MicroRNA Analysis of Human Stroke Brain Tissue Resected during Decompressive Craniectomy/Stroke-Ectomy Surgery.
Signaling pathways mediated by microRNAs (miRNAs) have been identified as one of the mechanisms that regulate stroke progression and recovery. Recent investigations using stroke patient blood and cerebrospinal fluid (CSF) demonstrated disease-specific alterations in miRNA expression. In this study, for the first time, we investigated miRNA expression signatures in freshly removed human stroke brain tissue. Human brain samples were obtained during craniectomy and brain tissue resection in severe stroke patients with life-threatening brain swelling. The tissue samples were subjected to histopathological and immunofluorescence microscopy evaluation, next generation miRNA sequencing (NGS), and bioinformatic analysis. miRNA NGS analysis detected 34 miRNAs with significantly aberrant expression in stroke tissue, as compared to non-stroke samples. Of these miRNAs, 19 were previously identified in stroke patient blood and CSF, while dysregulation of 15 miRNAs was newly detected in this study. miRNA direct target gene analysis and bioinformatics approach demonstrated a strong association of the identified miRNAs with stroke-related biological processes and signaling pathways. Dysregulated miRNAs detected in our study could be regarded as potential candidates for biomarkers and/or targets for therapeutic intervention. The results described herein further our understanding of the molecular basis of stroke and provide valuable information for the future functional studies in the experimental models of stroke.


Inducible and reversible NR1 knockout reveals crucial role of the NMDA receptor in preserving remote memories in the brain.
Long-term storage of information is a hallmark feature of the brain, yet routine turnover of synaptic receptors appears to be intrinsically paradoxical to this capability. To investigate how the brain preserves its delicate synaptic efficacies, we generated inducible and reversible knockout mice in which the NMDA receptor can be temporarily switched off in the forebrain specifically during the storage stage. Retention of 9-month contextual and cued fear memories is severely disrupted by prolonged, but not transient, loss of the NMDA receptor that occurs 6 months after initial training and at least 2 months prior to memory retrieval. Normal learning and memory function in subsequent tasks following the 9-month retention tests suggest that the observed retention deficits did not result from recall or performance impairment. Thus, our study reveals a hitherto unrecognized role of the NMDA receptor in dynamically maintaining the long-term synaptic stability of memory storage circuits in the brain.


[Does early analgesia interfere with diagnostic process in acute abdominal pain syndrome?].
Early pain management with opioid by patients admitted for abdominal pain is widely contested. Emergency physicians are feared to interfere with physical examination and the ability to make a correct diagnosis. The present review tends to show that opioids are safe in this context. The authors consider that early provision of pain management, even with opioids, should be effective.


Tissue remodeling in adult vernal keratoconjunctivitis.
Our aim is to describe local tissue remodeling in a cohort of adult VKC patients. Male patients diagnosed with active VKC were enrolled in an open pilot study into two groups according disease onset: childhood classic VKC and adult VKC. Visual acuity and ocular surface clinical examination focusing on chronic inflammatory sequelae and impression cytology were performed in all enrolled subjects. Conjunctival imprints were processed for molecular, biochemical and immunofluorescent analysis for tissue remodeling (TGFβ1,2,3 and αSMA) and epigenetic (DNMT3a, Keap1; Nrf2) markers as well as androgen receptors were investigated and compared between groups. Clinical assessment showed increased conjunctival scarring in adult VKC compared to classic VKC. Immunoreactivity for αSMA and expression of TGFβ were higher in adult VKC group. Significantly higher levels of TGFβ3 (3.44 ± 1.66; p < 0.05) were detected in adult VKC compared to childhood VKC, associated with an increasing trend of TGFβ1 (1.58 ± 0.25) and TGFβ2 (1.65 ± 0.20) isoforms levels. Molecular analysis showed a relative increase in tissue remodeling/fibrogenic transcripts (TGFβ isoforms and αSMA) associated to a significant increase of selective epigenetic targets (DNMT3, Nrf2 and keap1) in adult VKC phenotype. Increased local conjunctival androgen receptors was detected in patients with adult variants compared to classic childhood VKC and healthy subjects. Finally, a direct correlation between TGFβ and androgen receptor expression was also detected. A pro-fibrotic clinical and biomolecular trait was unveiled in adult variant of VKC, which causes ocular surface disease and visual impairment.


Evaluating the power of a recent method for comparing two circular distributions: an alternative to the Watson U2 test.
Some data are collected on circular (rather than linear) scales. Often researchers are interested in comparing two samples of such circular data to test the hypothesis that they came from the same underlying population. Recently, we compared 18 statistical approaches to testing such a hypothesis, and recommended two as particularly effective. A very recent publication introduced a novel statistical approach that was claimed to outperform the methods that we had indicated were highest performing. However, the evidence base for this claim was limited. Here we perform simulation studies to offer a more detailed comparison of the new "Angular Randomisation Test" (ART) with existing tests. We expand previous evaluations in two ways: exploring small and medium sized samples, and exploring a range of different shapes for the underlying distribution(s). We find that the ART controls type I error rates at the nominal level. The ART had greater power than established methods in detecting a difference in underlying distribution caused by a shift around the circle. Its performance advantage in this case was strongest when samples where small and unbalanced in size. When the difference between underlying unimodal distributions was in shape rather than central tendency, then the ART was at least as good (and sometimes considerably more powerful) than the established methods, except when distributions samples were small and uneven in size, and the smaller sample came from a more concentrated underlying distribution. In such cases its power could be markedly inferior to established alternatives. The ART was also inferior to alternatives in dealing with axially distributed data. We conclude that under widely-encountered circumstances the ART test can be recommended for its simplicity of implementation, but researchers should be aware of situations where it cannot be recommended.


GLO polymorphism in two Polish population samples.
The red cell GLO phenotypes were determined in two Polish population samples. A total of 1310 people from the region of Lublin (Southeastern Poland, n = 797) and Wrocław (Southwestern Poland, n = 513) were investigated. The gene frequencies were calculated for GLO1 (= 0.4427) and GLO2 (= 0.5573). The evaluation of 372 mother-child pairs showed no deviation from a hereditary hypothesis.


Assessment of pediatric Malone antegrade continence enema (MACE) complications: Effects of variations in technique.
The Malone antegrade continence enema (MACE) procedure is performed for patients with fecal incontinence and constipation who do not respond to medical therapy. The MACE procedure provides antegrade catheter access to the right colon and allows administration of enemas to help evacuate the bowel regularly. The objective of this study was to identify risk factors for surgical complications in children who undergo the MACE procedure. Records from 97 pediatric patients who underwent MACE procedure were reviewed retrospectively. Data collected included age, sex, weight (obese/not obese), stomal location, presence of a permanent button/catheter in the stoma, open vs. laparoscopic surgery, and etiology of fecal incontinence/constipation. The complications reviewed included stomal stenosis, leakage, and stomal site infection. The relationships between the independent variables and complications were assessed using chi-square tests and Fisher's exact test. Statistical significance was set at p < 0.05. Overall, 66 (68%) patients had at least one complication. Twenty-three (23.7%) patients developed stomal stenosis, and 27 (27.8%) patients had significant stomal leakage. Insertion of a stomal button/catheter device was associated with an increased risk of developing stomal leakage and stomal infection. The presence of a stomal button/catheter was also associated with a decreased risk of stomal stenosis (Figure). The non-intubated, imbricated sub-population, preteen patients (<12 years old) experienced more stomal leakage than teenage patients. In this subgroup, patients with umbilical stomas also experienced more leakage than patients with right lower quadrant (RLQ) stomas. The prevalence rates of stomal complications in our study were consistent with previously reported series. In our study, however, stomal leakage had a higher prevalence in comparison with stomal stenosis. This seems to be related to the heterogeneity of the study group, which contained two variants of the MACE procedure; non-imbricated, intubated MACE and imbricated, non-intubated MACE. The use of stomal buttons in conjunction with MACE has previously been reported without changes in complication rates. We found the use of stomal buttons/catheters to be associated with changes in the prevalence of stomal complications. Stomal complications are common in the MACE procedure. The use of a permanent stomal button/catheter is associated with changes in the rates of stomal complications. While many find an umbilical stomal site is more cosmetically appealing, there is an increased risk of leakage with imbricated, non-intubated stomas. In the non-intubated, imbricated sub-population, the MACE procedure results in a higher risk of stomal leakage in preteen patients in comparison with teenage patients.


Recurrent head-and-neck chemodectomas: a comparison of surgical and radiotherapeutic results.
To compare the outcome of salvage radiotherapy (RT) and surgery for recurrent head-and-neck chemodectomas. We retrospectively studied 70 patients with benign chemodectomas of the head and neck treated with surgery at the Cleveland Clinic between July 1969 and August 1999; 29 of these patients were diagnosed with recurrent tumors. Salvage RT was used in 12 patients (gamma knife radiosurgery for 7, conventional external beam RT for 4, and intensity-modulated RT for 1 patient). The median follow-up was 55 months for the entire group of 70 patients. The median time to recurrence was 36 months. Of the recurrences, 16 were glomus jugulare, 7 were carotid body tumors, 5 were glomus tympanicum, and 1 was thyroid paraganglioma. RT was used in 12 patients (9 patients with glomus jugulare, 2 with glomus tympanicum, and 1 with thyroid paraganglioma). Surgery was performed in 17 patients (7 patients with glomus jugulare, 7 with carotid body, and 3 with glomus tympanicum). For patients with glomus jugulare and glomus tympanicum tumors, the 5-year freedom from disease progression was 100% for patients treated with RT vs. 62% for those treated with surgery (p = 0.0124). Seven patients with carotid body tumors and 1 patient with thyroid paraganglioma were treated successfully with surgery and RT, respectively. No significant side effects were associated with RT; however, postoperative complications occurred in 8 of the 17 surgery patients (new cranial nerve palsies, meningitis, infection, and cerebrospinal fluid leak). Salvage RT appears superior to surgery and should be considered the treatment of choice for patients with recurrent glomus jugulare and glomus tympanicum tumors. For recurrent carotid body tumors, surgery produced excellent local control, most likely because of the easier resectability in this location.


