Pubertal development and pain incidence and characteristics in children: a 1-year prospective cohort study of a national sample.
Sex differences in pain become apparent during puberty. However, the influence of key pubertal characteristics and pubertal hormones on pain is largely unknown. We examined the prospective associations between self-reported and hormone-indicated pubertal characteristics and pain incidence and severity in 10- to 11-year-old pain-free youth in the Adolescent Brain Cognitive Development (ABCD) Study over 1 year. Puberty was measured at baseline and follow-up with self-report (Pubertal Development Scale [PDS]) and hormonal assessment (salivary dehydroepiandrosterone [DHEA], testosterone, and estradiol). Pain status (yes/no), intensity, and interference (0-10 numerical rating scale) in the past month were self-reported at follow-up. Pubertal maturity, progression, and asynchrony were examined in relation to pain onset and severity through confounder-adjusted generalized estimating equations modified Poisson and linear mixed regression models. Among 6631 pain-free youth at baseline, 1-year incident pain was 30.7%. In both sexes, higher PDS scores were associated with greater risk of pain onset (relative risk [RR] = 1.10 to 1.27, P s < 0.01). In boys, higher PDS item variance was associated with greater pain incidence (RR = 1.11, 95% CI, 1.03-1.20) and interference (beta = 0.40, 95% CI, 0.03-0.76); higher PDS overall and gonadal scores were associated with higher pain intensity ( P s < 0.05). Associations with hormones were seen in boys only, with each 10-fold higher testosterone levels associated with a 40% lower risk of pain incidence (95% CI, -55% to -22%) and 1.30-point lower (95% CI, -2.12 to -0.48) pain intensity, and higher DHEA levels were associated with lower pain intensity ( P = 0.020). Relationships between pubertal development and pain in peripubertal adolescents are sex specific and puberty measurement specific and warrant further investigation.


Observations on some locally available products.
A physical grading of some well-known sunburn protectors is described as a guide to the choice of preparation.


High CD45 expression of CD8+ and CD4+ T cells correlates with the size of HIV-1 reservoir in blood.
Using mass cytometry, we investigated the expression of 28 markers on CD8+ and CD4+ T cells from HIV-1 infected patients with a variable size of HIV-1 reservoir defined as high (HR) and low (LR) reservoir; we aimed at identifying phenotypic associations of T cells with size of HIV-1 reservoir. We showed that the frequency of CD45+ CD8+ and CD4+ T cells was directly proportional to the size of HIV-1 reservoir; HR patients had a significantly larger frequency of blood CD45high T cells and higher CD45 expression on both CD8+ and CD4+ T cells. CD45 is a receptor-type protein tyrosine phosphatase essential in TCR signaling. Functional and phenotypical analysis of CD45high cells revealed that they express activation and proliferation markers (CD38 + HLA-DR + and Ki-67) and produce cytokines upon in vitro activation. CD45high T cells also expressed high levels of immune check-point PD-1. Our results link CD45 expression on T cells to HIV-1 reservoir; PD-1 expression on CD45high T cells may contribute to their exhaustion.


Editorial: Defining the Clinical Boundary of Disruptive Mood Dysregulation Disorder Symptoms in Youth.
Disruptive mood dysregulation disorder (DMDD) is a novel diagnosis emerging from a continuing discourse on the best diagnostic home for children with severe, chronic irritability. DMDD emerged from a research diagnosis that was developed to test the hypothesis that severe, chronic irritability is a developmental phenotype of pediatric bipolar disorder.1 That is, such irritability is a phenomenon that emerges prior to a hypo/manic episode that defines bipolar disorder. For many, such irritability in conjunction with attention-deficit/hyperactivity disorder (ADHD) symptoms had been treated as a prodrome of bipolar disorder. Although this line of research did not establish a deterministic association between the DMDD syndrome and later bipolar disorder, it did provide guidance for assessing the risk of irritability for later bipolar disorder.2 Among the outcomes was the introduction of DMDD as a new diagnosis in DSM-5. It is defined by 2 core symptoms-temper outbursts and irritable/angry mood-the 2 major features of irritability. However, what qualifies as DMDD-level irritable mood and temper outbursts is unclear, and, unlike other mood disorders, no ancillary symptom criteria are available to establish a diagnosis of DMDD. Through the example of the relationship between DMDD and ODD, we will illustrate the clinical impact of this lack of clarity and describe the current efforts to establish a developmentally sensitive clinical nosology for irritability.


[A study of the inhibition effect of HIFU and its mechanism of action on the proliferation of human breast cancer cells].
To investigate the killing effect of high intensity focused ultrasound (HIFU) on human tumor cells and study the mechanism of its action. Human breast cancer cells MCF-7 were treated with different intensity of HIFU in vitro and incubated. The killing effect and proliferation inhibition effect of HIFU on tumor cells were investigated with the methods of trypan blue exclusion assay, MTT assay and colony formation assay. And the cell cycle, apoptotic cells and the expressions of P53, BCL-2, FAS and HSP70 were measured with flow cytometry. After HIFU treatment, the death rates of cancer cell increased, the proliferation of cell waned (P < 0.05), the number of colony formation decreased (P < 0.001), the cell number increased in G0/G1 phase (P < 0.05) and decreased in S phase, the apoptotic indices increased (P < 0.01), the expression of HSP70 was enhanced, and no significant changes of P53, BCL-2, FAS expressions were found (P > 0.05). HIFU produces significant effects such as killing, proliferation inhibition and colony formation inhibition on human breast cancer cells; its mechanism of action may be associated with the inhibition of DNA synthesis. In addition, HIFU treatment can induce apoptotic cell death, which may not be associated with the mediation and regulation of P53, BCL-2 and FAS genes.


Effects of environmental stress on intertidal mussels and their sea star predators.
Consumer stress models of ecological theory predict that predators are more susceptible to stress than their prey. Intertidal mussels, Mytilus californianus, span a vertical stress gradient from the low zone (lower stress) to the high zone (higher thermal and desiccation stress), while their sea star predators, Pisaster ochraceus, range from the low zone only into the lower edge of the mussel zone. In summer 2003, we tested the responses of sea stars and mussels to environmental stress in an experiment conducted on the Oregon coast. Mussels were transplanted from the middle of the mussel bed to cages in the low and high edges of the mussel bed. Sea star predators were added to half of the mussel cages. Mussels and sea stars were sampled between June and August for indicators of sublethal stress. Mussel growth was measured, and tissues were collected for heat shock protein (Hsp70) analyses and histological analyses of reproduction. Sea stars were weighed, and tissues were sampled for Hsp70 analyses. Mussels in high-edge cages had higher levels of total Hsp70 and exhibited spawning activity earlier in the summer than mussels in the low-edge cages. Sea stars suffered high mortality in the high edge, and low-edge sea stars lost weight but showed no differences in Hsp70 production. These results suggest that stress in the intertidal zone affected the mobile predator more than its sessile prey, which is consistent with predictions of consumer stress models.


Targeted next generation sequencing reveals a novel intragenic deletion of the TPO gene in a family with intellectual disability.
Next generation sequencing (NGS) approaches have revolutionized the identification of mutations underlying genetic disorders. This technology is particularly useful for the identification of mutations in known and new genes for conditions with extensive genetic heterogeneity. In the present study we investigated a consanguineous Pakistani family with intellectual disability (ID). Genotyping was carried out using 250k and 6k SNP microarrays in order to perform homozygosity mapping and copy number variation (CNV) analysis. Targeted NGS was performed to identify the genetic defect in this family. qPCR was performed to validate and confirm the NGS result. Homozygosity mapping positioned the causative defect on chromosome 2p25.3-p25.2. Subsequent targeted NGS revealed an intragenic deletion of five exons of the gene TPO. NGS is a powerful method to uncover submicroscopic structural variations. This result demonstrates that an unbiased screening approach such as NGS can help to identify even unexpected disease-causing mutations.


Input-dependent learning rule for the memory of spatiotemporal sequences in hippocampal network with theta phase precession.
Theta phase precession in rat hippocampal place cells is hypothesized to contribute to memory encoding of running experience in the sense that it provides the ideal timing for synaptic plasticity and enables the asymmetric associative connections under the Hebbian learning rule with asymmetric time window (Yamaguchi 2003). When the sequence of place fields is considered as the episodic memory of running experience, a given spatial route should be accurately stored in spite of differing overlap extent among place fields and varying running velocity. Using a hippocampal network model with phase precession and the Hebbian learning rule with asymmetric time window, we investigate the memory encoding of place field sequences in a single traversal experience. Computer experiments show that place fields cannot be stored correctly until an input-dependent feature is introduced into the learning rule. These experiments further indicate that there exists an optimum value for the saturation level of synaptic plasticity and the speed of synaptic plasticity in the learning rule, which are correlated with, respectively, the overlap extent of place field sequence and the running velocity of animal during traversal. A comparison of these results with biological evidences shows good agreement and suggests that behavior-dependent regulation of the learning rule is necessary for memory encoding.


Platelet membrane abnormality in Alzheimer's disease.
Fluorescence studies of membrane fluidity were conducted double-blind using platelet and red cell membranes prepared from 24 demented patients with probable Alzheimer's disease and 36 neurologically healthy subjects. The fluidity of the hydrocarbon and lipid-aqueous interface regions of cell membranes was determined at 37 degrees C by fluorescence spectroscopy using the lipid probes 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-[4-(trimethylamino)phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH), respectively. The rotation rate of TMA-DPH in labeled platelet membranes did not differ between the groups. In contrast, the rotation rate of DPH in labeled platelet membranes from the demented patients (2.15 +/- 0.24 X 10(8)/sec, SD) was greater than that for the normal controls (1.93 +/- 0.13 X 10(8)/sec, SD, p = 3.8 X 10(-5)). This difference was reflected by a reduction in the steady-state anisotropy of DPH in labeled platelets from the demented group (0.1887 +/- 0.0085, SD) when compared to the respective mean for the controls (0.2000 +/- 0.0060, SD; p = 1.3 X 10(-7)). Abnormal membrane fluidity was significantly correlated with severity of dementia, but not with duration of illness or apparent age of onset. The findings do not support the hypothesis that Alzheimer's disease results from a pathological acceleration of the normal aging process, since normal aging is associated with decreased fluidity of cell membranes from platelets, as well as from lymphocytes, hepatocytes, and neurons.


