In vitro anticancer activity of ethanolic extracts of Piper nigrum against colorectal carcinoma cell lines.
Piper nigrum (PN) is well known for its cytotoxic and pharmacological benefits. However, there is minimal documented evidence about its cytotoxic efficacy against colorectal carcinoma. We therefore sought to procure a precisely quantitative and qualitative result, pertaining the efficacy of an ethanolic extract of PN (EEPN) against colorectal carcinoma. EEPN was prepared by subjecting dried PN seeds to gradient ethanol fractionation. The total phenol content (TPC), antioxidant activity (AOA), and anti-inflammatory activity (AIA) were determined using Folin-Ciocalteu assay, ferric reducing ability of plasma and 2, 2-diphenyl-1-picrylhydrazyl methods, and human red blood cells membrane stabilizing assay, respectively. Colorectal carcinoma cell lines (HCT-116, HCT-15, and HT-29) were procured from National Centre for Cell Science, Pune, and were cultured in Dulbecco's modified eagle media supplemented with 10% fetal bovine serum and 1 mM L-glutamine. Cells were seeded into a 96-well plate, followed by treatment with increasing concentrations of EEPN. The cytotoxic efficacy was evaluated based on percentage inhibition of cells, using sulforhodamine-B assay. The IC-50 values were calculated using Prism software (Prism from GraphPad software, Inc. CA, USA). Biochemical analysis revealed that 50% EEPN exhibited higher TPC, AOA, and AIA when compared to 70% and 100% EEPN at any given concentration (P = 0.041). Cytotoxic analysis revealed a dose-dependent response with maximum cellular inhibition at TPC of 6 and 3 μg/ml, using 50% EEPN. However, 50% inhibition of cellular growth using 50% EEPN was seen with TPC of 3.2, 2.9, and 1.9 μg/ml at 24, 48, and 72 h, respectively, in HCT-15 cells. Hence, time- and dose-dependent increase in the cytotoxic efficacy of 50% EEPN against colorectal carcinoma cell lines were noted (P < 0.001). Given the significantly positive correlations exhibited between the biochemical and the cytotoxic properties evaluated in our study, we hereby conclude PN as a novel therapeutic spice for the treatment of colorectal carcinoma.


LncRNA TCONS_00145741 Knockdown Prevents Thrombin-Induced M1 Differentiation of Microglia in Intracerebral Hemorrhage by Enhancing the Interaction Between DUSP6 and JNK.
Background: The differentiation of microglia from M1 to M2 exerts a pivotal role in the aggression of intracerebral hemorrhage (ICH), and long non-coding RNAs (lncRNAs) are associated with the differentiation of microglia. However, the underlying mechanism had not been fully clarified. Methods: The expression profile of lncRNAs in thrombin-induced primary microglia was analyzed by RNA sequencing. Under thrombin treatment, the effect of lncRNA TCONS_00145741 on the differentiation of microglia was determined by immunofluorescence staining, quantitative real-time PCR, and Western blot. The potential mechanism and related signaling pathways of TCONS_00145741 in the M1 and M2 differentiation of microglia in ICH were assessed by Gene Ontology analysis, flow cytometry, RNA pull-down, RNA Immunoprecipitation, and RNA fluorescence in situ hybridization followed by immunofluorescence analysis. Results: LncRNA TCONS_00145741 expression was elevated in the thrombin-induced primary microglia, and the interference with TCONS_00145741 restrained the M1 differentiation of microglia and facilitated the M2 differentiation under thrombin treatment. The interference with TCONS_00145741 restrained the activation of the JNK pathway in microglia under thrombin treatment and repressed the JNK phosphorylation levels by enhancing the interaction between DUSP6 and JNK. In vivo experiments further illustrated that the interference with TCONS_00145741 alleviated ICH. Conclusion: LncRNA TCONS_00145741 knockdown prevented thrombin-induced M1 differentiation of microglia in ICH by enhancing the interaction between DUSP6 and JNK. This study might provide a promising target for the clinical treatment of ICH.


[The isolation and study of the properties of current influenza A viruses (H1N1) with a natural resistance to remantadine].
Studies of influenza A viruses (H1N1) isolated in 1985-1988 revealed 4 strains with natural resistance to chemical drugs (remantadine, adapromine, deitiforin). Three of them were isolated in Mongolia (A/Mongolia/230/85, A/Mongolia/231/85, and A/Mongolia/128/86) and one in the USSR (A/Moscow/771/88). These strains differed from other isolates by the following features: (i) antigenic remoteness from reference A/Chile/1/83 and A/Taiwan/1/86; (ii) similarity in antigenic specificity with A/Khabarovsk/74/77; (iii) resistance to chemical drugs; (iv) high electrophoretic mobility of genes M and NS in PAG. The possible origin of these strains is discussed.


Modeling and imaging of intestinal electrical impedance based on conjugate gradient method.
Colorectal disease is a digestive tract disease of high incidence worldwide. Its preliminary diagnosis methods such as anal digital diagnosis and enteroscopy are somewhat subjective. Moreover, it is difficult to locate precisely the lesions and their infiltration boundaries for an accurate diagnosis of disease. This study combines endoscope with electrodes placed on the inner wall of the intestine to obtain both the traditional image of the intestine lumen and its electrical impedance tomography (EIT). The spatial impedance distribution image is reconstructed from the data collected by different combination of excitation and detection electrodes. The multidimensional and multiparameter intestinal physiological and pathological changes can thus be analyzed by EIT. This study mainly consists of the following three contributions: (a) construct certain physical models that reflect corresponding characteristics of intestinal tissue and its pathological changes; (b) optimize targeted signal acquisition methods suitable for data processing and analysis of intestinal cavity; and (c) establish a method of image reconstruction that conforms to the morphological characteristics of the intestinal cavity, so that comparative analysis can be applied by using different algorithms for image reconstruction. Through the extraction and analysis of impedance information for intestinal characteristics, we aim to make this tool a supplementary diagnosis method of high sensitivity and specificity for related diseases. This may lay a foundation for more accurate clinical screening of high-risk population, more precise diagnosis and localization of lesion characteristics, and thus better treatment guidance.


Altered skin blood perfusion in areas with non blanchable erythema: an explorative study.
Non blanchable erythema, i.e. stage I pressure ulcer, is common in patients in acute and geriatric care and in nursing homes. Research has shown that this type of lesions is prone to develop into more severe pressure ulcers. The peripheral skin blood perfusion is of major importance for the development of pressure ulcers. The aim of this study was to explore the peripheral skin blood perfusion over time, in areas with non blanchable erythema and in corresponding undamaged areas on the opposite side of the body. A total of 19 measurements were performed, over time, using a laser Doppler perfusion imager. The blood flow distribution profiles over areas with non blanchable erythema and undamaged skin were found to be different. As the area of the non blanchable erythema decreased, the blood perfusion distribution profiles gradually became more heterogeneous; an area of high blood perfusion in the centre of the lesions was seen and the perfusion successively decreased closer to the edge. These results indicate that there are differences in blood perfusion between skin areas of non blanchable erythema and undamaged skin. The results also indicate that the visible redness in areas with non blanchable erythema is related to altered blood perfusion. The skin blood perfusion also seems to increase in relation to the size of the non blanchable erythema.


Professional burnout syndrome in doctors of surgical specialties in Ukraine: causes, consequences, labor optimization ways.
The professional burnout syndrome (PBS) affects quality of medical care provision for people, which is acquires the special actuality in terms of reforming the health care system. To study ways to improve the efficiency of doctors of surgical specialties based on analyzes of PBS and its consequences. A survey of psychological tests and 62 surgical doctors was carried out. It was found out that the PBS reaches a peak after 11 to 15 years of working experience. Anesthesiologists have high levels of PBS, emotional exhaustion, cynicism, low desire for career growth, frequent misunderstanding with the administration, they prefer 8-hour working day, and relieve stress by sleeping and consuming alcohol. Obstetrician-gynecologists show moderate level of PBS and emotional exhaustion, high degree of cynicism, strong desire for career growth, frequent misunderstandings with patients and their relatives, prefer 8-hour working day, relieve stress by smoking and socializing with family and friends. Traumatic surgeons have moderate level of PBS, emotional exhaustion, high degree of cynicism, strong desire for career growth, frequent misunderstandings with their colleagues of related specialties, prefer the 24-hour working day, and reli eve their stress with alcohol and sports. Surgeons have moderate level of PBS, emotional exhaustion, low degree of cynicism, moderate desire for career growth, frequent misunderstandings with their colleagues of related specialties, prefer the 8-hour working day, and relieve stress by smoking and sleeping. PBS is most expressed in doctors having working experience of 11 to 15 years and in anesthesiologists. They get professional deformations. These features should be considered in course of organization of working process of medical teams.


Laparoscopic enucleation of mesenteric cyst: a case report.
Intra-abdominal lesions, such as mesenteric cysts, are uncommon disorders. Most are discovered incidentally during routine abdominal examinations. They generally do not show typical clinical findings. Laparoscopic surgery has been used to remove a wide variety of mesenteric cysts. We report a patient with a mesenteric cyst, who was treated by laparoscopic enucleation.


Health information systems and the role of state government.
State government entities have created a range of innovative electronic information systems to support their diverse and evolving roles in the health care system. Primary goals of these initiatives include improvement of traditional public health programs, meaningful oversight of providers, simplification of administrative procedures, and support of state purchasing decisions. We establish a taxonomy of state efforts, describing primary capabilities to (1) provide meaningful data to state decisionmakers; (2) disseminate information to purchasers and consumers; (3) coordinate and improve government services; (4) establish mechanisms for electronic transactions; and (5) support telemedicine services. Reductions in the costs of technology and use of the Internet have dramatically increased state capabilities in recent years. Both the successes and failures of existing programs offer important lessons for states that are initiating new electronic communication initiatives.


