 14000-dalton component could not be detected in whole fresh myofibrils and the limited evidence available is compatible with its formation during the preparation of the troponin complex. 4. The 37000-dalton component could not replace the inhibitory factor, calcium-sensitizing factor or tropomyosin as components of the relaxing-protein system. 5. All three components had distinctive amino acid compositions, particularly in their cysteine content.


Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates.
Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoproteins (Envs) have proven difficult to elicit by immunization. Therefore, to identify effective Env neutralization targets, efforts are underway to define the specificities of bNAbs in chronically infected individuals. For a prophylactic vaccine, it is equally important to define the immunogenic properties of the heavily glycosylated Env in healthy primates devoid of confounding HIV-induced pathogenic factors. We used rhesus macaques to investigate the magnitude and kinetics of B cell responses stimulated by Env trimers in adjuvant. Robust Env-specific memory B cell responses and high titers of circulating antibodies developed after trimer inoculation. Subsequent immunizations resulted in significant expansion of Env-specific IgG-producing plasma cell populations and circulating Abs that displayed increasing avidity and neutralization capacity. The neutralizing activity elicited with the regimen used was, in most aspects, superior to that elicited by a regimen based on monomeric Env immunization in humans. Despite the potency and breadth of the trimer-elicited response, protection against heterologous rectal simian-HIV (SHIV) challenge was modest, illustrating the challenge of eliciting sufficient titers of cross-reactive protective NAbs in mucosal sites. These data provide important information for the design and evaluation of vaccines aimed at stimulating protective HIV-1 immune responses in humans.


Saprolegniaceae identified on amphibian eggs throughout the Pacific Northwest, USA, by internal transcribed spacer sequences and phylogenetic analysis.
We assessed the diversity and phylogeny of Saprolegniaceae on amphibian eggs from the Pacific Northwest, with particular focus on Saprolegnia ferax, a species implicated in high egg mortality. We identified isolates from eggs of six amphibians with the internal transcribed spacer (ITS) and 5.8S gene regions and BLAST of the GenBank database. We identified 68 sequences as Saprolegniaceae and 43 sequences as true fungi from at least nine genera. Our phylogenetic analysis of the Saprolegniaceae included isolates within the genera Saprolegnia, Achlya and Leptolegnia. Our phylogeny grouped S. semihypogyna with Achlya rather than with the Saprolegnia reference sequences. We found only one isolate that grouped closely with S. ferax, and this came from a hatchery-raised salmon (Idaho) that we sampled opportunistically. We had representatives of 7-12 species and three genera of Saprolegniaceae on our amphibian eggs. Further work on the ecological roles of different species of Saprolegniaceae is needed to clarify their potential importance in amphibian egg mortality and potential links to population declines.


Central nervous system complications of cardiac surgery.
The neurological complications of cardiac surgery are associated with significantly increased mortality, morbidity and resource utilization. The use of new surgical techniques, introduction of wider indications for surgery and increased public expectation has led to an increase in the average age of cardiac surgical patients and an increased incidence of repeat procedures. With these changes has come an increased risk of neurological complications. The likelihood of perioperative stroke varies between 1% and 5% in most published series and is dependent on a multitude of risk factors. Of these, patient age, aortic atheroma, symptomatic cerebrovascular disease, diabetes mellitus and the type of surgery appear to be most important. Cognitive deterioration after cardiac surgery is far more common, affecting as many as 80% of patients a few days after surgery and persisting in one-third. Despite an increase in the age of the cardiac surgical population, the reported incidence of cognitive dysfunction after cardiac surgery seems to have fallen in recent years. Whether this is a real phenomenon or the result of changes in the use of psychometric testing and the definition of cognitive decline remains unclear. Recognition that certain equipment, surgical practices and patient factors contribute to neurological morbidity has prompted 'neuroprotective' interventions. Some of these (e.g. arterial line filtration and alpha-stat management) have been shown to improve outcome. Despite these measures, a small number of patients will inevitably sustain cerebral injury during otherwise successful cardiac surgery. Although pharmacological neuroprotection may, in the future, offer some of these patients an improved outcome, it is unlikely that any single agent will prevent neurological injury. In the meantime, the CNS complications of cardiac surgery remain a fertile area of research.