Spinal injection of docosahexaenoic acid attenuates carrageenan-induced inflammatory pain through inhibition of microglia-mediated neuroinflammation in the spinal cord.
Neuroinflammation in the spinal cord plays a critical role in the processing of inflammatory pain. Docosahexaenoic acid (DHA), a predominant omega-3 polyunsaturated fatty acid in the central nervous system, is known to modulate inflammatory responses in various neurodegenerative disorders. In this study, we investigated whether DHA could reduce inflammatory pain and inhibit neuroinflammation in the spinal cord following carrageenan injection in mice. Intrathecal (i.t.) injection of DHA at 15min before carrageenan injection blocked carrageenan-induced pain hypersensitivity for more than 6h. In addition, i.t. injection of DHA at 3h after carrageenan transiently reversed carrageenan-induced heat hyperalgesia and mechanical allodynia. Furthermore, DHA treatment reduced carrageenan-induced activation of microglia, phosphorylation of p38 mitogen-activated protein kinase (MAPK), and production of proinflammatory cytokines (tumor necrosisfactor-α - TNF-α and interleukin-1β - IL-1β) in the L4-5 spinal cord. In cultured microglial cells, DHA dose-dependently reduced lipopolysaccharide (LPS)-induced phosphorylation of p38, production of proinflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines (CCL2, CCL3 and CXCL10). p38 inhibitor SB203580 inhibited LPS-induced expression of proinflammatory cytokines and chemokines in a dose-dependent manner. Taken together, these results provide evidence that DHA has antinociceptive effect in inflammatory pain, which may be attributed to, at least partially, suppressing a microglia-mediated inflammatory response through inhibition of p38 MAPK activation.


Whole-genome sequencing of clinical Clostridioides difficile isolates reveals molecular epidemiology and discrepancies with conventional laboratory diagnostic testing.
The high clinical burden of Clostridioides difficile infections merits rapid and sensitive identification of affected individuals. However, effective diagnosis remains challenging. Current best practice guidelines recommend molecular and/or direct toxin detection-based screening for symptomatic individuals, but previous work has called into question the concordance and performance of extant clinical assays. To better correlate the genomic and phenotypic properties of clinical C. difficile isolates with laboratory testing outcomes in both C. difficile-infected patients and asymptomatic carriers. Whole-genome sequencing of clinical C. difficile isolates collected from an inpatient population at a single healthcare institution was performed, enabling examination of their molecular epidemiology and toxigenic gene content. Genomic findings were compared with clinical testing outcomes, identifying multiple diagnostic discrepancies. Toxigenic culture, considered a 'reference standard', provided perfect sensitivity and specificity in predicting toxigenic gene content, whereas reduced performance was observed for Simplexa C. difficile Direct Assay (100% specificity, 88% sensitivity), Gene Xpert CD/Epi Assay (86% specificity, 83% sensitivity), and Quick Check Complete Tox A/B (100% specificity, 30% sensitivity). Genomic analysis additionally revealed variability in toxin gene sequences among C. difficile strains, phylogenomic equivalency between isolates from affected patients and carriers, and patient carriage with uncommon environmentally derived C. difficile lineages, as well as presenting opportunities for tracing pathogen transmission events. These results highlight the variable performance of clinical stool-based testing approaches as well as the potential diagnostic utility of whole-genome sequencing as an alternative to conventional testing algorithms.


The relative importance of spatial versus temporal structure in the perception of biological motion: an event-related potential study.
We investigated how the spatiotemporal structure of animations of biological motion (BM) affects brain activity. We measured event-related potentials (ERPs) during the perception of BM under four conditions: normal spatial and temporal structure; scrambled spatial and normal temporal structure; normal spatial and scrambled temporal structure; and scrambled spatial and temporal structure. As in a previous study, we identified two negative components at both occipitotemporal regions: N210 reflected general motion processing while N280 reflected the processing of BM. We analyzed the averaged ERPs in the 200-300 ms response time window and found that spatial structure had a substantial effect on the magnitude of the averaged response amplitude in both hemispheres. This finding suggests that spatial structure of point-lights elicits a stronger response in the occipitotemporal region than temporal structure for the BM perception.


Safety and tolerability of the ketogenic diet in pediatric epilepsy: effects of valproate combination therapy.
To evaluate safety and tolerability of ketogenic diet (KGD) and valproate (VPA) cotherapy in the treatment of intractable seizures. The patient records of children who underwent KGD initiation at the Massachusetts General Hospital for Children from February 2002 to September 2004 were retrospectively assessed. Efficacy was measured by comparing reported seizure frequency at baseline and at 3-month intervals thereafter. Adverse events and reasons for terminating the diet were tabulated. Of 71 patients who underwent KGD initiation, 24 were concomitantly using VPA at the time of initiation. The most serious adverse events were two cases of acute pancreatitis (2.8%), both of which occurred in patients not taking VPA. The most common complications in both groups were acidosis (39.4%), nausea and vomiting (23.9%), hypertriglyceridemia (21.1%), lethargy (18.3%), and behavioral changes and irritability (15.5%). No significant difference in adverse-event profiles was found between the VPA group and the non-VPA group. At 1 year, 32 patients remained on the diet, including 11 in the VPA group. Efficacy was nearly identical in these two groups. KGD and VPA combination therapy is relatively safe and effective in refractory pediatric epilepsy. Adverse-event profiles of patients on KGD and VPA cotherapy are similar to those of patients on the KGD without VPA. In considering possible treatment options for intractable seizures, cotherapy with these two modalities should not be excluded for safety or tolerability concerns. In some patients, this combination may provide optimal seizure control.


Unlocking the secrets of exchange rate determination in Malaysia: A Game-Changing hybrid model.
Nominal exchange rate determination is a puzzling phenomenon throughout the literature. Thus, the study aims to analyze the nominal exchange rate determination with a hybrid approach of macroeconomic and microstructure determinants, i.e., interest rate differential, oil price, order flow, and bid-ask spread over the long- and short-run horizons in the context of Malaysia. The dataset consists of high-frequency daily data from 2010 to 2017, employing a nonlinear ARDL approach. The results indicate that the bid-ask spread and interest rate differential were found to be key determinants of exchange rate dynamics in the long and short run. The findings show strong evidence of long-run asymmetry in the interest rate differential, while short-run asymmetry effects exist between microstructure determinants and the exchange rate. In addition, it indicates that the bid-ask spread holds informative content to explain the dynamics of the exchange rate in Malaysia. Additionally, the negative changes in the oil price could potentially act as macroeconomic news announcements and the bid-ask spread as liquidity determinants in Malaysia, which play a significant role in exchange rate determination. The study concluded that the prominent short-run asymmetry effects captured in cumulative order flow and bid-ask spread While a long-run asymmetry exists between the oil price and exchange rate in Malaysia. The empirical results allow for long-run and short-run asymmetric pricing impacts of a hybrid approach on the nominal exchange rate in Malaysia. This study is helpful in providing policy direction and practical implications for monetary authorities and market dealers. The bid-ask spread and oil price could be considered influential exchange rate determinants in the short run in Malaysia.


Trauma bypass performed by vascular surgeons demonstrate excellent long-term outcomes and limb preservation.
Long-term outcomes in civilian trauma patients requiring upper or lower extremity revascularization is poorly studied secondary to limitations of certain large databases and the nature of the patients in this specific vascular subset. This study reports on the experience and outcomes of a Level 1 trauma center that serves both an urban and a large rural population over a 20-year period to identify bypass outcomes and surveillance protocols. Database of a single vascular group at an academic center was queried for trauma patients requiring upper or lower extremity revascularization between January 1, 2002, and June 30, 2022. Patient demographics, indications, operative details, operative mortality, 30-day nonoperative morbidity, revisions, subsequent major amputations, and follow-up data were analyzed. A total of 223 revascularizations were performed, 161 (72%) lower and 62 (28%) upper extremities. One hundred sixty-seven patients (74.9%) were male, with a mean age of 39 years (range, 3-89 years). Comorbidities included hypertension (n = 34; 15.3%), diabetes (n = 6; 2.7%), and tobacco use (n = 40; 17.9%). Mean follow-up time was 23 months (range, 1-234 months), with 90 patients (40.4%) lost to follow-up. Mechanisms included blunt trauma (n = 106; 47.5%), penetrating trauma (n = 83; 37.2%), and operative trauma (n = 34; 15.3%). Bypass conduit was reversed vein (n= 171; 76.7%), prosthetic (n = 34; 15.2%), and orthograde vein (n = 11; 4.9%). Bypass inflow artery was superficial femoral (n = 66; 41.0%), above-knee popliteal (n = 28; 17.4%), and common femoral (n = 20; 12.4%) in the lower extremity, and brachial (n = 41; 66.1%), axillary (n = 10; 16.1%), and radial (n = 6; 9.7%) in the upper extremity. Lower extremity outflow artery was posterior tibial (n = 47; 29.2%), below-knee popliteal (n = 41; 25.5%), superficial femoral (n = 16; 9.9%), dorsalis pedis (n = 10; 6.2%), common femoral (n = 9; 5.6%), and above-knee popliteal (n = 10; 6.2%). Upper extremity outflow artery was brachial (n = 34; 54.8%), radial (n = 13; 21.0%), and ulnar (n = 13; 21.0%). Total operative mortality was nine patients (4.0%), all involving lower extremity revascularization. Thirty-day non-fatal complications included immediate bypass occlusion (n = 11; 4.9%), wound infection (n = 8; 3.6%), graft infection (n = 4; 1.8%), and lymphocele/seroma (n = 7; 3.1%). All major amputations (n = 13; 5.8%) were early and in the lower extremity bypass group. Late revisions in the lower and upper extremity groups were 14 (8.7%) and four (6.4%), respectively. Revascularization for extremity trauma can be performed with excellent limb salvage rates and has demonstrated long-term durability with low limb loss and bypass revision rates. The poor compliance with long-term surveillance is concerning and may require adjustment in patient retention protocols; however, emergent returns for bypass failure are extremely low in our experience.


