Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene.
We have detected deletions of portions of the Y chromosome long arm in 12 of 89 men with azoospermia (no sperm in semen). No Y deletions were detected in their male relatives or in 90 other fertile males. The 12 deletions overlap, defining a region likely to contain one or more genes required for spermatogenesis (the Azoospermia Factor, AZF). Deletion of the AZF region is associated with highly variable testicular defects, ranging from complete absence of germ cells to spermatogenic arrest with occasional production of condensed spermatids. We find no evidence of YRRM genes, recently proposed as AZF candidates, in the AZF region. The region contains a single-copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein. The possibility that DAZ is AZF should now be explored.


Hyperuricemia is associated with sympathovagal imbalance in older adults.
This study aimed to compare heart rate variability (HRV) parameters obtained through symbolic analysis (SA), between older adults with and without hyperuricemia. This is a cross-sectional study including 202 community-dwelling old adults, which was clinically stratified as with or without hyperuricemia, according to the cutoff point of serum uric acid ≥ 6 mg/dL for women and ≥ 7 mg/dL for men. Successive RR intervals were recorded along 5 min and analyzed with SA method. 0 V%, 1 V% and 2 V% patterns were quantified and compared between groups. Comparisons were carried out through parametric or nonparametric tests, according to the data distribution characteristics, evaluated by Kolmogorov-Smirnov test. The significance level was set as p ≤ 0.05 for all statistical procedures. The prevalence of hyperuricemia was 67.8 %, and the hyperuricemic older adults exhibited significant higher values for V0% and lower values for V2% parameters when compared to normouricemic older adults. These results suggesting a sympathovagal imbalance in hyperuricemic older adults, characterized by greater sympathetic predominance (0 V%) and lower vagal modulation (2 V%) at rest conditions.


The large sialoglycoprotein of human lymphocytes. II. Biochemical features.
Large sialoglycoprotein of human lymphocytes (L-LSGP) from thymocytes and from peripheral blood lymphocytes (PBL) of normal donor and of B chronic lymphocytic leukemia (CLL) patients was purified by affinity chromatography to Maclura pomifera agglutinin (MPA)-Sepharose followed by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). L-LSGP from the three different sources was very similar in amino acid composition. It contained a high proportion of acidic and hydroxy amino acids and also significant amounts of cysteine. No reduction in mobility in SDS-PAGE was noted for unreduced L-LSGP. The molecule may already in its native form have an extended conformation containing either free sulfhydryl groups or small S-S loops not affecting mobility in SDS-PAGE. L-LSGP was found to be highly glycosylated, the thymocyte glycoprotein containing somewhat less carbohydrate by weight (44%) than that of PBL (normal PBL 53% and B CLL 52%). This was due primarily to a lower content of sialic acid. The molecules contained mannose, galactose, N-acetyl galactosamine, N-acetylglucosamine and sialic acid in molar ratios 1.0:3.0:1.1:1.2:1.3 (thymocyte L-LSGP), 1.0:3.8:1.2:1.0:1.7 (PBL L-LSGP) and 1.0:3.5:2.2:1.3:2.8 (B CLL L-LSGP). The weak interaction of L-LSGP with lentil lectin, concanavalin A (Con A) and leucoagglutinin (La), its unchanged mobility in SDS-PAGE after tunicamycin treatment and its high amount of hydroxy amino acids suggest that most carbohydrate chains are O-glycosidically linked to the peptide chain. Native as well as Nase-treated L-LSGP show size microheterogeneity. This is probably due to small chemical differences in the L-LSGP molecules from different lymphocyte subsets.


Systems Genetics Analysis to Identify the Genetic Modulation of a Glaucoma-Associated Gene.
Loss of retinal ganglion cells (RGCs) is one of the hallmarks of retinal neurodegenerative diseases, glaucoma being one of the most common. Recently, γ-synuclein (SNCG) was shown to be highly expressed in the somas and axons of RGCs. In various mouse models of glaucoma, downregulation of Sncg gene expression correlates with RGC loss. To investigate the regulation of Sncg in RGCs, we used a systems genetics approach to identify a gene that modulates the expression of Sncg, followed by confirmatory studies in both healthy and diseased retinas. We found that chromosome 1 harbors an eQTL that modulates the expression of Sncg in the mouse retina and identified Pfdn2 as the candidate upstream modulator of Sncg expression. Downregulation of Pfdn2 in enriched RGCs causes a concomitant reduction in Sncg. In this chapter, we describe our strategy and methods for identifying and confirming a genetic modulation of a glaucoma-associated gene. A similar method can be applied to other genes expressed in other tissues.


