Neuropeptide Y1 receptor inhibits cell growth through inactivating mitogen-activated protein kinase signal pathway in human hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers, and its incidence is increasing worldwide. Neuropeptide Y (NPY) broadly expressed in the central and peripheral nervous system. It participates in multiple physiological and pathological processes through specific receptors. Evidences are accumulating that NPY is involved in development and progression in neuro- or endocrine-related cancers. However, little is known about the potential roles and underlying mechanisms of NPY receptors in HCC. In this study, we analyzed the expression of NPY receptors by real-time polymerase chain reaction, Western blot, and immunohistochemical staining. Correlation between NPY1R levels and clinicopathological characteristics, and survival of HCC patients were explored, respectively. Cell proliferation was researched by CCK-8 in vitro, and tumor growth was studied by nude mice xenografts in vivo. We found that mRNA and protein level of NPY receptor Y1 subtype (NPY1R) significantly decreased in HCC tissues. Low expression of NPY1R closely correlated with poor prognosis in HCC patients. Proliferation of HCC cells was significantly inhibited by recombinant NPY protein in vitro. This inhibitory effect could be blocked by selected NPY1R antagonist BIBP3226. Furthermore, overexpression of NPY1R could significantly inhibit HCC cell proliferation. Knockdown of NPY1R promoted cell multiplication in vitro and increased tumorigenicity and tumor growth in vivo. NPY1R was found to participate in the inhibition of cell proliferation via inactivating mitogen-activated protein kinase signal pathway in HCC cells. Collectively, NPY1R plays an inhibitory role in tumor growth and may be a promising therapeutic target for HCC.


Evaluation of Clinical Practice Guidelines for Rare Diseases in Japan.
The insufficient quantity and quality of clinical epidemiological evidence in the field of rare diseases have posed methodological challenges to develop clinical practice guidelines (CPGs). Guideline development groups struggle to provide patients and their families with beneficial guidance, such as that for medical care and in complex circumstances. Motivated by the challenges, we focused on information on resources for supporting the daily and social life to improve the CPGs for users. We aimed to assess the methodological quality of CPGs for rare diseases in Japan and to evaluate information on resources to support the daily and social life in the CPGs. We conducted a systematic search using PubMed, three electronic Japanese databases, and two hand-searched sources in Japan. The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument with six domains was used to assess the methodological quality of the CPGs. A content analysis of the CPG text was conducted using five keywords as information on non-medical resources, e.g., "Intractable Disease Consultation Support Center," "Japan Intractable Disease Information Center," and "Patient Association." A total of 55 CPGs met the inclusion criteria. Among four domains of AGREE II with low scores (Stakeholder Involvement, Rigor of Development, Applicability, and Editorial Independence), Rigor of Development had the lowest median score. As for information on non-medical resources, 41 CPGs included at least 1 of the 5 keywords, while 14 CPGs included none. At the Rigor of Development domain, methodological challenges may have resulted in an insufficient description of items regarding the translation evidence to recommendations. As the sufficiency of five keywords as information on non-medical resources could be improved, the information will be advocative as clues to provide pragmatic guidance, particularly for rare diseases with limited medical evidence.


Reaction pathways in the decomposition of hydrogen peroxide catalyzed by copper(II).
The kinetics of the decomposition of H(2)O(2) catalyzed by Cu(II) has been studied by the initial-rate method in aqueous phosphate media at near physiological pH. The activity of the catalyst is increased by [Fe(CN)(6)](3-) and decreased by VO(3)(-), CrO(4)(2-) and Zn(II). Three reaction pathways are involved in the Cu(II)-H(2)O(2) reaction, the kinetic orders of the catalyst being 1 (rate constant k1), 2 (rate constant k2) and 3 (rate constant k3). The three pathways present fractional apparent orders (>1) in H(2)O(2) and base catalysis. The apparent activation energies associated to rate constants k1, k2 and k3 are 102+/-4, 65+/-8 and 61+/-5 kJ mol(-1). Free-radical chain mechanisms are proposed for the three pathways.


Anesthesiology residents' medical school debt influence on moonlighting activities, work environment choice, and debt repayment programs: a nationwide survey.
The amount of education debt incurred by medical school graduates in the United States has grown considerably over the last 30 years; it has outpaced inflation to reach a mean of $158,000. With this dramatic increase in education debt, there has been limited information on how medical school debt loads of anesthesiology physicians impact their decisions concerning moonlighting and future career choices. Our aim was to survey current anesthesiology interns, residents, and fellows to assess the correlation between the amount of medical school debt they had collected and (1) their outlook toward moonlighting activities, (2) future career plans, and (3) choice of employer with a debt repayment program. We developed a web-based survey instrument and contacted residency training programs to obtain access to their anesthesiology interns, residents, and fellows (residents). We assessed each relationship of interest using a multivariable proportional odds model, adjusting for all available baseline potential confounding factors. Second, we compared participants with >$150,000 medical school debt versus participants with no debt on the same questions of interest, each using a multivariable proportional odds model with the same covariable adjustment. We had access to 2386 residents through their training programs and 537 completed the survey. Those respondents with a 1-category-larger amount of medical school debt (i.e., $30,000) were associated with 7%(99.3% confidence interval: 0%, 13%) increased odds of having the desire to moonlight during residency/fellowship, and were associated with 7% (1%, 13%) decreased odds of saying they would choose a career as an academic faculty, respectively. Also, those with a larger amount of medical school debt were more likely to be swayed to be interested in an anesthesiology group with an education debt repayment program (odds ratio: 1.3 [1.22, 1.39] for 1-category increase in the debt amount); furthermore, the corresponding odds ratio was increased to 4.6 (2.8, 7.5) comparing those with >$150,000 debt with those without debt. In an effort to compete with private practice anesthesiology groups and to reduce the impact of debt on future career choices of residents/fellows, academic anesthesiology groups would do well to (1) promote moonlighting activities that are within the Accreditation Council for Graduate Medical Education and institutional guidelines, (2) develop financial curriculum for residents/fellows, and (3) offer debt repayment programs as an incentive for new faculty to join academic medicine.


Dead leaves and fire survival in Southern African tree aloes.
Many aloe species in southern Africa have stems clothed with a layer of persistent dead leaves. The degree of stem coverage is species-specific. The suggestion that persistent dead leaves have an insulatory function and are adaptive in fire-prone habitat was tested on Aloe ferox. Field surveys demonstrated a significant negative relationship between mortality and degree of stem coverage and laboratory studies confirmed the insulating properties of dead leaves. The distribution of southern African tree aloes supprts the prediction that bare-stemmed species would be confined to fire-free habitat whilst fully clothed species would occur in both fire-prone and fire-free habitat. The study suggests that harvesting of Aloe ferox leaves for medicinal purposes could result in significant mortality in fires.


[Association of antigens of the histocompatibility system in A and B loci in systemic lupus erythematosus].
The typing of histocompatibility HLA-B and A antigens was made in 63 patients with systemic lupus erythematosus (SLE). It was shown that the carriership of some histocompatibility antigens and association of definite antigens, in particular, increases the relative risk of the development of SLE. This was especially applicable to the following gene combinations: HLA-B-8/B12, HLA-B-18/10, HIA-AII/AI/A3 and some others. Definite associations were revealed between carriership of some histocompatibility antigens and development of some manifestations of SLE.


Late N1 and postimperative negative variation analysis depending on the previous trial history in paradigms of increasing auditory complexity.
Predictive coding reflects the ability of the human brain to extract environmental patterns in order to reformulate previous expectations. The present report analyzes through the late N1 auditory component and the postimperative negative variation (PINV) the updating of predictions regarding the characteristics of a new trial, depending on the previous trial history, complexity, and type of trial (standard or deviant). Data were obtained from 31 healthy subjects recorded in a previous study based on two paradigms composed of stimulus sequences of decreasing or increasing frequencies intermingled with the sporadic appearance of unexpected tone endings. Our results showed a higher amplitude for the most complex condition and deviant trials for both the late N1 and PINV components. Additionally, the N1 and PINV presented a different amplitude response to the standard and deviant trials as a function of previous trial history, suggesting a continuous updating of trial categorization. The results suggest that the late N1 and PINV components are involved in the generation of an internal model about the rules of external auditory stimulation.NEW & NOTEWORTHY The present study showed a higher amplitude for the late N1 and the PINV with reference to both the prediction performed in auditory paradigms of higher abstraction and the unexpected breaking of the extracted rules. Additionally, both components were modulated depending on the local probability, which would suggest that they are continuously being updated by the previous stimulus history.


Mutations reducing replication from R-loops suppress the defects of growth, chromosome segregation and DNA supercoiling in cells lacking topoisomerase I and RNase HI activity.
R-loop formation occurs when the nascent RNA hybridizes with the template DNA strand behind the RNA polymerase. R-loops affect a wide range of cellular processes and their use as origins of replication was the first function attributed to them. In Escherichia coli, R-loop formation is promoted by the ATP-dependent negative supercoiling activity of gyrase (gyrA and gyrB) and is inhibited by topoisomerase (topo) I (topA) relaxing transcription-induced negative supercoiling. RNase HI (rnhA) degrades the RNA moiety of R-loops. The depletion of RNase HI activity in topA null mutants was previously shown to lead to extensive DNA relaxation, due to DNA gyrase inhibition, and to severe growth and chromosome segregation defects that were partially corrected by overproducing topo III (topB). Here, DNA gyrase assays in crude cell extracts showed that the ATP-dependent activity (supercoiling) of gyrase but not its ATP-independent activity (relaxation) was inhibited in topA null cells lacking RNase HI. To characterize the cellular event(s) triggered by the absence of RNase HI, we performed a genetic screen for suppressors of the growth defect of topA rnhA null cells. Suppressors affecting genes in replication (holC2::aph and dnaT18::aph) nucleotide metabolism (dcd49::aph), RNA degradation (rne59::aph) and fimbriae synthesis (fimD22::aph) were found to reduce replication from R-loops and to restore supercoiling, thus pointing to a correlation between R-loop-dependent replication in topA rnhA mutants and the inhibition of gyrase activity and growth. Interestingly, the position of fimD on the E. coli chromosome corresponds to the site of one of the five main putative origins of replication from R-loops in rnhA null cells recently identified by next-generation sequencing, thus suggesting that the fimD22::aph mutation inactivated one of these origins. Furthermore, we show that topo III overproduction is unable to complement the growth defect of topA rnhA null mutants at low temperatures that stabilizes hyper-negatively supercoiled DNA.