Optical coherence tomography in the assessment of suspicious oral lesions: an immediate ex vivo study.
Optical coherence tomography (OCT) is an evolving optical technology that is capable of delivering real-time, high-resolution signatures of tissue. The purpose of this immediate ex vivo prospective clinical study was: (1) to assess the sensitivity and specificity of OCT on biopsy material in identifying potentially malignant and malignant oral lesions, (2) to determine the inter-observer agreement in the analysis of specific image parameters, and (3) to find out the oral epithelial thickness for different pathology groups. This prospective study involved 125 suspicious oral lesions from 125 patients. The lesions were surgically biopsied and subjected to OCT in the immediate ex vivo phase. Two independent readers (surgeon and pathologist) examined the OCT images and assessed several cellular features including keratin layer, epithelial layer, basement membrane and lamina propria, and recorded their findings using special OCT reading score. The sensitivity, specificity and accuracy of OCT to predict "the future need for surgical biopsy in case of any similar lesion" were calculated. The epithelial thickness was also measured. The degree of agreement between the two readers was recorded. The pathological diagnosis revealed that the majority of lesions demonstrated microinvasive carcinomas (n=43). Forty-one had different degree of dysplasia. Benign oral lesions were less common and included 22 keratosis, 11 non-specific lesions, 6 mucocels and 2 papillomas. Optical coherence tomography achieved a sensitivity of 85% and a specificity of 78% in the assessment of oral potentially malignant and malignant disorders. The positive and negative predictive values were 86.5% and 77.5%, respectively. The accuracy was 82% and the kappa coefficient of inter-observer agreement was 0.72 on "the need for biopsy". OCT imaging of oral lesions provided valuable information on the oral epithelial thickness. This study proposes that OCT can accurately identify wide spectrum of oral tissue pathologies. Further studies can assess the role of OCT in evaluating and guiding surgical biopsies and monitoring disease.


Phenological adaptations of a colonizing insect: The southwestern corn borer, Diatraea grandiosella.
The developmental rate, critical photoperiod, and diapause intensity were determined for three populations of the southwestern corn borer, Diatraea grandiosella, from Missouri, Mississippi and Kansas. Mississippi larvae grew at the highest rate and Missouri larvae grew at the lowest rate. The zero developmental temperatures (°C) for the Missouri population were estimated from regression lines as follows: 10.5° (eggs), 10.8° (diapausing larvae), 13.3° (non-diapausing larvae) and 11.4° (pupae). The required heat units were: 85° (eggs), 588° (diapausing larvae), 333° (non-diapausing larvae) and 149° days (pupae). However, the observed low temperature limit for larval growth under constant temperature regimes was approximately 17°C.The critical day lengths for diapause induction observed at 25°C were: 15 h 11 min (Missouri); 15 h 20 min (Mississippi); and 15 h 22 min (Kansas). The photoperiodic response of the Mississippi larvae was more or less retained at 30°C, whereas the response of the Missouri larvae was completely suppressed at this temperature. Diapause was most easily terminated in the Kansas larvae. The most intense diapause was observed in the Mississippi larvae.Model seasonal life cycles of the three geographic populations were constructed using photothermograms. Although the models showed good agreement with the field situation for the Missouri and the Kansas populations, some unknown factor(s) remains to account for an extremely long critical photoperiod in the Mississippi population.


An element with long terminal repeats and its variant arrangements in the genome of Lilium henryi.
A 9.35 kbp element with long terminal direct repeats (LTRs) of 2.4 kbp has been characterized from the large genome of Lilium henryi. The organization of the element, named del, was examined in 20 fragments from a genomic DNA library constructed using phage EMBL3. Five fragments apparently contained full 9.35 kbp elements while in 11 del was recovered in part. Two clones carried tandem arrangements of del, with single LTRs and internal sequences alternating, and one insert contained a solo LTR. Evidence suggests that these arrangements, which can arise by unequal crossing over, have a genomic rather than a cloning origin. Finally, one cloned fragment had a complex del arrangement yet to be fully defined. Limited sequencing of five LTRs (from a full del, a tandem arrangement and a solo LTR) indicates that the consensus termini are 5'TGT...ACA3', with del sequences flanked by a 5 bp tandem repeat. Thus del shares properties with retrotransposons such as the copia family of Drosophila and Ty of yeast. However with more than 13,000 copies per genome it seems del has been amplified more than is usual for such elements.


Factors affecting utilization of sexual and reproductive health services among women with disabilities- a mixed-method cross-sectional study from Ilam district, Nepal.
Persons with disabilities can have physical, mental, intellectual, or sensory impairments which can hinder their social participation. Despite Sustainable Development Goals call for "universal access to sexual and reproductive health (SRH)", women with disabilities (WwDs) continue to experience barriers to access SRH services in Nepal. This study evaluated factors affecting the utilization of SRH services among WwDs in Ilam district, Nepal. A mixed-method study with 384 WwDs of reproductive age was conducted in Ilam district, eastern Nepal. Quantitative data were collected using a structured questionnaire. Relationships between utilization of SRH services and associated factors were explored using multivariate logistic regression analysis. Qualitative data were collected from focus groups with female community health volunteers and interviews with WwDs, health workers and local political leaders. They were audio-recorded, translated and transcribed into English and were thematically analyzed. Among 384 respondents (31% physical; 7% vision,16% hearing, 7% voice&speech,12% mental/psychosocial, 9% intellectual, 18% multiple disabilities), only 15% of them had ever utilized any SRH services. No requirement (57%) and unaware of SRH services (24%) were the major reasons for not utilizing SRH services. A majority (81%) of them reported that the nearest health facility was not disability-inclusive (73%), specifically referring to the inaccessible road (48%). Multivariate analysis showed that being married (AOR = 121.7, 95% CI: 12.206-1214.338), having perceived need for SRH services (AOR = 5.5; 95% CI: 1.419-21.357) and perceived susceptibility to SRH related disease/condition (AOR = 6.0; 95% CI:1.978-18.370) were positively associated with the utilization of SRH services. Qualitative findings revealed that illiteracy, poor socioeconomic status, and lack of information hindered the utilization of SRH services. WwDs faced socioeconomic (lack of empowerment, lack of family support), structural (distant health facility, inaccessible-infrastructure), and attitudinal (stigmatization, bad behaviour of health care providers, perception that SRH is needed only for married) barriers to access SRH services. Utilization of SRH services among WwDs was very low in Ilam district, Nepal. The findings of this study warrant a need to promote awareness-raising programs to WwDs and their family members, sensitization programs to health service providers, and ensure the provision of disability-inclusive SRH services in all health facilities.


A Single-Cell RNA-Seq-Based Approach for Genome-Wide Identification of Cell Essential Genes.
Identification of genes essential for structure, function, and survival of a cell type is critical for understanding of the underlying mechanisms. Unfortunately, there is no efficient way to identify such genes. Studies by single-cell RNA sequencing have shown that gene expressions of single cells of the same type are highly heterogeneous. We therefore speculate that the genes expressed in all individual cells of the same type are essential for the cell type, including the housekeeping genes and cell type-specific essential genes. Based on this rationale, we design a high-throughput approach to identify podocyte essential genes. In this approach, mouse podocytes are subjected to ultra-deep single-cell RNA-seq, and the genes expressed in all single podocytes are sorted out and considered as the candidates of podocyte essential genes. The essentiality of these genes for podocytes is assessed by bioinformatics, cross-species conserved expression, association with injury/disease, inclusion of known essential genes, and experimental validation. By comparison with the essential genes of other cell types, podocyte-specific essential genes can be distinguished. This approach applies to any cell types. In this chapter, we describe the approach and detailed methods.


Tertiary pentyl groups enhance salen titanium catalyst for highly enantioselective trimethylsilylcyanation of aldehydes.
tert-Pentyl groups are recognized to be highly effective steric groups that can enhance enantioselectivity of salen titanium complexes when they are used in asymmetrical cyanation of aromatic aldehydes. High ee (92-97%) has been obtained with several aldehyde substrates. Compared to its tert-butyl analogue, the tert-pentyl group has been found to improve enantioselectivity and in some cases quite dramatically.


Lipoblastoma and liposarcoma in children: an analysis of 9 cases and a review of the literature.
To review the experience at a children's hospital of lipoblastoma and liposarcoma and to identify any factors that would differentiate one type of tumour from the other. A retrospective case series. British Columbia's Children's Hospital a tertiary-care pediatric centre. All patients with a pathological diagnosis of lipoblastoma and liposarcoma recorded over 12 years. The frequency of lipoblastoma and liposarcoma, identified from biopsy specimens of pediatric adipose tumours. The clinical, pathological and cytogenetic variables between lipoblastoma and liposarcoma. One hundred and forty-nine adipose tumours were recorded. Seven (4.7%) were lipoblastomas and 2 (1.3%) were liposarcomas. All tumours presented as asymptomatic, slow-growing, soft-tissue masses. The children with lipoblastoma tended to be younger, but 29% were over 3 years of age. The liposarcoma patients were aged 9 and 14 years. One liposarcoma was of myxoid type and the other was a round cell variant. Karyotypes were reported for 1 lipoblastoma and 1 liposarcoma. The myxoid liposarcoma karyotype was 46,XY,t(12;16)(q13;p11), and the lipoblastoma was reported as 46,XY,der(8)?t(8q;?),+mar. Lipoblastoma is an unusual childhood neoplasm and liposarcoma is very rare in children. Both tumours may present in a similar fashion, and differentiating them histologically can be difficult. Age cannot be relied upon to accurately predict their behaviour. The tumour karyotype is very helpful in differentiating these neoplasms.


PASMVS: A perfectly accurate, synthetic, path-traced dataset featuring specular material properties for multi-view stereopsis training and reconstruction applications.
A Perfectly Accurate, Synthetic dataset for Multi-View Stereopsis (PASMVS) is presented, consisting of 400 scenes and 18,000 model renderings together with ground truth depth maps, camera intrinsic and extrinsic parameters, and binary segmentation masks. Every scene is rendered from 45 different camera views in a circular pattern, using Blender's path-tracing rendering engine. Every scene is composed from a unique combination of two camera focal lengths, four 3D models of varying geometrical complexity, five high definition, high dynamic range (HDR) environmental textures to replicate photorealistic lighting conditions and ten materials. The material properties are primarily specular, with a selection of more diffuse materials for reference. The combination of highly specular and diffuse material properties increases the reconstruction ambiguity and complexity for MVS reconstruction algorithms and pipelines, and more recently, state-of-the-art architectures based on neural network implementations. PASMVS serves as an addition to the wide spectrum of available image datasets employed in computer vision research, improving the precision required for novel research applications.


Microdensitometer-computer correlation analysis of two distinct, spatially segregated classes of microtubule bridges in Allogromia pseudopodia.
Previous video-light microscopic studies have shown that the microtubule bundles in the pseudopodia of foraminiferan protists display several types of movements in vivo, including active bending, zipping/splaying, and axial translocations. To gain insight into the types and arrangement of microtubule-associated proteins (e.g., mechanoenzymes, crosslinkers) in such a highly dynamic system, we employed microdensitometric-computer correlation methods to analyze, quantitatively, intermicrotubule bridges in thin-section electron micrographs of Allogromia laticollaris and Allogromia sp. (strain NF). Two distinct bridges occupying mutually exclusive zones between adjacent microtubules were identified. Type I bridges displayed a single axial repeat (34 nm for A. laticollaris and 28 nm for Allogromia sp.) and Type II bridges showed a typical 12-dimer helical superlattice pattern. In A. laticollaris, the two types of bridges were morphologically distinct: Type I bridges were aligned perpendicular to the microtubule wall and were 23-nm wide with an electron-lucent core; Type II bridges were irregular filaments projecting from the microtubules at various angles. When compared with the known distribution of microtubule-associated proteins in other systems, our findings indicate that, in vivo, Allogromia pseudopodial microtubules are decorated with MAP2-like bridges interrupted by discrete clusters of a dynein-like component.