Verapamil, a Ca2+ entry blocker, targets the pore-forming subunit of cardiac type KATP channel (Kir6.2).
This study investigated the mechanism by which verapamil, which blocks 10R1, l-type Ca2+ channel and the HERG channel, blocks ATP-sensitive K+ (K(ATP)) channels. In whole cell patch experiments, verapamil reversibly inhibited cardiac type K(ATP) (Kir6.2/SUR2A) channels previously activated by 100-micromol/L pinacidil. In inside-out patch experiments, verapamil inhibited the C-terminal truncated form of Kir6.2 (Kir6.2DeltaC36) in a concentration-dependent manner; half-maximal inhibition (IC(50)) was obtained at 11.5 +/- 2.8 micromol/L when Kir6.2DeltaC36 was expressed without SUR2A. Verapamil also inhibited Kir6.2/SUR2A with a similar potency; IC(50) was 8.9 +/- 2.1 micromol/L for Kir6.2/SUR2A (not statistically different from the value for Kir6.2DeltaC36 alone). Thus, verapamil appeared to target the pore-forming subunit Kir6.2 rather than SUR2A, a member of ABC superfamily. Verapamil did not decrease the single-channel conductance, but increased the closed time of Kir6.2/SUR2A. The mutations of Kir6.2DeltaC36 (Kir6.2DeltaC36-R50G, -K185Q, -G334D), which have much lower ATP sensitivity, had no significant effect on verapamil block, suggesting that the site at which verapamil mediates K(ATP) channel inhibition is not identical with that involved in ATP block.


Infections and risk-adjusted length of stay and hospital mortality in Polish Neonatology Intensive Care Units.
The objectives of this study were to analyze the impact of infections on prolonging hospital stay with consideration of underlying risk factors and determining the mortality rates and its association with infections. An electronic database developed from a continuous prospective targeted infection surveillance program was used in the study. Data were collected from 2009 to 2012 in five Polish tertiary academic neonatal intensive care units (NICUs). The length of stay (LOS) of 2,003 very low birth weight (VLBW) neonates was calculated as the sum of the number of days since birth until death or until reaching a weight of 1,800g. The median LOS for neonates with infections was twice as high as for neonates without infection. LOS was significantly affected by the overall general condition of the neonate, as expressed by both gestational age and birth weight as well as by the Clinical Risk Index for Babies (CRIB) score; another independent factor was presence of at least one infection. Risk of in-hospital mortality was significantly increased by male sex and vaginal birth and was lower among breastfed neonates. Deaths were significantly more frequent in neonates without infection. The general condition of VLBW infants statistically increase both their risk of mortality and LOS; this is in contrast to the presence of infection, which significantly prolonged LOS only.


Vocational training. My year as a guinea pig.
In the twilight of the first year of the new Vocational Training Scheme I am reflecting on my metamorphosis from a naive dental student to vocational trainee and ultimately (hopefully) to competent clinician.


Lacrimal gland and fossa lesions: an approach to diagnosis and management.
Lesions of the fossa of the lacrimal gland present special problems in diagnosis and management. Clinical recognition and differentiation of benign mixed cell lacrimal gland tumors from other inflammatory and neoplastic lesions of the lacrimal gland fossa are feasible and should provide the basis for the approach to proper management. Lesions conforming to the clinical picture of benign mixed cell lacrimal gland tumors need not undergo incisional biopsy, but require en bloc excision with adjacent tissues through a lateral orbitotomy to ensure complete excision and to prevent late recurrence. Incisional biopsy is indicated and should not be delayed in suspected infectious and noninfectious inflammatory lesions that have not responded rapidly to medical therapy, and in other lesions suspected of being neoplastic and not amenable to total local excision. An expedient approach to these lesions is essential if the prognosis of epithelial lacrimal gland neoplasms is to be improved.


Virulence Comparison of Four Porcine Circovirus Type 2 (PCV2) Genotypes (2a, 2b, 2d and 2e) in Pigs Single-Infected with PCV2 and Pigs Dual-Infected with PCV2 and Mycoplasma hyopneumoniae.
The objective of this study was to compare the virulence of four porcine circovirus type 2 (PCV2) genotypes (2a, 2b, 2d and 2e). Pigs were infected with one of these four genotypes. Pigs were also dually infected with Mycoplasma hyopneumoniae and one of the four PCV2 genotypes. Virulence was determined based on the amount of PCV2 loads in the blood and lymph nodes and the severity of lymphoid lesions. Marked differences in virulence were found among the four genotypes. Within the single infection model, PCV2a, PCV2b and PCV2d were more virulent than PCV2e, while significant differences in virulence were not found among the PCV2a, PCV2b and PCV2d groups. Within the dual infection model, PCV2d was more virulent than the other three PCV2 genotypes. Mycoplasma hyopneumoniae potentiated the severity of PCV2-associated lymphoid lesions and increased the amount of PCV2 loads in the blood and lymph nodes, regardless of the PCV2 genotype. By contrast, PCV2 was not able to potentiate the severity of mycoplasmal-induced lung lesions or the level of M. hyopneumoniae laryngeal load. The results of this study demonstrate that PCV2d is of major clinical importance, while PCV2e is of minor clinical importance.


PD-1 mediates decidual γδ T cells cytotoxicity during recurrent pregnancy loss.
Recurrent pregnancy loss (RPL) is one of the big challenges of normal pregnancy. Immune dysregulation has been proposed for the key underline mechanisms of RPL. However, the essential roles of T cells, especially γδ T cells, have not been defined. Decidua were obtained from normal pregnancy women or recurrent pregnancy loss patients and the surface molecules of γδ T cells in decidua were evaluated via flow cytometric analysis. The expression of PD-1 in clinical samples was analyzed by immunohistochemistry assay. The intracellular cytokines of decidual PD-1+ and PD-1- γδ T cells were evaluated by flow cytometric analysis. The cytotoxicity of PD-1- γδ T cells were confirmed via an in vitro co-culture experiment. The specific inhibitors for Erk, p38 and JNK against the MAPK pathway were added to the co-culture media to evaluate the functions of the Erk, p38 and JNK. We demonstrated that PD-1 was significantly decreased on decidual tissue γδ T cells of patients with RPL, resulting in the enhanced cytotoxicity of γδ T cells against trophoblasts. We further elucidated an Erk-dependent TNF-α production mediates the γδ T cell cytotoxicity against the trophoblast cells. Finally, the reduced expression of PD-L1 in the villi tissues of patients with RPL might be the cause of the reduction of PD-1 on the tissue γδ T cells. Our study uncovers an important role of PD-1 expression on decidual γδ T cells in maintaining the normal pregnancy, and may provide a new strategy for immune therapy against RPL.


Synergy between microalgae and microbiome in polluted waters.
Microalga-microbiome interactions are central to both health and disease of aquatic environments. Despite impressive advances in deciphering how microorganisms participate in and impact aquatic ecosystems, the evolution and ecological involvement of microalgae and the microbiome in polluted waters are typically studied independently. Here, the phycosphere (i.e., the consortia of microalgae and the related microbiome) is regarded as an independent and integrated life form, and we summarize the survival strategies exhibited by this symbiont when exposed to anthropogenic pollution. We highlight the cellular strategies and discuss the modulation at the transcriptional and population levels, which reciprocally alters community structure or genome composition for medium-term acclimation or long-term adaptation. We propose a 'PollutantBiome' concept to help the understanding of microalga-microbiome interactions and development of beneficial microbial synthetic communities for pollutant remediation.


Protective Role of Quercetin in Carbon Tetrachloride Induced Toxicity in Rat Brain: Biochemical, Spectrophotometric Assays and Computational Approach.
Carbon tetrachloride (CCL4) induces oxidative stress by free radical toxicities, inflammation, and neurotoxicity. Quercetin (Q), on the other hand, has a role as anti-inflammatory, antioxidant, antibacterial, and free radical-scavenging. This study explored protection given by quercetin against CCL4 induced neurotoxicity in rats at given concentrations. Male Wistar rats were divided into four groups Group C: control group; Group CCL4: given a single oral dose of 1 mL/kg bw CCL4; Group Q: given a single i.p injection of 100 mg/kg bw quercetin; and Group Q + CCL4: given a single i.p injection of 100 mg/kg bw quercetin before two hours of a single oral dose of 1 mL/kg bw CCL4. The results from brain-to-body weight ratio, morphology, lipid peroxidation, brain urea, ascorbic acid, reduced glutathione, sodium, and enzyme alterations (aspartate aminotransferase (AST), alanine aminotransferase (ALT), catalase, and superoxide dismutase) suggested alterations by CCL4 and a significant reversal of these parameters by quercetin. In silico analysis of quercetin with various proteins was conducted to understand the molecular mechanism of its protection. The results identified by BzScore4 D showed moderate binding between quercetin and the following receptors: glucocorticoids, estrogen beta, and androgens and weak binding between quercetin and the following proteins: estrogen alpha, Peroxisome proliferator-activated receptors (PPARγ), Herg k+ channel, Liver x, mineralocorticoid, progesterone, Thyroid α, and Thyroid β. Three-dimensional/four-dimensional visualization of binding modes of quercetin with glucocorticoids, estrogen beta, and androgen receptors was performed. Based on the results, a possible mechanism is hypothesized for quercetin protection against CCL4 toxicity in the rat brain.


Carbolithiation of meso-aryl-substituted 5,15-diazaporphyrin selectively provides 3-alkylated diazachlorins.
Treatment of meso-mesityl 5,15-diazaporphyrin with alkyllithiums in toluene at low temperature provided monoalkylated diazachlorins through highly regioselective nucleophilic addition at the β-position near the meso-nitrogen atom.


Gallium-67 scanning for malignant melanoma.
Melanoma is characterized by a tendency to metastasize widely throughout the body and its relative affinity for gallium-67. Because of the ability of this nuclide to image tumor sites in numerous organ systems, it has been used to detect metastases in patients with malignant melanoma. The effectiveness of this technique, however, has been controversial. This article documents the retrospective analysis of results from 296 gallium-67 scintiscans from 222 patients with melanoma. Patients were placed in two groups. The low suspicion group (148 patients undergoing 191 scans) consisted of patients with no evidence of disease; the gallium scans were performed solely for screening purposes. There were 175 true-negative scans, nine true-positive scans (eight of the nine were positive only at the untreated primary site), three false-negative scans, and four false-positive scans. Therefore, in only one patient (0.5%) did a "screening" gallium scan reveal disease that was not expected. The high suspicion group (85 patients undergoing 105 scans) consisted of patients with established evidence of metastatic disease; the gallium scan was performed to confirm those findings and to search for involvement of other organ systems. Of these scans, ten were true-negative, 73 true-positive, 21 false-negative, and one false-positive. In this group the 20% false-negative results indicate that gallium scanning is considerably less sensitive than the combination of clinical and standard radiographic assessment. It was concluded that gallium-67 scintiscanning of patients with melanoma, whether for screening or evaluation of patients with known metastases, provides little information that affects clinical staging or therapeutic design. Therefore, the technique is of limited value for routinely investigating the extent of disease.