Distinct contributions of TNF receptor 1 and 2 to TNF-induced glomerular inflammation in mice.
TNF is an important mediator of glomerulonephritis. The two TNF-receptors TNFR1 and TNFR2 contribute differently to glomerular inflammation in vivo, but specific mechanisms of TNFR-mediated inflammatory responses in glomeruli are unknown. We investigated their expression and function in murine kidneys, isolated glomeruli ex vivo, and glomerular cells in vitro. In normal kidney TNFR1 and TNFR2 were preferentially expressed in glomeruli. Expression of both TNFRs and TNF-induced upregulation of TNFR2 mRNA was confirmed in murine glomerular endothelial and mesangial cell lines. In vivo, TNF exposure rapidly induced glomerular accumulation of leukocytes. To examine TNFR-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wildtype and Tnfr-deficient mice following exposure to soluble TNF ex vivo. Most TNF-induced effects were exclusively mediated by TNFR1, including induced glomerular expression of adhesion molecules, chemokines, complement factors and pro-apoptotic molecules. However, TNFR2 contributed to TNFR1-dependent mRNA expression of inflammatory mediators in glomeruli when exposed to low TNF concentrations. Chemokine secretion was absent in TNF-stimulated Tnfr1-deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2. In vivo, TNF-induced glomerular leukocyte infiltration was abrogated in Tnfr1-deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils. These data demonstrate that activation of intrinsic glomerular cells by soluble TNF requires TNFR1, whereas TNFR2 is not essential, but augments TNFR1-dependent effects. Previously described TNFR2-dependent glomerular inflammation may therefore require TNFR2 activation by membrane-bound, but not soluble TNF.


Spasmolytic activity of aurapten analogs.
Seven coumaric compounds analogous to aurapten were synthesized. Their spasmolytic activity against Ba2+, acetylcholine and histamine was evaluated to investigate their structure-activity relationship. The results of the bioassay demonstrated the important roles of the cis type of double bond at C-2' and the epoxide between c-6' and 7'.


Stapled hemorrhoidectomy versus conventional excision hemorrhoidectomy for acute hemorrhoidal crisis.
We compared the safety and clinical outcomes of stapled hemorrhoidectomy and conventional excision hemorrhoidectomy in the treatment of acute hemorrhoidal crisis, and analyzed various factors associated with complications in stapled hemorrhoidectomy. Forty patients underwent stapled hemorrhoidectomy and forty underwent conventional excision hemorrhoidectomy. All had the operation under local anesthesia with conscious sedation within 24 h of admission. The length of surgery, hospital stay, disability, postoperative pain, and the use of analgesics were significantly less for patients in the stapled hemorrhoidectomy group. Stapled hemorrhoidectomy did not significantly increase the rate of complications. Five patients in the stapled group (12.5%) required further surgical intervention: three with thrombosed hemorrhoids and two with recurrent prolapse. No serious complications were reported in either group. Patient satisfaction was similar in the two groups. Increased age was identified as a factor that significantly elevated the risk of complications in the stapled group (OR, 1.06; 95% CI, 1.01-1.13). Anemia and time between the onset of prolapsed hemorrhoids and hospital admission were also risk factors for complications, although they were not significant. Stapled hemorrhoidectomy is a feasible treatment for selected patients with an acute hemorrhoidal crisis and has a similar complication rate to that of conventional excision hemorrhoidectomy. Stapled hemorrhoidectomy is superior in less-postoperative pain, shorter operation time, shorter hospital stay, and earlier return to normal activity. However, we suggest that older patients with anemia or a prolonged hemorrhoidal crisis are unsuitable for stapled hemorrhoidectomy.


Using social network position to understand early adolescents' power and dominance within a school context.
In social groups, such as school-based peer networks, youth often vie for power and dominance over others. Different strategies may be used to gain power (i.e., coercive and/or cooperative strategies), and with varying levels of success. Using a social networks approach, we examined whether and how social network centrality and social network prestige were associated with social strategies, social power, and peer reputation. Participants were fifth- to eighth-grade elementary school students (N = 466, 51% girls, 63% White) in southern Ontario, Canada. Peer nominations were used to assess social network centrality and prestige (via friendship nominations), social power strategies (coercive and cooperative strategies), social power, and peer reputation (popularity and likeability). Results indicated that coercive and cooperative strategies were used by youth high in both centrality and prestige, but that only high prestige related to power, popularity, and likeability. Results have implications for the usefulness of a social networks approach to understanding the structure of youths' social relationships and power in school settings, as well as practical implications for teachers and other school staff. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


The importance of the timing of a gap in radiotherapy of squamous cell carcinomas of the head and neck.
This paper analyses whether the timing of interruptions during radiotherapy of squamous cell carcinomas of the head and neck influences treatment results. Hundred and ninety-two patients irradiated with curative intent between 1975 and 1985 (63% after surgery and 37 as primary treatment) were analysed with regard to the occurrence, timing, duration and causes of treatment interruptions. In a multivariate analysis, these factors as well as stage, site, extent of surgery etc. were related to 5-year survival rates. Interruptions of the prescribed course of radiotherapy decreased the survival rate from 61% to 28%. No adverse effect of a break was seen if it occurred during the first 3 weeks whereas survival dropped to 18 to 25% with a break later in the course of radiotherapy. Timing of treatment interruption in squamous cell carcinomas is a crucial factor determining the chances of tumor cure. The detrimental effect of treatment interruptions increases as treatment progresses. This finding supports the hypothesis that tumor clonogen repopulation accelerates towards the end of radiotherapy of squamous cell carcinomas.


Evaluation of serverless computing for scalable execution of a joint variant calling workflow.
Advances in whole-genome sequencing have greatly reduced the cost and time of obtaining raw genetic information, but the computational requirements of analysis remain a challenge. Serverless computing has emerged as an alternative to using dedicated compute resources, but its utility has not been widely evaluated for standardized genomic workflows. In this study, we define and execute a best-practice joint variant calling workflow using the SWEEP workflow management system. We present an analysis of performance and scalability, and discuss the utility of the serverless paradigm for executing workflows in the field of genomics research. The GATK best-practice short germline joint variant calling pipeline was implemented as a SWEEP workflow comprising 18 tasks. The workflow was executed on Illumina paired-end read samples from the European and African super populations of the 1000 Genomes project phase III. Cost and runtime increased linearly with increasing sample size, although runtime was driven primarily by a single task for larger problem sizes. Execution took a minimum of around 3 hours for 2 samples, up to nearly 13 hours for 62 samples, with costs ranging from $2 to $70.


Topical steroid drops for the treatment of sinus ostia stenosis in the postoperative period.
Chronic oral steroid use causes significant morbidity, including osteoporosis, immunosuppression, and adrenal insufficiency. Refractory chronic rhinosinusitis patients often take repeated oral steroid courses to treat polypoid disease or sinus ostia stenosis. This study evaluated topical steroid drop efficacy in treating recurrent sinus ostia stenosis in the postoperative period. The 5-year single institution experience with topical steroid drop use after endoscopic sinus surgery (ESS) was evaluated by retrospective review. Patients were included if they began topical dexamethasone ophthalmic, prednisolone ophthalmic, or ciprofloxacin/ dexamethasone otic intranasally (used off-label) within 3 months after ESS. Outcomes (i.e., ostia patency, oral steroid use, revision surgery, and complications) were assessed for a 6-month period after steroid drop initiation. Thirty-six patients met inclusion criteria. Forty-four surgeries were performed during the study period; 67 sides were treated postoperatively with topical steroid drops. In 86.6% of cases, steroid drops were used to treat frontal ostium stenosis or frontal recess edema; 93.2% of surgeries were revision procedures. Sixty-four percent of sinuses were treated successfully with topical steroid drops, 14.9% remained stable, and 20.9% failed. Reasons for failure included persistent/worsening edema, scarring, or noncompliance. Ten patients (27.8%) required oral steroids and 4 patients (6%) underwent revision surgery during the study period. One case of adrenal suppression occurred. Topical steroid drops are beneficial in preventing sinus ostia stenosis in the postoperative period and may decrease the propensity toward repeated oral steroid therapy. This is particularly noteworthy in this challenging cohort, largely composed of revision frontal sinus surgery patients.


Prevalence of neurodevelopmental delays in infants with perinatal HIV infection in comparison with HIV exposure in rural South Africa.
Assessing neurodevelopmental functioning in early infancy is essential as this is a critical period for infant development. Infants born to mothers with HIV are at a greater risk of developmental delays than those born to mothers without HIV. In this study, we analyzed differences in early neurodevelopmental functioning for infants with HIV exposure versus HIV infection to inform infant screening and early intervention. Participants were recruited from community health centers in Mpumalanga Province, South Africa. Prenatally, mothers completed baseline demographic assessment at 8 to 24-week gestation periods. Infant neurodevelopment was assessed using the Bayley Infant Neurodevelopmental Screener (BINS) 12 months postnatally. Five areas of development were assessed: cognition, receptive communication, expressive communication, fine motor ability, and gross motor ability. Postnatal infant assessment using the BINS revealed that infants were at risk for neurodevelopmental delays across all domains assessed. Notably, infants exposed to HIV, regardless of HIV status, were 'at emerging risk' or 'at clear risk' for cognitive (43.5%), receptive communication (38.2%), expressive communication (53.1%), fine motor (49.9%), and gross motor delays (55.6%). Differences were noted by HIV status in the cognition domain, such that HIV-exposed infants were more likely to be at emerging or clear risk than HIV-infected infants. There was a different trend with gross motor delays, such that HIV-infected infants were at a greater risk for motor delays than HIV-exposed, uninfected infants. Screening tools for this vulnerable population provide valuable early life assessment to determine infant needs for intervention and treatment planning. Such interventions may mitigate the impact of HIV status on neurodevelopmental health generally and cognition.


Characterization of NTPase, RNA-binding and RNA-helicase activities of the cytoplasmic inclusion protein of tamarillo mosaic potyvirus.
The 66-kDa cytoplasmic inclusion protein of tamarillo mosaic potyvirus was purified to near homogeneity using organic solvent clarification, differential centrifugation and sucrose density gradient centrifugation. ATPase and GTPase activities were shown to co-purify with the 66-kDa protein. ATPase activity was stimulated up to fivefold in the presence of 20 microM poly(A). The Km value for ATP hydrolysis (18 microM), was minimally affected upon addition of poly(A). In contrast, the Vmax value for ATP hydrolysis was increased fivefold by the addition of poly(A). Binding of RNA by the cytoplasmic inclusion protein was demonstrated by gel electrophoresis of ultraviolet cross-linked enzyme-RNA complexes. In the absence of added NTP, complexes between the cytoplasmic inclusion protein and single-stranded RNA species formed rapidly in the pH range 3-7, but not at pH 8 or 9. Binding to single-stranded RNA was markedly decreased by the addition of NaCl (10 mM), suggesting a weak association between RNA and enzyme. The cytoplasmic inclusion protein bound single-stranded RNA or partially double-stranded RNA duplexes with single-stranded overhangs of 35 bases and 81 bases, respectively, but did not bind 16-bp blunt-ended double-stranded RNA. RNA binding occurred in the absence of NTP (ATP, GTP, CTP or UTP), whereas dissociation of bound RNA occurred only in the presence of NTP. RNA duplex unwinding (helicase) activity of the enzyme was demonstrated in the presence of any of the above four NTPs using partially double-stranded RNA duplexes with 3' single-stranded overhangs. We propose that the cytoplasmic inclusion protein of tamarillo mosaic virus is an RNA helicase, which translocates in the 3' to 5' direction in an energy-dependent manner, unwinding double-stranded regions.