Glaucoma Drainage Device Technique in a Cohort of Experienced Glaucoma Surgeons in Australia and New Zealand.
PRéCIS:: Glaucoma drainage devices (GDD) by Australian and New Zealand glaucomatologists are implanted superotemporally under a peribulbar anesthesia without the use of mitomycin C. Intraluminal stents and tube fenestration are utilized and covered with a scleral graft. To evaluate current practice patterns of surgical techniques for GDD among Australia and New Zealand Glaucoma Society members routinely performing GDD surgery. Survey of surgeons who performed more than 20 GDD in past 5 years. Surgeon participation rate was 31/32 (96.8%). The most common surgical techniques were Baerveldt GDD (24/32, 77.4%), superotemporal placement (31/31, 100%), and peribulbar anesthesia (21/31, 67.7%). Mitomycin C antimetabolite was used routinely by 9/31 surgeons (29.0%). Most surgeons employed intraluminal stents (23/31, 74.2%) with tube fenestrations (19/31, 61.3%). GDD was placed behind the recti muscles (27/31, 87.1%) and secured with nylon (8/0, 9/0 or 10/0) by 29/31 (93.6%). Most common sclerostomy techniques for tube insertion was a 23-G needle passed ab externo (18/31, 58.1%). Tube placement was in the sulcus (11/31, 35.5%) for pseudophakic patients. The external portion of the tube was most commonly covered with a full-thickness scleral patch graft (21/31, 67.7%). Majority of surgeons (21/31, 67.7%) reviewed patients 3 to 4 times in the first month. Although a wide range of practice patterns for GDD implantation exists among Australia and New Zealand Glaucoma Society surgeons, there are consistent techniques currently in use to optimize patient outcomes. This report can help surgeons seeking to improve outcomes and minimize complications when trialing the different surgical options.


Propentofylline: glial modulation, neuroprotection, and alleviation of chronic pain.
Propentofylline is a unique methylxanthine with clear cyclic AMP, phosphodiesterase, and adenosine actions, including enhanced synaptic adenosine signaling. Both in vitro and in vivo studies have demonstrated profound neuroprotective, antiproliferative, and anti-inflammatory effects of propentofylline. Propentofylline has shown efficacy in preclinical models of stroke, opioid tolerance, and acute and chronic pain. Clinically, propentofylline has shown efficacy in degenerative and vascular dementia, and as a potential adjuvant treatment for schizophrenia and multiple sclerosis. Possible mechanisms of action include a direct glial modulation to decrease a reactive phenotype, decrease glial production and release of damaging proinflammatory factors, and enhancement of astrocyte-mediated glutamate clearance. This chapter reviews the literature that supports a myriad of protective actions of this small molecule and implicates propentofylline as a potential therapeutic for the treatment of chronic pain. From these studies, we propose a CNS multipartite synaptic action of propentofylline that includes modulation of pre- and postsynaptic neurons, astrocytes, and microglia in the treatment of chronic pain syndromes, including, but not limited to, neuropathic pain.


A National Survey to Evaluate Graduate Medical Education in Disparities and Limited English Proficiency: A Report From the AAIM Diversity and Inclusion Committee.
This article presents the results of a national survey addressing issues related to patients with limited English proficiency. We disseminated a national confidential survey to 391 program directors of Internal Medicine residency programs accredited by the Accreditation Council for Graduate Medical Education. Seventy percent of program directors indicated that their residents cared for a patient population that was composed of more than 10% limited-English-proficiency patients. Nineteen percent of residency programs provided no education on caring for patients with limited English proficiency. Thirty percent of program directors felt that their faculty could not adequately evaluate residents on their ability to practice culturally competent care, and 68% cited lack of faculty expertise as a significant barrier to implementing a curriculum in cultural competency. Yet only 24% indicated that they had faculty development relevant to cultural competency and health care disparities. Internal Medicine residents care for many patients with limited English proficiency. While it seems clear that an effective training curriculum is necessary, such a curriculum was not found to be uniformly present. Additionally, the lack of faculty expertise and faculty development in cultural competency and health care disparities is a significant barrier to the correction of this problem.


Fluoride-induced histopathology and synthesis of stress protein in liver and kidney of mice.
Selective low (15 mg sodium fluoride (NaF)/L) and relatively high (150 mg NaF/L) doses of in vivo fluoride (F) treatment to Swiss albino mice through drinking water elicited organ-specific toxicological response. All the F-exposed groups showed severe alterations in both liver and kidney architectures, but there was no significant change in the rate of water consumption and body weight. Vacuolar degeneration, micronecrotic foci in the hepatocytes, and hepatocellular hypertrophy were evident in the mice exposed to low dose (15 mg NaF/L for 30 days) while sinusoidal dilation with enlarged central vein surrounded by deep-blue erythrocytes were preponderant when treated with the same dose for a period of 90 days. Blood filled spaces, disintegration of tubular epithelium, and atrophy of glomeruli were also recorded in the kidney of the same treatment group. Change in reduced glutathione level (GSH), glutathione-s-transferase (GST) activity, malondialdehyde (MDA) production in both liver and kidney, disturbances in liver function, induction of heat shock protein 70 (Hsp 70) expression in kidney and its down regulation in liver were positively correlated with histopathological lesion.


IgG Fc engineering to modulate antibody effector functions.
Therapeutic monoclonal antibodies are among the most effective biotherapeutics to date. An important aspect of antibodies is their ability to bind antigen while at the same time recruit immune effector functions. The majority of approved recombinant monoclonal antibody therapies are of the human IgG1 subclass, which can engage both humoral and cellular components of the immune system. The wealth of information generated about antibodies has afforded investigators the ability to molecularly engineer antibodies to modulate effector functions. Here, we review various antibody engineering efforts intended to improve efficacy and safety relative to the human IgG isotype. Further, we will discuss proposed mechanisms by which engineering approaches led to modified interactions with immune components and provide examples of clinical studies using next generation antibodies.


Viewpoint alignment and response conflict during spatial judgment.
Spatial judgment (e.g., identifying the relative location, such as left or right, of a target) from a reference point becomes more difficult with increasing disparity between the relevant allocentric viewpoint and the observer-centered viewpoint. The viewpoint alignment hypothesis suggests that this misalignment effect is due to a realignment process that reconciles two viewpoints, implying that providing an advance cue for a viewpoint should facilitate the subsequent judgment. We examined whether advance viewpoint information can reduce the misalignment effect and whether the misalignment effect reflects response conflict, as well as realignment of viewpoints. In Experiment 1, the misalignment effect decreased with advance viewpoint information, suggesting that the misalignment effect indeed reflects viewpoint realignment. In Experiment 2, the misalignment effect was greater with spatial response codes that might conflict with the spatially arranged response keys than with arbitrary responses with no such conflict. These results suggest that the misalignment effect may arise from both viewpoint realignment and response conflicts.


Does Vessel Noise Affect Oyster Toadfish Calling Rates?
The question we addressed in this study is whether oyster toadfish respond to vessel disturbances by calling less when vessels with lower frequency spectra are present in a sound recording and afterward. Long-term data recorders were deployed at the Neuse (high vessel-noise site) and Pamlico (low vessel-noise site) Rivers. There were many fewer toadfish detections at the high vessel-noise site than the low-noise station. Calling rates were lower in the high-boat traffic area, suggesting that toadfish cannot call over loud vessel noise, reducing the overall calling rate, and may have to call more often when vessels are not present.


A simple and economical modification of the Masson-Fontana method for staining melanin granules and enterochromaffin cells.
Enterochromaffin cells from the small intestine of man, guinea pig, dog, chicken, rabbit, cat and rat were stained using the Masson-Fontana ammoniacal silver method with varying dilutions of silver nitrate solution (0.25 to 5 g per 100 ml of distilled water) and incubation temperatures (60 C and 75 C). The 0.5% solution of silver nitrate gave an argentaffin pattern similar to that of the 5% solution and had two major advantages: economically, since much less silver nitrate is used, and methodologically, since low background resulted with tissue of those species (rat, cat and rabbit) that required unusually long incubation. The staining of melanocytes was similar for all dilutions at the usual staining time (15-30 min).


Decreased incidence of intraventricular hemorrhage in infants of opiate dependent mothers.
The incidence of intraventricular hemorrhage (IVH) in infants born to opiate dependent mothers was compared to infants whose mothers denied the use of addicting substances. The two groups were comparable in birth weight, gestational age, 1 and 5 min Apgar scores, and sex distribution. The incidence of breech presentations, PROM, and type of anesthesia at delivery were similar. However, more infants in the control group were delivered by cesarean section. The incidence of IVH was 52% in the controls and 23% in the opiate infants (p less than 0.05). Neonatal risk factors such as use of ventilators, incidence of pneumothorax, administration of pressor and sedative drugs, acidosis, use of alkali therapy and volume expanders, fluid therapy in the first three days and transfers to other hospitals were the same.


Endotoxin and muramyl dipeptide modulate surface receptor expression on human mononuclear cells.
Endotoxin (lipopolysaccharide (LPS), 100 ng/ml) and muramyl dipeptide (MDP 100 ng/ml), two immunomodulatory bacterial cell wall products, were incubated with human whole blood, and the expression of receptors involved in antigen presentation, costimulation, and cell activation was investigated by use of flow cytometry. On monocytes, LPS and MDP increased surface expression of human leukocyte antigen-DR (HLA-DR), CD18, CD54 (intercellular adhesion molecule-1, ICAM-1), and CD86 (B7-2). On lymphocytes, LPS but not MDP increased HLA-DR expression after 18 h. The expression of CD28, CD49d/CD29, and CD106 (vascular cell adhesion molecule-1, VCAM-1) remained unchanged on both monocytes and lymphocytes. The early increase (1-6 h) of CD18 and ICAM-1 expression led us to hypothesize that CD18-dependent costimulatory signals were involved in the later (6 h) increase of monocyte HLA-DR expression. However, blocking studies using monoclonal antibodies against CD18 (IB4, 15 microg/ml) demonstrated that the LPS- and MDP-induced increase of HLA-DR and ICAM-1 expression on monocytes was not mediated through CD18. LPS induced the expression of the early activation marker CD69 by a CD14-dependent but CD18-independent mechanism, whereas MDP did not induce CD69 expression. Analysis of leukocyte subsets demonstrated that CD4(+) T-cells, CD8(+) T-cell, CD19(+) B-cells, CD56(+) natural killer (NK)-cells, and CD14(+) monocytes increased the expression of CD69 after stimulation with LPS. Collectively, these data demonstrate a stronger immunomodulatory effect of LPS compared with MDP which may, in part, explain the established difference of toxicity between these two bacterial cell wall products.