RNA binding protein GNL3 up-regulates IL24 and PTN to promote the development of osteoarthritis.
Osteoarthritis (OA) is a degenerative disease, which has a high incidence in middle-aged and elderly people and tends to occur in weight-bearing or active joints. Current treatment can only relieve symptoms and delay the progression of OA in result of its indistinct pathogenesis. In recent years, more and more studies have focused on the pathogenesis of OA. Nucleolar GTP binding protein 3 (GNL3) is associated with chondrogenic differentiation and can participate in genomic regulation as RNA binding protein (RBP). We used RNA sequencing (RNA-seq) to analyze the overall transcription level of the human cervical cancer cell line HeLa after GNL3 deletion. The results showed that downstream genes IL24 and PTN were down-regulated. IL24 takes part in the progression of OA by inducing articular osteocyte apoptosis, while PTN conducts to the progression of OA by promoting angiogenesis. We validated the results in the human chondrosarcoma cell line SW1353 and OA patients. Compared with the control group, GNL3, IL24 and PTN genes were elevated in OA specimens. This study explored the relationship between GNL3 and these two downstream genes, hoping to find biomarkers in the pathogenesis of osteoarthritis that can be used as therapeutic targets in the future.


Argon laser treatment of a pupillary membrane in pseudophakia.
A method of opening an opacified, retrolental, intrapupillary membrane in a pseudophakic eye, using the argon laser, is presented. The procedure was safe, and the membrane remained retracted one year after treatment.


Correlation between 3',5', c-AMP levels and thyrotropin in separated rat pituitary thyrotropic cells.
The correlation between 3',5', c-AMP levels, TSH content and secretion of separated thyrotropic cells was studied. Incubation of the separated cells with 1, 10 and 100 ng of TRH does not change the 3',5',c-AMP levels, despite the significant rises of the TSH level. Dibutyryl c-AMP causes rise in TSH content, with no indication of its secretion. PGE2 10(-5) increased 3'5',c-AMP levels with no change in the content or secretion of TSH in separated thyrotropic cells.


Repair of Ramp Lesions of the Medial Meniscus With ACL Reconstruction Can Better Restore Knee Stability: A Cadaveric Study.
Ramp lesions of the medial meniscus have an impact on joint stability in anterior cruciate ligament (ACL)-deficient knees, but the impact of lesion length and repair is unclear. The purpose of this cadaveric study was to evaluate the effect of medial meniscal ramp lesion repair on the biomechanics of ACL-deficient knee joints. It was hypothesized that (1) ramp lesions will increase the anterior tibial translation (ATT), internal rotation (IR), and external rotation (ER) in ACL-deficient knee joints; (2) increasing the length of the ramp lesion will further increase the ATT, IR, and ER; and (3) repairing the ramp lesion will reduce the ATT, IR, and ER after ACL reconstruction. Controlled laboratory study. Included were 9 fresh-frozen cadaveric specimens (4 left knees, 5 right knees; 6 males and 3 females; mean age, 60 years [range, 40-73 years]). The specimens were tested on a biomechanical rig. Two external loading conditions were applied: a 134-N anterior tibial load and 5-N·m internal/external tibial torque with the knee at full extension and at 15°, 30°, 60°, and 90° of flexion. ATT was tracked via a high-speed video camera. The following knee states were tested: intact; ACL-deficient; ACL-deficient combined with a 5-, 10-, 15-, or 20 mm-long ramp lesion of the medial meniscus; ACL reconstruction; and ACL reconstruction combined with ramp lesion repair. The ATT, IR, and ER at all knee angles were analyzed by 1-way analysis of variance. The ATT, IR, and ER were significantly increased after cutting of the ACL (P < .05). The ATT, IR, and ER continued to increase when ACL deficiency was combined with ramp lesions of 5 to 20 mm in length (P < .05). The ATT, IR, and ER significantly decreased after ACL reconstruction and ACL reconstruction combined with ramp lesion repair (P < .05). The laxity of knees with ACL deficiency combined with a ramp lesion of the medial meniscus increased more obviously as the ramp lesion increased in length. In a cadaveric model, ACL reconstruction combined with ramp repair improved knee joint stability.


Simultaneous biodegradation of volatile and toxic contaminant mixtures by solid-liquid two-phase partitioning bioreactors.
Microbial inhibition and stripping of volatile compounds are two common problems encountered in the biotreatment of contaminated wastewaters. Both can be addressed by the addition of a hydrophobic auxiliary phase that can absorb and subsequently re-release the substrates, lowering their initial aqueous concentrations. Such systems have been described as Two Phase Partitioning Bioreactors (TPPBs). In the current work the performances of a solid-liquid TPPB, a liquid-liquid TPPB and a single phase reactor for the simultaneous degradation of butyl acetate (the volatile component) and phenol (the toxic component) have been compared. The auxiliary phase used in the solid-liquid TPPB was a 50:50 polymer mixture of styrene-butadiene rubber and Hytrel 8206, with high affinities for butyl acetate and phenol, respectively. The liquid-liquid TPPB employed silicone oil which has fixed physical properties, and had no capacity to absorb the toxic contaminant (phenol). Butyl acetate degradation was enhanced in both TPPBs relative to the single phase, arising from its sequestration into the auxiliary phase, thereby reducing volatilization losses. The solid-liquid TPPB additionally showed a substantial increase in the phenol degradation rate, relative to the silicone oil system, demonstrating the superiority and versatility of polymer based systems.


Educating Engineers for the Public Good Through International Internships: Evidence from a Case Study at Universitat Politècnica de València.
At Universitat Politècnica de València, Meridies, an internship programme that places engineering students in countries of Latin America, is one of the few opportunities the students have to explore the implications of being a professional in society in a different cultural and social context. This programme was analyzed using the capabilities approach as a frame of reference for examining the effects of the programme on eight student participants. The eight pro-public-good capabilities proposed by Melanie Walker were investigated through semi-structured interviews. The internship is an environment in which students can put into practice the knowledge they have acquired in undergraduate studies and to find practical relevance in what they studied. Occasionally, this also entails a critical questioning of what they have learned, a greater awareness of the limits of the contents of their studies and of the way things were taught, and interest in less explored issues that are closely linked to social justice. However, tensions can arise between the pro-public-good oriented perspectives of this programme, and a more instrumental vision. One way to overcome these tensions is to foster consideration of reflexivity, that is, the dynamic relationship between technology and society. To do so, the programme must create space before and during the internship, and upon the return of the students, to discuss and collectively reflect upon their lived experience. Additionally, it ought to engage supervisors in this educational journey, both at the university and in the host institutions, and also involve socially committed organisations in this task.


Microbial biotransformation of N-nitro-, C-nitro-, and C-nitrous-type mutagens by Lactobacillus delbrueckii subsp. bulgaricus in meat products.
Processed meats are classified by the International Agency for Research on Cancer (IARC) as carcinogenic to humans. However, information on the responsible agents and the influence of industrial processing on the increased risk of cancer is still lacking. This study aimed to use cultures of Lactobacillus delbrueckii subsp. bulgaricus LB-UFSC 01 to biodegrade harmful C-nitrous, N-nitro, and C-nitro compounds in processed meat matrix. Firstly, positive results for ethylnitrolic acid (ENA) (>5.00 μg kg-1) and 2-methyl-1,4-dinitro-pyrrole (DNMP) (>12.0 μg kg-1) were obtained in mortadellas produced under different experimental conditions employing preservatives and antioxidants. Mortadellas containing nitrite and sorbate in the ratio of 8:1 (w/w) yielded the highest concentrations of mutagens. However, the treatment with the LB-UFSC 01 culture was able to modulate the harmful compounds in the mortadella samples. Several analytical methods employing liquid chromatography coupled to mass spectrometry and statistical models were employed to identify the metabolites and reaction routes during microbial biotransformation. For the first time, relevant information regarding the formation and degradation of ENA and DNMP in a processed meat model simulating real conditions was presented.


An analysis of the presence of Fc receptors on bone marrow lymphoblasts in acute lymphoblastic leukemia. A Pediatric Oncology Group study.
The presence or absence of the Fc receptor (FcR) on bone marrow lymphoblasts was evaluated in 279 cases of acute lymphoblastic leukemia (ALL) by member institutions of the Pediatric Oncology Group (POG). The case material was classified as follows: 19 cases of positive (greater than or equal to 20% +), 24 additional cases as intermediate (greater than or equal to 10% but less than 20%), and the remaining 236 cases as negative (less than 10%). Intermediate and positive cases were relatively equally distributed between null cell leukemia and pre-B-cell leukemia, and there were one intermediate and two positive T-cell cases. One of two cases of B-cell leukemia was also positive. There were no distinguishing clinical or laboratory characteristics which distinguished the FcR+ cases, nor was the FcR of prognostic significance within ALL as a group or within immunologically defined phenotypes.


Novel triacsin C analogs as potential antivirals against rotavirus infections.
Recently our group has demonstrated that cellular triglyceride (TG) levels play an important role in rotavirus replication. In this study, we further examined the roles of the key enzymes for TG synthesis (lipogenesis) in the replication of rotaviruses by using inhibitors of fatty acid synthase, long chain fatty acid acyl-CoA synthetase (ACSL), and diacylglycerol acyltransferase and acyl-CoA:cholesterol acyltransferase in association with lipid droplets of which TG is a major component. Triacsin C, a natural ACSL inhibitor from Streptomyces aureofaciens, was found to be highly effective against rotavirus replication. Thus, novel triacsin C analogs were synthesized and evaluated for their efficacies against the replication of rotaviruses in cells. Many of the analogs significantly reduced rotavirus replication, and one analog (1e) was highly effective at a nanomolar concentration range (ED(50) 0.1μM) with a high therapeutic index in cell culture. Our results suggest a crucial role of lipid metabolism in rotavirus replication, and triacsin C and/or its analogs as potential therapeutic options for rotavirus infections.


Changes in the fatty acid composition of stored erythrocytes from sheep of different ages.
This study examined the profile in sheep erythrocyte fatty acids from animals of different ages during storage at 4 degrees C in a nutritive medium for up to 6 days. The changes found in the fatty acyl profile were a decrease (P < 0.01) in the percentage of arachidonic acid and an increase (P < 0.01) in the percentage of minor fatty acids (representing < 2% in each case; 20:2, 22:0 and 22:1) with respect to fresh erythrocytes in all age groups. However, the saturated/unsaturated ratios and unsaturated index started almost constant in all cases. The changes observed occurred after 24-48 h of storage, with significant increases (P < 0.01) in the fluorescence detected in the lipid extracts from stored erythrocytes during this period. The above findings suggest peroxidative damage and changes in the erythrocyte lipid membrane during storage.