A retrospective analysis of infections and antibiotic treatment in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.
Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare drug-related life-threatening acute conditions. Infection is a major cause of morbidity and mortality in these patients. The aim of this study was to analyze the infective characteristics and antimicrobial strategies in patients with SJS and TEN.Methods: A total of 125 patients who were diagnosed with SJS/TEN in West China Hospital from 2010 to 2017 were retrospectively analyzed.Results: There were 75 patients with coinfections (75/125, 60%), of whom 44 had SJS (44/90, 48.9%) and 31 had TEN (31/35, 88.6%). The most common infections were skin infections and pulmonary infections. Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) were the most frequently identified pathogenic organisms. The most common antibiotics used in patients with infections were vancomycin, carbapenems, quinolones, macrolides, and lincomycin.Conclusions: Antimicrobial therapy should be administered promptly if there are clinical signs of an infection. Empiric antibiotic selection is based on knowledge of the local microbiota, the different infected sites, the pathogens involved, and the severity of disease.


Multidisciplinary Point-of-Care Testing in South African Primary Health Care Clinics Accelerates HIV ART Initiation but Does Not Alter Retention in Care.
Lack of accessible laboratory infrastructure limits HIV antiretroviral therapy (ART) initiation, monitoring, and retention in many resource-limited settings. Point-of-care testing (POCT) is advocated as a mechanism to overcome these limitations. We executed a pragmatic, prospective, randomized, controlled trial comparing the impact of POCT vs. standard of care (SOC) on treatment initiation and retention in care. Selected POC technologies were embedded at 3 primary health clinics in South Africa. Confirmed HIV-positive participants were randomized to either SOC or POC: SOC participants were venesected and specimens referred to the laboratory with patient follow-up as per algorithm (∼3 visits); POC participants had phlebotomy and POCT immediately on-site using Pima CD4 to assess ART eligibility followed by hematology, chemistry, and tuberculosis screening with the goal of receiving same-day adherence counseling and treatment initiation. Participant outcomes measured at recruitment 6 and 12 months after initiation. Four hundred thirty-two of 717 treatment eligible participants enrolled between May 2012 and September 2013: 198 (56.7%) SOC; 234 (63.6%) POC. Mean age was 37.4 years; 60.5% were female. Significantly more participants were initiated using POC [adjusted prevalence ratio (aPR) 0.83; 95% confidence interval (CI): 0.74 to 0.93; P < 0.0001], the median time to initiation was 1 day for POC and 26.5 days for SOC. The proportion of patients in care and on ART was similar for both arms at 6 months (47 vs. 50%) (aPR 0.96; 95% CI: 0.79 to 1.16) and 12 months (32 vs. 32%) (aPR 1.05; 95% CI: 0.80 to 1.38), with similar mortality rates. Loss to follow-up at 12 months was higher for POC (36% vs. 51%) (aPR 0.82; 95% CI: 0.65 to 1.04). Adoption of POCT accelerated ART initiation but once on treatment, there was unexpectedly higher loss to follow-up on POC and no improvement in outcomes at 12 months over SOC.


Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptible to natural scrapie.
Natural scrapie has been viewed both as a recessive trait and as a contagious disease modulated by a host locus. To address this conundrum, we determined the structure of the sheep prion protein (PrP) gene, which contains three exons and extends over 20 kb of DNA. In the United States 86.4% of scrapie cases occur in Suffolk sheep, and within this breed 49 +/- 6% (+/- S.D., n = 69) of healthy animals carry one or more PrP alleles encoding Arg (R)-171. Four scrapie-affected sheep were homozygous for wild-type PrP open reading frames encoding the alternative Gln (Q)-171 allele. Analysis of additional cases revealed that all were Q/Q-171 homozygotes (n = 31), yielding a probability of 0.000004 that PrP genotype is unrelated to susceptibility. These data imply that homozygosity for Q-171 codons is necessary but not sufficient for the development of natural scrapie, echo reports of recessive manifestation, and parallel over-representation of PRNP codon 129 homozygotes in Creutzfeldt-Jakob disease of humans. Whereas progress has been substantial regarding experimental scrapie in rodents, the occurrence and spread of disease in flocks of sheep has remained enigmatic. Appreciation of the relationship between codon 171 genotype and susceptibility may help define the molecular basis of natural scrapie.


[Fatal pulmonary thromboembolism in a patient with paroxysmal nocturnal hemoglobinuria].
A 38 year old woman with paroxysmal nocturnal hemoglobinuria was admitted to our hospital because of hemoptysis. Pulmonary infarction was diagnosed by the perfusion lung scan. In spite of the administration of prednisolone, dextran, low molecular weight heparin, and warfarin, she died of pulmonary infarction and secondary pulmonary hypertension. Autopsy revealed thromboembolism of both pulmonary arteries and hepatic central vein thrombosis. Recent understanding of the pathogenesis and incidence of thromboembolism in paroxysmal nocturnal hemoglobinuria was discussed.


Addressing Ancestry and Sex Bias in Pharmacogenomics.
The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic variants and drug efficacy or toxicity, we are able to optimize pharmacological therapy according to an individual's genotype. Pharmacogenomics research has historically suffered from bias and underrepresentation of people from certain ancestry groups and of the female sex. These biases can arise from factors such as drugs and indications studied, selection of study participants, and methods used to collect and analyze data. To examine the representation of biogeographical populations in pharmacogenomic data sets, we describe individuals involved in gene-drug response studies from PharmGKB, a leading repository of drug-gene annotations, and showcase CYP2D6, a gene that metabolizes approximately 25% of all prescribed drugs. We also show how the historical underrepresentation of females in clinical trials has led to significantly more adverse drug reactions in females than in males. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


Neuromodulation of the lingual nerve: a novel technique.
The lingual nerve is a branch of the posterior trunk of the mandibular nerve. It provides sensation and taste to the ipsilateral anterior two-thirds of the tongue. Posttraumatic neuropathy of the lingual nerve can be chronic and debilitating long after the inciting trauma. In this operative video, the authors describe a novel technique for the treatment of lingual nerve neuropathy with neuromodulation. They present a case of a 69-year-old female with posttraumatic lingual nerve neuropathy after left molar extraction. The patient reported 95% symptom improvement after the procedure. This video demonstrates the feasibility of lingual nerve neuromodulation. The video can be found here: https://youtu.be/l-CKP8-8eqk.


Nitrergic inhibition of tachykininergic neuro-muscular transmission via cyclic GMP in the hamster ileum.
The present study was designed to explore the inhibitory mechanism by nitric oxide (NO) of the tachykininergic neuro-muscular transmissions in the hamster ileum. In the presence of guanethidine (1 µM), atropine (0.5 µM), nifedipine (0.1 µM) and apamin (100 nM), electrical field stimuli (EFS; 0.5 ms duration, 15 V) evoked non-adrenergic, non-cholinergic excitatory junction potentials (EJPs) in circular smooth muscle cells. The EJPs were markedly inhibited by the tachykinin NK1 receptor antagonists [D-Pro(4), D-Trp(7,9)]-SP(4-11) (3 µM). Both the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 200 µM) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 µM), did not affect on the resting membrane potentials, but enhanced the tachykininergic EJPs. In the presence of L-NAME (200 µM), exogenously applied NO (10 µM) and the membrane permeable analogue of guanosine 3',5'-cyclic monophosphate (cGMP), 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP, 3 mM), significantly inhibited the tachykininergic EJPs. Application of EFS (0.5 msec duration, 15 V) with trains of 20 pulses at 20 Hz increased amount of released substance P (SP). The release of SP was further increased by the treatment of L-NAME or ODQ, but markedly reduced by exogenously applied NO and 8-Br-cGMP. These results suggest that the endogenous NO may inhibit the tachykininergic neuro-muscular transmissions by the decrease of SP release from the tachykininergic neurons, possibly through a guanylate cyclase-cGMP-dependent mechanism in the hamster ileum.


[Psychometric evaluation of the psychoemotional stability in patients considered suitable for heart transplant].
The main purpose of this study was to make an objective assessment of emotional stability as a selection criterion in 14 heart transplant candidates (13 M, 1 F, 45.5 +/- 6.6 years). A psychometric study was conducted using Cognitive Behavioral Assessment (CBA 2.0 Primary-Scale Battery) and the Beck Depression Inventory. The main results of this study were the identification of: a) emotionally unstable patients (42%) who did not respond to the above mentioned selection criterion; b) stable psychological traits such as hostility, aloofness, extroversion as described in type A Behavior Pattern and c) the presence of secondary alexitimic responses suggesting a protective denial of the meaning of the disease. The psychometric method used seems useful in the selection of heart transplant candidates, however, a follow-up can better define the range of emotional stability.


[Anethole dithiolethione: an antioxidant agent against tenotoxicity induced by fluoroquinolones].
Tendinopathy and tendon rupture are the adverse effects observed with fluoroquinolone antibiotics in old patients. The aim of this study was to investigate the effect of anethole dithiolethione (5-[p-methoxyphenyl]3H-1,2-dithiole-3-thione) on the oxidative stress induced by three fluoroquinolones (pefloxacin, ofloxacin, ciprofloxacin) incubated with rabbit tenocyte cell line. Anethole dithiolethione is a well known antioxidant and glutathione inducer. Anethole dithiolethione is widely used in human therapy for its choleretic, sialogogic properties and recently proposed as cytoprotective agent in lung precancerous lesions prevention in smokers. In this purpose, protection against oxidative stress induced by fluoroquinolones has been assessed using cytofluorimetric probes to quantify cytotoxicity and reactive oxygen species production. Fluorescence signal was quantified in 96-well microplates, using cold light cytofluorometer. Significant reactive oxygen species production was detected after 45 minutes for all fluoroquinolones tested. Anethole dithiolethione has been evaluated on this parameter. Anethole dithiolethione significantly (*: P<0.05) reduces and normalizes reactive oxygen species induced by fluoroquinolones. So, anethole dithiolethione (Sulfarlem), well known for its antioxidant and glutathione inducing properties, good tissue diffusion and good tolerance in humans, could be beneficially associated to fluoroquinolones, and be proposed as a therapeutic adjuvant to prevent oxidative stress and tendinous adverse effects induced by xenobiotics and more precisely by fluoroquinolones.