[Trauma and stressor-related disorders: diagnostic conceptualization in DSM-5].
The Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) includes a distinct diagnostic group of trauma and stressor-related disorders that has been set apart from anxiety disorders. From a perspective of adult psychiatry this new disorder category includes posttraumatic stress disorder (PTSD), acute stress disorder (ASD), and adjustment disorders. The PTSD is based on narrower trauma criteria that focus on acute life-threatening situations, serious injury, or sexual violence by way of direct confrontation, witnessing or indirect confrontation. Indirect confrontation, however, is reserved only for violent or accidental events that occurred to close family members or friends. The former A2 criterion of an intense emotional reaction to trauma has been removed. A deliberately broad approach to clinical PTSD phenomenology has created an empirically driven new cluster of persistent negative alterations in cognition and mood due to experiencing traumatic events. The ASD has been reconceptualized as an intense stress syndrome with a clear need of acute treatment during the early course after traumatic exposure. Adjustment disorders continue to emphasize maladaptive emotional and behavioral responses to unspecific, non-traumatic stressors in an intensity that is beyond social or cultural norms. Neither complex PTSD nor prolonged grief disorders have received an independent diagnostic status within DSM-5. With respect to stress-related disorders major divergences between DSM-5 and the future International Classification of Diseases 11 (ICD-11) are to be expected.


Long Noncoding RNA PCAT18 Upregulates SPRR3 to Promote Colorectal Cancer Progression by Binding to miR-759.
Long noncoding RNAs (lncRNAs) play essential functions in the development of several cancers, including colorectal cancer (CRC). Nevertheless, how PCAT18 regulates CRC tumorigenesis remains unclear. In this research, we aimed to investigate the roles of PCAT18 in CRC. qRT-PCR and Western blot were used to analyze RNA and protein levels. CCK8, colony formation, transwell and wound healing assays were utilized to analyze proliferation, migration and invasion. Luciferase reporter assay was used to analyze RNA interactions. PCAT18 was found to be highly expressed in CRC tissues and cells. PCAT18 level was positively correlated with lymph node metastasis and TNM stage. Functionally, PCAT18 silencing induced impairment of CRC proliferation, migration and invasion. Besides, PCAT18 was identified to inhibit miR-759. PCAT18 promotes SPRR3 expression through binding to miR-759. Furthermore, miR-759 inhibitors or SPRR3 ectopic expression partially rescued the abilities of proliferation, migration and invasion in CRC cells transfected with sh-PCAT18. Therefore, our study demonstrated that PCAT18 contributes to CRC progression through regulating miR-759/SPRR3 axis, which provides a new theoretical basis of explaining CRC tumorigenesis.


Biphasic effect of somatostatin on oral glucose tolerance in maturity-onset diabetes.
Oral glucose tolerance was examined in five maturity-onset diabetics during the infusion of somatostatin or saline. Somatostatin inhibited glucose-stimulated insulin release and reduced plasma glucagon by 50%--65%. The rise in plasma glucose after glucose ingestion was initially (at 30--120 min) reduced by somatostatin. However, beyond 3 hr, plasma glucose levels were 50--200 mg/100 ml higher, with somatostatin reaching concentrations at 6 hr that were twofold higher than those observed with saline ( p less than 0.005). The degree of late glucose intolerance was inversely related to postglucose plasma insulin concentrations (p less than 0.01). These findings demonstrate a biphasic effect of somatostatin on oral glucose tolerance in maturity-onset diabetes. The exaggerated later hyperglycemia is related to suppression of insulin secretion. The initial blunting of postprandial hyperglycemia may reflect decreased carbohydrate absorption and/or hypoglucagonemia-mediated enhancement of glucose disposal.


GPs Meet Rare Lung Disorders Task Force factsheet: pulmonary arterial hypertension.
ERS GPs Meet Rare Lung Disorders Task Force factsheet: pulmonary arterial hypertension http://ow.ly/RlcYz.


Outcomes of Children with Inflammatory Bowel Disease who Develop Anti-tumour Necrosis Factor-induced Skin Reactions.
Anti-tumour necrosis factor [anti-TNF] induced skin reactions are common adverse events in paediatric inflammatory bowel disease [IBD]. We aimed to report on outcomes of children with anti-TNF induced skin reactions who switched to ustekinumab [UST] vs. continued anti-TNF therapy. Charts were reviewed for paediatric IBD patients with anti-TNF induced skin reactions. Skin reactions, including psoriasiform dermatitis [PD], were classified as mild or severe based on a severity score. Primary outcome was frequency of skin resolution at 6 months. Secondary outcomes were combined clinical remission and skin resolution at 6 months and skin resolution at latest follow-up. A total of 111/638 [17%] children ([85, 21%] infliximab [IFX]; [26, 11%] adalimumab [ADA]) developed skin reactions. Eighty [72%] had PD, 25 [23%] infections, and four [4%] alopecia areata; 71 [64%] continued anti-TNF; and 40 [36%] switched to UST. In all, 73 [66%] had severe reactions and were more likely to switch to UST than if mild (37 [51%] vs. 3 [8%]; p <0.0001). Switching to UST had a higher rate and odds of resolution (29 [73%] vs. 24 [34%]; p <0.0001; odds ratio [OR] = 19.7, 95% confidence interval [CI]: 5.6, 69.5; p <0.0001) and combined remission (21 [52%] vs. 22 [31%]; p = 0.03; OR = 8.5, 95% CI: 2.5, 28.4; p = 0.0005] vs. continuing anti-TNF at 6 months. Children who switched to UST after anti-TNF induced skin reactions were more likely to have improved outcomes than those who continued anti-TNF therapy. Future studies are needed to determine immune mechanisms of anti-TNF induced skin reactions and treatment response.


Cognitive Variables in Social Anxiety Disorder in Children and Adolescents: A Network Analysis.
Clark and Wells' prominent model of social anxiety disorder (SAD) assumes that cognitive variables such as negative expectations or dysfunctional cognitions play a central role in the symptomatology of SAD. In contrast to adults, it is less clear how well the cognitive model can be applied to children and adolescents. A network analysis with seven nodes was conducted to explore the importance of cognitive variables and their interaction with symptoms of SAD based on N = 205 children and adolescents (8-18 years, M = 11.54 years). Cognitive variables had a high but differential impact within the positively connected network of SAD. Dysfunctional cognitions were most strongly connected within the network. Dysfunctional cognitions, as predicted by Clark and Wells' model, seem to act as a hub affecting several symptoms. The association between negative expectations and avoidance indicates that negative expectations may particularly contribute to the maintenance of SAD.


Macrophage activation and polarization modify P2X7 receptor secretome influencing the inflammatory process.
The activation of P2X7 receptor (P2X7R) on M1 polarized macrophages induces the assembly of the NLRP3 inflammasome leading to the release of pro-inflammatory cytokines and the establishment of the inflammatory response. However, P2X7R signaling to the NLRP3 inflammasome is uncoupled on M2 macrophages without changes on receptor activation. In this study, we analyzed P2X7R secretome in wild-type and P2X7R-deficient macrophages polarized either to M1 or M2 and proved that proteins released after P2X7R stimulation goes beyond caspase-1 secretome. The characterization of P2X7R-secretome reveals a new function of this receptor through a fine-tuning of protein release. We found that P2X7R stimulation in macrophages is able to release potent anti-inflammatory proteins, such as Annexin A1, independently of their polarization state suggesting for first time a potential role for P2X7R during resolution of the inflammation and not linked to the release of pro-inflammatory cytokines. These results are of prime importance for the development of therapeutics targeting P2X7R.


A monoclonal antibody reactive with terminal lactotriaosyl residue-containing oligosaccharides and its application to characterizing cell surface expression of the glyco-epitopes in COS-1 cells.
A new monoclonal antibody (MoAb), designated JF12, reactive strongly with Lc3 (GlcNAc beta 1-->3Gal beta 1-->4Glc beta 1-->Cer) but only slightly with nLc5 (GlcNAc beta 1-->3Gal beta 1-->4GlcNAc beta 1-->3Gal beta 1-->4Glc beta 1-->Cer) has been prepared after immunization of Balb/c mice with Lc3. By the flowcytometrical analyses of COS-1 cells, which was strongly stained with JF12, the reactivity completely disappeared in the confluent condition upon harvesting by the protease treatments of the cell surface. In the sparse condition, however, the cells still retained JF12 reactivity in spite of the protease treatments. This strongly suggests that the expression of terminal GlcNAc-containing glycoconjugates on the surface of COS-1 cells may be dramatically modulated by protease-sensitive membranous components being dependent upon the cell density.


Swift production of rhamnolipid biosurfactant, biopolymer and synthesis of biosurfactant-wrapped silver nanoparticles and its enhanced oil recovery.
Microbial enhanced oil recovery (MEOR) is a kind of enhanced oil recovery (EOR) development, often used as a tertiary stage where oil recovery is no longer possible utilizing primary and secondary conventional techniques. Among a few potential natural operators valuable for MEOR, biosurfactants, biopolymers and biosurfactant based nanoparticles assume key jobs. Biosurfactant which are produced by microorganisms' act as are surface active agents that can be used as an alternative to chemically synthesized surfactants. Pseudomonas aeruginosa TEN01, a gram-negative bacterium isolated from the petroleum industry is a potential biosurfactant (Rhamnolipid) producer using cassava waste as the substrate. This work focuses on production and characterization of rhamnolipid from P. aeruginosa TEN01 and its use in enhanced oil recovery. The effectiveness of Chitosan that is deacetylated form of chitin which is a biopolymer that provides density and viscosity to the fluids is not known in enhanced oil recovery yet and so it is studied. Moreover, the fabrication of biosurfactant-mediated silver nanocrystals and its application in enhanced oil recovery is also studied. Sand-Pack column was constructed and the mechanism of oil recovery in the column was studied. While incubating the crude oil containing sand packed column with Biosurfactant-biopolymer and brine flooding in the ratio of 1:2, and Biosurfactant incubation - flooding with 3 g/l of biopolymer was found to be 34.28% and 44.5% respectively. The biosurfactant based silver nanoparticles are non-toxic and have better stability when compared to chemically synthesized silver nanoparticles. The oil recovery percentage by chemical based Ag NPs and biosurfactant based Ag NPs are 14.94% and 14.28% respectively.