Classification of portal vein tributaries in Thai cadavers including a new type V.
To compare portal vein tributaries in Thai with Thompson classification. In 211 Thai cadavers, abdominal regions were dissected to identify the portal veins and their tributaries. The subjects were classified into types based on modes of drainage of the left gastric and inferior mesenteric veins. Percentages of all types of venous drainage were counted. There are four types of portal tributaries as defined by Thompson, type I_47.87 %, type II_13.27 %, type III_7.58 %, and type IV_29.86 %. There were 1.42 % of whose inferior mesenteric veins entered the joining angle of the superior mesenteric and splenic veins, and were classified as type V. The left gastric vein mostly drained into the portal vein in 79.15 %, while the inferior mesenteric vein emptied into the splenic vein mainly in 55.45 %. A new variance of portal tributaries in Thai cadavers is reported. The variations of portal vein formations are critical for liver surgery and interventional radiological procedures.


Performance of cone-beam computed tomography (CBCT) renal arteriography for renal tumor embolization.
To evaluate tumor feeders, image quality, and performance of cone-beam computed tomography (CBCT) renal arteriography for renal tumor embolization. Fifty-four patients with renal tumors were included in this study. The performance of CBCT renal arteriography was classified into three groups: group A, all tumor feeders could be confirmed solely based on the CBCT maximum intensity projection (MIP); group B, all feeders were detected in CBCT MIP, but there were some possible feeders which needed to be confirmed with selective digital subtraction angiography (DSA); and group C, tumor feeders were not detected in CBCT MIP, hence, the feeder was detected based on selective DSA. Tumor size, location, and enhancement on pre-procedure CT and tumor identification, overall image quality, breathing motion and opacification of the renal collecting system on CBCT MIP were also evaluated. There were 32 (59.2%) patients in group A, 15 (27.8%) patients in group B, and 7 (13.0%) patients in group C. Significant determining factors for performance of CBCT renal arteriography were age, tumor identification, overall image quality, and breathing motion (all p < 0.05). In six out of seven cases in group C, overall image quality deteriorated due to breathing motion (significant blurring of renal artery branches with difficulty in identifying the interlobar artery level). In most cases, CBCT renal arteriography was sufficient to detect tumor feeders for renal tumor embolization. However, additional selective DSA is required when the overall image quality deteriorates owing to the patient's motion.


Assembly-dependent phosphorylation of myosin and paramyosin of native thick filaments in Caenorhabditis elegans.
Phosphorylation of the thick filament proteins myosin and paramyosin was studied in Caenorhabditis elegans. We have incubated partially purified, native thick filaments with [gamma 32P] ATP in the presence of 50-750 mM NaCl, pH 6.5-8.0. Myosin heavy chain and paramyosin were phosphorylatable only upon solubilization at 450 mM and higher NaCl concentrations. Under conditions preserving native structures, no phosphorylation of these proteins occurred. The phosphorylation required Mg2+ but was unaffected by cAMP, cGMP or Ca2+. The specific inhibitor of cAMP and cGMP kinase catalytic subunits, H8, inhibits the activity. Sedimentation experiments show that the kinase may associate with but is not an intrinsic component of thick filaments. In C. elegans, phosphorylation by the thick filament associated activity of myosin and paramyosin is dependent upon the state of their assembly.


A bibliometric analysis of carbon neutrality: Research hotspots and future directions.
Global attention has shifted in recent years to climate change and global warming. The international community has set the objective of carbon neutrality to address the climate crisis. Carbon neutrality has drawn significant attention as a crucial step in the fight against climate change, with individual nations having established their carbon neutrality targets. This paper aims to use bibliometric analysis to investigate research hotspots and trends in carbon neutrality research, and accesses the literature through the Web of Science (WoS) core database and undertakes an in-depth examination of 909 publications linked to carbon neutrality around the world using Vosviewer and Bibliometrix software. According to the findings, the number of carbon neutrality publications has increased dramatically in recent years. There are also notable differences in carbon neutrality research across countries and regions. China and the US are the primary drivers and leaders of carbon neutrality research, and developing countries have relatively little carbon neutrality research. Research has concentrated on carbon neutrality's practical, technical, policy, and economic aspects, as well as renewable energy sources, carbon conversion technologies, and carbon capture and storage technologies are also research hotspots. The paper also outlines opportunities for the advancement of carbon neutrality research in the future, including how it might be further integrated with Artificial intelligence (AI) and the metaverse, and how to attack the difficulties and uncertainties faced by the post-epidemic rebound. This study aids in understanding the current state of the field of carbon neutrality research and can be used to guide future studies.


Concerning steric effects in antimalarial agents.
Acridine, the parent nucleus of atabrine, is much more toxic than its 4,5-dimethyl derivative. The 4,5-dimethyl derivative of atabrine was therefore synthesized in the hope of producing a better-tolerated drug. The analogue was considerably more toxic than atabrine.


Cancer chemotherapy II: atypical hepatic injuries.
Although chemotherapy generally is accompanied by regular testing for liver enzyme abnormalities, atypical reactions may occur that escape ordinary detection, because hepatocyte injury is not the primary event. The presence of fatty liver, mitochondrial changes, and even biliary abnormalities can be associated with normal or nearly normal liver enzyme levels. This article discusses unique aspects of liver damage associated with cancer chemotherapy. These unique reactions merit special attention and a special vigilance from clinicians.


Contractile effects of perivascularly applied vasopressin on the pial artery of the cat brain.
1. The effects of perivascularly applied vasopressin on the diameter of pial arteries (control 298 +/- 14 S.E. micron) of the brain were examined after chronic implantation of a cranial window in fifteen anaesthetized cats. 2. Application of vasopressin resulted in a dose-dependent contraction. The threshold concentration for contraction was 3 X 10(-10) M, the half-maximal effective concentration (ED50) (1.6 +/- 0.2) X 10(-9) M, and the maximum reduction in artery diameter 37 +/- 2%. 3. The contraction was powerfully inhibited by perivascular application of a 10(-7) M solution of the vasopressin antagonist, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine]arginine vasopressin. 4. Perivascular application of noradrenaline induced a dose-dependent contraction of the pial artery. The ED50 was (8.9 +/- 2.5) X 10(-7) M, and the maximum reduction in artery diameter was 33 +/- 2%. 5. Such noradrenaline-induced contraction was not modified at all in the presence of a subthreshold dose (2 X 10(-10) M) of vasopressin (P greater than 0.05, for the over-all difference in size of the contraction, ED50 and maximum contraction). 6. In another experimental setting it was also found that neither the subthreshold nor a suprathreshold (10(-9) M) dose of vasopressin modified the contraction induced by 10(-6) M-noradrenaline (P greater than 0.05, compared to the contraction in the absence of vasopressin). 7. Thus a powerful and sensitive contractile response of the pial arteries to perivascularly applied vasopressin was demonstrated. However, the modifying effect of vasopressin on the contraction induced by perivascularly applied noradrenaline was minimal.


Developing a Flipped Classroom for Clinical Anatomy: Approaches to Pre-class Recordings and a Novel Approach to In-Class Active Learning.
For centuries the established pedagogy for teaching in academia has been the lecture, in which an expert in a given subject speaks from a pulpit while a collection of students listens and takes notes. In recent decades, however, advances in technology have allowed educators to rethink the way in which they deliver course content. One approach that has been given attention is that of the flipped classroom, in which lectures are delivered outside of the class through video recording, and the class session is dedicated to more interactive activities. This chapter provides a rationale for this approach to learning, provides guidance in the development of pre-recorded lectures, and introduces a novel approach to the classroom sessions using audience response software.


Long term parenteral nutrition in the management of severe Crohn's disease.
Twelve patients with active severe Crohn's disease, who failed to respond to medical treatment, received total parenteral nutrition (T.P.N.) via a Broviac long term feeding catheter for periods of 35-190 days prior to surgery. The 10 patients who were non-oedematous increased their mean weight by 3.3 Kg (p<0.01) and their mean plasma albumin by 5.80 g/l (p<0.025) after 28 days T.P.N. There were two episodes of catheter-related sepsis. Although the mean Crohn's disease activity index was significantly reduced from 364.50 (+/-91.51) to 236.75 (+/-121.29) (p<0.005) after 28 days T.P.N., all 12 patients were found to have active disease at operation. There was no post-operative mortality and the only major post-operative morbidity was a pelvic abscess following a panproctocolectomy. It is concluded that long term T.P.N. does not eliminate the need for surgery, but it may improve the nutritional status and reduce the post operative morbidity of malnourished patients with severe Crohn's disease.


Helitron mediated amplification of cytochrome P450 monooxygenase gene in maize.
The mass movement of gene sequences by Helitrons has significantly contributed to the lack of gene collinearity reported between different maize inbred lines. However, Helitron captured-genes reported to date represent truncated versions of their progenitor genes. In this report, we provide evidence that maize CYP72A27-Zm gene represents a cytochrome P450 monooxygenase (P450) gene recently captured by a Helitron and transposed into an Opie-2 retroposon. The four exons of the CYP72A27 gene contained within the element contain a putative open reading frame (ORF) for 428 amino acid residues. We provide evidence that Helitron captured CYP72A27-Zm is transcribed. To identify the progenitor gene and the evolutionary time of capture, we searched the plant genome database and discovered other closely related CYP72A27-Zm genes in maize and grasses. Our analysis indicates that CYP72A27-Zm represents an almost complete copy of maize CYP72A26-Zm gene captured by a Helitron about 3.1 million years ago (mya). The Helitron-captured gene then duplicated twice, approximately 1.5-1.6 mya giving rise to CYP72A36-Zm and CYP72A37-Zm. These data provide evidence that Helitrons can capture and mobilize intact genes that are transcribed and potentially encode biologically relevant proteins.