Hemodialysis Catheter Care: Identifying Best Cleansing Agents.
In an attempt to create a standardized resource for cleansing both non-tunneled and tunneled hemodialysis catheters, it was discovered that all disinfectants are not compatible with all catheters. This article describes the process used to identify best practices for hemodialysis catheter care and steps taken to standardize practice throughout a hospital network. Standardized evidence-based practice preserves the integrity of catheters while allowing nurses to provide quality care to patients.


ZNRF proteins constitute a family of presynaptic E3 ubiquitin ligases.
Protein ubiquitination has been implicated recently in neural development, plasticity, and degeneration. We previously identified ZNRF1/nin283, a protein with a unique, evolutionarily conserved C-terminal domain containing a juxtaposed zinc finger/RING finger combination. Here we describe the identification of a closely related protein, ZNRF2, thus defining a novel family of ZNRF E3 ubiquitin ligases. Both ZNRF1 and ZNRF2 have E3 ubiquitin ligase activity and are highly expressed in the nervous system, particularly during development. In neurons, ZNRF proteins are located in different compartments within the presynaptic terminal: ZNRF1 is associated with synaptic vesicle membranes, whereas ZNRF2 is present in presynaptic plasma membranes. Mutant ZNRF proteins with a disrupted RING finger, a domain necessary for their E3 function, can each inhibit Ca2+-dependent exocytosis in PC12 cells. These data suggest that ZNRF proteins play a role in the establishment and maintenance of neuronal transmission and plasticity via their ubiquitin ligase activity.


Congenital aortic stenosis: follow-up of surgical management.
We have reviewed the cases operated upon for correction of congenital aortic stenosis at l'Hôpital Ste-Justine between 1959 and 1969.Twenty-five of the 26 patients were readmitted for complete clinical, radiological and hemodynamic investigation. Fourteen had a valvular stenosis, eight a diaphragmatic subvalvular lesion, and three had mixed lesions.The results lead us to believe that the surgical treatment of this malformation is justified. The indications for surgery must take into account all available clinical, radiological, electrocardiographic and hemodynamic data.


Elevated concentrations of soluble adhesion molecules and large platelets in diabetic patients: are they markers of vascular disease and diabetic nephropathy?
P-selectin, E-selectin, and mean platelet volume are markers associated with platelet reactivity that have been demonstrated to be increased in diabetes. We were particularly interested to see if there was a difference in mean platelet volume and selectins between diabetics and nondiabetics, and in diabetics with and without nephropathy, and whether there was a correlation between mean platelet volume and selectins. One hundred and fourteen diabetic patients and 31 healthy controls were investigated. Plasma levels of P-selectin and E-selectin were higher in the diabetic group than in controls (P = .001 and P = .007, respectively) and in diabetic patients with proteinuria than in patients without proteinuria (P = .002 and P = .004, respectively). Protein excretion was lower in patients with low mean platelet volume values (P = .004). In conclusion, elevated platelet volume and high selectin values may play a role in the development of vasculopathies and complications in diabetes mellitus. Further studies are needed to prove these results.


Dopaminergic loss of cyclin-dependent kinase-like 5 recapitulates methylphenidate-remediable hyperlocomotion in mouse model of CDKL5 deficiency disorder.
Cyclin-dependent kinase-like 5 (CDKL5), a serine-threonine kinase encoded by an X-linked gene, is highly expressed in the mammalian forebrain. Mutations in this gene cause CDKL5 deficiency disorder, a neurodevelopmental encephalopathy characterized by early-onset seizures, motor dysfunction, and intellectual disability. We previously found that mice lacking CDKL5 exhibit hyperlocomotion and increased impulsivity, resembling the core symptoms in attention-deficit hyperactivity disorder (ADHD). Here, we report the potential neural mechanisms and treatment for hyperlocomotion induced by CDKL5 deficiency. Our results showed that loss of CDKL5 decreases the proportion of phosphorylated dopamine transporter (DAT) in the rostral striatum, leading to increased levels of extracellular dopamine and hyperlocomotion. Administration of methylphenidate (MPH), a DAT inhibitor clinically effective to improve symptoms in ADHD, significantly alleviated the hyperlocomotion phenotype in Cdkl5 null mice. In addition, the improved behavioral effects of MPH were accompanied by a region-specific restoration of phosphorylated dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa, a key signaling protein for striatal motor output. Finally, mice carrying a Cdkl5 deletion selectively in DAT-expressing dopaminergic neurons, but not dopamine receptive neurons, recapitulated the hyperlocomotion phenotype found in Cdkl5 null mice. Our findings suggest that CDKL5 is essential to control locomotor behavior by regulating region-specific dopamine content and phosphorylation of dopamine signaling proteins in the striatum. The direct, as well as indirect, target proteins regulated by CDKL5 may play a key role in movement control and the therapeutic development for hyperactivity disorders.


APIM-peptide targeting PCNA improves the efficacy of docetaxel treatment in the TRAMP mouse model of prostate cancer.
Docetaxel is the chemotherapeutic choice for metastatic hormone-refractory prostate cancer, however, it only marginally improves the survival rate. The purpose of the present study was to examine if a peptide targeting the cellular scaffold protein PCNA could improve docetaxel's efficacy. We found that docetaxel given in combination with a cell penetrating peptide containing the AlkB homolog 2 PCNA interacting motif (APIM-peptide), reduced the prostate volume and limited prostate cancer regrowth in vivo in the immunocompetent transgenic adenocarcinoma model of prostate cancer (TRAMP). In accordance with this, we found that the APIM-peptide enhanced the efficacy of docetaxel in vitro. Gene expression analysis on prostate cancer cell lines indicated that the combination of docetaxel and APIM-peptide alters expression of genes involved in cellular signaling, apoptosis, and prostate cancer development. These changes were not detected in single agent treated cells. Our results suggest that targeting PCNA and thereby affecting multiple cellular pathways simultaneously has the potential to improve docetaxel therapy of advanced prostate cancer.


[Knowledge of adolescents about the fetal alcohol syndrome].
The level of knowledge of the risks of drinking during pregnancy in 175, 17-18 years olds from kibbutzim in the eastern Upper Galilee was studied in January 1996. This population had the highest rate of involvement with alcohol in Israel and had been involved in alcohol education activities in previous years. About 53.71% of the sample believed that heavy drinking increases the risk of birth defects, but only 20.57% could correctly describe the fetal alcohol syndrome.


In vitro and in vivo antibacterial activity of Pogostone.
Our pervious antibacterial studies on several traditional Chinese medicines have found that Patchouli oil from Pogostemon cablin had significant antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), which has spread worldwide and infected innumerable people. In order to find the more active natural substances in Patchouli oil, one of the major components, Pogostone, was isolated and its antibacterial activity was evaluated in vitro and in vivo in this study. In vitro test, Pogostone was screened for antimicrobial properties against 83 bacteria comprising 35 gram positive and 48 gram negative bacteria strains via the agar double dilution method. In vivo test, specific pathogen free (SPF) strain of both male and female white Kunming mice, weighing 18-22 g, were used to test the protective ability of Pogostone after being injected with the median lethal doses (MLDs) of the tested strains. In vitro test, Pogostone could inhibit both gram negative bacteria (0.098-1 600 µg/ml) and gram positive bacteria (0.098-800 µg/ml). For Corynebacterium xerosis and some Chryseobacterium indologenes, the minimum inhibitory concentration (MIC) values of Pogostone were extremely low (<0.098 µg/ml). It was significant that Pogostone was also active against some drug-resistant bacteria like MRSA. Furthermore, Pogostone showed antibacterial activity in vivo against Escherichia coli (E. coli) and MRSA via intraperitoneal injection. Ninety percent of the mice infected with E. coil could be protected at the concentrations of 50 and 100 mg/kg, and 60% of the mice at 25 mg/kg, while the rate of protection for the mice infected with MRSA was 60% and 50% at doses of 100 and 50 mg/kg, respectively. Pogostone could be developed as a potential antibacterial agent for clinical therapy.


Spatio-temporal TGV denoising for ASL perfusion imaging.
In arterial spin labeling (ASL) a perfusion weighted image is achieved by subtracting a label image from a control image. This perfusion weighted image has an intrinsically low signal to noise ratio and numerous measurements are required to achieve reliable image quality, especially at higher spatial resolutions. To overcome this limitation various denoising approaches have been published using the perfusion weighted image as input for denoising. In this study we propose a new spatio-temporal filtering approach based on total generalized variation (TGV) regularization which exploits the inherent information of control and label pairs simultaneously. In this way, the temporal and spatial similarities of all images are used to jointly denoise the control and label images. To assess the effect of denoising, virtual ground truth data were produced at different SNR levels. Furthermore, high-resolution in-vivo pulsed ASL data sets were acquired and processed. The results show improved image quality, quantitative accuracy and robustness against outliers compared to seven state of the art denoising approaches.


pH-responsive non-ionic diblock copolymers: ionization of carboxylic acid end-groups induces an order-order morphological transition.
A carboxylic acid based reversible additionfragmentation transfer (RAFT) agent is used to prepare gels composed of worm-like diblock copolymers using two non-ionic monomers, glycerol monomethacrylate (GMA) and 2-hydroxypropyl methacrylate (HPMA). Ionization of the carboxylic acid end-group on the PGMA stabilizer block induces a worm-to-sphere transition, which in turn causes immediate degelation. This morphological transition is fully reversible as determined by TEM and rheology studies and occurs because of a subtle change in the packing parameter for the copolymer chains. A control experiment where the methyl ester derivative of the RAFT agent is used to prepare the same diblock copolymer confirms that no pH-responsive behavior occurs in this case. This end-group ionization approach is important for the design of new pH-responsive copolymer nano-objects as, unlike polyacids or polybases, only a minimal amount of added base (or acid) is required to drive the morphological transition.