Analysis of the bromate-sulfite-ferrocyanide pH oscillator using the particle filter: toward the automated modeling of complex chemical systems.
This study was aimed at identifying a quantitatively accurate reaction model of the bromate-sulfilte-ferrocyanide (BSF) pH oscillator by using the simulation-based model estimation algorithm known as the particle filter. The Rbai-Kaminaga-Hanazaki (RKH) model proposed for the BSF system was extended by adding the protonation equilibrium of SO42-, for which the particle filter analysis was carried out to optimize the rate constants involved with reference to the measured pH oscillation data. The extended RKH model with the optimized rate constants almost completely reproduced the measured pH oscillations and the state diagram, showing the validity of the present analysis. Chemical oscillators such as the BSF system show drastic switching of the dominant reaction path, which strongly disturbs the convergence of the rate constants if the objective function is defined in a conventional manner to reflect only a single time step datum. In this study, the objective function was defined as the residual sum of squares with respect to pH taken over an interval longer than one oscillatory period, so that all of the relevant reaction steps can contribute to the objective function. This is the first report which exemplifies the effectiveness of the particle filter in the analysis of real complex chemical systems.


[Apoptosis and proliferation of epithelial cells in papillomaviral and chlamydial cervicitis].
Patients with chlamydial and papillomaviral cervicitis show a significantly higher activity of the ectocervical epithelium which is particularly pronounced in papillomaviral infection. This is, however, matched by progressively reduced apoptosis of epithelial cells which in turn suggests the possibility of papillomaviruses and chlamydiae contributing to inhibition of infected cells and, thus, paving the way for development of precancer and cancer of cervix uteri.


Prediction of genotoxicity of chemical compounds by statistical learning methods.
Various toxicological profiles, such as genotoxic potential, need to be studied in drug discovery processes and submitted to the drug regulatory authorities for drug safety evaluation. As part of the effort for developing low cost and efficient adverse drug reaction testing tools, several statistical learning methods have been used for developing genotoxicity prediction systems with an accuracy of up to 73.8% for genotoxic (GT+) and 92.8% for nongenotoxic (GT-) agents. These systems have been developed and tested by using less than 400 known GT+ and GT- agents, which is significantly less in number and diversity than the 860 GT+ and GT- agents known at present. There is a need to examine if a similar level of accuracy can be achieved for the more diverse set of molecules and to evaluate other statistical learning methods not yet applied to genotoxicity prediction. This work is intended for testing several statistical learning methods by using 860 GT+ and GT- agents, which include support vector machines (SVM), probabilistic neural network (PNN), k-nearest neighbor (k-NN), and C4.5 decision tree (DT). A feature selection method, recursive feature elimination, is used for selecting molecular descriptors relevant to genotoxicity study. The overall accuracies of SVM, k-NN, and PNN are comparable to and those of DT lower than the results from earlier studies, with SVM giving the highest accuracies of 77.8% for GT+ and 92.7% for GT- agents. Our study suggests that statistical learning methods, particularly SVM, k-NN, and PNN, are useful for facilitating the prediction of genotoxic potential of a diverse set of molecules.


Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy.
Metachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late-infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD.


Invited commentary: Biological and clinical insights from epidemiologic research into HIV, HPV, and anal cancer.
Anal cancer is common among people infected with human immunodeficiency virus (HIV). This cancer is caused by human papillomavirus, and immunosuppression likely contributes to its development. In this issue of the Journal, Bertisch et al. (Am J Epidemiol. 2013;178(6):877-884) present the results of a case-control study of anal cancer among HIV-infected people in Switzerland. They demonstrate that anal cancer risk is increased in association with a low CD4+ cell count (a clinical measurement of immune status). In particular, HIV-induced immunosuppression was most severe among cases approximately 6-7 years prior to the diagnosis of anal cancer. A plausible biological interpretation is that immunosuppression is important at an early stage of the development of anal cancer, but that the neoplastic process becomes irreversible over time with persistent human papillomavirus infection and genetic damage. With current efforts to provide earlier combination antiretroviral therapy to HIV-infected people, anal cancer incidence may start to decline. Bertisch et al. also demonstrate a strong association between serum antibodies against the human papillomavirus type 16 protein E6 and anal cancer risk, highlighting the role of this viral oncoprotein in carcinogenesis. Additional biomarkers could help refine clinical approaches to anal cancer screening and prevention for the HIV-infected population.