Study on antiplatelet effect of a new thiophenopyridine platelets P2Y12 receptor antagonist DV-127.
P2Y12 receptor antagonists are a class of drugs that act on platelet P2Y12 receptors and inhibit adenosine diphosphate-induced platelet aggregation. As a thienopyridine antiplatelet agent which is approved by the US Food and Drug Administration for the treatment of cardiovascular diseases, currently, clopidogrel was once considered to be the most safe and effective antiplatelet drug in the P2Y12 receptor antagonists, however, it has become increasingly clear that clopidogrel does not satisfactorily inhibit the platelets of approximately one-third of patients. This is in part due to clopidogrel is a prodrug and reliance on multiple cytochrome P450 enzymes for conversion into its active metabolite. Prasugrel and ticagrelor reduces the risk of adverse cardiovascular events compared to clopidogrel in acute coronary syndromes patients, however, the cardiovascular benefit of both drugs is counter-balanced by increased rates of spontaneous bleeding. Unlike clopidogrel, which is a prodrug, cangrelor is an active drug not requiring metabolic conversion, despite fewer bleeding events during cardiac surgery, cangrelor carries the risk of potential autoimmune reactions manifesting as breathlessness. DV-127 was synthesized by using three generations of thienopyridine P2Y12 receptor antagonists as research models, using high resolution mass spectrometry, selective deuteration, and 2,7-position replacement groups technologies in order to maximize cardiovascular benefit while minimizing adverse effects on hemostasis. Our results show that although the dose of DV-127 is greatly reduced, it can achieve similar anticoagulant and antiplatelet effects as clopidogrel, and DV-127 can more strongly inhibit the release of α-granules even though the inhibitory effect of dense granules is similar to clopidogrel.


Longitudinal use of three different navigational bronchoscopy systems to sample lung nodules in a single patient.
Bronchoscopic techniques to sample suspicious lung nodules have progressed from traditional bronchoscopy to guided navigational bronchoscopy systems. Here we present the case of a patient who underwent navigational bronchoscopies using three different systems over a period of 41 months that diagnosed two primary and one metastatic thoracic malignancy. As guided bronchoscopy systems for the diagnosis of lung nodules continue to advance, it is important to recognize that the full utilization of accessible tools and technologies combined with shared decision making may often lead to a successful procedure and accurate diagnosis.


Drug eluting stents: developments and current status.
Coronary stenting has revolutionized current perspective of coronary artery disease management. Bare-metal stents (BMS) were introduced in 1994, but long-term results have been shattered by the dual problems of in-stent restenosis (ISR) and stent thrombosis associated with BMS. Though stent thrombosis became much less frequent after the introduction of antiplatelet therapy, restenosis however remained as a significant problem. Intense work on stent development has successfully led to the introduction of drug-eluting stents (DES) in 2002, as an effort to address restenosis problem. First generation DES (sirolimus and paclitaxel eluting) were introduced first and found to be more effective than BMS. The use of first generation DES dealt with the problem of restenosis. But, despite early successes, uncertainty remains on the overall safety, especially for late adverse clinical events such as stent thrombosis. Thus, the second generation (everolimus and zotarolimus eluting) stents were developed and introduced with lower thrombosis rates. Today, in the search for improving the performance of available DES various developments and clinical studies are ongoing. Research and developments is primarily centred on increasing the long-term safety and efficacy of stents.