Effect of chromium source on tissue concentration of chromium in pigs.
The concentration of Cr in several tissues in response to high-level, short-term supplementation was used to determine the relative bioavailability among 4 organic Cr sources and to assess the relative safety of high levels of supplementation. Crossbred pigs (n = 40; mean BW = 48.1 +/- 0.9 kg) were allotted to 5 diets: a control diet with no added Cr, or 5,000 microg/kg of Cr from Cr tripicolinate (CrTP), Cr propionate (CrPrp), Cr methionine (CrMet), or Cr yeast (CrY). Twenty gilts were housed individually and barrows were housed in pairs. Average duration of feeding before slaughter was 75 d. For the total experiment, pigs fed the unsupplemented diet had less ADG than pigs fed CrY (P < 0.05). Serum clinical chemistry values, obtained during the final week of the experiment, demonstrated few effects with no responses that would raise concern about metabolic changes in response to the Cr sources. The effects of the forms of Cr fed on carcass measurements and meat quality were also minimal. All Cr sources reduced cooler shrink (P < 0.05) and most resulted in some meat color change on d 1 postslaughter. For tissue Cr content, 4 of 5 tissues (bone, kidney, liver, and ovary) were increased (P < 0.05) in Cr content by supplementation with CrTP and CrMet, whereas only 2 tissues (bone and kidney) were increased (P < 0.05) by CrY, and none were increased by CrPrp. In all tissues of response, CrTP exceeded CrMet and CrMet exceeded CrY. Comparing the relative increase in tissue Cr for all responsive tissues (bone, kidney, liver, and ovary) gave a range of responses, for which the mean bioavailability relative to CrTP across tissues was 13.1% for CrPrp (0.2 to 19.0%), 50.5% for CrMet (36.2 to 79.1%), and 22.8% for CrY (2.5 to 47.9%). In summation, these results show very clear Cr effects on multiple tissues, which is conclusive evidence of absorption and deposition. The lack of a negative response in growth performance, carcass measures, and clinical chemistry at the increased quantities used herein provides assurance that normal quantities of addition are extremely safe.


Serum erythropoietin levels in healthy humans after a short period of normobaric and hyperbaric oxygen breathing: the "normobaric oxygen paradox".
Renal (peritubular) tissue hypoxia is a well-known physiological trigger for erythropoietin (EPO) production. We investigated the effect of rebound relative hypoxia after hyperoxia obtained under normo- and hyperbaric oxygen breathing conditions. A group of 16 healthy volunteers were investigated before and after a period of breathing 100% normobaric oxygen for 2 h and a period of breathing 100% oxygen at 2.5 ATA for 90 min (hyperbaric oxygen). Serum EPO concentration was measured using a radioimmunoassay at various time points during 24-36 h. A 60% increase (P < 0.001) in serum EPO was observed 36 h after normobaric oxygen. In contrast, a 53% decrease in serum EPO was observed at 24 h after hyperbaric oxygen. Those changes were not related to the circadian rhythm of serum EPO of the subjects. These results indicate that a sudden and sustained decrease in tissue oxygen tension, even above hypoxia thresholds (e.g., after a period of normobaric oxygen breathing), may act as a trigger for EPO serum level. This EPO trigger, the "normobaric oxygen paradox," does not appear to be present after hyperbaric oxygen breathing.


Determinants and Predictors of Grief Severity and Persistence: The Rotterdam Study.
We aimed to explore correlates and predictors of bereavement severity and persistence (triggered by "loss of a loved one"; referent group partner loss) in the Rotterdam cohort. We used linear regression to examine factors associated with grief severity using a cross-sectional analysis and logistic regression to determine prospective associations. Cross-sectionaly, females, child-lost, higher depressive symptoms, lower education, and difficulties in daily activities were independently associated with a higher bereavement severity. Prospectively (6 years; response rate 71%), the baseline value of the grief severity was the single predictor significantly associated with grief persistence. Our results suggest that only grief severity is independently associated with grief persistence. Further studies are needed to confirm our findings.


Open Adoption Placement by Birth Mothers in Their Twenties.
The purpose of this study was to summarize birth mothers' descriptions of unplanned pregnancy experienced in their twenties and how open adoption influenced their lives. Naturalistic inquiry was used with purposive sampling from one agency and telephone interviews of women who experienced unplanned pregnancy in their twenties and relinquishment through open adoption. Recorded, transcribed, and deidentified interviews were analyzed for qualitative themes. Fifteen participants judiciously weighed the open adoption decision. Over half parented other children prior to placement. Most knew they could not have parented this child due to life stressors. Placement was a hard decision, but ongoing contact with birth child and adoptive family was valued. Open adoption processes made them stronger by being happy that their child experienced family life with greater opportunities than birth mothers could offer at the time. Summarized themes used the acronym COMMITTED: C-care deeply about what is best for the child, O-ongoing open adoption: good and hard, M-meeting together regularly, M-moving on in personal growth, accomplishments, and milestones, I-independence from previous stressors or crises, T-transitions, T-therapeutic support, E-emotions, D-depression giving way to deepened strength and personal direction. Open adoption is reinforced as a positive resolution of unintended pregnancy for birth mothers in their twenties.


[Dynamic characteristics of SARA during liver fibrogenesis in rats].
To investigate the dynamic characteristics of Smad anchor for receptor activation (SARA) expression during liver fibrogenesis in rats and the relationship between SARA and liver fibrosis. Liver fibrosis was induced in 74 rats by intraperitoneal injection of dimethylnitrosamine (DMN) with a dosage of 10 microl/kg body weight, once a day, 3 days per week for 4 weeks. The model rats were randomly divided into 9 groups for studying the changes: 1 d, 3 ds, 1 week, 2 weeks, 3 weeks and 4 weeks after starting the ip injections (intoxicating phase), and 1 week, 2 weeks and 4 weeks after stopping the injections (5th w, 7th w and 8th w, recovery phase). Each group included 5 to 8 rats. In addition, 10 non-treated rats served as normal controls. The rat liver tissues were examined. Collagen deposition was stained with Sirius red, and hydroxyproline (Hyp) was measured with Jamall' method. SARA spatial expression in the livers was detected by immunohistochemistry, and the expressions of TGFbeta1, alpha-SMA and SARA protein were detected by Western blot. The relationships of SARA with Hyp, TGFbeta1 and alpha-SMA were analyzed. During the intoxicating phase, the rat hepatic collagen production (Hyp content) and deposition increased as DMN intoxication continued, and there was marked fibrous septum and pseudo-lobule formation at the end of the 4th w. During the recovery phase, the rat hepatic collagen deposition and fibrous septum formation were lessened, but the Hyp content in the livers of the model rats at the end of 4th w, 5th w, 6th w and 8th w was still higher than that of the controls (193.04+/-39.15, 188.49+/-39.92, 174.39+/-21.22, 163.59+/-31.47 vs 125.64+/-19.51; t from 3.43 to 4.9, P<0.01). SARA was mainly stained positively in interstitial cells surrounding the hepatic sinusoids in both normal and fibrotic livers, and the number of the positive stained cells decreased as liver fibrosis developed, and gradually returned to normal after stopping the intoxication. The expressions of TGFbeta1 and alpha-SMA were gradually increased, as shown with Western blot, but SARA decreased as liver fibrosis developed. The expressions of TGFbeta1 and alpha-SMA were slightly decreased, SARA expression recovered to the normal level after stopping the DMN intoxication. During liver fibrosis developing and recovery phases, SARA was significantly negatively correlated with TGFbeta1 and alpha-SMA expressions and Hyp contents. SARA was mainly expressed in the liver interstitial cells, and it was negatively correlated with liver fibrosis formation.


Hierarchical and Heterogeneous Bioinspired Composites-Merging Molecular Self-Assembly with Additive Manufacturing.
Biological composites display exceptional mechanical properties owing to a highly organized, heterogeneous architecture spanning several length scales. It is challenging to translate this ordered and multiscale structural organization in synthetic, bulk composites. Herein, a combination of top-down and bottom-up approach is demonstrated, to form a polymer-ceramic composite by macroscopically aligning the self-assembled nanostructure of polymerizable lyotropic liquid crystals via 3D printing. The polymer matrix is then uniformly reinforced with bone-like apatite via in situ biomimetic mineralization. The combinatorial method enables the formation of macrosized, heterogeneous composites where the nanostructure and chemical composition is locally tuned over microscopic distances. This enables precise control over the mechanics in specific directions and regions, with a unique intrinsic-extrinsic toughening mechanism. As a proof-of-concept, the method is used to form large-scale composites mimicking the local nanostructure, compositional gradients and directional mechanical properties of heterogeneous tissues like the bone-cartilage interface, for mechanically stable osteochondral plugs. This work demonstrates the possibility to create hierarchical and complex structured composites using weak starting components, thus opening new routes for efficient synthesis of high-performance materials ranging from biomaterials to structural nanocomposites.


Optofluidic characterization of marine algae using a microflow cytometer.
The effects of global warming, pollution in river effluents, and changing ocean currents can be studied by characterizing variations in phytoplankton populations. We demonstrate the design and fabrication of a Microflow Cytometer for characterization of phytoplankton. Guided by chevron-shaped grooves on the top and bottom of a microfluidic channel, two symmetric sheath streams wrap around a central sample stream and hydrodynamically focus it in the center of the channel. The lasers are carefully chosen to provide excitation light close to the maximum absorbance wavelengths for the intrinsic fluorophores chlorophyll and phycoerythrin, and the excitation light is coupled to the flow cytometer through the use of an optical fiber. Fluorescence and light scatter are collected using two multimode optical fibers placed at 90-degree angles with respect to the excitation fiber. Light emerging from these collection fibers is directed through optical bandpass filters into photomultiplier tubes. The cytometer measured the optical and side scatter properties of Karenia b., Synechococcus sp., Pseudo-Nitzchia, and Alexandrium. The effect of the sheath-to-sample flow-rate ratio on the light scatter and fluorescence of these marine microorganisms was investigated. Reducing the sample flow rate from 200 μL/min to 10 μL/min produced a more tightly focused sample stream and less heterogeneous signals.


[Incorporation of uridine into RNA, nucleic acid content and UTP content at functional different lymphocyte subpopulations of the human tonsil (author's transl)].
B- and T-lymphocytes isolated from the human tonsil are separated by means of E-rosette formation in preparative scale. The T-lymphocytes are furthers purified by affinity chromatography on anti-human-light-chain-sepharose. The separated cell fractions are characterized by the distribution of immunological surface markers. - The specific radioactivity of RNA, the uptake rate of labelled uridine as well as the DNA- and RNA-content are higher in the proliferation B-cell fraction. In the size of UTP-pool are no differences between the cell fractions detectable. Because both cell populations contain the same amount of the RNA precursor UTP, the higher specific radioactivity of RNA is in proof of an increased proliferation rate at the B-cells.