Cathelicidin LL-37 and HSV-1 Corneal Infection: Peptide Versus Gene Therapy.
To evaluate the potential utility of collagen-based corneal implants with anti-Herpes Simplex Virus (HSV)-1 activity achieved through sustained release of LL-37, from incorporated nanoparticles, as compared with cell-based delivery from model human corneal epithelial cells (HCECs) transfected to produce endogenous LL-37. We tested the ability of collagen-phosphorylcholine implants to tolerate the adverse microenvironment of herpetic murine corneas. Then, we investigated the efficacy of LL-37 peptides delivered through nanoparticles incorporated within the corneal implants to block HSV-1 viral activity. In addition, LL-37 complementary DNA (cDNA) was transferred into HCECs to confer viral resistance, and their response to HSV-1 infection was examined. Our implants remained in herpetic murine corneas 7 days longer than allografts. LL-37 released from the implants blocked HSV-1 infection of HCECs by interfering with viral binding. However, in pre-infected HCECs, LL-37 delayed but could not prevent viral spreading nor clear viruses from the infected cells. HCECs transfected with the LL-37 expressed and secreted the peptide. Secreted LL-37 inhibited viral binding in vitro but was insufficient to protect cells completely from HSV-1 infection. Nevertheless, secreted LL-37 reduced both the incidence of plaque formation and plaque size. LL-37 released from composite nanoparticle-hydrogel corneal implants and HCEC-produced peptide, both showed anti-HSV-1 activity by blocking binding. However, while both slowed down virus spread, neither was able on its own to completely inhibit the viruses. LL-37 releasing hydrogels may have potential utility as corneal substitutes for grafting in HSV-1 infected corneas, possibly in combination with LL-37 producing therapeutic cells.


Inefficient phospholipase C activation and reduced Lck expression characterize the signaling defect of umbilical cord T lymphocytes.
Adult and neonatal immunocompetent cells exhibit important functional distinctions, including differences in cytokine production and susceptibility to tolerance induction. We have investigated the molecular features that characterize the immune response of cord blood-derived T lymphocytes compared with that of adult T lymphocytes. Our findings demonstrate that phospholipase C (PLC) isozymes, which play a pivotal role in the control of protein kinase C activation and Ca2+ mobilization, are differently expressed in cord and adult T lymphocytes. PLCbeta1 and delta1 are expressed at higher levels in cord T cells, while PLCbeta2 and gamma1 expression is higher in adult T lymphocytes. PLCdelta2 and gamma2 appear to be equally expressed in both cell types. In addition, a functional defect in PLC activation via CD3 ligation or pervanadate treatment, stimuli that activate tyrosine kinases, was observed in cord blood T cells, whereas treatment with aluminum tetrafluoride (AlF4-), a G protein activator, demonstrated a similar degree of PLC activation in cord and adult T cells. The impaired PLC activation of cord blood-derived T cells was associated with a a very low expression of the Src kinase, Lck, along with a reduced level of ZAP70. No mitogenic response to CD3 ligation was observed in cord T cells. However, no signaling defect was apparent downstream of PLC activation, as demonstrated by the mitogenic response of cord T cells to the pharmacologic activation of protein kinase C and Ca2+ by treatment with PMA and ionomycin. Thus, neonatal cord blood-derived T cells show a signaling immaturity associated with inadequate PLCgamma activation and decreased Lck expression.


Characterization of a new adenovirus type 5 assembly intermediate.
Adenovirus H5 (Ad5) DNA-protein complexes were extracted with ammonium sulphate (0.2 M) from virus-infected HeLa cell nuclei at 18 h after infection. Analysis of the material by centrifugation through discontinuous sucrose gradients in heavy water revealed the existence of several populations of molecules which were identified, in order of increasing buoyant density, as mature DNA-protein complexes, replication complexes, assembly intermediates and virions. When observed under the electron microscope, some of the assembly intermediates showed a capsid with a tail of entirely double-stranded (ds) DNA, or of dsDNA continued by a portion of single-stranded (ss) DNA thickened by a coat of E-72 K DNA binding protein. Singly or doubly-forked Ad5 replicating DNA molecules partially packaged in virus capsids were also observed. It is suggested that these molecules could be assembly intermediates, i.e. one of the first steps of assembly corresponding to virus DNA entering pre-formed capsids or their precursors. The fact that replication was still going on at one end of many of the DNA molecules in the intermediates, while encapsidation was taking place at the other, raises the possibility of a coupled DNA replication-packaging process in the formation of adenovirions.


The effects of e-cigarette use on the oral microbiome.
To investigate the effects of electronic cigarette (EC) use on the oral microbiome and gingival inflammation. Saliva and gingival crevicular fluid samples were collected from 150 adult humans between 18 and 34 years in age (50% EC users). Exclusion criteria included professional dental cleaning, antibiotic, or corticosteroid therapy in the last 3 months. Convenience sampling occurred between June 2017 and October 2018. Clinical gingival inflammation was recorded by a single operator using a novel 4-point scale. RNA sequencing was used to determine microbial composition of samples (16S rRNA amplicon sequencing). Statistical analysis included synthesizing alpha and beta diversity using various indices, taxonomic differential abundance analysis, functional differential abundance analysis and mediation analysis. Taxonomic annotation was performed using QIIME2 with functional annotations generated using PICRUSt2. Age, sex, and frequency of tooth brushed were adjusted for. EC users exhibited significantly greater alpha diversity in microbial species and greater differences between EC users and users in beta diversity. Saliva samples were typically more diverse than subgingival samples. EC users demonstrated greater gingival inflammation when adjusted for age, sex and toothbrushing frequency. EC use may increase oral dysbiosis. Further clinical studies on the effects of EC use on the oral microbiome and oral diseases are recommended.