An oxaliplatin + 5-fluorouracil bolus + folinic acid (BFOL) regimen as first-line treatment in metastatic colorectal cancer patients.
The purpose of the study was to evaluate the outcome of metastatic colorectal cancer patients treated, as first line, with 5-fluorouracil bolus/leucovorin + oxaliplatin, in terms of response, progression-free and overall survival. A retrospective cohort of consecutive metastatic colorectal cancer patients, treated from 2003 to 2006, was identified and analyzed. All patients, without a central venous device, were treated with oxaliplatin + 5-fluorouracil and leucovorin. Twenty-five metastatic colorectal cancer patients were treated. No 3-4 grade toxicity was observed. Five of 23 patients achieved a partial response: one of them resulted in a complete response after radiofrequency and another one after surgery. Fifteen of 23 patients had stable disease (one underwent radical surgery after chemotherapy, obtaining a complete remission) and 3 had progressive disease. Median progression-free survival was 7.2 months, and median overall survival was 30 months. Based on this case-series study, the regimen seems to offer a good control of disease (86.9%) and can be considered as an alternative choice for patients who cannot receive continuous infusion.


Controlling liquid crystal boojum defects on fixed microparticle arrays via capillarity-assisted particles assembly.
Colloidal particles in nematic liquid crystals (LCs) are of high interest for self-assembly of soft matter systems. When two free particles approach within a uniaxially-oriented nematic LC, an elastic force is generated due to the distorted nematic director configuration around them, allowing particles to self-assemble by an attractive force. We hypothesize that if particles are immobilized, repulsive forces emerge instead, causing the deflection of the interacting defects to compensate for the energy increase. We fabricated tailored arrays of spherical silica microparticles via capillarity-assisted particle assembly (CAPA) to investigate the interactions of defects as a function of particle separation. By transferring the particle arrays from the CAPA templates to a glass substrate, we studied interacting boojum defect textures within thin LC films sandwiched between two substrates using polarized optical microscopy (POM). We observed deflected boojum defects on arrays of fixed silica particles, confirming our hypothesis that the elastic repulsive force between the particles affects the defect orientation. The nematic director configuration is reconstructed by Landau-de Gennes q-tensor modeling, and simulated POM images are obtained by the Jones-Matrix method. Our results provide a new platform for controlling defect interactions and pave the way for future work to study topology and implement new defect based applications in LC films.


Micro-ultrasound Versus Magnetic Resonance Imaging in Prostate Cancer Active Surveillance.
Accurate assessment of tumor grade is critical for active surveillance (AS) in prostate cancer. We compared magnetic resonance imaging (MRI) and micro-ultrasound scoring (Prostate Imaging-Reporting and Data System [PI-RADS] v2.1 vs Prostate Risk Identification using Micro-ultrasound [PRI-MUS]) in 128 men on AS. The primary outcome was upgrading to Gleason grade group (GG) ≥2. There was no difference in GG ≥2 detection between the imaging techniques (PRI-MUS score ≥3: 33/34, 98%; PI-RADS score ≥3: 29/34, 85%; p = 0.22). The sensitivity, specificity, and positive and negative predictive values for GG ≥2 detection were 97%, 32%, 34%, and 97% with PRI-MUS ≥3, and 85%, 53%, 40%, and 91% with PI-RADS ≥3, respectively. Upgrading to GG ≥2 was more likely for PRI-MUS ≥3 than for PRI-MUS ≤2 scores (odds ratio 15.5, 95% confidence interval 2.0-118.5). A limitation is the lack of blinding to the MRI results. In conclusion, detection of upgrading to GG ≥2 during AS appears similar when using micro-ultrasound or MRI to inform prostate biopsy. We looked at a novel imaging technology, micro-ultrasound, in patients undergoing biopsy during active surveillance for prostate cancer. We found that micro-ultrasound can detect prostate cancer that may require treatment at a similar rate to that with magnetic resonance imaging (MRI) scans.


Trypsin, elastase, plasmin and MMP-9 activity in the serum during the human ageing process.
the aim of this work was to define the influence of the ageing process on the activity of proteolytic enzymes, such as trypsin, elastase, plasmin and active MMP-9 concentration, as well as the inhibitor alpha 1-antitrypsin. Moreover, we assessed associations between enzyme activity and selected clinical and biochemical parameters. healthy normotensive volunteers (n = 60, 30 women) aged 20-82 years were split into subgroups: young (aged 20-22), middle-aged (49-52) and elderly (77-82). Serum enzyme activity was assessed using fluorometric methods. overall, active MMP-9 concentration and trypsin activity decreased with age, and alpha1-antitrypsin concentration and plasmin activity increased. Activity of elastase increased with age when compared to the young age group. An inverse correlation was identified between MMP-9 concentration and BMI and a direct correlation found between BMI and elastase, plasmin activity and alpha1-antitrypsin concentration. In the middle-aged group, glucose correlated directly with trypsin activity and inversely with MMP-9 concentration. Trypsin activity and MMP-9 concentration correlated inversely with cholesterol concentration and plasmin and elastase activity, and the alpha1-antitrypsin concentration correlated with cholesterol concentration in the overall group. the results confirm the influence of the ageing process on the activity of serum proteolytic enzymes. The activity of individual proteolytic enzymes in the serum changes with age.


Cemental tear: To know what we have neglected in dental practice.
Cemental tear is a special kind of root surface fracture, contributing to periodontal and periapical breakdown. However, it is a challenge for doctors to diagnose, resulting in delayed or improper treatment. We reviewed the predisposing factors, location, radiographic/clinical characteristics, diagnosis and treatments of cemental tears. From the literature, patients with cemental tear were mainly males, over 60 year-old. Possible predisposing factors include gender, age, tooth type, traumatic occlusal force and vital teeth. Cemental tears were common in upper and lower anterior teeth, single or multiple, and can be present in cervical, middle and apical third of roots. Morphology of cemental tears can be either piece-shaped or U-shaped. Clinically, cemental tear shows a unitary periodontal pocket and signs/symptoms mimicking localized periodontitis, apical periodontitis and vertical root fractures. Treatment of cemental tears include scaling, root planning, root canal treatment, periodontal/periapical surgery, guided tissue regeneration, bone grafting, and intentional replantation. Recurrence of cemental tear is possible especially when the fracture involves root apex. Extraction is recommended for teeth with poor prognosis. In conclusion, cemental tears can involve both periodontal and periapical area. Dentists should understand the predisposing factors and clinical features of cemental tears for early diagnosis/treatment to prevent bone loss/tooth extraction.


New dosing regimens for amifostine: a pilot study to compare the relative bioavailability of oral and subcutaneous administration with intravenous infusion.
A phase I clinical trial was conducted to assess thefeasibility of a more convenient and safe dosing regime for the cytoprotective drug amifostine. Two alternative routes of administration, oral and subcutaneous (s.q.), each with a dose of 500 mg, were compared to a 7.5-minute intravenous (i.v.) infusion, with a dose of 200 mg/m2, in normal, healthy volunteers (N = 12). Bioavailability of amifostine (parent drug) and its pharmacologically active metabolite, WR-1065, was evaluated by comparing the area under the concentration-time curve (AUC) derived from HPLC analysis of amifostine and both protein-free and protein-bound WR-1065 in all three routes of administration. Results showed that SQ (but not oral) administration of amifostine could provide a more effective dosing regimen, in terms of both a reasonable AUC for the bound form of WR-1065 and decreased toxicity, compared to i.v. delivery. These data suggest that the protein-bound form of WR-1065 plays an important role in contributing to the bioavailability of this clinically useful cytoprotective drug.


Transport of beta-aminopropionitrile through intact skin or scar tissue.
A lathyrogen, [C14]aminopropionitrile (beta APN), was administered to 34 rats either in K-Y jelly or saline vehicles onto intact shaven skin or onto a healed splinted deep excision wound. The dynamics of beta APN transport and content in the skin or repair tissue was observed after 2, 5, 8, and 24 hr of topical administration. The repair tissue quickly absorbed the lathyrogen and reached maximum at the 2-hr sampling. The content of beta APN in the repair tissue was twice as high as that in K-Y jelly vehicle and remained high and stable for at least 24 hr only when beta APN was administered through a saline vehicle. The transport of beta APN through intact skin, irrespective of the vehicle tested, was slow and continuously increased. The study showed that almost 20% of the beta APN administered onto the wounded skin area was transported into the repair tissue within 2 hr. We suggest that, due to the absence of epidermal stratum corneum from the repair tissue, drugs, such as beta APN, penetrate quickly into the wound.


Response to long- and short-term salinity in populations of the C4 nonhalophyte Andropogon glomeratus Walter B.S.P.
This research was undertaken to investigate differences in salt tolerance under conditions in which salinity is increased gradually and maintained for long periods or increased rapidly and maintained for shorter periods. The responses of populations of a C4 nonhalophytic grass, Andropogon glomeratus, to long- and short-term salinity were measured under controlled environment conditions. Additionally, plants from a salt marsh population and an inland population were transplanted into a salt marsh and their survival compared. The relative growth reductions in the salt marsh and the inland populations under long-term salinity were similar. Survival of seedlings of 4 populations inundated with full-strength seawater over a relatively short period indicated differential capacities to tolerate soil salinities imposed in a manner similar to tidal inundation in a salt marsh. The greater survival of plants from the marsh population transplanted into the salt marsh further indicated genetic differentiation between the populations. These results indicate that genetic differentiation to salt tolerance in A. glomeratus is better reflected by survival after shortterm salinity events, rather than growth inhibition due to long-term salinity imposed gradually.


Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene.
Irreversible cardiomyopathy was caused by the therapeutic of anthracyclines in the chemotherapy of cancers. The cell apoptosis and autophagy were induced by anthracyclines in AC16 cells. MiR-223-3p ascends in anthracycline-treated AC16, but the expression of nuclear factor I-A (NFIA) was specifically down-regulated. However, the underlying molecular mechanism between NFIA and miR-223-3p is unclear now in AC16 cells. In our research, NFIA expression was dampened in AC16 cells by miR-223-3p mimics. Additionally, miR-223-3p knockdown hindered the apoptosis and autophagy in anthracycline-treated AC16. Furthermore, NFIA was predicted and verified as a miR-223-3p's downstream target and rescued the functions of miR-223-3p. These findings illustrated that miR-223-3p advances anthracycline-stimulated cardiomyocyte damage progression by targeting NFIA, implying the promising therapeutic function of miR-223-3p on cardiomyocyte damage in cancer patients.