[Practice of botulism].
Botulism is a rare but potentially life-threatening motor and autonomic paralytic syndrome caused by the action of neurotoxins released by Clostridium botulinum. The modern syndromes of botulism have 6 forms: 4 naturally occurring syndromes and 2 human-induced syndromes. Food-borne botulism is caused by ingestion of foods contaminated with botulinum toxin. Wound botulism is caused by C. botulinum infection of a wound and in situ toxin production. Infant botulism and adult intestinal botulism are caused by intestinal colonization and in situ toxin production. Air-borne botulism results from aerosolization of botulinum toxin, whereas iatrogenic botulism occurs due to injection of a large dose of the toxin. Another human-induced form may occur when the aerosolized toxin is released as an act of bioterrorism. All forms of botulism produce a similar syndrome: symmetrical cranial motor nerve palsies followed by descending, symmetrical motor weakness, which may progress to respiratory failure requiring intubation and respiratory support. The clinical diagnosis can be confirmed by electrophysiological studies. Laboratory diagnosis includes serum analysis of toxin by bioassay in mice. Analysis of stool, vomitus, and suspected food items may reveal the toxin. In wound botulism, isolation of C. botulinum from the wound site is diagnostic. The mainstays of therapy are meticulous intensive care including respiratory support, when necessary, and timely administration of the antitoxin.


High molecular weight antigens present on human T cells.
A series of eight high molecular weight (140,000-220,000) glycoproteins on human peripheral T cells were recognized by radioimmunoprecipitation with a rabbit antiserum. The pattern of antigens present on each of eight human T cell lines studied was unique, and no line displayed the range of antigens present on peripheral T cells. The pattern of bands on peripheral T cells changed after allogeneic or lectin stimulation. Adsorption/elution experiments with antiserum showed that some of these proteins were antigenically related, and at least three different groups of proteins were present. Two of these groups could be partially distinguished by their ability to bind to ricin or lentil lectin and by their reactivity with two additional rabbit antisera. On some cell lines, it was found that proteins bound by lentil lectin but not ricin were precursors of higher molecular weight material recognized by ricin. Taken together, the data suggest that these proteins may be the products of a multigenic or multiallelic system, probably equivalent to the murine Ly 5 antigens.


Class II malocclusion treatment changes with the Jones jig, Distal jet and First Class appliances.
Objective Maxillary molar distalization with intraoral distalizer appliances is a non-extraction orthodontic treatment used to correct molar relationship in patients with Class II malocclusion presenting maxillary dentoalveolar protrusion and minor skeletal discrepancies. This study compares the changes caused by three distalizers with different force systems. Methodology 71 patients, divided into three groups, were included. The Jones jig group (JJG, n=30; 16 male, 14 female, 13.17 years mean age) was treated with the Jones jig for 0.8 years. The Distal jet group (DJG, n=25; 8 male, 17 female, 12.57 years mean age) was treated with the Distal jet for 1.06 years. The First Class group (FCG, n=16; 6 male, 10 female, 12.84 years mean age) was treated with the First Class for 0.69 years. Intergroup treatment changes were compared using one-way ANOVA, followed by post-hoc Tukey's tests. Results Intergroup comparisons showed significantly greater maxillary incisor protrusion in DJG than in FCG (2.56±2.24 mm vs. 0.74±1.39mm, p=0.015). The maxillary first premolars showed progressive and significantly smaller mesial angulation in JJG, FCG and DJG, respectively (14.65±6.31º, 8.43±3.99º, 0.97±3.16º; p<0.001). They also showed greater mesialization in JJG than FCG (3.76±1.46 mm vs. 2.27±1.47 mm, p=0.010), and greater extrusion in DJG compared to JJG (0.90±0.77 mm vs 0.11±0.60 mm, p=0.004). The maxillary second premolars showed progressive and significantly smaller mesial angulation and mesialization in JJG, FCG and DJG, respectively (12.77±5.78º, 3.20±3.94º, -2.12±3.71º and 3.87±1.34 mm, 2.25±1.40 mm, 1.24±1.26 mm, respectively; p<0.001). DJG showed smaller distal angulation of maxillary first molars (-2.14±5.09º vs. -7.73±4.28º and -6.05±3.76º, for the JJG and FCG, respectively; p<0.001) and greater maxillary second molars extrusion (1.17±1.41 mm vs -0.02±1.16 mm and 0.16±1.40 mm, for the JJG and FCG, respectively; p=0.003). Overjet change was significantly larger in DJG compared to FCG (1.79±1.67 mm vs 0.68±0.84; p=0.046). Treatment time was smaller in FCG (0.69±0.22 years vs 0.81±0.33 years and 1.06±0.42 years, comparing it with the JJG and DJG, respectively; p=0.005). Conclusion The three appliances corrected the Class II molar relationship by dentoalveolar changes. The Distal jet produced smaller molar distal angulation than the Jones jig and First Class. The First Class appliance showed less anchorage loss, greater percentage of distalization and shorter treatment time than the Jones jig and Distal jet.


Taxonomy and Chemotaxonomy of the Genus Hypericum.
The genus Hypericum L. (St. John's Wort, Hypericaceae) includes, at the most recent count, 469 species that are either naturally occurring on, or which have been introduced to, every continent in the world, except Antarctica. These species occur as herbs, shrubs, and infrequently trees, and are found in a variety of habitats in temperate regions and in high mountains in the tropics, avoiding only zones of extreme aridity, temperature and/or salinity. Monographic work on the genus has resulted in the recognition and description of 36 taxonomic sections, delineated by specific combinations of morphological characteristics and biogeographic distribution ranges. Hypericum perforatum L. (Common St. John's wort, section Hypericum), one of the best-known members of the genus, is an important medicinal herb of which extracts are taken for their reported activity against mild to moderate depression. Many other species have been incorporated in traditional medicine systems in countries around the world, or are sold as ornamentals. Several classes of interesting bioactive secondary metabolites, including naphthodianthrones (e.g. hypericin and pseudohypericin), flavonol glycosides (e.g. isoquercitrin and hyperoside), biflavonoids (e.g. amentoflavone), phloroglucinol derivatives (e.g. hyperforin and adhyperforin) and xanthones have been identified from members of the genus. A general overview of the taxonomy of the genus and the distribution of relevant secondary metabolites is presented.


Radiologists' Rating for Comparative Qualitative Assessment of Intravoxel Incoherent Motion Using Novel Analysis Methods.
The objective was to assess qualitative interpretability and quantitative precision and reproducibility of intravoxel incoherent motion (IVIM) parametric images evaluated using novel IVIM analysis methods for diagnostic accuracy. Intravoxel incoherent motion datasets of 55 patients (male/female = 41:14; age = 17.8 ± 5.5 years) with histopathology-proven osteosarcoma were analyzed. Intravoxel incoherent motion parameters-diffusion coefficient (D), perfusion fraction (f), and perfusion coefficient (D*)-were estimated using 5 IVIM analysis methods-(i) biexponential (BE) model, (ii) BE-segmented fitting 2-parameter (BESeg-2), (iii) BE-segmented fitting 1-parameter (BESeg-1), (iv) BE model with total variation penalty function (BE + TV), and (v) BE model with Huber penalty function (BE + HPF). Qualitative scoring in a 5-point Likert scale (uninterpretable: 1; poor: 2; fair: 3; good: 4; excellent: 5) was performed by 2 radiologists for 4 criteria: (a) tumor shape and margin, (b) morphologic correlation, (c) noise suppression, and (d) overall interpretability. Interobserver agreement was evaluated using Spearman rank-order correlation (rs). Precision and reproducibility were evaluated using within-subject coefficient of variation (wCV) and between-subject coefficient of variation (bCV). BE + TV and BE + HPF produced significantly (P < 10-3) higher qualitative scores for D (fair-good [3.3-3.8]) than BE (poor [2.3]) and for D* (poor-fair [2.2-2.7]) and f (fair-good [3.2-3.8]) than BE, BESeg-2, and BESeg-1 (D*: uninterpretable-poor [1.3-1.9] and f: poor-fair [1.5-3]). Interobserver agreement for qualitative scoring was rs = 0.48-0.59, P < 0.009. BE + TV and BE + HPF showed significantly (P < 0.05) improved reproducibility in estimating D (wCV: 24%-31%, bCV: 21%-31% improvement) than the BE method and D* (wCV: 4%-19%, bCV: 5%-19% improvement) and f (wCV: 25%-49%, bCV: 25%-47% improvement) than BE, BESeg-2, and BESeg-1 methods. BE + TV and BE + HPF demonstrated qualitatively and quantitatively improved IVIM parameter estimation and may be considered for clinical use further.


Melphalan and total body irradiation (TBI) versus cyclophosphamide and TBI as conditioning for allogeneic matched sibling bone marrow transplants for acute myeloblastic leukaemia in first remission.
Between June 1981 and April 1986 63 patients with acute myeloid leukaemia (AML) in first remission and HLA-identical sibling donors were entered into a prospective study comparing cyclophosphamide (CY) + total body irradiation (TBI) with melphalan + TBI as conditioning therapy prior to transplantation. Thirty-six patients received CY/TBI and 27 received melphalan/TBI. The actuarial probability of remaining in remission for patients receiving melphalan/TBI was 94% compared with 66% following CY/TBI (p greater than 0.01). By including a comparable group of 41 patients with AML in first remission, conditioned with CY/TBI prior to the onset of the study, the greater anti-leukaemic effect of melphalan/TBI compared to CY/TBI was unchanged and statistically the chance of this being wrong is 1 in 10 (p less than 0.1). The overall survival in remission of both arms of the study was the same with 15/27 patients (55%) surviving in remission following melphalan/TBI compared with 19/36 patients (53%) following CY/TBI. The benefit obtained in reduced relapse was offset by the combined nephrotoxic effect of melphalan and cyclosporin which was not identified until the programme had been underway for a period of time. This shows that misinterpretation of 'no survival advantage' for the new treatment may occur due to unforeseen and preventable toxicities.


Nitric Oxide Synthase (NOS) Isoform Expression after Peripheral Nerve Transection in Mice.
Localization of the nitric oxide (NO)-producing enzyme, nitric oxide synthase (NOS), and its functions are currently being investigated in several tissues and organs. It has been suggested that NO is involved in nerve cell death and the development of neurodegenerative disease. The purpose of this study was to immunohistochemically investigate expression of NOS to clarify its function in the degeneration and regeneration of transected mouse sciatic nerve. Scattered neuronal NOS (nNOS)-positive Schwann cells observed on the central side of the stump on day 1 after transection showed an increase in number on day 7. None were observed at the stump on day 14, however. Expression of nNOS was observed in axons extending from the stump. The number of nNOS-positive axons increased on day 21. Inducible NOS was expressed in inflammatory cells at the stump on day 1. This positive reaction subsequently weakened by day 7, however. Endothelial NOS was expressed in blood vessels at the stump on day 7, but decreased thereafter. The results of the present study suggest that NO is involved in the proliferation and migration of Schwann cells, as well as in axon regeneration at an early stage following nerve transection.