Glutathione depletion in a liver microsomal assay as an in vitro biomarker for reactive metabolite formation.
Glutathione (GSH) plays a major role in cytoprotection, acting as a nucleophile trap for reactive species derived from xenobiotics. This has led to the development of an assay for the detection of reactive species generated by liver microsomal metabolism of xenobiotics. This assay has been used extensively to study reactive metabolites which initiate toxicity through a direct (non-immunological) mechanism, but there are few data on its ability to detect reactive metabolites that initiate toxicity through neo-antigen formation, or to detect xenobiotics that cause GSH loss by oxidation mediated by a redox cycling process. Accordingly, the ability of rat and human liver microsomes to metabolize xenobiotics to GSH-depleting metabolites has been investigated further. Of the five neo-antigen-forming xenobiotics tested, four (amodiaquine, phenobarbitone, procainamide, and sulphanilamide) displayed GSH reactivity that was either dependent or independent (amodiaquine) on metabolism. The other neo-antigen-forming xenobiotic (carbamazepine) was inactive in all microsomal samples tested. Four quinones believed to exert toxcity through arylation (1,4-benzoquinone) and/or redox cycling (duroquinone, menadione, mitomycin c) displayed GSH reactivity, as did nitrofurantoin and diquat, two other redox cycling xenobiotics. Induction of the mixed function oxidase system with Aroclor afforded little advantage when using rat liver microsomes, whilst there was considerable inter-individual variation in the ability of human liver microsomes to mediate metabolism-dependent GSH depletion. It is concluded that the liver microsome GSH depletion assay may be of general utility as a screen for a number of xenobiotic-derived reactive species.


A Moisture-Wicking Passive Radiative Cooling Hierarchical Metafabric.
Developing functional textiles with a cooling effect is important for personal comfort in human life and activities. Although existing passive cooling fabrics exhibit promising cooling effects, they do not meet the thermal comfort requirements under many practical conditions. Here, we report a nanofiber membrane-based moisture-wicking passive cooling hierarchical metafabric that couples selective optical cooling and wick-evaporation cooling to achieve efficient temperature and moisture management. The hierarchical metafabric showed high sunlight reflectivity (99.16% in the 0.3-0.76 μm wavelength range and 88.60% in the 0.76-2.5 μm wavelength range), selective infrared emissivity (78.13% in the 8-13 μm wavelength range), and good moisture permeability owing to the optical properties of the material and hierarchical morphology design. Cooling performance experiments revealed that covering simulated skin with the hierarchical metafabric prevented overheating by 16.6 °C compared with traditional textiles, including a contribution from management of the humidity (∼8.2 °C). In addition to the personal thermal management ability, the hierarchical metafabric also showed good wearability.


Intrauterine exposure to diethylstilbestrol: long-term effects in humans.
DES is the most carefully scrutinized EDC and its history provides valuable insights into the current evaluation of less well-studied EDCs. This review summarizes the health effects of prenatal exposure to diethylstilbestrol (DES) and emphasizes the role of DES as the first endocrine disrupting chemical (EDC). Vaginal clear cell adenocarcinoma (CCAC), the most severe consequence of prenatal exposure to DES, affected only 0.1% of exposed females, while the far more prevalent teratogenic and reproductive effects of DES were only discovered when DES daughter were screened for CCAC. Initial studies, conducted before most DES daughters had tried to conceive, examined vaginal cancer and vaginal, cervical and uterine abnormalities. Subsequently, several controlled studies demonstrated the increased risk of adverse reproductive outcomes in DES daughters. While most DES daughters can eventually experience a live birth, this is less likely in women with genital tract abnormalities, in whom there is a two-thirds chance that each pregnancy will be unsuccessful. In DES sons, who have been far less studied, results suggest male reproductive toxicity, but are less consistent. The importance of dose and gestational age at initial exposure are discussed, and the implications of DES findings for the evaluation of risks from current EDCs emphasized.