Current management of pain associated with multiple sclerosis.
While pain is a common problem in patients with multiple sclerosis (MS), it is not frequently mentioned by patients and a more direct approach is required in order to obtain information about pain from patients. Many patients with MS experience more than one pain syndrome; combinations of dysaesthesia, headaches and/or back or muscle and joint pain are frequent. For each pain syndrome a clear diagnosis and therapeutic concept needs to be established. Pain in MS can be classified into four diagnostically and therapeutically relevant categories: (i) neuropathic pain due to MS (pain directly related to MS); (ii) pain indirectly related to MS; (iii) MS treatment-related pain; and (iv) pain unrelated to MS. Painful paroxysmal symptoms such as trigeminal neuralgia (TN), or painful tonic spasms are treated with antiepileptics as first choice, e.g. carbamazepine, oxcarbazepine, lamotrigine, gabapentin, pregabalin, etc. Painful 'burning' dysaesthesias, the most frequent chronic pain syndrome, are treated with TCAs such as amitriptyline, or antiepileptics such as gabapentin, pregabalin, lamotrigine, etc. Combinations of drugs with different modes of action can be particularly useful for reducing adverse effects. While escalation therapy may require opioids, there are encouraging results from studies regarding cannabinoids, but their future role in the treatment of MS-related pain has still to be determined. Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents such as baclofen or tizanidine and in patients with phasic spasticity, gabapentin or levetiracetam are administered. In patients with severe spasticity, botulinum toxin injections or intrathecal baclofen merit consideration. While physiotherapy may ameliorate malposition-induced joint and muscle pain, additional drug treatment with paracetamol (acetaminophen) or NSAIDs may be useful. Moreover, painful pressure lesions should be avoided by using optimally adjusted aids. Treatment-related pain associated with MS can occur with subcutaneous injections of interferon-beta or glatiramer acetate, and may be reduced by optimizing the injection technique and by local cooling. Systemic (particularly 'flu-like') adverse effects of interferons, e.g. myalgias, can be reduced by administering paracetamol, ibuprofen or naproxen. A potential increase in the frequency of pre-existing headaches after starting treatment with interferons may require optimization of headache attack therapy or even prophylactic treatment. Pain unrelated to MS, such as back pain or headache, is common in patients with MS and may deteriorate as a result of the disease. In summary, a careful analysis of each pain syndrome will allow the design of the appropriate treatment plan using various medical and nonmedical options (multimodal therapy), and will thus help to improve the quality of life (QOL) of the patients.


[Follow-up results of reconstructing the knee joint with ligaments of Lavasan (author's transl)].
Recommendation of synthetic material for reconstructing the knee joint ligaments. 15 years experience in 262 patients (sportsmen, ballet dancers, circus artistis,. The Lavasan implant was used in isolated as well as in combined injuries of the ligaments. The long-term results (13 years) yielded satisfactory results in 91%.


Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation.
Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+ T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand, ex vivo study revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.


Behavioral and cortisol responses to stress in newborn infants: Effects of mode of delivery.
Suboptimal birth characteristics have been associated with altered reactivity to stress in infants. However, previous studies have not controlled for mode of delivery, which may influence the neonatal onset of stress responses. The present study assessed stress-related behavior and salivary cortisol before and after an inoculation at two hours after birth, and compared infants born through VD (N=70) and elective CS (N=72). The results indicated that overall stress behavior and body movements were increased immediately after inoculation in infants born through CS compared to VD. Infants born through CS did not show significant cortisol increases following inoculation and their overall cortisol reactivity (i.e., AUCG) was lower compared to infants born through VD. However, unexpectedly, cortisol levels in infants born through VD were highest before inoculation and subsequently decreased. Cortisol was significantly related to behavior in both groups, but in opposite directions. These results support the view that mode of delivery influences neonatal stress reactivity, although future studies should try to disentangle the effects of mode of delivery and related variables.


Using human-centered design to co-design dedicated menstrual health spaces with people who menstruate in Bidi Bidi refugee settlement, Uganda: Learnings for further adaptation and scale in humanitarian settings.
Many people who menstruate in low- and middle-income countries struggle to manage their menstruation safely, hygienically, and with dignity. This is exacerbated in humanitarian settings with limited access to menstrual products and safe, private spaces for changing, washing, and disposing of menstrual products. To address these challenges, Youth Development Labs (YLabs) used a human-centered design approach to co-design the Cocoon Mini, a safe, physical structure for managing menstruation in the Bidi Bidi Refugee Settlement in Uganda. The study comprised five phases, including background research, design research, rough prototyping, live prototyping, and a pilot study. A total of 340 people, including people who menstruate, male community members, and community stakeholders, participated in interviews, focus groups, and co-design sessions. Solution prototypes were created, evaluated, and iterated upon in each successive project phase. The final intervention design, the Cocoon Mini, was evaluated qualitatively for feasibility and acceptability during a three-month pilot using structured interviews with 109 people who menstruate utilizing Cocoon Mini structures, 64 other community members, and 20 Cocoon Mini supervisors. Results showed widespread desirability and acceptability of the Cocoon Mini among people who menstruate and other community members. Overall, 95% (104/109) of people who menstruate stated the space had made menstrual health management easier, primarily by providing designated waste bins, solar lights, and additional water sources. The Cocoon Mini provided an increased sense of physical and psychological safety in knowing where to privately manage menstruation. Furthermore, the Cocoon Mini demonstrated that an intervention could be run and maintained sustainably at the household level in humanitarian contexts, without continued external stakeholder intervention. Each Cocoon Mini structure costs approximately $360 USD to build and maintain and serves 15-20 people who menstruate, leading to a cost per person of $18-$24. Furthermore, attaching an incinerator to the structure for easier and quicker disposal of waste bin contents (compared to transporting full waste bins elsewhere) costs $2110 USD. People who menstruate lack access to safe, private spaces for menstrual health and product disposal in humanitarian settings. The Cocoon Mini provides a solution for the safe and effective management of menstruation. Customizing and scaling up dedicated menstrual health spaces should be considered a high-priority intervention in humanitarian settings.


Building Programs to Eradicate Toxoplasmosis Part IV: Understanding and Development of Public Health Strategies and Advances "Take a Village".
Review international efforts to build a global public health initiative focused on toxoplasmosis with spillover benefits to save lives, sight, cognition and motor function benefiting maternal and child health. Multiple countries' efforts to eliminate toxoplasmosis demonstrate progress and context for this review and new work. Problems with potential solutions proposed include accessibility of accurate, inexpensive diagnostic testing, pre-natal screening and facilitating tools, missed and delayed neonatal diagnosis, restricted access, high costs, delays in obtaining medicines emergently, delayed insurance pre-approvals and high medicare copays taking considerable physician time and effort, harmful shortcuts being taken in methods to prepare medicines in settings where access is restricted, reluctance to perform ventriculoperitoneal shunts promptly when needed without recognition of potential benefit, access to resources for care, especially for marginalized populations, and limited use of recent advances in management of neurologic and retinal disease which can lead to good outcomes. The online version contains supplementary material available at 10.1007/s40124-022-00268-x.


Adaptive evolution of β-globin gene in subterranean in South America octodontid rodents.
The convergent evolution of subterranean rodents is an excellent model to study how natural selection operates and the genetic bases of these adaptations, but the study on the different taxa has been very uneven and still insufficient. In the octodontoid caviomorph rodent superfamily there are two independent lineages where they have recently evolved into totally underground lifestyles: the genera Ctenomys (tuco-tucos) and Spalacopus (coruro). The underground habitat is characterized by an hypoxic and hypercapnic atmosphere, thus gas exchange is one of the most important challenges for these animals. The invasion of the underground niche could have modified the selective regimes of proteins involved in the respiration and transport of O2 of these rodents, positively selecting mutations of higher affinity for O2. Here we examine the sequence variation in the beta globin gene in these two lineages, within a robust phylogenetic context. Using different approaches (classical and Bayesian maximum likelihood (PAML/Datamonkey) and alternatives methods (TreeSAAP)) we found at least three sites with evidence of positive selection in underground lineages, especially the basal branch that leads to the Octodontidae family and the branch that leads to the coruro, suggesting some adaptive changes to the underground life. We also found a convergence with another underground rodent, which cannot be identified by the above methods.


A new method for rapid and quantitative detection of the Bacillus cereus emetic toxin cereulide in food products by liquid chromatography-tandem mass spectrometry analysis.
The Bacillus cereus emetic toxin cereulide causes foodborne intoxication, which may occasionally result in severe disease, and even death. To differentially diagnose the emetic-type of foodborne disease caused by B. cereus and assess the safety of commercial food, we developed a rapid method to quantitate cereulide. This method was combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for the extraction of cereulide from food using a normal-phase silica gel cartridge. The limits of detection and quantification were 0.1 and 0.5 ng of cereulide ml(-1), respectively. Spiked cereulide was reproducibly recovered with over 67% efficiency from nine diverse foods implicated in cereulide food poisoning. The recovery rate, reproducibility, and intermediate precision for this single laboratory validation using boiled rice were 87.1%, 4.4%, and 7.0%, respectively. Further, we detected a wide range of cereulide concentrations in leftover food and vomitus samples from two emetic foodborne outbreaks. LC-MS/MS analysis correlated closely with those acquired using the HEp-2 cell assay, and quantitated cereulide from 10 food samples at least five times faster than the bioassay. This new method will provide clinicians with an improved tool for more rapidly and quantitatively determining the presence of cereulide in food and diagnosing food poisoning caused by cereulide.