Prevalence of salmonellae, shigellae and Plesiomonas shigelloides in dogs in Zaria, Nigeria.
The prevalence of salmonellae, shigellae and Plesiomonas shigelloides among 303 dogs in Zaria was determined. Salmonella serotypes including S. kofandoka, a new serotype, were recovered from three dogs giving a proportion of 1.0%. None of the dogs from which salmonellae were isolated was showing evidence of gastroenteritis at the time of presentation. Neither Shigella nor Plesiomonas shigelloides was isolated from any of the dogs.


Aliens in Paradise. Boat density and exotic coastal mollusks in Moorea Island (French Polynesia).
Pacific islands are particularly vulnerable to the effects of invasive species. After habitat destruction or modification, invasive species are responsible for more biological extinctions than any other cause. Further, the rate of extinction of native species has been higher on islands than anywhere else in the world. Invasive species have also degraded native ecosystems. In order to detect exotic intertidal mollusk species, an extensive sampling around Moorea Island, a more or less unspoiled island surrounded by a rich coral reef habitat, has been developed considering that sampled points have different characteristics in wave exposure, algae coverage, type of substrate, distance to ports, distance to freshwater, distance sewage and boat traffic. Samples were DNA barcoded for unequivocal species assignation. The presence of five NIS among 26 species seems an important signal of introduction of alien biota in Moorea Island coast. However they were represented by a total of 38 individuals among 1487 mollusks (2.55%). While the distance to relatively big ports influenced directly species richness, the intensity of maritime traffic measured as boat density near sampling points was significantly associated with the frequency of exotic species. Other environmental factors did not show significant correlation with the frequency of exotics, suggesting that in an environment without big discontinuities, with little habitat modification, local boat traffic is the most influential factor in the spread of exotic species. This could be mitigated relatively easily by reducing boat density in local zones of ecological interest.


Reduced fitness of Daphnia magna fed a Bt-transgenic maize variety.
Genetically modified (GM) maize expressing the Bt-toxin Cry1Ab (Bt-maize) was tested for effects on survival, growth, and reproduction of the water flea Daphnia magna, a crustacean arthropod commonly used as a model organism in ecotoxicological studies. In three repeated experiments, D. magna were fed 100% ground maize in suspension, using either GM or isogenic unmodified (UM) maize. D. magna fed GM-maize showed a significantly reduced fitness performance: The mortality was higher, a lower proportion of females reached sexual maturation, and the overall egg production was lower compared to D. magna fed UM isogenic maize. We conclude that the tested variety of Bt-maize and its UM counterpart do not have the same quality as food sources for this widely used model organism. The combination of a reduced fitness performance combined with earlier onset of reproduction of D. magna fed Bt-maize indicates a toxic effect rather than a lower nutritional value of the GM-maize.


Bacterial nitric oxide reductase: a mechanism revisited by an ONIOM (DFT:MM) study.
Bacterial nitric oxide reductase (cNOR) is an important binuclear iron enzyme responsible for the reduction of nitric oxide to nitrous oxide in the catalytic cycle of bacterial respiration. The reaction mechanism of cNOR as well as the key reactive intermediates of the reaction are still under debate. Here, we report a computational study based on ONIOM (DFT:MM) calculations aimed at investigating the reaction mechanism of cNOR. The results suggest that the reaction proceeds via the mono-nitrosyl mechanism which starts off by the binding of an NO molecule to the heme b3 center, N-N hyponitrite bond formation as a result of the reaction with a second NO molecule was found to proceed with an exothermic energy barrier to yield a hyponitrite adduct forming an open (incomplete) ring conformation with the non-heme FeB center (O-N-N-O-FeB). N-O bond cleavage to yield N2O was shown to be the rate-limiting step with an activation barrier of 22.6 kcal mol(-1). The dinitrosyl (trans) mechanism, previously proposed by several studies, was also examined and found unfavorable due to high activation barriers of the resulting intermediates.


Effect of Immunosuppressive Treatments on Kidney Outcomes After Gross Hematuria-Related Acute Kidney Injury in Older Patients With IgA Nephropathy.
Macroscopic hematuria (MH) bouts, frequently accompanied by acute kidney injury (AKI-MH) are one of the most common presentations of IgA nephropathy (IgAN) in the elderly. Immunosuppressive therapies are used in clinical practice; however, no studies have analyzed their efficacy on kidney outcomes. This is a retrospective, multicenter study of a cohort of patients aged ≥50 years with biopsy-proven IgAN presenting with AKI-MH. Outcomes were complete, partial, or no recovery of kidney function at 1 year after AKI-MH, and kidney survival at 1, 2, and 5 years. Propensity score matching (PSM) analysis was applied to balance baseline differences between patients treated with immunosuppression and those not treated with immunosuppression. The study group consisted of 91 patients with a mean age of 65 ± 15 years, with a mean follow-up of 59 ± 36 months. Intratubular red blood cell (RBC) casts and acute tubular necrosis were found in all kidney biopsies. The frequency of endocapillary hypercellularity and crescents were low. Immunosuppressive therapies (corticosteroids alone or combined with mycophenolate mofetil or cyclophosphamide) were prescribed in 52 (57%) patients, whereas 39 (43%) received conservative treatment. There were no significant differences in the proportion of patients with complete, partial, or no recovery of kidney function at 1 year between patients treated with immunosuppression and those not treated with immunosuppression (29% vs. 36%, 30.8% vs. 20.5% and 40.4 % vs. 43.6%, respectively). Kidney survival at 1, 3, and 5 years was similar among treated and untreated patients (85% vs. 81%, 77% vs. 76% and 72% vs. 66%, respectively). Despite the PSM analysis, no significant differences were observed in kidney survival between the two groups. Fourteen patients (27%) treated with immunosuppression had serious adverse events. Immunosuppressive treatments do not modify the unfavorable prognosis of patients with IgAN who are aged ≥50 years presenting with AKI-MH, and are frequently associated with severe complications.


Morphological evaluation and clinical significance of the supracondylar process and supratrochlear foramen: an anatomic and radiological study.
In our literature review, we did not encounter any study examining the supracondylar process (SP) and the supratrochlear foramen (STF) with a three-dimensional (3D) reconstruction method. The present study aimed to evaluate SP and STF morphologically by employing the 3D reconstruction method and emphasize their clinical significance. The research was carried out on dried human humeri of unknown sex and without pathological alterations. A total of 81 humeri (42 right, 39 left) were obtained from the Departments of Anatomy of Gazi University Faculty of Medicine and Lokman Hekim University Faculty of Medicine. The morphometric measurements of SP and STF were made with a digital vernier calliper. The computed tomography images acquired for radiological evaluation were analysed with the 3D reconstruction method. The narrower distal medullary canal widths of humeri with STF were found to be statistically significant. No statistically significant difference was found between the transverse diameters (TD), vertical diameters (VD), the distance of the medial edge to the medial epicondyle, and the distance of the lateral edge to the lateral epicondyle of the supratrochlear foramen of the right and left humeri. The supracondylar process is often evaluated by mistake as a pathological condition of the bone, not as a normal anatomical variation. Knowing different shapes and dimensions, e.g. the TD and VD distance in which STF emerges, can assist in avoiding the misinterpretation of radiographs.


Homoharringtonine production by endophytic fungus isolated from Cephalotaxus hainanensis Li.
Homoharringtonine (HHT), a natural plant alkaloid derived from Cephalotaxus, has demonstrated to have a broad antitumor activity and efficacy in treating human chronic myeloid leukemia. An alternative source is required to substitute for the slow-growing and scarce Cephalotaxus to meet the increasing demand of the drug market. The objective of this study was to screen HHT-producing endophytic fungi from Cephalotaxus hainanensis Li. By screening 213 fungal isolates obtained from the bark parts of Cephalotaxus hainanensis Li, one isolate was found to be capable of biosynthesizing HHT. The fungus was identified as Alternaria tenuissima by morphological characteristics and internal transcribed spacer (ITS) sequence analysis and was named as CH1307. HHT obtained from CH1307 was analyzed through the HPLC and LC-MS/MS and NMR spectroscopy. The extract of the fermentation broth of CH1307 showed antiproliferative activities against K562 (chronic myelocytic leukemia), NB4 (acute promyelocytic leukemia), and HL-60 (promyelocytic leukemia) human cancer cell lines with IC50 values of 67.25 ± 4.26, 65.02 ± 4.75, and 99.23 ± 4.26 μg/mL, respectively. The findings suggest that HHT-producing endophytic fungus, Alternaria tenuissima CH1307 might provide a promising source for the research and application of HHT.


Peroxisomes and peroxisomal functions in muscle. Studies with muscle cells from controls and a patient with the cerebro-hepato-renal (Zellweger) syndrome.
In the present study we investigated peroxisomal functions in cultured human muscle cells from control subjects and from a patient with the Zellweger syndrome, a genetic disease characterized by the absence of morphologically distinguishable peroxisomes in liver and kidney. In homogenates of cultured muscle cells from control subjects, catalase is contained within subcellular particles, acyl-CoA:dihydroxyacetonephosphate acyltransferase activity is present and palmitoyl-CoA can be oxidized by a peroxisomal beta-oxidative pathway; these findings are indicative of the presence of peroxisomes in the cells. In homogenates of cultured muscle cells from the patient with the Zellweger syndrome, acyl-CoA:dihydroxyacetonephosphate acyltransferase activity was deficient, peroxisomal beta-oxidation of palmitoyl-CoA was impaired and catalase was not particle-bound. These findings indicate that functional peroxisomes are absent in muscle from patients with the Zellweger syndrome. We conclude that cultured human muscle cells can be used as a model system to study peroxisomal functions in muscle and the consequences for this tissue of a generalized dysfunction of peroxisomes.


Effect on maturation of kidney function in newborn infants of repeated administration of water and electrolytes.
In newborn infants of various ages, the influence of repeated administration of water and electrolytes on renal excretion of urine, sodium, potassium, free and bound hydrogen ions and on urine osmolarity was studied. In 14- and 21-day-old infants the repeated administration of water and electrolytes was followed by diminution of renal excretion of hydrogen ions and potassium, possibly caused by stimulation of hormonal regulation of ion exchange in the kidney. In animal studies performed with a larger water and electrolyte load, stimulation of renal excretion of sodium was caused by the pretreatment.