Association of apolipoprotein B XbaI gene polymorphism and lipid profile in northern Indian obese.
Over the last few decades, obesity, diabetes, and hypertension have become main health evils. The health problems of obesity are well-recognized. However, the fact that all obese individuals are not at the same risk of developing a disease is also recognized. The apolipoprotein B (APOB) plays a central role in lipid metabolism. So we compare the association of APOB XbaI gene polymorphism and lipid profile total in obese north Indian population. A total of 132 obese (body mass index [BMI] >25 kg/m(2)) and 132 age matched non-obese (BMI ≤ 25 kg/m(2)) subjects were studied after taking detailed clinical profile. Lipid profile in serum/plasma was done using commercial kits. Genetic analysis of APOB XbaI was done using Polymerase Chain Reaction-Restriction Fragment Leanth polymorphism (PCR-RFLP). Statistical analysis was performed by Statistical Package for the Social Sciences (SPSS) (version 11.5) software (IBM Corporation). All continuous variables were expressed as mean ± SD and tested by analysis of variance test. Comparisons of categorical variables were assessed using χ(2) tests or Fisher's exact test. P < 0.05 was considered as significant. Analysis showed that obese subjects had significantly higher value of the waist-to-hip ratio, blood pressure (systolic and diastolic), and lipid profile. In APOB XbaI gene polymorphism, we did not find significant differences in genotype or allele frequencies. Moreover, none of the studied metabolic parameters (lipid profile) showed any association with the gene polymorphism. Study reveals no considerable association of APOB XbaI gene polymorphism with obesity and lipid profile in north Indians.


Curcumin attenuates rat thoracic aortic aneurysm formation by inhibition of the c-Jun N-terminal kinase pathway and apoptosis.
Recent studies have suggested that c-Jun N-terminal kinase (JNK) plays an important role in the formation of abdominal aortic aneurysms, and that direct blockade of JNK by specific inhibitors can effectively prevent the progression of aortic aneurysms. A study has demonstrated that curcumin can suppress the development of experimental abdominal aortic aneurysms by inhibiting inflammation. We sought to investigate whether curcumin could inhibit JNK pathways and apoptosis in thoracic aortic aneurysms. We used a rat model of a CaCl₂-induced thoracic aortic aneurysm followed by daily oral gavage with curcumin 100 mg/kg or vehicle alone. After treatment for 4 wk, tissue specimens were obtained for histologic assessments, and tissue composition was evaluated using immunohistochemistry, western blotting, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Curcumin significantly suppressed the CaCl₂-induced expansion of the thoracic aortic diameter and the structural preservation of medial elastin fibers. Most importantly, curcumin treatment significantly inhibited the phosphorylation of JNK and c-Jun, accompanied by less cell apoptosis in thoracic aortic aneurysm tissues. Furthermore, the expression levels of caspase-3 and the Bax/Bcl-2 ratio were significantly decreased in the aortic walls of curcumin-treated rats. The present study indicates that the beneficial effect of curcumin on degenerative aortic aneurysms is related to the inhibition of JNK and apoptosis in the walls of thoracic aortic aneurysms.


Longitudinal evolution of unidentified bright objects in children with neurofibromatosis-1.
Neurofibromatosis type-1 (NF-1) is the most common autosomal dominant disorder affecting the central nervous system. Magnetic resonance imaging (MRI) has revealed distinctive T2-weighted hyperintense foci (termed unidentified bright objects, UBOs) which appear to represent spongiform changes in the white matter. Cross-sectional and longitudinal analyses suggest that UBOs disappear over time; however, none of these studies have examined comprehensively these foci. We conducted a quantitative MRI longitudinal study of number of affected regions, number of UBOs per region, and UBO volume per region, in a sample of 12 children with NF-1. We applied semi-automatic morphometric methods and comprehensive statistical approaches, within a detailed anatomical parcellation framework. Our data demonstrate that, despite a similar UBO regional distribution (e.g., prevalent globus pallidus/internal capsule (GP/IC) location), UBO evolution was more complex than previously reported. In some subjects, the total number of UBO-occupied locations demonstrated a decrease between approximately ages 7 and 12 years, followed by a progressive increase during adolescence. This pattern was also found for UBO number and/or volume for all regions, with the exception of the cerebellar hemispheres. This REGIONAL distinction may reflect differences in white matter structure between affected long tract fiber bundles and that of cerebral and cerebellar myelinated fibers. The findings are also discussed in the context of previous MR and behavioral studies. We conclude that studies like the present one, in association with other MR modalities, are necessary to characterize more completely the nature and evolution of UBOs and their role in the cognitive phenotype of NF-1.


Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor.
The N-methyl-d-aspartate (NMDA) receptors play critical roles in synaptic plasticity, neuronal development, and excitotoxicity. Tyrosine phosphorylation of NMDA receptors by Src-family tyrosine kinases such as Fyn is implicated in synaptic plasticity. To precisely address the roles of NMDA receptor tyrosine phosphorylation, we identified Fyn-mediated phosphorylation sites on the GluR epsilon 2 (NR2B) subunit of NMDA receptors. Seven out of 25 tyrosine residues in the C-terminal cytoplasmic region of GluR epsilon 2 were phosphorylated by Fyn in vitro. Of these 7 residues, Tyr-1252, Tyr-1336, and Tyr-1472 in GluR epsilon 2 were phosphorylated in human embryonic kidney fibroblasts when co-expressed with active Fyn, and Tyr-1472 was the major phosphorylation site in this system. We then generated rabbit polyclonal antibodies specific to Tyr-1472-phosphorylated GluR epsilon 2 and showed that Tyr-1472 of GluR epsilon 2 was indeed phosphorylated in murine brain using the antibodies. Importantly, Tyr-1472 phosphorylation was greatly reduced in fyn mutant mice. Moreover, Tyr-1472 phosphorylation became evident when hippocampal long term potentiation started to be observed, and its magnitude became larger in murine brain. Finally, Tyr-1472 phosphorylation was significantly enhanced after induction of long term potentiation in the hippocampal CA1 region. These data suggest that Tyr-1472 phosphorylation of GluR epsilon 2 is important for synaptic plasticity.


Enhanced Oral Bioavailability of Diltiazem by the Influence of Gallic Acid and Ellagic Acid in Male Wistar Rats: Involvement of CYP3A and P-gp Inhibition.
The oral bioavailability of diltiazem is very low due to rapid first pass metabolism in liver and intestine. The purpose of the study was to investigate the effect of gallic acid and ellagic acid on intestinal transport and oral bioavailability of diltiazem in rats. The intestinal transport and permeability of diltiazem was evaluated by in vitro non-everted sac method and in situ single pass intestinal perfusion study. The oral pharmacokinetics was evaluated by conducting oral bioavailability study. The intestinal transport and apparent permeability of diltiazem were significantly enhanced in duodenum, jejunum, and ileum of gallic and ellagic acid-treated groups. The effective permeability of diltiazem was significantly enhanced in ileum part of gallic and ellagic acid-treated groups. When compared with control group, the presence of these two phytochemicals significantly enhanced the area under plasma concentration-time curve and the peak plasma concentration of diltiazem (Cmax ). Gallic acid and ellagic acid significantly increased the bioavailability of diltiazem due to the inhibition of both CYP3A-mediated metabolism and P-glycoprotein-mediated efflux in the intestine and/or liver. Based on these results, the clinical experiments are warranted for the confirmation to reduce the dose of diltiazem when concomitantly administered with these phytochemicals. Copyright © 2017 John Wiley & Sons, Ltd.


Biochemical and cellular mechanisms of pulmonary fibrosis.
This review summarizes the manner in which a variety of agents may induce fibrogenic reactions in the lung. The extent of reaction is dependent on dose, time scale of exposure, and chemical reactivity. The regime of multiple dosing with chemicals or gases with recovery periods is important in disease progression. The means by which biochemists and histopathologists assess fibrosis, the advantages and disadvantages of each of the methods as related to subjectivity, quantitation, and speed of analysis are compared. The mechanisms which control the step from fibrogenesis (a potentially reversible reaction) to fibrosis (irreversible) may be linked to the maturation of collagen, calcification, or the formation of cross-linked protein masses. Attention is given to hydroxylysine cross-links in newly formed "fibrotic" collagen but focusses on gamma-glutamyl-epsilon-lysyl cross-links formed by calcium-dependent transglutaminases. It is suggested that these enzymes, released by replacement epithelial cells, could be responsible for the formation of stabilized protein masses in the lung, thus contributing to a progressive fibrosis.


Candida albicans Genetic Background Influences Mean and Heterogeneity of Drug Responses and Genome Stability during Evolution in Fluconazole.
The importance of within-species diversity in determining the evolutionary potential of a population to evolve drug resistance or tolerance is not well understood, including in eukaryotic pathogens. To examine the influence of genetic background, we evolved replicates of 20 different clinical isolates of Candida albicans, a human fungal pathogen, in fluconazole, the commonly used antifungal drug. The isolates hailed from the major C. albicans clades and had different initial levels of drug resistance and tolerance to the drug. The majority of replicates rapidly increased in fitness in the evolutionary environment, with the degree of improvement inversely correlated with parental strain fitness in the drug. Improvement was largely restricted to up to the evolutionary level of drug: only 4% of the evolved replicates increased resistance (MIC) above the evolutionary level of drug. Prevalent changes were altered levels of drug tolerance (slow growth of a subpopulation of cells at drug concentrations above the MIC) and increased diversity of genome size. The prevalence and predominant direction of these changes differed in a strain-specific manner, but neither correlated directly with parental fitness or improvement in fitness. Rather, low parental strain fitness was correlated with high levels of heterogeneity in fitness, tolerance, and genome size among evolved replicates. Thus, parental strain background is an important determinant in mean improvement to the evolutionary environment as well as the diversity of evolved phenotypes, and the range of possible responses of a pathogen to an antimicrobial drug cannot be captured by in-depth study of a single strain background.IMPORTANCE Antimicrobial resistance is an evolutionary phenomenon with clinical implications. We tested how replicates from diverse strains of Candida albicans, a prevalent human fungal pathogen, evolve in the commonly prescribed antifungal drug fluconazole. Replicates on average increased in fitness in the level of drug they were evolved to, with the least fit parental strains improving the most. Very few replicates increased resistance above the drug level they were evolved in. Notably, many replicates increased in genome size and changed in drug tolerance (a drug response where a subpopulation of cells grow slowly in high levels of drug), and variability among replicates in fitness, tolerance, and genome size was higher in strains that initially were more sensitive to the drug. Genetic background influenced the average degree of adaptation and the evolved variability of many phenotypes, highlighting that different strains from the same species may respond and adapt very differently during adaptation.