Quantification of survivin mRNA in testes of infertile patients and in testicular germ cell tumours: high levels of expression associated with normal spermatogenesis.
Deregulated apoptosis of germ cells may contribute to male infertility as well as malignant transformation. Survivin, an inhibitor of apoptosis (IAP), is overexpressed in all the most common human malignancies, but barely detectable in normal tissues. We used real-time polymerase chain reaction (PCR) to quantify survivin mRNA expression in normal testes (n = 22), testes with defective spermatogenesis (n = 26) and testicular germ cell tumours (TGCTs; n = 16). Survivin was expressed at high levels in normal testes. Testicular survivin levels in infertile patients were related inversely to the severity of spermatogenic failure (p < 0.001), with a lack of expression in most specimens with pre-meiotic spermatogenic arrest and in all those with germ cell aplasia. Lower levels of expression were observed in TGCTs than in normal testes. While survivin expression was detected in most TGCTs with undifferentiated components (12 of 13), it was absent in all mature teratomas (n = 3). These data show that survivin is expressed in normal and transformed germ cells. Its downregulation in spermatogenic disorders indicates that survivin may contribute to the normal balance between germ cell proliferation and apoptosis. In TGCTs, survivin expression appears to be lost with somatic differentiation.


Histological alterations found in the ureter during organ preservation and early phases of renal transplantation.
There are no studies on the phenomena that occur on the ureter during organ preservation and immediately after transplantation. We studied ureteral fragments obtained during organ harvesting in the cadaver (n = 9), after cold preservation period (n = 18), and immediately after kidney graft reperfusion (n = 126). In addition to the histological analysis, we evaluated the risk factors for the development of lesions and their relation to the evolution of the transplant. Alterations were detected in 120 of the 126 fragments studied after graft reperfusion. Global cellular infiltration was considered to be normal, mild, and moderate to severe in 34.9%, 41.3%, and 23.8%, respectively, consisting mainly of CD8(+) T lymphocytes. Urothelial exfoliation and cell vacuolization were detected in 42% and 52.4% of the cases, respectively. There was an inverse relationship between donor ventilation time and the intensity of the cellular infiltration. Seven and three of the nine fragments obtained during organ harvesting showed mild cellular infiltration of the chorion and urothelium, respectively. Cold storage promoted minor histological changes. After reperfusion, there was increased urothelial infiltration in 11 of the 18 cases. There was no relation between the lesions encountered and human leukocyte antigen compatibilities, renal rejections episodes, or the evolution of the graft itself. Consequences of brain death mechanical ventilation were detected at the ureteral level, with abnormal lymphocytic infiltration in most cases. Cold storage did not produce any major histological changes. The lesions detected after graft reperfusion do not seem to involve immunological phenomena.


Direct referral of posterior capsular opacification by optometrists.
To study referrals of posterior capsular opacification (PCO) for laser capsulotomy by optometrists and compare direct referral with that via the general practitioner (GP). A prospective analysis of optometrist referrals with regard to diagnostic accuracy, appropriateness of referral, quality of letters and patient waiting times. Of 222 referrals, 156 were direct and 66 via the GP. Forty-five (20.3%) letters were of good quality, 141 (63.5%) were average and 36 (16.2%) were poor. Waiting times for direct referrals ranged from 2 to 30 weeks (mean 8.3 weeks, S.D. 4.1); that for referrals via the GP ranged from 4 to 25 weeks (mean 10.3 weeks, S.D. 3.6). Directly referred patients thus waited 2 weeks shorter than patients referred via GPs (95% confidence interval 0.7-3.1, p = 0.002). Diagnostic concurrence was 99% (211/213 patients). The rate of laser capsulotomy was 98.2% (215/219); 103 (46.4%) letters utilised a referral form (GOS18); 146 (65.8%) discussed subjective visual problems and five (2.3%) incorporated patient consent for provision of feedback to the referring optometrist. Direct optometrist referral is effective, accurate and reduces patient waiting time and GP workload. Referral letters should be typed or printed to optimise legibility. Patient consent for feedback should be obtained by the referring optometrist.


Role of chromosomal abnormalities in chronic lymphocytic leukemia.
Chromosomal aberrations occur in both B-CLL and T-CLL. The polyclonal B-cell mitogens, in particular Epstein-Barr virus and lipopolysaccharide from E. coli, have been used successfully to reveal chromosomal abnormalities in 40-60% of patients with B-CLL, while T-cell mitogens have shown chromosomal aberrations in T-CLL. The most common clonal chromosomal aberration in B-CLL is an extra chromosome 12, alone or together with other abnormalities. Other common aberrations are 14q+, structural aberrations on 6, 11, 12 and 13. Proto-oncogenes are frequently located close to breakpoints. The proto-oncogene c-K-ras is located on chromosome 12 and an abnormal transcript has recently been implicated in a subset of B-CLL-patients. An extra chromosome 12 as well as multiple chromosomal abnormalities in B-CLL appear to predict a less favourable prognosis. T-CLL is in most patients characterized by an inv(14), an extra 8q and structural abnormalities in chromosome 7. The genes for the specific T-cell receptor as well as the immunoglobulin heavy chain are located on these chromosomes. Chromosomal aberrations appear to have pathogenetic importance in both B-CLL and T-CLL.


PAK4, a target of miR-9-5p, promotes cell proliferation and inhibits apoptosis in colorectal cancer.
Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. P21-activated kinase 4 (PAK4) and miR-9-5p have emerged as attractive therapeutic targets in several tumor types, but in CRC, the regulation of their biological function and their target association remain unclear. The expression of PAK4 in CRC tissues was determined using quantitative real-time PCR and immunohistochemistry analyses. The targeted regulation between miR-9-5p and PAK4 was predicted and confirmed with bioinformatics analysis and the dual-luciferase reporter assay. Functional experiments, including the MTT assay and flow cytometry, were performed to investigate the impact of PAK4 knockdown and miR-9-5p overexpression on cell proliferation and apoptosis in CRC cells. We found that the expression of PAK4 was upregulated in CRC tissues. PAK4 knockdown significantly suppressed cell proliferation and promoted apoptosis in cells of the CRC cell lines HCT116 and SW1116. We also found that miR-9-5p directly targeted the 3'-UTR of PAK4 mRNA and negatively regulated its expression. The degree of downregulation of miR-9-5p inversely correlated with PAK4 expression. Intriguingly, enforced expression of miR-9-5p suppressed cell proliferation and promoted apoptosis. This could be partially reversed by PAK4 overexpression. These results suggest that miR-9-5p targeting of PAK4 could have therapeutic potential for CRC treatment.


Posttranslational modification of Aurora A-NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma.
t(4;14)(p16;q32) cytogenetic abnormality renders high level of histone methyltransferase NSD2 in multiple myeloma (MM) patients, and predicts poor clinical prognosis, but mechanisms of NSD2 in promoting chemoresistance have not been well elucidated. An epigenetics compound library containing 181 compounds was used to screen inhibitors possessing a prior synergistic effect with bortezomib (BTZ) in vitro. Molecular biology techniques were applied to uncover underlying mechanisms. Transcriptome profile assay was performed by RNA-seq. NSG mouse-based xenograft model and intra-bone model were applied to qualify the synergistic effect in vivo. We identified an Aurora kinase A inhibitor (MLN8237) possessed a significant synergistic effect with BTZ on t(4;14) positive MM cells. Aurora A protein level positively correlated with NSD2 level, and gain- and loss-of-functions of Aurora A correspondingly altered NSD2 protein and H3K36me2 levels. Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. Transcriptome profile assay of MM cells with AURKA depletion identified IL6R, STC2 and TCEA2 as the downstream target genes responsible for BTZ-resistance (BR). Clinically, higher expressions of these genes correlated with poorer outcomes of MM patients. Combined administration of MLN8237 and BTZ significantly suppressed tumour growth in LP-1 cells derived xenografts, and remarkably alleviated bone lesion in femurs of NSG mice. Aurora A phosphorylates NSD2 at S56 residue to enhance NSD2 methyltransferase activity and form a positive regulating loop in promoting MM chemoresistance, thus pharmacologically targeting Aurora A sensitizes t(4;14) positive MM to the proteasome inhibitors treatment. Our study uncovers a previously unknown reason of MM patients with t(4;14) engendering chemoresistance, and provides a theoretical basis for developing new treatment strategy for MM patients with different genomic backgrounds.


Tolerability of bevacizumab and chemotherapy in a phase 3 clinical trial with human epidermal growth factor receptor 2-negative breast cancer: A trajectory analysis of adverse events.
E5103 was a study designed to evaluate the efficacy and safety of bevacizumab. It was a negative trial for the end points of invasive disease-free survival and overall survival. The current work examines the tolerability of bevacizumab and other medication exposures with respect to clinical outcomes and patient-reported outcomes (PROs). Adverse events (AEs) collected from the Common Terminology Criteria for Adverse Events were summarized to form an AE profile at each treatment cycle. All-grade and high-grade events were separately analyzed. The change in the AE profile over the treatment cycle was delineated as distinct AE trajectory clusters. AE-related and any-reason early treatment discontinuations were treated as clinical outcome measures. PROs were measured with the Functional Assessment of Cancer Therapy-Breast + Lymphedema. The relationships between the AE trajectory and early treatment discontinuation as well as PROs were analyzed. More than half of all AEs (57.5%) were low-grade. A cluster of patients with broad and mixed AE (all-grade) trajectory grades was significantly associated with any-reason early treatment discontinuation (odds ratio [OR], 2.87; P = .01) as well as AE-related discontinuation (OR, 4.14; P = .001). This cluster had the highest count of all-grade AEs per cycle in comparison with other clusters. Another cluster of patients with primary neuropathic AEs in their trajectories had poorer physical well-being in comparison with a trajectory of no or few AEs (P < .01). A high-grade AE trajectory did not predict discontinuations. A sustained and cumulative burden of across-the-board toxicities, which were not necessarily all recognized as high-grade AEs, contributed to early treatment discontinuation. Patients with neuropathic all-grade AEs may require additional attention for preventing deterioration in their physical well-being.