Cloning, expression and characterization of a Trichinella spiralis serine protease gene encoding a 35.5 kDa protein.
Serine proteases are found in the excretory-secretory (ES) products from Trichinella spiralis muscle larvae, have collagenolytic and elastolytic activities, and may be related to the larval invasion of intestinal epithelial cells. In this study, the serine protease gene (TspSP-1.2, GenBank accession No. EU302800) encoding a 35.5 kDa protein from T. spiralis was cloned, and recombinant TspSP-1.2 protein was produced in an Escherichia coli expression system. An anti-TspSP-1.2 serum recognized the native protein migrating at 35.5 kDa by the Western blotting of the crude or ES antigens from muscle larvae at 42 days post infection. An immunolocalization analysis identified TspSP-1.2 in the cuticle and internal organs of the parasite. Transcription and expression of the TspSP-1.2 gene was observed at all developmental stages of T. spiralis (adult worms, newborn larvae, pre-encapsulated larvae and muscle larvae). An in vitro invasion assay showed that, when anti-TspSP-1.2 serum, serum of infected mice and normal mouse serum were added to the medium, the invasion rate of the infective larvae in an HCT-8 cell monolayer was 33.0%, 89.4%, and 96.2%, respectively (P<0.05), indicating that the anti-TspSP-1.2 serum partially prevented the larval invasion of intestinal epithelial cells. After a challenge infection with T. spiralis infective larvae, mice immunized with the recombinant TspSP-1.2 protein displayed a 34.92% reduction in adult worm burden and 52.24% reduction in muscle larval burden. The results showed that the recombinant TspSP-1.2 protein induced a partial protective immunity in mice and could be considered as a potential vaccine candidate against T. spiralis infection.


17O-NMR studies of the conformational and dynamic properties of enkephalins in aqueous and organic solutions using selectively labeled analogues.
The synthesis of Leu-enkephalin selectively 17O-enriched in Gly2 and Gly3 is reported. The 17O-nmr chemical shifts of [17O-Gly2, Leu5]- and [17O-Gly3, Leu5]-enkephalins in H2O are almost identical and independent of the pH. Since hydrogen bonding is the dominant factor governing the chemical shifts of the peptide oxygen, it can be concluded that the hydration state of both oxygens is identical and independent of the pH. The 17O chemical shifts of the [17O-Leu5]-enkephalin terminal carboxyl group at pH approximately 1.9 and 5.6 are very different in H2O but very similar in CH3CN/DMSO (4:1) solution. This suggests that the protonation state of the carboxyl group at both pH values in CH3CN/DMSO solution is the same and consequently that Leu-enkephalin exists in the neutral form at pH approximately 5.6. In this organic mixed solvent system both Gly2 and Gly3 oxygen resonances exhibit a significant shift to high frequency by the same extent (delta delta approximately 30 ppm). It is concluded that both peptide oxygens are not hydrogen bonded to an appreciable extent and that no specific 2----5 hydrogen bonding exists to an appreciable extent. This conclusion is in agreement with the energy of activation for molecular rotation, as determined from T1 measurements, which was found to be almost identical for both [17O-Gly2, Leu5]- and [17O-Gly3, Leu5]-enkephalins in CH3CN/DMSO (4:1) mixed solvent.


Identification of the nuclear receptor CAR:HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital.
The nuclear receptor CAR, a phenobarbital (PB)-responsive transcription factor, translocates into the nucleus of hepatocytes after PB induction. In non-induced mice, CAR forms a physical complex with heat shock protein 90 (HSP90) in the cytoplasm. In response to PB induction, protein phosphatase 2A is recruited to the CAR:HSP90 complex. This recruitment may lead CAR to translocate into the nucleus, consistent with the inhibitions of nuclear CAR accumulation in PB-induced mouse primary hepatocytes by okadaic acid as well as by geldanamycin.


Primary palliative care clinic pilot project demonstrates benefits of a nurse practitioner-directed clinic providing primary and palliative care.
The purpose of the Primary Palliative Care Pilot Project was to determine if patients with a life-limiting illness who receive their primary care and palliative care from a consistent provider via a nurse practitioner (NP)-founded and-directed Primary Palliative Care Clinic at a public hospital would have improved symptom management and decreased emergency department utilization over time. All patients followed in the Harborview Primary Palliative Care Clinic from January to March 2010. The results of this project demonstrate that patients with a life-limiting illness who receive their primary care and palliative care in an NP-founded and -directed Primary Palliative Care Clinic have decreased utilization of the emergency department, and some experience improvement in symptom assessment scores. Palliative care providers and administrators should explore opportunities to expand outpatient palliative care clinics with an emphasis on primary care and continuity of care. NPs by experience and education are ideally suited to manage both primary and palliative care needs for people at the end of life.


Signal characteristics of focal bone marrow lesions in patients with multiple myeloma using whole body T1w-TSE, T2w-STIR and diffusion-weighted imaging with background suppression.
This study analyses the diagnostic potential of Diffusion-Weighted Imaging with Background Suppression (DWIBS) in the detection of focal bone marrow lesions from multiple myeloma. The signal and contrast properties of DWIBS are evaluated in correlation with the serum concentration of M-component (MC) and compared with established T1- and T2-weighted sequences. Data from 103 consecutive studies in 81 patients are analysed retrospectively. Signal intensities and apparent Diffusion Coefficients (ADC) of 79 focal lesions in the lumbar spine or pelvis of 38 patients are determined and contrast-to-noise-ratio (CNR) is calculated. Data from patients with low (<20 g/L) and high (>20 g/dL) MC are evaluated separately. Signal intensities of focal myeloma lesions on T2w-STIR vary significantly depending on the MC, which leads to a loss in CNR in patients with high MC. No signal variation is observed for T1w-TSE and DWIBS. The CNR values provided by DWIBS in patients with high MC are slightly higher than those of T2w-STIR. ADC values in patients with low MC are significantly higher than in patients with high MC. Whole-body DWIBS has the potential to improve the conspicuity of focal myeloma lesions and provides additional biological information by ADC quantification.


[Scientific advice by the national and European approval authorities concerning advanced therapy medicinal products].
The aim of scientific advice is to support pharmaceutical developers in regulatory and scientific questions, thus facilitating the development of safe and efficacious new medicinal products. Recent years have shown that the development of advanced therapy medicinal products (ATMPs) in particular needs a high degree of regulatory support. On one hand, this is related to the complexity and heterogeneity of this group of medicinal products and on the other hand due to the fact that mainly academic research institutions and small- and medium-sized enterprises (SMEs) are developing ATMPs. These often have limited regulatory experience and resources. In 2009 the Paul-Ehrlich-Institut (PEI) initiated the Innovation Office as a contact point for applicants developing ATMPs. The mandate of the Innovation Office is to provide support on regulatory questions and to coordinate national scientific advice meetings concerning ATMPs for every phase in drug development and especially with view to the preparation of clinical trial applications. On the European level, the Scientific Advice Working Party (SAWP) of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicinal Agency (EMA) offers scientific advice. This article describes the concepts of national and EMA scientific advice concerning ATMPs and summarizes the experience of the last six years.


Stick insects (Phasmida) as prey of spiders: size, palatability and defence mechanisms in feeding tests.
The maximum body length of the phasmid Carausius morosus which the ctenid spider Cupiennius salei can overwhelm is 2-3x larger than the length of crickets. Eight phasmid species were offered to Cupiennius salei in feeding tests. Among them, Carausius morosus was raised on 4 different food plants. All species of prey items were accepted by the spider predator very readily (>80%). This indicates that phasmids are a highly palatable prey group for spiders. The possible importance of chemical defence and its obvious lack under laboratory conditions are discussed.


Oculomotor system of the weakly electric fish Gnathonemus petersii.
The peripheral and central aspects of the extraocular system were studied in the weakly electric fish Gnathonemus petersii. All six extraocular muscles show a similar composition of large and small fibers grouped characteristically in the proximal and distal regions respectively. The exit of the three extraocular nerves from the brain is similar to that in other vertebrates. However, the intracephalic and intracranial course of the trochlear nerve is unusual, partly because of the extraordinary hypertrophy of the cerebellum. The three nerves course rostrally on the ventral brain surface; the trochlear nerve penetrates the orbital cavity separately from the two other nerves. The fiber-diameter spectrum of each extraocular nerve is bimodal; unmyelinated fibers were not observed in any of the nerves. The location of the extraocular motor nuclei was established by retrograde axonal transport of HRP or cobaltic-lysine complex. The oculomotor nucleus is situated ventral to the posterior pole of the magnocellular mesencephalic nucleus and the trochlear nucleus is found caudal and dorsal to this. The abducens nucleus is situated at the level of the octavolateral efferent nucleus and consists of a single group of cells on each side of the ventral tegmentum. The oculomotor nucleus of G. petersii shows a somatotopic organization. The superior rectus muscle receives a contralateral innervation whereas the inferior rectus and oblique muscles and the internal rectus muscles receive an ipsilateral innervation. The superior oblique muscle is innervated by contralateral trochlear motoneurons and the external rectus by ipsilateral abducens motoneurons. The majority of extraocular motoneurons have piriform perikarya and long beaded dendrites that extend laterally in the oculomotor and abducens nuclei and rostrally in the trochlear nucleus. The terminal dendritic portions of trochlear motoneurons widely overlap with oculomotor dendrites and perikarya. In all three nuclei the axon originates opposite to the main dendrite. Collaterals of the hairpin-bend abducens axons could be identified in a few cases. The oculomotor system of G. petersii appears basically similar to that of other teleosts; the differences observed concern mainly the structure of the abducens nucleus, the intracranial and intracephalic course of the trochlear nerve, and the relatively small number of axons in each nerve.


CT findings at the primary site of oropharyngeal squamous cell carcinoma within 6-8 weeks after definitive radiotherapy as predictors of primary site control.
To determine whether findings on CT studies, done 6 weeks after radiotherapy (RT), can predict the likelihood of ultimate control at the primary site in oropharyngeal carcinoma. Forty-six patients with oropharyngeal squamous cell carcinoma underwent RT with curative intent. A minimal 2-year clinical follow-up after RT was required. The primary site CT findings were graded for risk of recurrence on a modified 3-point scale as follows: Grade 0, no detectable focal abnormalities; Grade 1, anatomic asymmetry or focal mass <1 cm; Grade 2, focal mass >10 mm (2a) or <50% shrinkage of the mass as seen on pretreatment studies (2b). No patients with CT findings of Grade 0 (n = 26) or Grade 1 (n = 5) had a primary site recurrence. One of the 13 patients with CT findings of Grade 2a had a primary site recurrence 1 year after completion of RT. None of the 2 patients with CT findings of Grade 2b had a primary site recurrence. Ultimately, 45 of the 46 patients in this study group had disease control at the primary site. In the evaluation of oropharyngeal squamous cell carcinoma on post-RT CT studies, diffuse and symmetric post-RT changes of the soft tissue or asymmetry without detectable mass or a discrete mass < or =10 mm always indicated ultimate control at the primary site. Even when post-RT CT shows a discrete mass >10 mm at the primary site, the likelihood of local control is high (93%). The study results indicate that CT findings, based on this relatively small series, may not add incremental information beyond that of clinical examination for predicting local control but may be useful as a baseline if imaging surveillance is contemplated.