[Source of variation in the diagnosis of Helicobacter pylori-associated multifocal atrophic gastritis.]
Multiple sampling from different sites of the stomach as well as the number of fragments of gastric mucosa available for histopathologic evaluation are important sources of variation when classifying and grading chronic gastritis. To estimate the sensitivity of the number of fragments of gastric mucosa necessary to establish the diagnosis of atrophic gastritis with intestinal metaplasia, gastric dysplasia and H. pylori infection. In addition, this study will attempt to assess the intra-observer variability in the classification of these premalignant gastric lesions. This is a 6 year-cohort study, wherein 1958 gastric endoscopic procedures performed by two gastroenterologists were reviewed. Five gastric biopsy samples were obtained from the antrum, body and lesser curvature during each procedure. One pathologist was in charge of reviewing the five histopathology samples for each subject and providing a definitive diagnosis which was used as the gold standard. Each gastric mucosa sample reviewed led to an individual diagnosis for that sample which was compared with the gold standard. Intra-observer variability was assessed in 127 individuals who correspond to a random sample of 20% of the total endoscopic procedures performed during the 72 month-follow-up. The sensitivity of the diagnosis of intestinal metaplasia (IM) and gastric dysplasia increased proportionally with the number of gastric mucosa samples reviewed. The lesser curvature of the stomach had the highest sensitivity for the diagnosis of IM and dysplasia, among all the stomach regions studied. Just one sample of gastric mucosa attained a sensitivity of 95.9% for the detection of H. pylori infection. The intra-observer agreement for the diagnosis of multifocal atrophic gastritis was 86.1% and the kappa value was 0.79 (95% CI 0.76-0.85). Alcohol-fixed biopsy specimens were inadequate to diagnose H. pylori infection and to assess dysplasia. The number of mucosa gastric fragments reviewed, the fixation method used, and the biopsy site are all important factors in order to ensure a correct classification of chronic gastritis.


Pharmacophore and 3D-QSAR characterization of 6-arylquinazolin-4-amines as Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitors.
Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) are protein kinases that are promising targets for treatment of diseases caused by abnormal gene splicing. 6-Arylquinazolin-4-amines have been recently identified as potent Clk4 and Dyrk1A inhibitors. In order to understand the structure-activity correlation of these analogs, we have applied ligand-based pharmacophore and 3D-QSAR modeling combined with structure-based homology modeling and docking. The high R(2) and Q(2) (0.88 and 0.79 for Clk4, 0.85 and 0.82 for Dyrk1A, respectively) based on validation with training and test set compounds suggested that the generated 3D-QSAR models are reliable in predicting novel ligand activities against Clk4 and Dyrk1A. The binding mode identified through docking ligands to the ATP binding domain of Clk4 was consistent with the structural properties and energy field contour maps characterized by pharmacophore and 3D-QSAR models and gave valuable insights into the structure-activity profile of 6-arylquinazolin-4-amine analogs. The obtained 3D-QSAR and pharmacophore models in combination with the binding mode between inhibitor and residues of Clk4 will be helpful for future lead compound identification and optimization to design potent and selective Clk4 and Dyrk1A inhibitors.


Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia.
AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations. We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity. We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age. Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration.