Dequalinium-induced cell death of yeast expressing alpha-synuclein-GFP fusion protein.
Intracellular toxic effects of the dequalinium-induced protofibrils of alpha-synuclein have been investigated with the yeast system expressing alpha-synuclein-GFP fusion protein in single copy, which appears in the green halo around the plasma membrane. Intracellular responses of the green fluorescent protein were analyzed as the cells were treated with dequalinium (DQ) and lactacystin. Yeast cells expressing alpha-synuclein-GFP were susceptible to both compounds in alpha-synuclein-dependent manner. Upon DQ treatment, the green halo became smeared throughout the cytoplasm while lactacystin induced a few discrete green dots, reflecting intracellular formation of the protofibrils and the protein inclusions, respectively. The DQ-treated yeast cells were intensely stained with the nucleic acid stains of cell-permeable Hoechst 33342 and cell-impermeable propidium imidione, indicating that nucleus has been disrupted in addition to plasma membrane destabilization. Those DQ-treated yeast cells, however, still contained active mitochondria identified with MitoTracker Red. Therefore, the DQ-induced protofibrillar state of alpha-synuclein-GFP has been suggested to cause the nuclear damage either independently or in combination with the membrane destabilization without affecting mitochondria.


Properdin factor b-polymorphism in the population of Hessen, Germany.
The polymorphism of properdin factor B (Bf, C3 proactivator) in a population sample from Hessen, Germany has been investigated by agarose gel electrophoresis and immunofixation. In 522 unrelated individuals seven different phenotypes were observed and the following allele frequencies calculated: BfS = 0.7998, BfF = 0.1772, BfS0.7 = 0.0163 and BfF1 = 0.0077. Investigations of 100 families with 198 children and 30 mother-child combinations support the assumed autosomal codominant way of inheritance.


Femoral head bone mineral density patterns may identify hips at risk of degeneration.
Developmental dysplasia of the hip (DDH) is a common abnormality that causes elevated contact stress and early onset osteoarthritis (OA). We hypothesized that adaptation of femoral head bone mineral density (BMD) patterns to focal loading during postnatal development could be used to identify hips at risk of degeneration. Evolving BMD patterns of the femoral head secondary center of ossification (SCO) were quantified and tested for differences with hip subluxation and degeneration. BMD was measured using quantitative computed tomography of hips in a canine model of DDH from 4 weeks to early skeletal maturity at 32 weeks. During body weight and SCO volumetric growth deceleration, SCO mean BMD increased rapidly and local regions of high BMD formed. Greater subluxation was associated with a lower mean BMD up to 14 weeks. At 32 weeks, greater subluxation was associated with a larger area of high BMD that was more laterally located and had a greater maximum BMD. BMD differences were associated with a higher probability of cartilage degeneration. Measurement and visualization of BMD pattern changes due to altered mechanical loading provide a basis for identifying hips at risk of early onset OA and a tool for surgical planning of contact stress reduction procedures.


Dual promoted ciprofloxacin degradation by Fe0/PS system with ascorbic acid and pre-magnetization.
As a widely used and hard-to-degrade pharmaceuticals and personal care product (PPCP), ciprofloxacin (CIP) was frequently found in water environment and the detected concentration was gradually increased. Although zero-valent iron (ZVI) has been shown to be effective in destroying refractory organic pollutants, the practical application and sustained catalytic performance is not satisfactory. Herein, introduction of ascorbic acid (AA) and employment of pre-magnetized Fe0 was achieved to maintain a high-concentration of Fe2+ during persulfate (PS) activation. Pre-Fe0/PS/AA system presented the best performance for CIP degradation, achieving almost complete elimination of 5 mg/L CIP within 40 min in the reaction conditions of 0.2 g/L pre-Fe0,0.05 mM AA and 0.2 mM PS. The CIP degradation retarded as excess pre-Fe0 and AA were added, therefore, the optimum dosages of pre-Fe0 and AA were determined to be 0.2 g/L and 0.05 mM, respectively. The CIP degradation gradually decreased as the initial pH increased from 3.05 to 11.03. The presence of Cl-, HCO3-, Al3+, Cu2+ and humic acid significantly influenced the performance of CIP removal, while Zn2+, Mg2+, Mn2+, and NO3- slightly affected the CIP degradation. Combined with the results of HPLC analysis and previous literature, several possible degradation pathways of CIP were proposed.


Patient-related risk factors as predictors of results following isolated mitral valve replacement.
Results following isolated mitral valve replacement in 897 consecutive patients over a twelve-year period were analyzed with regard to the influence of various preoperative patient-related risk factors. Actuarial data analysis allowed definition of major preoperative, etiological, clinical, and hemodynamic correlates to both perioperative and long-term postoperative patient survival. Patient age below 60 years, preoperative New York Heart Association Functional Class of III or less, cardiac index greater than 2.0, and left ventricular end-diastolic pressure of less than 12 mm Hg were all highly significant correlates of improved perioperative as well as long-term patient survival. Patients whose predominant functional lesion was mitral insufficiency had only a 53% five-year survival (187 of 352 patients) following mitral valve replacement as opposed to 70% (521 of 745 patients) for those who had mixed or stenotic mitral lesions. Primary ischemic mitral dysfunction was associated with only 31% five-year survival (17 of 54 patients) after mitral valve replacement in contrast to 69% (480 of 695 patients) for patients with rheumatic mitral lesions. The presence of occlusive coronary artery disease coexisting with, but not the primary cause of, mitral dysfunction was associated with decreased perioperative and late postoperative survival. Results support both earlier operative intervention and wider use of associated procedures, ie, coronary bypass grafting, with mitral valve replacement. Recognition of major preoperative patient-related risk factors should enhance survival following this procedure.


ATP-sensitive potassium channels gene polymorphism rs1799858 affects the risk of macro-/micro-vascular arteriosclerotic event in patients with increased low-density lipoprotein cholesterol levels.
Plasma concentration of low-density lipoprotein cholesterol (LDL-C) is causally related to the risk of arteriosclerotic events. Whether ATP-sensitive potassium channels (KATP) genetic variants predict increased LDL-C concentration (≥1.8 mmol/L) and risk of macro-/micro-vascular arteriosclerotic event remain elusive. A total of 320 subjects with increased LDL-C concentration (≥1.8 mmol/L) and 320 counterpart subjects (< 1.8 mmol/L) from the South China were enrolled in this study. Three KATP polymorphisms (rs1799858, rs4148671 and rs78148713) were genotyped by the Sequenom MassARRAY system. Binary logistic regression analysis was used to evaluate the association of the 3 KATP variants with increased LDL-C concentration and carotid artery stenosis (CAS) ≥50%. Two-way ANOVA was used to analyze the association of the 3 KATP variants with microalbumin in urine (MAU) and high-sensitivity C-reactive protein (HsCRP) levels. Cox proportional hazards regression analysis was used to retrospectively analyse the association of the optimal variant with the risk of new onset/recurrent acute myocardial infarction (AMI). Among the 3 studied KATP gene single nucleotide polymorphisms (SNPs), only rs1799858 (TT + CT genotype) was associated with elevated risk of LDL-C ≥ 1.8 mmol/L (adjusted OR = 2.25, 95% CI: 1.31-3.85, P = 0.003) and CAS ≥50% (adjusted OR = 2.80, 95% CI: 1.12-6.98, P = 0.028). KATP SNP rs1799858 was also associated with increased MAU (P = 0.013) and HsCRP (P = 0.027) levels. The follow-up for an average of 51.1-months revealed that participants carrying the T-allele (TT + CT) of rs1799858 was associated with high risk of new onset/recurrent AMI (adjusted HR = 2.90, 95% CI: 1.06-7.94, P = 0.038). The KATP SNP rs1799858 may be an optimal genetic predisposition marker for increased LDL-C concentration (≥1.8 mmol/L) and its related macro-/micro-vascular arteriosclerotic event risk. The KATP variant rs1799858 was associated with higher risk of macro-/micro-vascular arteriosclerotic events in patients with elevated serum LDL-C levels.


Two new compounds from Schisandra glaucescens.
One new lignan (7S,8R,7'R,8'R)-7-(3,4-methylenedioxyphenyl)-8,8'-dimethyl-8'-hydroxyl-7'-methoxyl-7'-(3',4'-methylenedioxyphenyl)-tetrahydrofuran (1), one new sesquiterpene 2-hydroxy-11,12-dehydrocalamenene (2), one new natural product erythro-1-(3,4-dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane (3), and two known lignans (+)-anwulignan(erythro-1-(4-hydroxy-3-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane) (4) and ( - )-zuonin-A (5) were isolated from the stems of Schisandra glaucescens Diels. Their structures were elucidated by spectroscopic methods. The cytotoxicity of compounds 1 and 2 was assayed.


Targeting the functional properties of cortical neurons using fMR-adaptation.
The introduction of functional brain imaging based on BOLD-fMRI, twenty years ago, has revolutionized the field of human brain research. However, right from its inception it became clear that the BOLD signal suffers from a serious limitation--it reflects the averaged activity of large neuronal populations and hence can not, on its own, index the functional properties of individual neurons. The method of fMR-adaptation (also termed repetition suppression) was developed to circumvent this problem and use the BOLD signal to assess functional specializations at the individual neuron level. The approach is based on the tendency of cortical neurons to reduce their activity upon stimulus repetition. By examining the sensitivity of the adaptation effect to stimulus manipulation, insight can be gained about the invariant and selective properties of neuronal networks. It has been argued that the adaptation effect occurs at the level of synaptic inputs--and hence may be mislocalized. However, it is critical to consider the adaptation effect in the context of the cortical network architecture. This cortical anatomical organization, dominated by short range intrinsic connections, ensures that the fMR-adaptation largely reflects the response profile of the neurons located within the imaged voxel proper.


Cytodifferentiation of the paraventricular nucleus in the chick embryo. A Golgi and electron-microscopic study.
The developmental changes in the cytoarchitecture of the hypothalamic paraventricular nucleus of the chick embryo were studied with particular emphasis on the differentiation of the magnocellular neurons. These cells can be distinguished from the parvocellular elements starting from stages 34--35 (Hamburger and Hamilton 1951) in Golgi-impregnated specimens. At the same stages, electron microscopy reveals dense-core granules, resembling the characteristic elementary granules of the neurosecretory material in the cytoplasm of the larger neurons. In addition, a few immature synapses were observed on these magnocellular perikarya. The present observations suggest that the early onset of neurosecretion in this area may be neurally regulated during early phases of development.


The legal proceeding on the use of genotypic assays for the detection of HIV antiretroviral resistance in Italy: background and rationale for a consensus conference to establish guidelines.
Do the genotypic assays for the detection of antiretroviral resistance represent a useful tool in the management of HIV-infected patients? The rationale for this legal proceeding is all included in this question. No health care technology assessment has been performed on antiretroviral genotypic assays in HIV-infected patients. Assays to measure drug resistance are available only in specialized laboratories and warnings are related to possible expanded use of these assays in the absence of randomised studies with prolonged clinical endpoint and in the absence of unambiguous and exhaustive general recommendations for the use of resistance assays in clinical practice.