Recognition and management of perinatal depression in general practice--a survey of GPs and postnatal women.
To identify ways to improve detection and access to treatment. A survey of general practitioners and postnatal women across Australia addressing knowledge of, and attitudes to, postnatal depression using case vignettes. General practitioners were significantly more likely to recognise depression than postnatal women, who were likely to seek help for more general or baby related issues. Both GPs and women favoured help from partners and counselling, but GPs significantly favoured antidepressants and women, natural therapies. Women have a low likelihood of presenting for depression, suggesting a role for screening by GPs. Women preferred psychological and social management than drugs for depression perinatally.


Post-COVID-19 Cholangiopathy: A Systematic Review.
Post-COVID-19 cholangiopathy (PCC) is a rare but poorly understood and serious complication of COVID-19 infection. We sought to better understand the epidemiology, mechanism of action, histology, imaging findings, and outcomes of PCC. We searched PubMed, Cochrane Library, Embase, and Web of Science from December 2019 to December 2021. Mesh words used "post-Covid-19 cholangiopathy," "COVID-19 liver injury," "Covid-19 and cholangiopathy," and "COVID-19 liver disease." The data on epidemiology, mechanism of action, histology, imaging findings, and outcomes were collected. PCC was reported in 30 cases during the study period. The mean (standard deviation [SD]) age was 53.7 (5). Men accounted for cases (83.3%). All patients had required intensive level of care and mechanical ventilation. Mean (SD) number of days from COVID infection to severe disease or liver disease was 63.5 (38). Peak mean (SD) alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and total bilirubin were 2014 (831.8) U/L, 1555 (2432.8) U/L, 899.72 (1238.6) U/L, and 10.32 (9.32) mg/dl, respectively. Four patients successfully underwent liver transplantation. PCC is a severe and progressive complication of COVID-19 infection. More research is needed to better understand the pathophysiology and best treatment approach. Clinicians should suspect PCC in patients with cholestatic liver injury following COVID-19 infection.


Propylene glycol pharmacokinetics and effects after intravenous infusion in humans.
Knowledge of the pharmacokinetics of propylene glycol (PG) is scarce, though it is used in a number of preparations for intravenous use. Although systemic toxicity appears to be uncommon, PG has been reported to cause lactic acidosis and other adverse effects. We describe a rapid gas chromatographic assay method for PG and the plasma pharmacokinetics after intravenous administration to six patients on nine occasions. The pharmacokinetics were nonlinear, based on a saturable clearance. The apparent first-order half-life was 2.3 +/- 0.7 h. There was no evidence of lactic acidosis, hemolysis, or increase in osmolality at 3-15 g/m2 PG infused over periods of 4 h.


Association of systemic beta-defensin-1 and -20G/A DEFB1 gene polymorphism with Behçet's disease.
Behçet's disease (BD) is a multisystem inflammatory disease of unknown etiology. Beta-defensins are antimicrobial peptides involved in epithelial host defense. To explore whether beta-defensins might be involved in BD pathogenesis, we examined plasma human beta-defensin-1 (hBD-1) and DEFB1 -20G/A polymorphism in BD patients. This case-control study included 106 BD patients fulfilling the criteria of the International Study Group for BD and 156 controls. The -20G/A genotypes were determined by PCR-RFLP analysis in all participants, and plasma hBD-1 was assessed by ELISA in 77 BD patients and 44 controls, only. Stepwise multiple regression models were applied to determine independent predictors for plasma hBD-1 in BD patients. Distribution of -20G/A genotypes was different between BD patients and controls. Compared to GG genotype, "GA" genotype [OR (95% CI), 3.12 (1.56-6.16); p = .001] and "AA" genotype [2.57 (1.10-5.96); p = .027)] were associated with increased risk for BD. Plasma hBD-1 concentrations were significantly higher in BD patients than controls (9.81 ± 3.52 ng/mL vs. 5.30 ± 3.02 ng/mL; p < .001), and in BD patients with neurological involvement than those without (11.1 ± 4.12 ng/mL vs. 9.19 ± 3.10 ng/mL; p = .040). No variation was noted according to other clinical features, treatment received or -20G/A genotypes. In multivariate analysis, neurological involvement was the only predictor for plasma hBD-1 (β, 0.274; p = .029). Findings suggest that hBD-1 and its encoding gene DEFB1 could modulate the risk for BD, especially for BD neurological involvement. Further work is needed for a better understanding of role of hBD-1 and its genetic variants in the pathogenesis of BD.


The Sulfo-Click Reaction and Dual Labeling of Nucleosides.
This article contains detailed synthetic procedures for the implementation of the sulfo-click reaction to nucleoside derivatives. First, 3'-O-TBDMS-protected nucleosides are converted to their corresponding 4'-thioacid derivatives in three steps. Then, various conjugates are synthetized via a biocompatible and chemoselective coupling procedure using sulfonyl azide partners. Finally, to illustrate the potential of the sulfo-click reaction, a nucleoside bearing two orthogonal azido groups is synthesized and engaged in one-pot dual labeling through a sulfo-click/copper-catalyzed azide-alkyne cycloaddition (CuAAC) cascade. The high efficiency of the sulfo-click reaction as applied to nucleosides opens up new possibilities in the context of bioconjugation. © 2020 Wiley Periodicals LLC. Basic Protocol 1: General protocol for the synthesis of 4'-thioacid-nucleoside derivatives Basic Protocol 2: Implementation of the sulfo-click reaction Basic Protocol 3: Synthesis of 3'-azido-4'-(carboxamido)ethane-sulfonyl azide-3'-deoxythymidine Basic Protocol 4: Detailed synthetic procedure for one-pot double-click conjugations.


Intern nursing students' perceived barriers to providing end-of-life care for dying cancer patients in a death taboo cultural context: A qualitative study.
Internationally, intern nursing students' experiences with dying patients and death are an area of great concern. However, barriers to providing end-of-life care for dying cancer patients have not been extensively investigated in mainland China, where death remains a taboo issue. Therefore, this study aimed to elucidate intern nursing students' perceived barriers to their performance in providing end-of-life cancer care in the Chinese cultural context. This was a descriptive, qualitative study. Twenty-one intern nursing students from three cancer centers in mainland China were interviewed between January 2021 and June 2022. A thematic analysis method was used to analyze the data. The theory of planned behavior was adopted to design the study and identify themes. A range of barriers related to attitudes, subjective norms, and perceived behavioral control that hindered intern nursing students from acquiring abilities to deal with patient dying and death were identified in the Chinese cultural context. Chinese intern nursing students encountered many barriers that affected their provision of end-of-life care to dying cancer patients. Strategies to improve their ability to provide appropriate end-of-life care should focus on helping them develop appropriate attitudes toward dying and death and how to overcome subjective norms and behavioral control barriers.


[Neurological soft signs in pervasive developmental disorders].
Many studies have focused on specific motor signs in autism and Asperger's syndrome, but few has been published on the complete range of neurological soft signs (NSS) in children with pervasive developmental disorder (PDD). Scarce are the studies evaluating NSS in children suffering from PDD not otherwise specified (PDDNOS). This study compared performance of 11 autistic children (AD) and 10 children with PDDNOS, with controls matched on age, sex and cognitive performance on Krebs et al.'s NSS scale. Because of the duration of the assessments and specific difficulties encountered in managing some items, an adaptation of the scale had to be made during a pilot study with the agreement of the author. To be eligible, patients had to meet the following inclusion criteria: an age range of 6-16 years, a diagnosis of autistic disorder or PDDNOS based on the DSM IV criteria (American Psychiatric Association 1994). The autism diagnostic interview-revised (ADI-R) was used in order to confirm the diagnosis and to evaluate the association of the symptoms to the severity of the NSS. The childhood autism rating scale (CARS) was completed for the patients in order to evaluate symptoms at the time of the NSS examination. Cognitive ability was assessed with Raven's progressive matrices. Were excluded patients with: history of cerebral palsy, congenital anomaly of the central nervous system, epilepsy, known genetic syndrome, tuberous sclerosis, neurofibromatosis, antecedent of severe head trauma, Asperger's syndrome, obvious physical deformities or sensory deficits that would interfere with neurological assessment, deep mental retardation and recent or chronic substance use or abuse. Healthy controls shared the same exclusion criteria, with no personal history of neurological, psychiatric disorder or substance abuse, no family history of psychiatric disorder and normal or retardation in schooling. All study procedures were approved by the local Ethics Committee (Comité d'éthique, Razi Hospital), according to the declaration of Helsinki. There was no difference between patients and controls with respect to sex, age and cognitive function. All children had an IQ higher than 81. Significant differences were found between AD children and control group in the motor integration function and sensory integration function. Different NSS scores were significantly higher in the PDDNOS group than in controls: the total scores, motor coordination, motor integration function, sensory integration and abnormal movements. Lower performance in motor coordination skills was associated with higher ADI-R communication score in the AD group. No relationship was found between NSS and CARS' total sore. This study confirms the impaired neurological functioning in autistic as well as PDDNOS children. The association of motor impairment with autistic symptoms highlights the argument that motor control problems can be part of the autism spectrum disorders. The lack of relationship between NSS and intellectual aptitude in the clinical sample provides new elements for the neurodevelopment model of the autism spectrum.


Validation of vessel size imaging (VSI) in high-grade human gliomas using magnetic resonance imaging, image-guided biopsies, and quantitative immunohistochemistry.
To evaluate the association between a vessel size index (VSIMRI) derived from dynamic susceptibility contrast (DSC) perfusion imaging using a custom spin-and-gradient echo echoplanar imaging (SAGE-EPI) sequence and quantitative estimates of vessel morphometry based on immunohistochemistry from image-guided biopsy samples. The current study evaluated both relative cerebral blood volume (rCBV) and VSIMRI in eleven patients with high-grade glioma (7 WHO grade III and 4 WHO grade IV). Following 26 MRI-guided glioma biopsies in these 11 patients, we evaluated tissue morphometry, including vessel density and average radius, using an automated procedure based on the endothelial cell marker CD31 to highlight tumor vasculature. Measures of rCBV and VSIMRI were then compared to histological measures. We demonstrate good agreement between VSI measured by MRI and histology; VSIMRI = 13.67 μm and VSIHistology = 12.60 μm, with slight overestimation of VSIMRI in grade III patients compared to histology. rCBV showed a moderate but significant correlation with vessel density (r = 0.42, p = 0.03), and a correlation was also observed between VSIMRI and VSIHistology (r = 0.49, p = 0.01). The current study supports the hypothesis that vessel size measures using MRI accurately reflect vessel caliber within high-grade gliomas, while traditional measures of rCBV are correlated with vessel density and not vessel caliber.