Enhancing the reactivity of nickel(ii) in hydrogen evolution reactions (HERs) by β-hydrogenation of porphyrinoid ligands.
Fine-tuning of the porphyrin β-periphery is important for naturally occurring metal tetrapyrroles to exert diverse biological roles. Here we describe how this approach is also applied to design molecular catalysts, as exemplified by Ni(ii) porphyrinoids catalyzing the hydrogen evolution reaction (HER). We found that β-hydrogenation of porphyrin remarkably enhances the electrocatalytic HER reactivity (turnover frequencies of 6287 vs. 265 s-1 for Ni(ii) chlorin (Ni-2) and porphyrin (Ni-1), and of 1737 vs. 342 s-1 for Ni(ii) hydroporpholactone (Ni-4) and porpholactone (Ni-3), respectively) using trifluoroacetic acid (TFA) as the proton source. DFT calculations suggested that after two-electron reduction, β-hydrogenation renders more electron density located on the Ni center and thus prefers to generate a highly reactive nickel hydride intermediate. To demonstrate this, decamethylcobaltocene Co(Cp*)2 was used as a chemical reductant. [Ni-2]2- reacts ca. 30 times faster than [Ni-1]2- with TFA, which is in line with the electrocatalysis and computational results. Thus, such subtle structural changes inducing the distinctive reactivity of Ni(ii) not only test the fundamental understanding of natural Ni tetrapyrroles but also provide a valuable clue to design metal porphyrinoid catalysts.


Enzyme-aided investigation of the substituent distribution in cationic potato amylopectin starch.
The distribution of substituents along the polymer chain in cationic potato amylopectin starch, modified in solution, granular slurry, or dry state, was investigated. The starch derivatives were successively hydrolyzed by different enzymes, followed by characterization of the hydrolysis products obtained by means of electrospray mass spectrometry (ESI-MS) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). ESI-MS and MALDI-MS were proved to be appropriate techniques for identification of the substituted hydrolysis products, for which there are no standard compounds available. No highly substituted oligomers were found in the hydrolysates, which was taken as an indication of a more or less homogeneous distribution of cationic groups in the amylopectin molecules. Furthermore, from the results obtained it was suggested that the enzymes cleave glucosidic linkages only between unsubstituted glucose units and, preferentially, linkages in sequences containing more than two adjacent unsubstituted units. The determination of the amount of unsubstituted glucose produced from every successive hydrolysis step revealed slight differences between the different starch samples with respect to the homogeneity of the substitution pattern. Among the three samples under investigation, starch cationized in solution was found to have the most and dry-cationized starch the least homogeneous distribution of substituents.


Increased incidence and shift in the location of gunshot wound injuries in dogs and cats during the COVID-19 pandemic.
To investigate the incidence and patterns of gunshot wound trauma in patients that were presented to an urban level 1 veterinary trauma center before and after the start of the coronavirus disease of 2019 (COVID-19) pandemic. 24 dogs and 1 cat. Medical records were retrospectively reviewed for patients presenting with gunshot wound injuries between March 2018 and February 2020 (prepandemic) and March 2020 and February 2022 (pandemic). The total number of patients presented to the hospital during those same time periods was also obtained. Patient data were collected including species, breed, age, sex, location of injury, trauma score (if available), surgical procedures performed, length of hospitalization, and case outcome. In the prepandemic period, 9 patients were presented for gunshot wound injuries, whereas there were 16 patients evaluated for gunshot wound injuries during the pandemic period. The total number of gunshot wound cases increased by 77.8% in the pandemic period. The total number of hospital patient visits, however, decreased by 12.2% in the pandemic period as compared to the prepandemic period: 65,168 versus 74,262 patients, respectively. Injuries were predominantly localized to the extremities (55%) in the prepandemic period versus maxillofacial (56%) in the pandemic period. There was an increased number of gunshot wound injuries in companion animals presenting to an urban level 1 veterinary trauma center during the COVID-19 pandemic. A shift in the predominant location of injury was also identified during the pandemic period. This study highlights the ramifications that societal dynamics can have on animal health and welfare.


Evidence-based management of central cord syndrome.
Evidence-based medicine is used to examine the current treatment options, timing of surgical intervention, and prognostic factors in the management of patients with traumatic central cord syndrome (TCCS). A computerized literature search of the National Library of Medicine database, Cochrane database, and Google Scholar was performed for published material between January 1966 and February 2013 using key words and Medical Subject Headings. Abstracts were reviewed and selected, with the articles segregated into 3 main categories: surgical versus conservative management, timing of surgery, and prognostic factors. Evidentiary tables were then assembled, summarizing data and quality of evidence (Classes I-III) for papers included in this review. The authors compiled 3 evidentiary tables summarizing 16 studies, all of which were retrospective in design. Regarding surgical intervention versus conservative management, there was Class III evidence to support the superiority of surgery for patients presenting with TCCS. In regards to timing of surgery, most Class III evidence demonstrated no difference in early versus late surgical management. Most Class III studies agreed that older age, especially age greater than 60-70 years, correlated with worse outcomes. No Class I or Class II evidence was available to determine the efficacy of surgery, timing of surgical intervention, or prognostic factors in patients managed for TCCS. Hence, there is a need to perform well-controlled prospective studies and randomized controlled clinical trials to further investigate the optimal management (surgical vs conservative) and timing of surgical intervention in patients suffering from TCCS.