ERPs associated with decisions based on slowly increasing warm and painful stimuli.
The event-related potential (ERP), produced by subjects who were experiencing a gradually increasing heat stimulus, was recorded 3.5 sec before and 1 sec after a motor response. Subjects responded when the stimulus was 'just warm,' 'just at prickling pain' or 'above the temperature of just prickling pain.' Two control procedures mimicked the readiness potential (RP) and motor potential (MP) experiments. The results showed that the steadily rising negative MP was modified to a positive wave before the decision of 'warm.' During the 'pain' and 'above pain' conditions, the pre-decision slow wave was less negative than the MP but less positive than that of the 'warm' condition. A temperature control condition confirmed that rising temperature alone did not produce these results. Principal components analysis confirmed these differences by producing factors which were interpreted as representing the ERPs of the conditions of 'warm,' 'pain,' 'above pain,' RP and MP. It was evident from pilot studies that uncontrolled electrical activity from the skin potential response (SPR) was contaminating the results. SPR forced all ERP curves in the positive direction and several attempts to eliminate the SPR from the ERP data failed. While the SPR was produced differentially across conditions and across the experimental session, the smaller the variability in the electro-oculogram (EOG) recorded from above and below the orbits, the smaller was the SPR contamination that we recorded in the ERP. Therefore, we selected subjects for this experiment who showed a stable orbital EOG.


A new treatment for reliable functional and esthetic outcome after local facial flap reconstruction: a transparent polycarbonate facial mask with silicone sheeting.
Facial flap surgery predominantly leads to good functional results. However, in some cases, it can cause unsatisfactory esthetic results. They include persistent erythema, pincushioning, and development of hypertrophic scars. Conservative, reliable treatment for facial flaps is lacking. Pressure and silicone therapy have proven to result in significant improvement in scar erythema, pliability, and thickness in postburn hypertrophic scars. By combining these therapies in a facial mask, the esthetic outcome of facial flaps could be improved. In this retrospective study, the efficacy of a unique transparent face mask containing silicone sheets on the esthetic outcome of postsurgical facial flaps is assessed. Twenty-one patients were assigned to facial pressure mask therapy after they underwent facial flap surgery between July 2012 and September 2015. Patients were treated for a mean duration of 46 weeks. The effects of pressure mask therapy were examined by means of the Patient and Observer Scar Assessment Scale (POSAS). All POSAS components showed a reduction between start and end of therapy, while itchiness, pigmentation, pliability, thickness, and relief of the flap improved significantly (P < 0.05). Mean total and patient score showed significant reduction between start and end of therapy. This study shows that a facial pressure mask layered with silicone results in noticeable flap improvement with a long-lasting result. Level of Evidence: Level III, therapeutic study.


Prognostic value of tricuspid annular tissue Doppler velocity in heart failure with atrial fibrillation.
Right ventricular function is associated with long-term outcomes of heart failure (HF), particularly with atrial fibrillation (AF). The aim of this study was to evaluate the prognostic value of Doppler tissue imaging at the mitral and tricuspid annuli in patients with HF and AF. In this prospective observational study, 457 patients (mean age, 67 years; 283 men) referred for HF with AF were enrolled and underwent conventional echocardiography including pulsed-wave Doppler tissue imaging. Systolic (s') and early diastolic (e') velocities of the tricuspid and mitral annuli were recorded from the apical four-chamber view. The development of clinical adverse events during the follow-up period was defined as the composite of cardiac death and readmission for HF. During the follow-up period (median, 20 months), 37 patients reached the primary end point (nine deaths and 28 cases of HF). Patients with cardiac events were significantly older and more often had previous HF admissions and diuretic use, higher New York Heart Association classes, and greater average ratios of peak early diastolic mitral inflow to annular velocity. Additionally, Doppler tissue imaging of s' and e' at the tricuspid, septal, and lateral mitral annuli were all reduced. Multivariate analysis showed that tricuspid s' and septal e' remained significant predictors of cardiac events. By Kaplan-Meier analysis, the occurrence of cardiac events was more frequent when tricuspid s' was <9.0 cm/sec (P < .001) and when septal e' was <7.3 cm/sec (P < .001). In patients with HF and AF with a high risk for cardiac events, tricuspid s' and septal e' can be independent risk predictors of outcomes.


Allergic reaction and metal hypersensitivity after shoulder joint replacement.
Metal ion release may cause local and systemic effects and induce hypersensitivity reactions. The aim of our study is first to determine if implant-related hypersensitivity correlates to patient symptoms or not; second, to assess the rate of hypersensitivity and allergies in shoulder arthroplasty. Forty patients with shoulder replacements performed between 2015 and 2017 were studied with minimum 2-year follow-up; no patient had prior metal implants. Each patient underwent radiographic and clinical evaluation using the Constant-Murley Score (CMS), 22 metal and cement haptens patch testing, serum and urine tests to evaluate 12 metals concentration, and a personal occupational medicine interview. At follow-up (average 45 ± 10.7 months), the mean CMS was 76 ± 15.9; no clinical complications or radiographic signs of loosening were detected; two nickel sulfate (5%), 1 benzoyl peroxide (2.5%) and 1 potassium dichromate (2.5%) positive findings were found, but all these patients were asymptomatic. There was an increase in serum aluminum, urinary aluminum and urinary chromium levels of 1.74, 3.40 and 1.83 times the baseline, respectively. No significant difference in metal ion concentrations were found when patients were stratified according to gender, date of surgery, type of surgery, and type of implant. Shoulder arthroplasty is a source of metal ion release and might act as a sensitizing exposure. However, patch test positivity does not seem to correlate to hypersensitivity cutaneous manifestations or poor clinical results. Laboratory data showed small constant ion release over time, regardless of gender, type of shoulder replacement and implant used. Level II.


Vitamin D and Major Chronic Illness.
To review the current literature regarding vitamin D insufficiency and supplementation in major illnesses. We reviewed Pubmed-indexed, English language manuscripts from January, 2003 to June, 2012 using search terms related to vitamin D, all-cause mortality, cardiovascular disease, pulmonary disease, diabetes mellitus, and cancer. Incidence of disease, risk ratios associated with 25-hydroxyvitamin D [25(OH)D] levels, and/or vitamin D supplementation schedules were documented. Although 25(OH)D levels ≥20 ng/mL were often associated with improved health outcomes, evidence suggests that 25(OH)D levels ≥30 ng/mL may confer additional health benefits. Based on the available evidence, vitamin D supplementation to restore 25(OH)D levels within a range of 30-50 ng/mL is reasonable in order to optimize potential benefits and minimize potential risks. This, of course, should be considered in the context of individual patient needs and co-morbidities.


Abdominal surgery induces c-fos expression in the nucleus of the solitary tract in the rat.
In a model of abdominal surgery, which consisted of cecal manipulation and induces postoperative ileus in rats, we studied c-fos protein expression in the nucleus of the solitary tract (NTS), the spinal cord and dorsal root ganglia. Abdominal surgery resulted in a significantly higher number of c-fos protein immunoreactive cells in the NTS compared with controls but not in dorsal root ganglia and resulted in only a few scattered cells in the spinal cord. Neurons expressing c-fos protein were concentrated in NTS regions where cecal afferents terminate. These findings support the hypothesis that sensory vagal pathways partly mediate abdominal surgery-induced postoperative ileus.


[The estimation of the time of death of corpses recovered from water (author's transl)].
Putrefaction, autolysis and maceration of water corpses follow a regular sequence depending on the water temperature and the interval in the water, the socalled water period. We have determined the beginning of characteristic exterior and interior changes in 395 water corpses of adult persons with known immersion intervals and water temperatures at the place of discovery at the time of recovery. The corpses had been kept in a cooling-rrom at 4 degrees C for 2 to 3 days until they were studied. Altogether 10 parameters have been considered and plotted (Fig. 1-3): intensive dyscoloration of the skin, gasformation, loosening of hair, loss of hair, putridity transsudate of more than 500 ml into the pleural cavitiesn, bloodlessness of heart, softening and liquefaction of the brain, loosening of fingernails, loss of washer-woman's skin from the hands and loss of fingernails. Several parameters are synchronous (Fig. 1,2). The studied intervals of exposure to water were from 2 to 47 days at water temperatures between 22 and 3 degrees C. - By means of the three diagrams it can be found out how many days at the minimum a corpse had been submerged, if the water temperature at the place of discovery is known and storage in a cooling-room has taken place for 2 to 3 days. Also statements are possible about the maximal period of time. - Corpses found in the Rhine will develop washer-woman's skin on hands and feet after no less than 5 hours, even at summer temperatures, and adipocere after no less than 2.5 to 3 months. There is no difference between running and stagnant water in the chronological developments of the parameters investigated. Also the degree of water pollution does not affect the estimation of the time of death.


Nonmuscle myosin IIA facilitates vesicle trafficking for MG53-mediated cell membrane repair.
Repair of injury to the plasma membrane is an essential mechanism for maintenance of cellular homeostasis and integrity that involves coordinated movement of intracellular vesicles to membrane injury sites to facilitate patch formation. We have previously identified MG53 as an essential component of the cell membrane repair machinery. In order for MG53 and intracellular vesicles to translocate to membrane injury sites, motor proteins must be involved. Here, we show that nonmuscle myosin type IIA (NM-IIA) interacts with MG53 to regulate vesicle trafficking during cell membrane repair. In cells that are deficient for NM-IIA expression, MG53 cannot translocate to acute injury sites, whereas rescue of NM-IIA expression in these cells can restore MG53-mediated membrane repair. Compromised cell membrane repair is observed in cells with RNAi-mediated knockdown of NM-IIA expression, or following pharmacological alteration of NM-IIA motor function. Together, our data reveal NM-IIA as a key cytoskeleton motor protein that facilitates vesicle trafficking during MG53-mediated cell membrane repair.