Maternal smoking among blacks and whites.
Data from a random sample of mothers and children participating in a study on the sequelae of low birth weight were used to examine potential risk factors of maternal smoking. It was hypothesized that maternal smoking will vary by race, age, education, psychiatric status, employment status, single mother status and indicators of the burden of child care. Low education, young age, current psychiatric disorder and having a child with a psychiatric disorder or a physical illness predicted maternal smoking. The association of maternal smoking with other factors, specifically maternal employment and indicators of the burden of child care, varied between blacks and whites. Single mother status and having pre-school children in the home was associated with a higher odds ratio for smoking in whites, but not in blacks. On the other hand, maternal employment was associated with a lower odds ratio for smoking in blacks only. This study identified common and race-specific predictors of smoking in white and black mothers. It emphasizes the need for a greater understanding of the social context of maternal smoking in different ethnic populations, and highlights the importance of the burden of child care as a factor in maternal smoking.


In situ regeneration of bone-to-tendon structures: Comparisons between costal-cartilage derived stem cells and BMSCs in the rat model.
Bone-tendon interface (BTI), also called enthesis, is composed of the bone, fibrocartilage, and tendon/ligament with gradual structural characteristics. The unique gradient structure is particularly important for mechanical stress transfer between bone and soft tissues. However, BTI injuries result in fibrous scar repairs and high incidences of re-rupture, which is attributed to the lack of local stem cells with tenogenic and osteogenic potentials. In the rat model, we identified unique stem cells from costal cartilage (CDSCs) with a high in situ regeneration potential of BTI structures. Compared to bone-marrow mesenchymal stem cells (BMSCs), CDSCs exhibit higher self-renewal capacities, better adaptability to low-oxygen and low-nutrient post-transplantation environments, as well as strong bi-potent differentiation abilities of osteogenesis and tenogenesis. After transplantation, CDSCs can survive, proliferate, and in situ gradually regenerate BTI structures. Therefore, CDSCs have a great potential for tissue engineering regeneration in BTI injuries, and have future clinical application prospects. STATEMENT OF SIGNIFICANCE: Tissue engineering is a promising technique for bone-to-tendon interface (BTI) regeneration after injury, but it is still a long way from clinical application. One of the major reasons is the lack of suitable seed cells. This study found an ideal source of seed cells derived from costal cartilages (CDSCs). Compared to the traditional seed cell BMSCs, CDSCs have higher proliferation ability, strong chondrogenic and tenogenic differentiation potential, and better adaptability to low-oxygen and low nutrient conditions. CDSCs were able to survive, proliferate, and regenerate BTI structures in situ, in contrast to BMSCs. CDSCs transplantation showed strong BTI structures regeneration potential both histologically and biomechanically, making it a suitable seed cell for the tissue engineering regeneration of BTI.


Psoriatic keratinocytes prime neutrophils for an overproduction of superoxide anions.
Psoriatic plaques result from an abnormal proliferation of keratinocytes associated with the local presence of T lymphocytes and neutrophils. The exact role of neutrophils in psoriatic lesions remains unclear. The present investigation was aimed at deciphering the capacity of psoriatic keratinocytes to alter in vitro functions of neutrophils. Blood neutrophils from healthy donors were incubated with psoriatic (PK) or healthy keratinocytes (HK) with and without IL-2-activated healthy T lymphocytes. The study was focussed on neutrophil capacity of adherence, viability and superoxide anion production. PK or HK with or without T lymphocytes similarly augmented neutrophil viability after 48 h of co-incubation. PK or HK did not directly activate the superoxide production by neutrophils. However, they both primed neutrophils for an increased fMLF-induced production of superoxide, an effect enhanced by the presence of T lymphocytes. PK were 1.5-fold more efficient than HK to augment this superoxide production. PK cultured with T lymphocytes induced the adhesion of neutrophils 4.7 times more efficiently than HK. The adherence of neutrophils was mediated through ICAM-1, LFA-1 and Mac-1, independently of bioactive lipids. The effects of PK and HK on neutrophil viability and priming were independent of direct cellular contact. In conclusion, keratinocytes can impact neutrophils by increasing their lifespan, and by priming them to overproduce superoxide. PK are more efficient than HK in priming neutrophils, an effect enhanced by T lymphocytes. These results indicate that neutrophils could contribute to psoriasis pathogenesis partly through their pathological interactions with PK.


Using Advanced Continuous Simulation Language (ACSL) to simulate, solve, and fit mathematical models in nutrition.
The ACSL programs (AEgis Technologies, 2000a, b) are fairly easy to use and provide a good combination of canned programming with the flexibility to do more, if one is willing to learn the language (for Fortran and m files). The manuals are fairly easy to understand but are not detailed enough. The manuals are geared toward operating the software. For the Optimize software, the best references are the Simusolv manuals (Steiner et al., 1990). ACSL also provides an interface (Open API or ACSL Server) which can be purchased separately. The interface allows compiled models to be distributed and run as independent programs with Visual Basic or C/C++. For models built with the Graphic Modeler, the interface is shareware.


[Assessment of psycho-trauma caused by the aggressions committed by patients with psychosis against their family caregivers: across-sectional survey].
the management of patients with psychosis is associated with a risk of exposure to violence which can affect all the stakeholders, in particular the family entourage. Caregiving role generates violence and this can have a psychological impact on the caregivers. The purpose of this study is to evaluate the prevalence of aggressions perpetrated by patients with psychosis on their family caregivers as well as to assess the psychological and traumatic impact on family caregivers and to identify factors associated with it. family caregivers of patient with psychosis were interviewed. We used two psychometric scales: the perception of prevalence of aggression scale (POPAS) and the impact of event scale-revised. the whole number of participants was 95. Three out of four caregivers (75.8%) reported having been subjected to moderate to severe aggressions by their sick relatives during the past year. Moderate to severe aggressions were significantly more common among older male caregivers, parents of patients with psychosis living in a different home. Fifty-four point seven percent of caregivers had possible posttraumatic stress disorder (PTSD) and the risk of developing this disorder increased significantly as the perceived severity of aggressions increased. The same sociodemographic profile of the caregivers, related to the severity of the aggressions, was associated with a risk of developing PTSD in the caregivers. the aggressions committed by patients with psychosis against their family caregivers appear to have a significant psychological and traumatic impact. Interventions targeting violence committed by patients with psychosis in their family environment should also be integrated into patient management.


An outbreak of cryptosporidiosis associated with exposure to swimming pool water.
An outbreak of cryptosporidiosis among visitors to a public swimming pool occurred in the late summer of 2002. We performed a retrospective cohort study, including 3 cohorts, A) 178 school-children who visited the pool on a single occasion, B) 263 arbitrarily chosen school children, aged 6-12 y, and their household members, living within the municipality where the outbreak occurred, and C) an additional 28 individuals with laboratory confirmed cryptosporidiosis. The outbreak lasted 4 weeks and affected an estimated 800-1000 individuals. The primary attack rate was 40-50%. The median incubation period was 5 d (range 2-13 d). The secondary attack rate was 8-10%. Diarrhoea was reported by 93% of the patients, abdominal pain 89%, nausea 73%, and fever 40%. Fifty-four percent had<5 loose stools and 20% had>10 loose stools per d. The duration of symptoms was 4-10 d for 52% and>10 d for 34% of the cases. This is the first reported outbreak of pool associated cryptosporidiosis in Sweden and emphasizes the importance of proper control routines of swimming pools with continuous assessment of the quality of the water sources and filtration processes.


Threat captures attention but does not affect learning of contextual regularities.
Some of the stimulus features that guide visual attention are abstract properties of objects such as potential threat to one's survival, whereas others are complex configurations such as visual contexts that are learned through past experiences. The present study investigated the two functions that guide visual attention, threat detection and learning of contextual regularities, in visual search. Search arrays contained images of threat and non-threat objects, and their locations were fixed on some trials but random on other trials. Although they were irrelevant to the visual search task, threat objects facilitated attention capture and impaired attention disengagement. Search time improved for fixed configurations more than for random configurations, reflecting learning of visual contexts. Nevertheless, threat detection had little influence on learning of the contextual regularities. The results suggest that factors guiding visual attention are different from factors that influence learning to guide visual attention.


The cyclin-dependent kinase family in the social amoebozoan Dictyostelium discoideum.
Cyclin-dependent kinases (Cdk) are a family of serine/threonine protein kinases that regulate eukaryotic cell cycle progression. Their ability to modulate the cell cycle has made them an attractive target for anti-cancer therapies. Cdk protein function has been studied in a variety of Eukaryotes ranging from yeast to humans. In the social amoebozoan Dictyostelium discoideum, several homologues of mammalian Cdks have been identified and characterized. The life cycle of this model organism is comprised of a feeding stage where single cells grow and divide mitotically as they feed on their bacterial food source and a multicellular developmental stage that is induced by starvation. Thus it is a valuable system for studying a variety of cellular and developmental processes. In this review I summarize the current knowledge of the Cdk protein family in Dictyostelium by highlighting the research efforts focused on the characterization of Cdk1, Cdk5, and Cdk8 in this model Eukaryote. Accumulated evidence indicates that each protein performs distinct functions during the Dictyostelium life cycle with Cdk1 being required for growth and Cdk5 and Cdk8 being required for processes that occur during development. Recent studies have shown that Dictyostelium Cdk5 shares attributes with mammalian Cdk5 and that the mammalian Cdk inhibitor roscovitine can be used to inhibit Cdk5 activity in Dictyostelium. Together, these results show that Dictyostelium can be used as a model system for studying Cdk protein function.


[Botulinum toxin A as a treatment of traumatic salivary gland fistulas].
Injury of salivary gland tissue in the head and neck, as the result of extensive trauma, can often be overlooked on initial examination. In two case reports, the primary treatment and further follow-up of injuries of the head resulting in a parotid-maxillary sinus fistula as well as a fistula between the skin and sublingual gland are illustrated. The successful use of botulinum toxin in the treatment of traumatic salivary gland fistulas is documented in both cases. Alternative diagnostic and treatment measures of salivary gland fistulas are discussed. Surgical repair of salivary fistulas as primary treatment should be carefully considered. Treatment of a salivary fistula with the injection of botulinum toxin is possibly advantageous compared to spontaneous fistula closure. The injection of botulinum toxin shortens fistula closure time, is minimally invasive, effective and tolerable for the patient.