Is hip dysplasia a common deformity in skeletally mature patients with hereditary multiple exostoses?
Various deformities appear in hereditary multiple exostoses (HMEs). Deformities around the knee or ankle joints are easy to detect in this disease because such deformities are visible in appearance. However, deformities in the hip joints of skeletally mature patients are not well understood because their tumors are invisible. To understand deformities around the hip joint in HMEs, we investigated 36 hip joints in 19 skeletally mature patients (12 males, 7 females). The mean age at last X-ray imaging investigation was 29.2 years (14.5-66.5 years). We evaluated the lesions of exostoses around the acetabulum and proximal femur, Wiberg's center-edge angle (CEA), neck-shaft angle (NSA), acetabular depth-width ratio (ADR), and Sharp's acetabular angle. No exostoses were present in four hips of three cases. Thirty-one hip joints had exostoses on the medial side of the femoral neck. Exostoses existed on the lateral side of the femoral neck in 16 hips. None of the patients had acetabuluar tumors. One patient experienced pain because of impingement between the acetabular rim and medial tumors of the femoral neck. The increase in NSA, which is an index of proximal femoral deformity, was common with a mean NSA of 147.3 °. Two indices of acetabular deformity, Sharp's angle and ADR, were within normal limits with a mean Sharp's angle of 41.3 ° and mean ADR of 269. The average CEA was 29.9 °. Hip dysplasia is not necessarily common in skeletally mature patients with HMEs. To determine the possibility of hip dysplasia in skeletally immature patients with HMEs, ADR may be a useful reference index.


A Hybrid Supramolecular Polymeric Nanomedicine for Cascade-Amplified Synergetic Cancer Therapy.
Supramolecular nanomedicines have shown great merits in cancer therapy, but their clinical translation is hampered by monotonous therapeutic modality and unsatisfactory antitumor performance. Herein, a hybrid supramolecular polymeric nanomedicine (SNPs) is developed based on β-cyclodextrin/camptothecin (CPT) host-guest molecular recognition and iron-carboxylate coordination. Iron ions stabilizing SNPs catalyze the conversion of intracellular hydrogen peroxide into highly toxic hydroxyl radical through a Fenton reaction, which further cleaves the thioketal linker of the supramolecular monomer to release potent CPT, thus amplifying the therapeutic efficacy by combining chemodynamic therapy and chemotherapy. The combination therapy stimulates antitumor immunity and promotes intratumoral infiltration of cytotoxic T lymphocytes by triggering immunogenic cell death. In synergy with PD-L1 checkpoint blockade, SNPs enables enhanced immune therapy and a long-term tumor remission.


Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 Sepsis Investigator Group.
To determine the efficacy and safety of using natural platelet-activating factor receptor antagonist (PAFra), BN 52021, to treat patients with severe Gram-negative bacterial sepsis. A prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial. Fifty-nine academic medical center intensive care units in Europe. Six hundred nine patients with severe sepsis, suspected to be related to Gram-negative bacterial infection, who received PAFra or placebo. Patients were randomized to receive either a dose of PAFra (120 mg iv) every 12 hrs over a 4-day period or placebo over a 4-day period. The patients were well matched at study entry for severity of illness and for risk factors known to influence the outcome of sepsis. Among all randomized patients, the 28-day, all-cause mortality rate was 49% (152/308) in the placebo group, and 47% (140/300) in the PAFra group (p=.50). When analyzed on the basis of the previously defined target population, the 28-day, all-cause mortality rate was 50% (115/232) in the placebo group and 44% (94/212) in the PAFra group, yielding a 12% reduction in mortality rate (p=.29). In patients with documented infection involving other organisms, there was no difference between treated and placebo groups. When the outcomes of organ dysfunctions were examined in the overall population and in the documented Gram-negative bacterial infection population, the number of patients who resolved hepatic dysfunction tended to be higher in the treated group than in the placebo group (p=.06). The number of adverse events reported were not different between the two groups. A 4-day administration of the studied PAFra (BN 52021) failed to demonstrate a statistically significant reduction in the mortality rate of patients with severe sepsis suspected to be related to Gram-negative bacterial infection. If PAFra treatment has any therapeutic activity in severe Gram-negative bacterial sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.


Isolation of Elizabethkingia spp. from Diagnostic Specimens from Dogs and Cats, United States, 2019-2021.
We retrospectively reviewed Elizabethkingia spp. culture and susceptibility results from 86 veterinary diagnostic laboratory results from US dogs and cats. We noted 26 E. menigoseptica, 1 E. miricola, and 59 unspeciated Elizabethkingia isolates from 9 US states (2-22 isolates per state). Elizabethkingia infections in animals might increase risks to humans.


[Eccrine sweat gland carcinoma of the skin].
Sweat gland carcinomas represent a group of morphological heterogeneous tumors with clear differences regarding clinical course and prognosis. The most relevant and accepted entities are described clinically and histopathologically with special reference to the differentiation from benign adnexal tumors. Carcinomas arising from preexisting benign adnexal tumors such as spiradenocarcinoma, cylindrocarcinoma, malignant mixed tumors of the skin are easily recognized. To establish the diagnosis of microcystic adnexal carcinoma or aggressive digital papillary adenocarcinoma can be more difficult, because these carcinomas do not show cytological criteria for malignancy and may therefore resemble benign adnexal tumors especially in small specimens.


Case of autoimmune polyglandular syndrome type 2: how we uncovered the diagnosis.
A 24-year-old man with no significant medical history presented to the medical clinic with vomiting and giddiness for 2 days, loss of appetite for 1 month and progressive fatigability for the preceding 4 months. On examination, he was found to be hypotensive and was admitted to the hospital for work-up. Considering his abnormal labs and physical findings, he was worked up and was diagnosed with primary adrenal insufficiency. On further work-up for the aetiology of his Addison's disease, he was found to have concurrent autoimmune thyroiditis and vitiligo. A final diagnosis of autoimmune polyglandular syndrome type 2 was made. The patient was started on hormone replacement therapy and reported improvement of symptoms on 3-month follow-up visit.


A novel approach for the rapid decomposition of Actinide resin and its application to measurement of uranium and plutonium in natural waters.
A rapid and robust procedure is described for the decomposition of Actinide resin permitting the routine application of this resin as a preconcentrator. Although the classical Fe(OH)3 precipitation is effective in scavenging actinides, the need for careful handling to recover the sticky precipitate makes the new method much more attractive. The known difficulty of decomposing Actinide resin, which is required prior to the subsequent separation of adsorbed actinides, is innovatively overcome by using a borate fusion attack. This procedure effectively solves the normally encountered problem by safely and speedily decomposing the resin in minutes rather than hours. The alternative and apparently simpler technique of direct ashing of the Actinide resin is not used since it leads to a residue that is not readily leachable. The new technique has been incorporated into a procedure for the isolation of Pu and U from natural water samples and their subsequent quantification by alpha spectrometry. The efficiency of loading of the elements onto Actinide resin has been tested using both batch and column-based approaches. The integrated method involving Actinide resin preconcentration, borate fusion, anion and UTEVA chromatography and electrodeposition provides limits of detection of 0.001 BqL(-1) and chemical recoveries in excess of 80% from groundwater and seawater samples as large as 5L. Comparative data, presented for the analysis of independently analysed river, borehole and surface run-off waters using both the described procedure and other competing techniques, show very good agreement.


Large scale sequence alignment via efficient inference in generative models.
Finding alignments between millions of reads and genome sequences is crucial in computational biology. Since the standard alignment algorithm has a large computational cost, heuristics have been developed to speed up this task. Though orders of magnitude faster, these methods lack theoretical guarantees and often have low sensitivity especially when reads have many insertions, deletions, and mismatches relative to the genome. Here we develop a theoretically principled and efficient algorithm that has high sensitivity across a wide range of insertion, deletion, and mutation rates. We frame sequence alignment as an inference problem in a probabilistic model. Given a reference database of reads and a query read, we find the match that maximizes a log-likelihood ratio of a reference read and query read being generated jointly from a probabilistic model versus independent models. The brute force solution to this problem computes joint and independent probabilities between each query and reference pair, and its complexity grows linearly with database size. We introduce a bucketing strategy where reads with higher log-likelihood ratio are mapped to the same bucket with high probability. Experimental results show that our method is more accurate than the state-of-the-art approaches in aligning long-reads from Pacific Bioscience sequencers to genome sequences.


Modulation of glucocorticoid, mineralocorticoid and androgen production in H295 cells by Trimesemine™, a mesembrine-rich Sceletium extract.
Stress-related illnesses rate among the most prevalent non-fatal diseases globally. With the global trend for consumer bias towards natural medicine, the Sceletium plant has become more prominent in the field of natural products. Although potentially useful effects of Sceletium tortuosum on the central nervous system have been reported, limited data is available on effects of the plant in the peripheral compartment. The current study aimed to elucidate the effect(s) of a Sceletium extract (TRI) rich in mesembrine (1% of plant extract w/w), on adrenal steroid biosynthesis. Steroidogenesis was assessed basally and in response to stimuli (forskolin, angiotensin II, KCl), in human adrenocortical carcinoma cells (H295R). Steroid hormone levels were assessed using UPLC-MS/MS. UPLC-MS analyses of TRI identified major alkaloids Δ7-mesembrenone, mesembrenone and mesembrine. Highest dose TRI treatment (1 mg/ml, 34.5 μM mesembrine) increased pregnenolone and decreased 16-hydroxyprogesterone levels (both P<0.00001) in forskolin-stimulated conditions only, suggesting CYP17 enzyme inhibition. This led to significant inhibition of forskolin-associated increases in cortisol levels at the highest dose (P<0.001) and basal cortisol levels across all doses (P<0.0001). Independently of forskolin, TRI inhibited androstenedione and testosterone production across all doses (both P<0.00001), suggesting inhibition of 3βHSD and 17βHSD respectively. TRI decreased both the angiotensin II- (P<0.05) and forskolin-induced (P<0.0001) increases in aldosterone production. Our data suggest potentially beneficial effects of TRI in the context of stress and hypertension. These should be further investigated in a whole organism model, while the effects on the androgenic pathway should also be further elucidated.