Association between medication and risk of suicide, attempted suicide and death in nationwide cohort of suicidal patients with schizophrenia.
Mortality among schizophrenia patients is substantially higher than in the general population. The aim of this study was to investigate, in a nationwide cohort of suicidal schizophrenic individuals, how the risks of suicide, severe suicide attempts and death are associated with usage of antidepressant or antipsychotic treatment. The study population included all individuals in Finland who were hospitalised with a diagnosis of attempted suicide between 1 January 1997 and 31 December 2003, who also had at least one hospitalisation due to schizophrenia diagnosis (ICD-10 F20), and were at least 16 years old when the index hospitalisation began. Cox's proportional hazards modelling and Bayesian intensity estimation were used in the analysis. There were 1611 patients with a mean follow-up time of 4.3 years. Current use of antipsychotics was associated with decreased mortality due to suicide (HR 0.52, 95% CI 0.34-0.81, p = 0.004), but no significant decrease in mortality was observed during current use of antidepressants (0.66, 0.41-1.08, p = 0.099), when compared to past use. In more detailed analysis when current users were compared to non-users, olanzapine, and mixed use of antipsychotics, were associated with reduced all-cause mortality, and mixed use also with reduced risk of suicide mortality. Current use of citalopram was associated with decreased all-cause and suicide mortality. In a population of suicidal schizophrenic individuals antipsychotic medication, treatment was associated with lower mortality from suicide and all-causes. Antidepressive medication was associated with lower all-cause mortality when used in combination with antipsychotics.


An integrative in silico and in vitro study identifies Leishmania donovani MAP kinase12 as a probable virulence factor.
Visceral leishmaniasis (VL), a potentially fatal vector-borne disease caused by the intracellular protozoan parasite Leishmania donovani, remains a major health problem due to restricted repertoire of drugs, deleterious side effects, high cost and increasing drug resistance. Therefore, identifying newer drug targets and developing efficacious affordable treatments with minimal or no side effects are pressing needs. Being regulators of diverse cellular processes, Mitogen-Activated Protein Kinases (MAPKs) are potential drug targets. Herein, we report L.donovani MAPK12 (LdMAPK12) as a probable virulence factor implying it as a plausible target. LdMAPK12 sequence is distinct from human MAPKs and is highly conserved in different Leishmania species. LdMAPK12 is expressed in both promastigotes and amastigotes. In comparison with the avirulent and procyclic promastigotes, the virulent and metacyclic promastigotes have higher expression of LdMAPK12. Pro-inflammatory cytokines reduced, whereas anti-inflammatory cytokines increased LdMAPK12 expression in macrophages. These data suggest a probable novel role of LdMAPK12 in parasite virulence and identifies it as a plausible drug target.


Cryoballoon in atrial fibrillation ablation.
Encouraging results of ablation therapy in patients with paroxysmal atrial fibrillation (AF) have prompted changes in professional practice guidelines. The most recent European guidelines have suggested that ablation might be offered as first-line therapy in selected patients. Cryoballoon ablation is a promising technology in interventional AF therapy. Two different sizes of the cryoballoon are currently available: a smaller (23 mm) and a larger (28 mm) balloon relative to the ostial diameter of the pulmonary veins. New tools, the circular mapping catheter and the use of intracardiac echocardiography, provide important periprocedural information. A meta-analysis of previous studies revealed outcome data with an AF-free survival rate of 72.83% at the 1-year follow-up in paroxysmal AF patients undergoing cryoballoon ablation. The most frequent, but reversible complication is phrenic nerve palsy with reported incidences up to 10%. All efforts must be taken to overcome this limitation, since the overall major complication rate tends to be lower in cryoballoon compared to radiofrequency ablation. In persistent AF, reported results in cryoballoon ablation had a limited success rate below 50% after a single procedure. A double balloon approach using both cryoballoon sizes might overcome some of the limitations in persistent AF. Prospective data and randomized studies are required. This article outlines the current status of cryoballoon technology in AF ablation therapy.


Trans-scrotal varicocelectomy in adolescents: clinical and surgical outcomes.
The gold standard to treat varicocele in adolescents is still under discussion. The aim of this study is to evaluate the role of trans-scrotal varicocelectomy and show the results obtained by using local anesthesia in combination with preoperative sedation. Between January 2010 and January 2012, this surgical and anesthesiology procedure was proposed to study patients. Inclusion and exclusion criteria were created. Patients received trans-scrotal varicocelectomy with lymphatic and artery sparing technique under local anesthesia with mild sedation anesthesia. Patients were followed for 6 months after surgery, and complications were recorded. Eighteen patients were treated with this technique. Three patients required additional sedation with propofol. None had recurrence of varicocele, and one patient showed post-operative hydrocele. All patients were discharged within 24h following surgery. Three patients used ibuprofen and paracetamol for two days after surgery. Local anesthesia in the pediatric age group could be used for varicocelectomy with mild sedation anesthesia.


Giant mammary hamartoma--case report and review of the literature.
A case of giant mammary hamartoma is presented. Macroscopically the tumor resembled giant fibroadenoma and cystosarcoma phylloides. Histological criteria for diagnosis include encapsulation, preservation of lobular integrity and the presence of adipose tissue. The radiological picture is described and the differential diagnosis discussed.


Light scattering changes of edetic acid-treated, washed rat platelets: effect of adenosine diphosphate and calcium ion in relation to chilling.
The effe-ts of adenosine diphosphate (ADP) and Ca2+ on platelet morphology were studied in edetic acid (EDTA)-treated, washed platelets of rat by means of light scattering measurement at right angles. ADP caused a transient change of light scattering, which was independent of concentration above 5 muM and of pH between 4 and 10. When the platelets were pretreated with ADP or chilled persistently, Ca2+ also caused another transient change of light scattering. The effect of Ca2+ was abolsihed at pH below 6.5. The velocity of both ADP- and Ca2+-induced response was dependnet on temperature, and the magnitude was reduced by metabolic inhibitors and SH-blocking agents. Adenosine triphosphate (ATP) competitively inhibited the ADP-induced response, but not the Ca2+-induced one. The response to Ca2+ of the control and chilled platelets was compared by scanning electron microgram. Apparent similarity of the effect of chilling on membrane structure to that of ADP was suggested.


The impact of cystic fibrosis on recovery from orthopedic trauma: a case study.
Cystic Fibrosis has effects on many body systems, including the skeletal system. In this case, we describe the impact of respiratory and endocrine disease on bone healing following orthopedic trauma in a 22-year-old woman. Limitations to mobility resulting from trauma complicated her respiratory condition. Disease-related effects on bone health and healing delayed her recovery from the trauma. It is important to recognize the multisystemic nature of CF, even when managing acute orthopedic injuries.


Association/dissociation of the nucleotide-binding domains of the ATP-binding cassette protein MsbA measured during continuous hydrolysis.
In ATP-binding cassette proteins, the two nucleotide-binding domains (NBDs) work as dimers to bind and hydrolyze ATP, but the molecular mechanism of nucleotide hydrolysis is controversial. It is still unresolved whether hydrolysis leads to dissociation of the ATP-induced dimers or partial opening of the dimers such that the NBDs remain in contact during the hydrolysis cycle. We studied the bacterial lipid flippase MsbA by luminescence resonance energy transfer (LRET). The LRET signal between optical probes reacted with single-cysteine mutants was employed to follow NBD association/dissociation in real time. The intermonomer distances calculated from LRET data indicate that the NBDs separate completely following ATP hydrolysis, even in the presence of mm MgATP, and that the dissociation occurs following each hydrolysis cycle. The results support association/dissociation, as opposed to constant contact models, for the mode of operation of ATP-binding cassette proteins.


Understanding the adoption of the mask-supply information platforms during the COVID-19.
Since late 2019, coronavirus disease 2019 (COVID-19) has led to a significant increase in the demand for medical resources. To publish data on face mask supplies, the Taiwanese government collaborated with program developers to construct a mask-supply information transitional platform (MITP). To comprehend the adoption of MITP, the study proposes a research model that integrates the health behavior model (HBM) and IS/IT continuance model for examining the factors affecting intention to use an MITP. Survey data collected from 524 respondents indicated that (1) intention to use an MITP is directly influenced by perceived threat of COVID-19 and beliefs toward using the MITP; (2) cues to action directly influence the perceived threat of COVID-19; and (3) perceived ease of use of MITP is a significant determinant of perceived usefulness of MITP. These results provide practical guidelines for health authorities and government to develop health information systems and strategies to control pandemics.


Design, synthesis, and pharmacological evaluation of new neuroactive pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives with in vivo hypnotic and analgesic profile.
The present study describes the synthesis and pharmacological profiles of four novel pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives 2-5, which were structurally designed by using the sedative and analgesic drug zolpidem 1 as lead compound. The heterotricyclic system present in the target compounds 2-5 was constructed in good yields, exploiting a regioselective hetero Diels-Alder reaction of the key azabutadiene derivative 7 and functionalized N-phenylmaleimides 9-12. Additionally, we identified that 1-methyl-7-(4-nitrophenyl)-3-phenyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8-dione derivative (LASSBio-873, 5) presented not only the most potent ability to promote sedation, which was similar to that induced by the standard benzodiazepine drug midazolam, but also potent central antinociceptive effect.


Generation of four induced pluripotent stem cell lines (FHUi003-A, FHUi003-B, FHUi004-A and FHUi004-B) from two affected individuals of a familial neurohypophyseal diabetes insipidus family.
Four disease-specific induced pluripotent stem cell (iPSC) lines were respectively derived from peripheral blood mononuclear cells of two affected individuals in a family affected by familial neurohypophyseal diabetes insipidus carrying the c.314G>C mutation. The expression of pluripotency markers (NANOG, OCT4, and SOX2), maintenance of a normal karyotype, absence of episomal vectors used for iPSC generation, and presence of the original pathogenic mutation were confirmed for each iPSC line. The ability to differentiate into three germ layers was confirmed by a teratoma formation assay. These iPSC lines can help in disease recapitulation in vitro using organoids and elucidation of disease mechanisms.