The role of the vascular endothelial growth factor/vascular endothelial growth factor receptors axis mediated angiogenesis in curcumin-loaded nanostructured lipid carriers induced human HepG2 cells apoptosis.
Curcumin (diferuloylmethane), the active constituent of turmeric extract has potent anti-cancer properties have been demonstrated in hepatocellular carcinoma (HCC). However, its underlying molecular mechanism of therapeutic effects remains unclear. Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have crucial roles in tumor angiogenesis. The goal of this study was to investigate the role of the VEGF/VEGFRs mediated angiogenesis during the proliferation and apoptosis of human HepG2 hepatoma cell line and the effect of curcumin-loaded nanostructured lipid carriers (Cur-NLC). The proliferation of HepG2 cells was determined by methyl thiazolyl tetrazolium after exposure to Cur-NLC and native curcumin. Apoptosis was quantified by flow cytometry with annexin V-fluorescein isothiocyanate and propidium iodide staining. Cellular internalization of Cur-NLC was observed by fluorescent microscope. The level of VEGF was detected by enzyme-linked immunosorbent assay kits. The expression of VEGFRs was quantified by Western blotting. Cur-NLC was more effective in inhibiting the proliferation and enhancing the apoptosis of HepG2 cells than native curcumin. Fluorescent microscope analysis showed that HepG2 cells internalized Cur-NLC more effectively than native curcumin. Furthermore, Cur-NLC down-regulated the level of VEGF and the expression of VEGFR-2, but had a slight effect on VEGFR-1. These results clearly demonstrated that Cur-NLC was more effective in anti-cancer activity than the free form of curcumin. These studies demonstrate for the 1 st time that Cur-NLC exerts an antitumor effect on HepG2 cells by modulating VEGF/VEGFRs signaling pathway.


Multiple molecular forms of glia maturation factor.
Glia maturation factor from the pig brain can be detected in two molecular forms: the high molecular weight form which is 200 000 dalton in size and the low molecular weight form which is 40 000 dalton in size, as determined by Sephadex gel filtration. The former accounts for 85% of the total biological activity extracted at physiologic pH. The proportion of the low molecular weight form increases following freeze-thawing and ion-exchange chromatography. In addition to the morphological effects, both forms possess mitogenic activity but no esteropeptidase activity. Both forms show similar enzyme susceptibility, being inactivated by papain, ficin and pronase but resistant to subtilisin, thermolysin and trypsin. The high molecular weight form is more resistant to denaturation by low pH, heating and urea than the low molecular weight form. The high molecular weight factor has an isoelectric point of 4.27 whereas the low molecular weight factor has one of 5.04.


High-quality Japanese flounder genome aids in identifying stress-related genes using gene coexpression network.
The Japanese flounder is one of the most economically important marine flatfish. However, due to the increased frequency of extreme weather events and high-density industrial farming, an increasing number of environmental stresses have become severe threats to the healthy development of the Japanese flounder culture industry. Herein, we produced a high-quality chromosome-scale Japanese flounder genome using PacBio Circular Consensus Sequencing technologies. The assembled Japanese flounder genome spanned 588.22 Mb with a contig N50 size of 24.35 Mb. In total, 105.89 Mb of repetitive sequences and 22,565 protein-coding genes were identified by genome annotation. In addition, 67 candidate genes responding to distinct stresses were identified by gene coexpression network analysis based on 16 published stress-related RNA-seq datasets encompassing 198 samples. A high-quality chromosome-scale Japanese flounder genome and candidate stress-related gene set will not only serve as key resources for genomics studies and further research on the underlying stress responsive molecular mechanisms in Japanese flounder but will also advance the progress of genetic improvement and comprehensive stress-resistant molecular breeding of Japanese flounder.


Multimodal ultrasound imaging of persistent urogenital sinus with uterus didelphys and double vagina malformation: A case report.
Persistent urogenital sinus (PUG) with uterus didelphys and double vagina is a rare urogenital anomaly. The diagnosis is based on magnetic resonance examination and cystoscopy. To the best of our knowledge, there is no literature report of PUG diagnosed by ultrasound alone. A 23-year-old woman presented with atypical menstruation and recurrent hematuria for 13 years and recurrent lower abdominal pain for 12 years. PUG was diagnosed through multiple ultrasound modalities, including transabdominal 2-dimensional ultrasound, transrectal bi-plane high-frequency ultrasound, and contrast-enhanced ultrasound. We diagnosed this malformation preoperatively by accurately measuring the length of urethra and common channel through multimodal ultrasound imaging. Urethra separation and reconstruction, vaginal pull-through and artificial vaginoplasty, and bilateral hysterosalpingectomy were performed. The postoperative course was uneventful. She was urinating normally after half a year and used continuous vaginal dilatation to avoid stenosis. PUG associated with uterus didelphys and double vagina is an extremely rare malformation of the reproductive system. Multimodal ultrasound imaging can be used to diagnose this malformation preoperatively clearly and to accurately measure the length of urethra and common channel, providing an imaging basis for preparing an operative plan.


[Serological and histological investigations as well as studies on changed food uptake during adrenaline application by intraperitoneal depot capsule].
The authors have developed a method for long-term permanent application of water soluble substances by a intraperitoneal depot capsule [KLINGENBERG et al., Exp. Path. 13, 302-311 (1977)]. The present study deals with the effects on the liver and several metabolic processes induced by continuous long-term adrenaline application by means of such a depot capsule.


Factors influencing the choice between laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass.
While laparoscopic sleeve gastrectomy (LSG) continues to be the most commonly performed bariatric operation, several variables influence surgeons' practice patterns and patients' decision-making in the type of bariatric procedure to perform. The aim of this study was to evaluate patient factors that influence the decision between laparoscopic Roux-en-Y gastric bypass (LRYGB) versus LSG. The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database was queried for patients undergoing LSG and LRYGB between 2015 and 2017. Univariate analysis and multivariate logistic regression were used to evaluate factors associated with performing LRYGB compared to LSG. A total of 252,117 (72.3%) LSG and 96,677 (27.7%) LRYGB cases were identified. Patients undergoing LSG were younger (44.3 ± 12.0 vs 45.2 ± 11.8 years; p < 0.01) and had a lower body mass index (BMI; 45.1 ± 7.8 vs 46.2 ± 8.1 kg/m2; p < 0.01). Most of the patients were females (79.4%), white (73.0%), with an American Society of Anesthesiology (ASA) class ≤ 3 (96.4%). The factors associated with undergoing LRYGB compared to LSG were diabetes mellitus, gastroesophageal reflux disease, BMI ≥ 50 kg/m2, ASA class > 3, obstructive sleep apnea, hypertension, and hyperlipidemia. However, patients with kidney disease, black race, chronic steroid use, age ≥ 60 years, recent smoking history, chronic obstructive pulmonary disease, and coronary artery disease were more likely to undergo LSG. The decision to perform LRYGB is primarily driven by obesity-associated comorbidities and higher BMI, whereas LSG is more likely to be performed in higher risk patients.


Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1.
The Notch1-mediated signaling pathway has a central role in the maintenance of neural stem cells and contributes to growth and progression of glioblastomas, the most frequent malignant brain tumors in adults. Here, we demonstrate that the Notch1 receptor promotes survival of glioblastoma cells by regulation of the anti-apoptotic Mcl-1 protein. Notch1-dependent regulation of Mcl-1 occurs cell type dependent at a transcriptional or post-translational level and is mediated by the induction of epidermal growth factor receptor (EGFR). Inhibition of the Notch1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation, the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or the Bcl-2/Bcl-XL inhibitor ABT-737. In conclusion, targeting Notch1 might represent a promising novel strategy in the treatment of glioblastomas.


Modification of lipopolysaccharide non-responder cells in low cell density culture.
Lipopolysaccharide (LPS) fails to induce polyclonal antibody responses in LPS non-responder C3H/HeJ mice in vivo and also in in vitro cultures of 10(7) cells/ml of C3H/HeJ spleen cells. However, this study shows that LPS elicits polyclonal antibody synthesis in low cell density cultures of C3H/HeJ cells by activation of a translational process without an increase in total RNA and messenger RNA synthesis. Polyclonal antibody synthesis by LPS non-responder cells in low cell density culture was significantly increased by LPS in either serum-free medium or medium containing serum. LPS-induced antibody production by LPS non-responder cells in low cell density was not due to the relative elevation of LPS concentrations.


Outcomes after Failed Pneumatic Retinopexy for Retinal Detachment.
To provide visual and anatomic outcomes for patients with retinal detachment (RD) in whom primary pneumatic retinopexy (PR) failed. Retrospective, single-center, consecutive case series. Eyes with RD that failed a primary PR. Anatomic and functional outcomes were evaluated for patients receiving treatment for failed PR. Three secondary procedures were compared, including repeat PR, pars plana vitrectomy (PPV), and combined scleral buckle (SB) plus PPV (SB+PPV). Anatomic reattachment and visual acuity (VA) at 1 year. Of a total of 423 primary PRs performed for RD, this study included 73 cases that failed. The overall single surgery anatomic success rate for the secondary procedure was 75%; the final success rate at 1 year was 100%. There was no statistically significant difference in success rates between repeat PR (63%), PPV (76%), and SB+PPV (88%). Improvement in VA was similar at 1 year between all 3 groups. Visual acuity at 1 year was similar between eyes undergoing PPV and SB+PPV (0.47 logMAR VA [Snellen equivalent, 20/59] for PPV and 0.52 logMAR VA [Snellen equivalent, 20/66] for SB+PPV; P = 0.75). Visual acuity at 1 year was better for those without macular involvement at the time of secondary procedure compared with eyes whose maculae detached (0.29 logMAR VA [Snellen equivalent, 20/39] vs. 0.73 logMAR VA [Snellen equivalent, 20/106]; P < 0.005). Fifty percent of PR failures underwent a secondary procedure within 1 week of primary PR; 80% occurred within 1 month. Anatomic success rates for secondary PR, PPV, and SB+PPV after failed PR were lower than published success rates for their use in primary RD. This suggests that a failed primary PR selects for RDs that are inherently more difficult to reattach. There was a trend suggesting that anatomic success rates are greater with SB+PPV than PPV and, in turn, with PPV than repeat PR. However, these differences were not statistically significant and did not translate into better VA gains at 1 year for either procedure. The suitable procedure after failed PR thus depends on patient presentation, surgeon preference, and patient preference.