Clinico-Haematological Features of Paroxysmal Nocturnal Haemoglobinuria.
The aim of this study was to determine the frequency of various clinico-haematological features in patients suffering from paroxysmal nocturnal haemoglobinuria (PNH). It was an observational study carried out from October 2008 - January 2016. All the patients of PNH, diagnosed on the basis of clinical and laboratory findings and confirmed by CD55 and CD59 deficiency on red cells by means of flow cytometry, were included in the study. A total of 22 patients were diagnosed which included 18 (81.8%) males and 4 (18.1%) females. Median age was 27 years. Pallor, fever, fatigability and haemoglobinuria were the most common clinical features. Pancytopenia was seen in 13 (59.09%) and hypocellular marrow was found in 14 (63.6%) patients. One patient presented with Budd Chiari syndrome.


Global investigation of potential energy surfaces for the pyrolysis of C(1)-C(3) hydrocarbons: toward the development of detailed kinetic models from first principles.
Detailed kinetic models (DKMs) are the most fundamental "bottom-up" approaches to computational investigation of the pyrolysis and oxidation of fuels. The weakest points of existing DKMs are incomplete information about the reaction types that can be involved in the potential energy surfaces (PESs) in pyrolysis and oxidation processes. Also, the computational thermodynamic parameters available in the literature vary widely with the level of theory employed. More sophisticated models require improvement both in our knowledge of the type of the reactions involved and the consistency of thermodynamic and kinetic parameters. In this paper, we aim to address these issues by developing ab initio models that can be used to describe early stages of pyrolysis of C1-C3 hydrocarbons. We applied a recently developed global reaction route mapping (GRRM) strategy to systematically investigate the PES of the pyrolysis of C1-C3 hydrocarbons at a consistent level of theory. The reactions are classified into 14 reaction types. The critical points on the PES for all reactions in the network are calculated at the highly accurate UCCSD(T)-F12b/cc-pVTZ//UM06-2X/cc-pVTZ level of theory. The data reported in this paper can be used for first principle calculations of kinetic constants and for a subsequent study on modeling the evolution of the species from the reaction network of the pyrolysis and oxidation of C1-C3 hydrocarbons.


Equilibrium-based sampler for determining Cu2+ concentrations in aquatic ecosystems.
The bioavailability of potentially toxic metals in aquatic systems is frequently related to the dissolved free metal ion (M2+) concentration. However, typical methods used to determine M2+ are labor intensive or require sophisticated equipment. We developed an inexpensive, in situ sampling device--the "gellyfish"--that simplifies Cu2+ determinations in seawater. The gellyfish is a thin disk of polyacrylamide gel embedded with iminodiacetate (Id) groups bound to immobile beads. The sampler operates on the principle that the immobilized Id groups equilibrate with the Cu2+ concentration of the surrounding solution. Cu is then back-extracted into a known volume of 10% HNO3 and measured by inductively coupled plasma mass spectrometry (ICP-MS). In laboratory tests, we varied Cu2+ concentrations between 10(-12) and 10(-8) M and salinity between 5 and 35 ppt. Id-bound Cu (CuId(measured)) did not respond to changes in total Cu. However, CuId(measured) does increase in a predictable manner with increasing Cu2+, and prototype gellyfish precision (average coefficient of variation = 10%) is sufficient to resolve small differences in Cu2+ (+/-30%). Modeled Cu uptake, based on thermodynamic equilibrium speciation of Id within gellyfish, is a good predictor of CuId(measured) (r2 = 0.96 and n = 45).


Development of a Real-Time PCR Assay for Detection of Macrolide Resistance Mutations in Mycoplasma genitalium and Its Application for Epidemiological Surveillance in Russia.
A real-time PCR assay based on probe fluorescence quenching by a primer was developed and validated for detection of macrolide resistance (MR)-associated mutations in the 23S rRNA gene of Mycoplasma genitalium. The assay involves identification of any nucleotide substitutions at positions 2058, 2059, and 2611 of 23S rRNA (Escherichia coli numbering) by the probe-based melting curve analysis immediately after amplification and was capable of detecting target mutations in clinical specimens and spiked samples with 92% sensitivity and 100% specificity. We applied this new assay to assess the prevalence of MR-associated mutations in 949 nonduplicate urogenital samples positive for M. genitalium by routine diagnostic PCR, which were collected from symptomatic patients in five cities in the European part of Russia during the period 2009-2019. Forty-three (4.92%) samples revealed the presence of MR mutations, and no trend toward an increase in resistance prevalence was observed over the 10-year period of the study. The most commonly detected mutations were A2058G (26/43; 60.47%) and A2059G (13/43; 30.23%), while other mutations were rare: A2058T (3/43; 6.98%) and C2611T (1/43; 2.33%). The data obtained underline the need for regular epidemiological monitoring to ensure effective patient management, rational use of antibiotics, and prevention of further spread of resistance.


'Leaving no one behind': reflections on the design of community-based HIV prevention for migrants in Johannesburg's inner-city hostels and informal settlements.
Unmanaged urban growth in southern and eastern Africa has led to a growth of informal housing in cities, which are home to poor, marginalised populations, and associated with the highest HIV prevalence in urban areas. This article describes and reflects on the authors' experiences in designing and implementing an HIV intervention originally intended for migrant men living in single-sex hostels of inner-city Johannesburg. It shows how formative research findings were incorporated into project design, substantially shifting the scope of the original project. Formative research activities were undertaken to better understand the demand- and supply-side barriers to delivering HIV prevention activities within this community. These included community mapping, a baseline survey (n = 1458) and client-simulation exercise in local public sector clinics. The intervention was designed and implemented in the study setting over a period of 18 months. Implementation was assessed by way of a process evaluation of selected project components. The project scope expanded to include women living in adjacent informal settlements. Concurrent sexual partnerships between these women and male hostel residents were common, and HIV prevalence was higher among women (56%) than men (24%). Overwhelmingly, hostel residents were internal migrants from another province, and most felt 'alienated' from the rest of the city. While men prioritised the need for jobs, women were more concerned about water, sanitation, housing and poverty alleviation. Most women (70%) regarded their community as unsafe (cf. 47% of men). In the final intervention, project objectives were modified and HIV prevention activities were embedded within a broader health and development focus. 'Community health clubs' were established to build residents' capacity to promote health and longer term well-being, and to initiate and sustain change within their communities. To improve efforts to address HIV in urban informal settings, intervention designers must acknowledge and engage with the priorities set by the marginalised communities that live here, which may well encompass more pressing issues associated with daily survival.


Re-thinking lactation-related nipple pain and damage.
Nipple pain is a common reason for premature cessation of breastfeeding. Despite the benefits of breastfeeding for both infant and mother, clinical support for problems such as maternal nipple pain remains a research frontier. Maternal pharmaceutical treatments, and infant surgery and bodywork interventions are commonly recommended for lactation-related nipple pain without evidence of benefit. The pain is frequently attributed to mammary dysbiosis, candidiasis, or infant anatomic anomaly (including to diagnoses of posterior or upper lip-tie, high palate, retrognathia, or subtle cranial nerve abnormalities). Although clinical protocols universally state that improved fit and hold is the mainstay of treatment of nipple pain and wounds, the biomechanical parameters of pain-free fit and hold remain an omitted variable bias in almost all clinical breastfeeding research. This article reviews the research literature concerning aetiology, classification, prevention, and management of lactation-related nipple-areolar complex (NAC) pain and damage. Evolutionary and complex systems perspectives are applied to develop a narrative synthesis of the heterogeneous and interdisciplinary evidence elucidating nipple pain in breastfeeding women. Lactation-related nipple pain is most commonly a symptom of inflammation due to repetitive application of excessive mechanical stretching and deformational forces to nipple epidermis, dermis and stroma during milk removal. Keratinocytes lock together when mechanical forces exceed desmosome yield points, but if mechanical loads continue to increase, desmosomes may rupture, resulting in inflammation and epithelial fracture. Mechanical stretching and deformation forces may cause stromal micro-haemorrhage and inflammation. Although the environment of the skin of the nipple-areolar complex is uniquely conducive to wound healing, it is also uniquely exposed to environmental risks. The two key factors that both prevent and treat nipple pain and inflammation are, first, elimination of conflicting vectors of force during suckling or mechanical milk removal, and second, elimination of overhydration of the epithelium which risks moisture-associated skin damage. There is urgent need for evaluation of evidence-based interventions for the elimination of conflicting intra-oral vectors of force during suckling.


Clinical, virologic, and histopathologic observations of induced porcine parvovirus infection in boars.
Twelve 8- to 12-month-old crossbred boars were inoculated with a virulent strain (NADL-8) of porcine parvovirus (PPV). Hemicastrations were performed on 6 boars 3, 7, 10, 14, 21, and 28 days after an IM injection of 10(8) median cell culture infectious dose (CCID50) of PPV (n = 3) or injection of 10(7.4) CCID50 given intratesticularly (IT, n = 3). Noninfected cell culture medium (0.25 ml) was injected into each testicle of a 7th boar (IT inoculated control). Virus or viral antigen was detected in testicular and epididymal tissues up to 14 days after inoculation. Direct immunofluorescence indicated that viral antigen was mainly associated with the vasculature of the interstitium. Microscopic lesions were not evident in the testicles and epididymides of IM inoculated boars. Acute-to-chronic testicular degeneration was evident in the IT inoculated boars, as well as in the IT inoculated control boar. Six boars were inoculated IM or orally/nasally with 10(7.9) CCID50 of PPV. Semen was collected twice weekly for 8 weeks after inoculation. Virus was not detected in any ejaculates. Semen also was collected from 4 boars for 5 weeks before inoculation, and preinoculation and post-inoculation semen quality was compared. Pronounced changes in sperm output, ejaculate volume, motility, or morphologic defects were not observed. The reproductive consequences of experimental PPV infection in boars were minimal because reproductive function was unaffected and venereal transmission of PPV was not detected.


Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma.
The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an anti-angiogenesis monoclonal antibody.