Topical tetracaine versus topical tetracaine plus intracameral lidocaine for cataract surgery.
To compare topical tetracaine 0.5% alone and with intracameral lidocaine 1% as a local anesthetic agent in phacoemulsification with intraocular lens (IOL) implantation. The Toronto Hospital-Western Division, Toronto, Canada. Fifty-nine consecutive patients (60 eyes) having phacoemulsification with implantation of a foldable acrylic IOL (AcrySof) were randomized into 1 of 2 groups: The intracameral balanced salt solution (BSS) group received topical tetracaine 0.5% plus intracameral BSS; the intracameral lidocaine group received topical tetracaine 0.5% with preservative-free intracameral lidocaine 1%. The patients' subjective experience of pain was measured at 4 points during surgery using a 4-point pain scale. Patient and surgeon satisfaction with the anesthesia used was measured using a 5-point satisfaction scale. Central endothelial cell counts were obtained preoperatively and 1 month postoperatively. Best corrected visual acuity (BCVA) was measured preoperatively and 1 hour, 1 day, 1 week, and 1 month postoperatively. The mean pain score after phacoemulsification was significantly higher in the intracameral BSS group than in the intracameral lidocaine group (0.63 +/- 0.7 [SD] and 0.23 +/- 0.4, respectively, P < .019). The mean pain score at the end of surgery was also significantly higher in the intracameral BSS group than in the intracameral lidocaine group (0.60 +/- 0.6 and 0.21 +/- 0.4, respectively; P < .014). The surgeon satisfaction score was significantly lower for the intracameral BSS group than for the intracameral lidocaine group (3.90 +/- 1.2 and 4.73 +/- 0.8, respectively; P < .0007). There was no difference in patient satisfaction between the intracameral BSS and intracameral lidocaine groups (4.60 +/- 0.6 and 4.70 +/- 0.8). Endothelial cell loss 1 month postoperatively was similar between the 2 groups (6.1% +/- 8% and 6.7% +/- 6%). Ninety-seven percent of patients (29/30) in each group noted BCVA improvement from preoperatively. The rate of potential visual acuity recovery was similar in both groups. Topical tetracaine 0.5% with intracameral lidocaine was safe and effective in patients having phacoemulsification with IOL implantation. The advantage of using intracameral lidocaine 1% over a placebo was a significant decrease in the patients' subjective experience of pain and in the surgeon's satisfaction with the anesthesia used. None of the other parameters measured in this study differed significantly between the 2 groups.


Novel gene therapy approaches to pancreatic cancer.
One of the most lethal human malignancies, pancreatic adenocarcinoma has remained a therapeutic challenge. Historically, the only curable treatment modalities available to patients with this disease have included pancreaticoduodenectomy with adjuvant chemoradiation. Few patients, however, have resectable disease at the time of presentation, and even for those who are offered this radical course of treatment, post-surgical survival is dismally short. Recently, however, advances in the understanding of the molecular biology of pancreatic cancer have enabled researchers to investigate novel gene therapy approaches to the treatment of this disease. In this paper, we review the common genetic mutations found in pancreatic adenocarcinomas, discuss strategies for the manipulation of genetic targets, and assess current progress in the field of gene therapy as it relates to pancreatic cancer.


Evaluation of entropy generation in cubic autocatalytic unsteady squeezing flow of nanofluid between two parallel plates.
Nanomaterials have advanced behaviors that make them possibly beneficial in various applications in mass and heat transports such as engine cooling, pharmaceutical processes, fuel cells, engine cooling and domestic refrigerator etc. Therefore here we deliberated the entropy generation in unsteady magnetohydrodynamic squeezing flow of viscous nanomaterials between two parallel plates. The upper plate is squeezing towards lower plate. The lower plate exhibits porous character. Energy attributes are discussed through heat flux, dissipation and Joule heating. Furthermore the irreversibility analysis with cubic autocatalysis chemical reaction is also accounted. Nonlinear differential systems are converted to ordinary differential system by transformations. For convergent series solution the given system are solved by homotopy analysis method (HAM). Characteristics of various interesting variables on velocity, Bejan number, concentration, entropy optimization and temperature are deliberated through graphs. Gradient of velocity (Cfx) and Nusselt number (Nux) are numerically computed against various physical variables. Entropy generation and Bejan number both quantitatively enhance versus radiation parameter. For larger squeezing parameter the velocity and temperature field are increased. The obtained results show that for larger squeezing parameter the velocity field boosts up. Velocity have opposite impact For larger magnetic and porosity parameters. Temperature is decreased for higher values of radiation parameter and Prandtl number. Temperature and concentration have same outcome for thermophoresis parameter. Entropy generation and Bejan number both quantitatively enhance versus radiation parameter, while reverse is hold for Brinkman number.


Influence of continuous ambulatory peritoneal dialysis on the anemia of endstage renal disease.
To evaluate the effect of continuous ambulatory peritoneal dialysis (CAPD) on the anemia of endstage renal disease, serial measurements of red cell mass and other hematological parameters were performed in 34 patients. Twenty-five patients were measured at the start and at 6 months (group 1), 13 at the start, at 6 and 12 months (group 2), and 11 were followed during their second year of treatment with measurements at 12, 18, and 24 months (group 3). In group 1 the hematocrit rose from 24.6 +/- 0.9 to 29.9 +/- 0.8% (P less than 0.01). The red cell mass increased from 879 +/- 44 to 1019 +/- 47 ml (P less than 0.01). The calculated plasma volume decreased from 2915 +/- 174 to 2568 +/- 136 ml (P less than 0.01). In group 2 at 6 months the hematocrit rose from 24.7 +/- 1.2 to 30.7 +/- 1.0% (P less than 0.01); the red cell mass increased from 924 +/- 66 to 1059 +/- 71 ml (P less than 0.05). The calculated plasma volume decreased at 6 months from 3001 +/- 201 to 2555 +/- 170 ml (P less than 0.01). No significant changes occurred between 6 and 12 months. In group 3 no significant changes in hematocrit, red cell mass, or plasma volume were observed. It is concluded that the rise in hematocrit in CAPD patients is due to an increase in red cell mass and also to a decrease in plasma volume. These changes are manifest within 6 months of treatment. The rise in red cell mass represents an improvement in renal anemia in these patients.


The Struggle Between Protecting Children From and Preparing Them for the Death of Their Parent: A Qualitative Study.
The aim of this study was to gain a greater understanding of communicating with children about parental terminal illness from the perspective of the surviving parents. A qualitative descriptive study was conducted using semi structured interviews with eligible participants. Data was analyzed using thematic analysis. The results highlight the pressures experienced by surviving parents, grappling with trying to support their children's needs on a practical and emotional level, while coping with the emotional upheaval of the impending death of their partner. The issue of communication with the children starts long before the terminal phase of illness and the results confirm that this is an ongoing process that continues after the death of the parent. The need for services to be more responsive to the diverse needs of families was also apparent as a key factor in supporting families during this time. This research provides valuable insights into the complexity of communicating with children about terminal illness from the perspective of the surviving parents. It reveals diverse views and experiences in terms of approaching communication with children and illustrates the need for services to be acutely attuned to the unique needs of parents and children throughout the disease trajectory.


Stereotactic body radiation therapy in combination with systemic therapy for metastatic renal cell carcinoma: a prospective multicentre study.
Tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors have been established as effective treatment for metastatic renal cell carcinoma (mRCC), but only a minority of patients achieve complete response. Additional strategies are necessary to improve these agents' efficacy. Patients with stable disease for at least 4 months on TKI or checkpoint inhibitors were included. Stereotactic body radiotherapy (SBRT) was delivered to an organ with comparable lesions, where one lesion was in the treatment target and the other one was intentionally left untreated (control lesion). Response in both lesions was scored using the Response Evaluation Criteria in Solid Tumors V.1.1 criteria 2 months after completion of SBRT. The primary endpoint was the rate of SBRT adverse events, and the secondary endpoints included the rate of reduction in target lesion size. 17 patients were enrolled (14 men and 3 women, median age: 54.5 years old). SBRT was delivered to the lungs (n=5), bones (n=4), lymph nodes (n=4), liver (n=1), primary renal cell carcinoma (RCC) (n=1) and locally recurrent RCC (n=2). The equivalent dose in 2 Gy with an alpha to beta ratio of 2.6 was 114 Gy. With a median follow-up of 8 months, the cumulative rate of SBRT-related toxicity (grade 1) was 12% (n=2), consisting of oesophagitis and skin erythema. No grade 2 or higher toxicity was detected. Radiographic response in the target lesion was seen in 13 patients (76%), with complete response in 5 (29%) patients and partial response in 8 (47%), including abscopal effect in 1 patient. Control lesions remained stable in 16 patients. The difference between response in the target and control lesions as judged by the mean sizes of these lesions before and at 2 months after SBRT was statistically significant (p<0.01). Fraction size of 10 Gy or greater was associated with complete response (p<0.01). Extracranial SBRT in patients with mRCC treated with TKI or checkpoint inhibitors is well tolerated and could be effective. NCT02864615.


Optical resolution of silicone and polymethylmethacrylate intraocular lenses.
The optical resolution and contrast of 18 silicone and 18 polymethylmethacrylate (PMMA) intraocular lenses were determined before implantation in and after removal from rabbit eyes. A specially designed microphotographic system that allows documentation and comparison of the image quality of different lens types was used. Silicone intraocular lenses showed a mean axial resolution of 1.25, PMMA lenses showed 1.60, of an optotype analogous resolution target (1.0 = 20/20) at a 3 mm pupil opening preoperatively. At one to 16 weeks postoperatively, both types of IOLs demonstrated nearly unchanged resolution. Contrast, however, decreased to between 60% and 85% of the preoperative 100% standard. This decrease was due to precipitates deposited on the lens surface, to posterior capsule opacification, and to lens decentration.


Identifying developmental QTL alleles with favorable effect on grain yield components under late-terminal drought in spring barley MAGIC population.
Barley is the fourth most cultivated cereal worldwide, and drought is a major cause of its yield loss by negatively affecting its development. Hence, better understanding developmental mechanisms that control complex polygenic yield-related traits under drought is essential to uncover favorable yield regulators. This study evaluated seven above-ground yield-related traits under well-watered (WW) and late-terminal drought (TD) treatment using 534 spring barley multiparent advanced generation intercross double haploid (DH) lines. The analysis of quantitative trait loci (QTL) for WW, TD, marker by treatment interaction, and drought stress tolerance identified 69, 64, 25, and 25 loci, respectively, for seven traits from which 15 loci were common for at least three traits and 17 were shared by TD and drought stress tolerance. Evaluation of allelic effects for a QTL revealed varying effect of parental alleles. Results showed prominent QTL located on major flowering time gene Ppd-H1 with favorable effects for grain weight under TD when flowering time was not significantly affected, suggesting that this gene might be linked with increasing grain weight by ways other than timing of flowering under late-terminal drought stress. Furthermore, a desirable novel QTL allele was identified on chromosome 5H for grain number under TD nearby sucrose transporter gene HvSUT2. The findings indicated that spring barley multiparent advanced generation intercross population can provide insights to improve yield under complex condition of drought.