Non-homogeneous infinite sites model under demographic change: mathematical description and asymptotic behavior of pairwise distributions.
We developed a mathematical model, which makes possible to predict joint distributions of numbers of mismatches in two or more linked regions of the genome, based on the Infinite Sites Models, under mutation-drift equilibrium as well as under various patterns of population growth. With mutation rates varying in the region, one of the predictions is different correlation between numbers of mismatches in the two regions, depending on the pattern of the past population growth (constant, slowly growing, or rapidly growing). Also, for slower growth patterns of population sizes, the coalescence tree is not necessarily 'starlike'. Thus, the joint distribution of mismatches, predicted by the model, provides additional insights into the demographic history of the populations. We also developed expectations and variances of sample statistics under different growth scenarios. As an application we used a sample of mitochondrial sequences from hypervariable regions 1 and 2 (HV1 and HV2), representing major world populations (Europeans, Asians and Africans). The patterns of joint distributions of numbers of mismatches differ markedly from one population to another. In addition, there is a considerable variability in the proportion of numbers of mismatches between HV1 and HV2 sequences. The patterns of bivariate distributions from the HV1 and HV2 data in these data are consistent with those generated by the model involving a stepwise change in population size.


Signaling microdomains: InsP(3) receptor localization takes on new meaning.
A fundamental question in cell biology is how different receptor-mediated signaling cascades, despite utilizing many of the same intracellular components, can generate specific cellular responses. Delmas and colleagues (in this issue of Neuron) address this question in relation to the muscarinic acetylcholine receptor (M(1)AchR) and the B(2) bradykinin receptor (B(2)R). Using Trp channel isoforms as biosensors for PLC stimulation in response to agonist activation, they demonstrate a role for signaling microdomains in the induction of such selective responses.


Mycobacterial infection of the hand: clinical features and functional results.
The clinical and laboratory features of twenty-eight patients with mycobacterial infection of hand are presented and discussed. Hand function assessment in fourteen patients showed that the majority had satisfactory results. The possibility of atypical mycobacterial infection is emphasised.


Bilateral Pneumothorax Post Emergency Airway Intervention.
A patient with diffuse axonal injury, with compound type 2 fracture of left tibia and fat embolism, post road traffic accident, was taken up for tracheostomy. He was diagnosed to have developed bilateral pneumothorax following the procedure, which according to literature has been of rare incidence. The causes of the pneumothorax following the procedure could be attributed to a tear or trauma in the posterior tracheal wall while inserting the tube or due to the rupture of alveolar bullae or bleb.


Amnion-derived cellular cytokine solution: a physiological combination of cytokines for wound healing.
Wound repair is a complex integration of dynamic processes mediated by humeral messages controlling the levels of cytokines, growth factors, and matrix metalloproteinases in the wound space. Isolated growth factors and growth factor combinations have been used to accelerate wound healing with limited success. A cellular cytokine solution can be collected by harvesting the proteins released from amnion-derived multipotent progenitor cells. The purpose of this study was to compare levels of cytokines/growth factors in amnion-derived cellular cytokine solution with physiological levels reported in the medical literature. Amnion-derived multipotent progenitor cells were grown to confluency, and the proteins secreted were characterized by qualitative and quantitative analysis. These results were compared with physiologic levels reported in the medical literature. The results demonstrated that amnion-derived cellular cytokine solution contained physiologic levels of cytokines relevant to wound healing, including platelet-derived growth factor, vascular endothelial growth factor, angiogenin, transforming growth factor beta 2, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2. The ranges (mean +/- standard deviation) were as follows: platelet-derived growth factor, 86 +/- 33 pg/mL; vascular endothelial growth factor, 5.7 +/- 1.5 ng/mL; angiogenin, 1.0 +/- 0.33 ng/mL; transforming growth factor beta 2, 500 +/- 330pg/mL; tissue inhibitor of metalloproteinase-1, 530 +/- 140 ng/mL; and tissue inhibitor of metalloproteinase-2230 +/- 40 ng/mL. These levels are comparable with the physiologic levels reported in the literature. The physiologic levels of cytokines important to healing found in amnion-derived cellular cytokine solution suggest that amnion-derived cellular cytokine solution may be of benefit in healing certain acute and chronic wounds.


Subject specific finite element modeling of periprosthetic femoral fracture using element deactivation to simulate bone failure.
Subject-specific finite element (FE) modeling methodology could predict peri-prosthetic femoral fracture (PFF) for cementless hip arthoplasty in the early postoperative period. This study develops methodology for subject-specific finite element modeling by using the element deactivation technique to simulate bone failure and validate with experimental testing, thereby predicting peri-prosthetic femoral fracture in the early postoperative period. Material assignments for biphasic and triphasic models were undertaken. Failure modeling with the element deactivation feature available in ABAQUS 6.9 was used to simulate a crack initiation and propagation in the bony tissue based upon a threshold of fracture strain. The crack mode for the biphasic models was very similar to the experimental testing crack mode, with a similar shape and path of the crack. The fracture load is sensitive to the friction coefficient at the implant-bony interface. The development of a novel technique to simulate bone failure by element deactivation of subject-specific finite element models could aid prediction of fracture load in addition to fracture risk characterization for PFF.


Internal derangement of the knee caused by a loose fragment of methylmethacrylate following uni-compartmental total knee arthroplasty: a case report.
Internal derangement of the knee joint following uni-compartmental total knee arthroplasty was caused by a loose fragment of methylmethacrylate lodging in the normal compartment of the knee joint.


Sex differences in airway volume and 3-dimensional shape in Japanese adults.
(1) To establish normative data for three-dimensional (3D) measurements of the upper airway in young Japanese adults, and (2) to investigate sex-related differences in linear and volumetric measurements, as well as shape. This study employed cone-beam computed tomography (CBCT) images of 56 Japanese young adults preselected from among 1000 patients, so that samples matched a historic 2D cephalometric cohort with normal occlusion using propensity score matching. Three-dimensional models of the oropharynx and hypopharynx were reconstructed from CBCT images and their volumes were calculated. We defined 20 landmarks on the surface of the 3D model and performed seven linear measurements between them. The mean and standard deviation of the linear measurements were calculated as the normative data for each sex as well as the volumes. Sex-related differences were analyzed using t-test (p < 0.05). Principal component discriminant analysis of the coordinate values of the landmarks was also performed to examine sex differences in shape. The normative ranges of the 3D measurements of the oropharynx and hypopharynx were determined according to sex. Sex-related differences in the measurement results were observed in hypopharyngeal length but not in volume. The hypopharynx length in males was significantly longer than that in females. The discriminant analysis showed that males tended to show longer and straight shapes, while females showed inversed triangular shapes from the frontal view. This result will allow clinicians to evaluate how patient airway characteristics differ from the normative 3D morphology of the upper airway.


Polymeric and small molecule-conjugates of temozolomide as improved therapeutic agents for glioblastoma multiforme.
Temozolomide (TMZ), an imidazotetrazine, is a second-generation DNA alkylating agent used as a first-line treatment of glioblastoma multiforme (GBM). It was approved by FDA in 2005 and declared a blockbuster drug in 2008. Although TMZ has shown 100% oral bioavailability and crosses the blood-brain barrier effectively, however it suffers from limitations such as a short half-life (∼1.8 h), rapid metabolism, and lesser accumulation in the brain (∼10-20%). Additionally, development of chemoresistance has been associated with its use. Since it is a potential chemotherapeutic agent with an unmet medical need, advanced delivery strategies have been explored to overcome the associated limitations of TMZ. Nanocarriers including liposomes, solid lipid nanoparticles (SLNs), nanostructure lipid carriers (NLCs), and polymeric nanoparticles have demonstrated their ability to improve its circulation time, stability, tissue-specific accumulation, sustained release, and cellular uptake. Because of the appreciable water solubility of TMZ (∼5 mg/mL), the physical loading of TMZ in these nanocarriers is always challenging. Alternatively, the conjugation approach, wherein TMZ has been conjugated to polymers or small molecules, has been explored with improved outcomes in vitro and in vivo. This review emphasized the practical evidence of the conjugation strategy to improve the therapeutic potential of TMZ in the treatment of glioblastoma multiforme.


Radiation-induced generation of chlorine derivatives in N2O-saturated phosphate buffered saline: toxic effects on Escherichia coli cells.
The radiolysis of aqueous chloride solutions has been investigated using pulse and steady-state methods. We have found a correlation between the yields of Cl2- and HOCl formed in pulse-irradiated N2O-saturated solutions. The yields increased with the increasing concentrations of Cl- and phosphate. Phosphate enhanced the yield of Cl2- in neutral solutions because of a proton transfer from H2PO4- to HOCl- with a rate constant of (2.6 +/- 0.5) x 10(8) M-1s-1. HOCl could not be detected in pulse-irradiated He or air-saturated, phosphate-buffered saline (PBS) solutions or in gamma-irradiated N2O, He, or air-saturated PBS solutions. The results are discussed in light of previously suggested mechanisms for the formation and decay of Cl2-. Pulse-irradiated N2O-saturated PBS solutions have a lethal effect on Escherichia coli cells, which is proportional to the amount of HOCl in the solutions. Gamma-irradiation of cells in N2O-saturated PBS solution also raises the radiosensitivity of the cells, although HOCl does not accumulate in this system. The effects of the radiation-induced toxic products on E. coli cells are similar to the effects of NaOCl. The cell membrane is probably the site of physiological injury induced by the radiation products.


Using behavioral economics to promote healthy behavior toward sun exposure in adolescents and young adults.
Skin cancer represents an important public health problem, and it is associated with ultraviolet radiation exposure, particularly at early ages. Unhealthy sun exposure and intentional tanning continue to be the trend among young people. Multiple interventions to raise awareness of the risks of sun exposure have been implemented, without necessarily translating into decreased unhealthy behaviors or skin cancer incidence rates. Behavioral economics adds a set of concepts and tools to potentially boost the efficacy of existing approaches to decrease unhealthy sun exposure. This paper reviews public health interventions that have been based in behavioral economics concepts and their results, and provides examples of new and creative ways physicians and health professionals can actively apply insights from behavioral economics to counsel teenagers and young adults about skin cancer prevention.


The influence of the ev 3 locus on the inducibility of serum antibody reactivity for envelope glycoprotein group-specific determinants.
Chickens segregating for the ev 3 locus were bred by backcross matings of line 6(3) to line 15B. Analysis of RAV-1-infected segregants indicated that inducibility of antibody reactivity for envelope glycoprotein group-specific determinants correlated with the absence of ev 3, whereas noninducibility correlated with the presence of ev 3. Since the ev 3(+) and ev 3(-) segregants possessed similar genetic backgrounds, these results provide direct evidence that the ev 3 locus determines the phenotype of noninducibility.