Preparation and Application of Bismuth/MXene Nano-Composite as Electrochemical Sensor for Heavy Metal Ions Detection.
A nano-form composite of MXenes (Ti3C2Tx, Tx = -O, -OH, -F) was synthesized through depositing bismuth-nanoparticle (BiNPs) onto Ti3C2Tx sheets. Because of the preventive effect of the two-dimensional layered structure of Ti3C2Tx, the nanoparticles of Bi were uniform and well attached on the Ti3C2Tx. The obtained BiNPs/Ti3C2Tx nano-composite was applied for sensors construction of electrochemical detecting of Pb2+ and Cd2+ heavy metal ions. The produced BiNPs@Ti3C2Tx-based sensor showed high effective surface area and excellent conductivity. Also, the BiNPs were efficient for anodic-stripping voltammetric to detect heavy metal ions. After conditions optimization, the BiNPs@Ti3C2Tx nano-sensor could detect Pb2+ and Cd2+ simultaneously and the detection limits were 10.8 nM for Pb2+ and 12.4 nM for Cd2+. The BiNPs@Ti3C2Tx was promising for detecting heavy metal ions due to their high surface area, fast electron-transfer ability, environmental friendliness, and facial preparation.


Hinge positioning method of Ilizarov apparatus in correcting radial head luxation caused by multiple hereditary exostoses.
In this study, we present a specified hinge positioning method to achieve satisfying and steerable lengthening and angulation to correct forearm multiple hereditary exostoses (MHE) combined with severe radiocapitellar joint dislocation using Ilizarov ring fixators. Between January 2014 and December 2018, a total of 30 forearms of 23 patients (11 males, 12 females; mean age: 18.3±6.8 years; range, 8 to 35 years) who suffered from type IIa (n=2) or IIb (n=28) MHE with severe radiocapitellar joint luxation were retrospectively analyzed. All patients were treated with Ilizarov external fixators with our specified hinge positioning method. Range of motion of the elbow, forearm and wrist and Visual Analog Scale (VAS), as well as Disabilities of Arm, Shoulder, and Hand (DASH) score, and radiological parameters, including radial articular angle (RAA), ulnar variance (UV) and carpi slip (CS), were recorded preoperatively and at final follow-up and were compared. Clinical and radiological outcomes were evaluated. Range of motion of the elbow, forearm and wrist, VAS, DASH and radiological features, including RAA, CS, and UV were significantly improved, except for range of motion of the forearm supination. Temporary nail track infection was seen in two of the forearms and was controlled with oral antibiotics. None of the patients developed radial head dislocation again. Clinical and radiological outcomes of this novel hinge positioning method are satisfactory in treating MHE with severe radial head dislocation, and this method can be an alternative treatment for MHE by setting a milestone for accurate radiocapitellar joint reduction.


A bottom-up characterization of transfer functions for synthetic biology designs: lessons from enzymology.
Within the field of synthetic biology, a rational design of genetic parts should include a causal understanding of their input-output responses-the so-called transfer function-and how to tune them. However, a commonly adopted strategy is to fit data to Hill-shaped curves without considering the underlying molecular mechanisms. Here we provide a novel mathematical formalization that allows prediction of the global behavior of a synthetic device by considering the actual information from the involved biological parts. This is achieved by adopting an enzymology-like framework, where transfer functions are described in terms of their input affinity constant and maximal response. As a proof of concept, we characterize a set of Lux homoserine-lactone-inducible genetic devices with different levels of Lux receptor and signal molecule. Our model fits the experimental results and predicts the impact of the receptor's ribosome-binding site strength, as a tunable parameter that affects gene expression. The evolutionary implications are outlined.


Involvement of TSLC1 in progression of esophageal squamous cell carcinoma.
Frequent allelic losses of 11q23 in esophageal squamous cell carcinoma (ESCC) have been reported previously, but no tumor suppressor genes in this region have been identified in ESCC. TSLC1 was identified on chromosome 11q23.2 as a tumor suppressor gene in non-small cell lung cancer by functional complementation of a lung adenocarcinoma cell line. The purpose of this study is to evaluate the role of TSLC1 in ESCC. Loss of TSLC1 expression was observed by reverse transcription-PCR in 75% of the cell lines (27 of 36) and 50% of the primary tumors from ESCC patients (28 of 56). In a clinicopathological analysis, loss of TSLC1 expression correlated significantly with depth of invasion (pT) and status of metastasis (pM; P = 0.012 and 0.036, respectively). Patients with tumors lacking TSLC1 expression tended to have a poorer prognosis than those with tumors expressing TSLC1. (P = 0.079). Moreover, TSLC1 expression was an independent prognostic factor in a multivariate analysis (P = 0.049). Methylation analyses revealed that TSLC1 expression or loss correlated with the promoter methylation status, as determined by bisulfite sequencing, and that TSLC1 expression could be restored by a demethylating agent in certain cell lines. The growth of TSLC1-transfected ESCC cells was significantly suppressed both in vitro and in vivo (P < 0.01), possibly by a G(1) cell cycle arrest. TSLC1 expression also suppressed motility and invasion of ESCC cells in vitro significantly (P < 0.01). These findings suggest that loss of TSLC1 expression has an important role in tumor growth, cell motility, and invasion and is associated with aggressive tumor behavior in ESCC.


Effect of bovine somatotropin on the distribution of immunoreactive insulin-like growth factor-I in lactating bovine mammary tissue.
The distribution pattern of immunoreactive insulin-like growth factor-I in normal lactating bovine mammary tissue and in tissue obtained after bovine somatotropin treatment was determined by indirect immunofluorescence. In normal tissue, insulin-like growth factor-I immunoreactivity was observed almost exclusively associated with stromal elements. Intralobular stromal cells, small blood vessels, and capillaries all expressed moderate to high immunoreactivity. In contrast, mammary epithelial cells displayed only sparse cytoplasmic immunoreactivity. Immunoreactive material was also present in the periductular connective tissue area, possibly associated with the basal plasma membrane of epithelial cells. Somatotropin treatment of animals resulted in elevated serum insulin-like growth factor-I concentrations and altered the distribution of insulin-like growth factor-I-stainable material in mammary tissue. After somatotropin treatment, immunoreactivity was still detected in mammary stroma; however, prominent staining was also observed in the cytoplasm of mammary epithelial cells. Given the possible role of insulin-like growth factor-I in the regulation of bovine mammary epithelial cell growth and function, our findings raise the possibility that somatotropin may induce insulin-like growth factor-I production in mammary tissue, or other tissues, to influence indirectly the growth or function of the epithelial cells. This offers a possible mechanism for bovine somatotropin stimulation of lactation.


Folate and homocysteine levels in pregnancy.
This study aims to determine serum folate and plasma homocysteine levels in healthy pregnant women following a live birth and compare them with healthy non-pregnant women. Fifty healthy gravid multiparous women are included in the study and 25 normal non-pregnant female subjects act as controls (group I). The pregnant women are divided into two groups according to interpregnancy interval: group II (six months or less); group III (18-24 months). Venous blood samples are analysed for red blood cell folate and homocysteine, vitamin B12, serum folate and albumin, and serum aminotransferases (ALT and AST). There was a significant decrease in red cell folate and serum folate in group II compared to the control group (P<0.001). Serum vitamin B12 showed no significant difference. Plasma homocysteine and serum albumin showed significant decreases in both groups II and III compared to the control group. (P<0.001) There was significant positive correlation between homocysteine and serum albumin in the three studied groups. (r=0.42, P<0.001; r=0.45, P<0.001; r=0.51, P<0.001, respectively). There was significant negative correlation between red cell folate and homocysteine in the three studied groups. (r=-0.48, P<0.001; r=-0.53, P<0.001; r=-0.49, P<0.001, respectively). Two cases in group II showed signs of intrauterine growth retardation. The results suggest that pregnant females with short interpregnancy intervals are more likely to develop folate deficiency. Educational strategies are required to increase folate awareness among women to promote the benefits of folic acid supplementation. Mandatory folate fortification of foods should be defined and monitored.


T regulatory cells in contact hypersensitivity.
The review summarizes the recent investigations focused on T regulatory cells in hapten diseases. Multiple mechanisms ensure tolerance to small chemicals penetrating the skin. Among these, specific T regulatory cells play a major role in controlling harmful immune responses to environmental antigens. Most of the T regulatory cells involved in this process belongs to the CD4 subset and suppress hapten-specific immune response through the release of IL-10 and through direct interaction with effector T cells, blocking their function. Methods for in-vitro and in-vivo expansion of specific T regulatory cells may represent an innovative approach for the cure of contact hypersensitivity.


Expected Basal Insulin Requirement During Continuous Subcutaneous Insulin Infusion Therapy by Age Group, Sex, and Body Mass Index, Based on 25,718 Young People with Type 1 Diabetes in the DPV Registry.
Background: Since the introduction of insulin pumps into the therapy of pediatric subjects, different approaches have been taken to find optimal basal rates. Previously, the DPV registry provided circadian basal rate patterns for different age groups. As the number of pump users has increased recently and short-acting insulin analogues are now predominant, we performed a new analysis with a larger data pool. Methods: We included all recent basal profiles from type 1 diabetes (T1D) patients between 1 and 25 years from the DPV 2021 data pool. We excluded night-time-only pump users, human regular insulin users, and daily basal rates <0.05 and >1.0 U/(kgBW·d). Results: In the analysis of profiles from 25,718 young persons with T1D, differences in the daily pattern of basal rates were found between age groups. In addition, we saw significant (P < 0.001) differences in total daily basal dose between genders in all age groups except adults. In addition, the shape of the expected basal-rate pattern differed by body mass index, HbA1c, and use of continuous glucose monitoring. Discussion: This analysis demonstrates multiple factors influencing basal patterns and insulin requirement, including age group, gender, overweight, HbA1c, bolus frequency, and sensor use. As circadian basal rates are still mandatory for initiating insulin pump therapy with or without automation, a multimodal approach is necessary to estimate optimal basal rates.


Lymphatic filariasis in Ghana: establishing the potential for an urban cycle of transmission.
Lymphatic filariasis is a significant public health and economic problem in many tropical and sub-tropical regions. Unplanned urbanization leading to a lack of proper sanitary conditions has resulted in an increase in the urban-based transmission of a number of vector-borne diseases, including lymphatic filariasis. It has been well established that lymphatic filariasis is endemic in rural areas of Ghana. The goal of this study was to determine if there is a potential of establishing urban transmission cycles in Ghana's major cities. We clinically and immunologically assessed 625 individuals from the three major urban areas (Bawku, Bolgatanga and Secondi/Takoradi), finding that the prevalence of infection with Wuchereria bancrofti ranged from 0 to 12.5%. The results of a polymerase chain reaction based analysis of mosquitoes collected from these areas suggested that there is a low but detectable prevalence of mosquitoes infected with W. bancrofti. We conclude that there may be a potential for an established urban transmission of lymphatic filariasis in Ghana.