Effect of Hospital Pharmacist Counseling on Clinical Outcomes of Type 2 Diabetes Mellitus Outpatients.
In Indonesia, the role of a hospital pharmacist in pharmaceutical care is still limited or even absent. This study aimed to determine whether counseling by a pharmacist could improve medication adherence, controlling the glycemic status, lipid profile, and blood pressure of type 2 diabetes mellitus (T2DM) outpatients. We conducted an interventional study at RSUD Kota Depok, a secondary public hospital, Indonesia, from April to October 2018. Counseling was given three times during the 4-month study. The study design was quasi-experimental with pretest-posttest group design on 77 respondents divided into intervention group (IGs) (n = 39 people) who received counseling and booklets from the hospital pharmacist and control group (CG) (n = 38 people) who were only given the booklets. We measured adherence with the Medication Adherence Questionnaire and conducted blood tests for fasting blood glucose (FBG), postprandial blood glucose (PPBG), glycosylated hemoglobin A1, lipid profiles (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and TG), and blood pressure measurements. In the IG, adherence parameters such as HbA1c and lipid profile improved, whereas in the CG, there were no statistically significant changes in clinical parameters and even nonadherence score increased (P = 0.008). IG showed statistically significant improvement in medication adherence, in parameters such as FBG, PPBG, and HbA1c, compared to CG. Based on the Chi-square test, IG also showed a statistically significant improvement in the number of controlled FBG (P = 0.05) and HbA1c (P < 0.001) compared to CG. In addition, a multivariate analysis showed that counseling by hospital pharmacist was 2.764 times (95% confidence interval [CI]: 1.096-6.794) and 9.964 times (95% CI: 3.434-28.917) better than no counseling in improvement of FBG and HbA1c, respectively. However, the significance disappeared after adjusted by type of medicine, duration of diabetes mellitus drug use, and medication adherence. Hospital pharmacist counseling is an important and significant factor in improving FBG and HbA1c levels of T2DM outpatients.


Vascular smooth muscle oxygen consumption is reversibly stimulated by sera from women with preeclampsia.
Preeclampsia is a complication of pregnancy that causes maternal vasoconstriction and hypertension. The disease may progress to eclampsia, which is thought to be related to cerebral vasospasm. Although there is evidence for more than one circulating factor that causes endothelial cell dysfunction in preeclampsia, little work has focused on the possibility that vascular smooth muscle function might be directly stimulated by a circulating factor. The aim of this study was to determine whether such a factor or factors could be detected by the vessels. Excessive vascular smooth muscle oxygen consumption was used as a screen for metabolic stimulation because pathologic arterial constriction would require oxidative metabolism to generate adenosine triphosphate. De-endothelialized porcine carotid artery (a well-validated model of human arterial contractile function) was exposed to sera from patients with preeclampsia (1:30 dilution) in a sealed chamber with an oxygen electrode, and the rate of oxygen consumption by the tissue was measured. Comparisons with the effects of sera from matched normal pregnant patients and from nonpregnant women were made. Exposure of vascular smooth muscle to sera from women with preeclampsia for 90 minutes resulted in greater oxygen consumption by the tissue (0.66 +/- 0.16 micromol O2 /min per gram of dry weight) than did exposure to sera of matched pregnant and nonpregnant control subjects (0.34 +/- 0.08 micromol O2 /min per gram of dry weight, P <.001, and 0.29 +/- 0.03 micromol O2 /min per gram of dry weight, P <.001, respectively). This stimulation was completely reversed by rinsing. There is a factor in the circulation of women with preeclampsia that has the reversible effect on vascular smooth muscle of accelerating oxygen consumption. We discuss the implications of this observation in terms of known aspects of vascular smooth muscle contractile function.


Intersex in wild roach (Rutilus rutilus) from Danish sewage effluent-receiving streams.
Roach (Rutilus rutilus) from Danish streams that receive discharges of domestic sewage effluent were examined for the presence of alterations to gonadal development. In male roach, intersex was observed at a prevalence of 4.5-5% at reference sites and 6.7-6.5% at sewage effluent-impacted sites. A positive correlation was found between sewage effluent load and intersex frequency among male roach. The highest frequency of intersex (26.5%) was found in the stream Kristrup Landkanal, which had the highest percentage and load of sewage effluent (87,578 population equivalents). Further, a tendency to an average higher severity of the phenomenon (calculated as an intersex index value) was seen in males from streams impacted by sewage effluent compared to males from reference sites. However, this was significant only in male fish from Egaa Brook. Among roach from the Kristrup Landkanal 5.8% of male and 0.8% of female roach were infected with the parasite Pleistophora mirandellae, causing degenerative changes in testes and ovaries. No correlation was seen between the intersex condition and the presence of P. mirandellae in the gonads of roach.


Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome.
Insulin resistance and its compensatory hyperinsulinemia play a key pathogenic role in the infertility of the polycystic ovary syndrome. Numerous studies indicate that insulin-sensitizing drugs can be used to enhance spontaneous ovulation and the induction of ovulation in the syndrome. The aim of this review is to summarize the studies in which insulin-sensitizing drugs were used to increase ovulation rate or improve fertility in women with the PCOS and to translate the information into practical guidelines for the use of these drugs by reproductive endocrinologists. Review and critique of studies in which an insulin-sensitizing drug was used to increase ovulation rate or improve infertility in women with the polycystic ovary syndrome. Ovulation rate and pregnancy rate. Studies have demonstrated that insulin-sensitizing drugs can increase spontaneous ovulation, enhance the induction of ovulation with clomiphene citrate, and increase clinical pregnancy rates. An algorithmic approach is provided for the use of insulin-sensitizing drugs to treat the anovulation and infertility of women with the polycystic ovary syndrome.


The subjective visual vertical: validation of a simple test.
The study sought to provide norms for a simple test of visual perception of verticality (subjective visual vertical). The study was designed as a cohort study with a balanced design. The setting was the Rehabilitation Department of a University Hospital. Twenty-two healthy adults, of 23-58 years, 11 men (three left handed) and 11 women (three left handed) were enrolled. A luminous bar was displayed on a PC screen, and rotated in steps of 0.4° until the participant perceived it as vertical. A positive sign was attributed to a clockwise rotation of the bar. The detection threshold was set at the angle corresponding to a perceived vertical, which the participant then selected out of three subsequent alternatives (each at +0.4 or -0.4°). The participant's position (sitting vs. standing) and the preset angle of presentation (clockwise vs. counterclockwise) were balanced across sex. The constant or deviation error (dE, in degrees) and the absolute errors (aE, in degrees) were computed. An analysis of variance model tested the dependence of dE on sex, posture, age, handedness, and the preset angle. Both dE and aE were unrelated to sex, posture, handedness, and the preset angle, but were dependent on age (junior, ≤43 years; senior, >43 years). The mean dE was -0.14 ± 0.60 in the junior and 0.42 ± 0.64 in the senior group, respectively. The minimal real difference of the dE was 0.75 and 0.25 in the junior and the senior group, respectively. The overall median aE was 0.4 (5th-95th percentile 0-1.2) in the junior and 0.8 (0.4-1.46) in the senior group, respectively. The whole test took no longer than 15 min in healthy participants, and 25 min in stroke patients. The test was applied to three subacute stroke patients with left hemiparesis, of whom two showed left spatial hemineglect. All three patients presented with a significant clockwise dE. This simple test appears to be valid for the routine assessment of spatial disorders in neurological impairments.


A left-sided approach for wide mobilization of the pancreas with complete dissection of the Treitz ligament (with video).
In recent years, the number of minimally invasive pancreatoduodenectomy (MIPD) has been increasing; however, the procedure has not been widely accepted due to its complexity and difficulty. We have developed a technique to mobilize the pancreas head using a left-sided approach with a focus on the complete dissection of the Treitz ligament. This technique focuses on the secure mobilization of the pancreas head using a left-sided approach. First, the transverse mesocolon is flipped upward and the anterior side of the mesojejunum is excised to expose the first jejunal artery (1st JA) from the distal side to its origin. During the procedure, the left sides of the SMA and Treitz ligament are exposed. The Treitz ligament is retracted to the left side and dissected anteriorly. Thereafter, the jejunum is flipped to the right side and the retroperitoneum around the origin of the jejunum and duodenum is dissected to identify the inferior vena cava (IVC). The rest of the Treitz ligament is dissected posteriorly and complete resection of the Treitz ligament releases the limitation of duodenal immobility. Thereafter, dissection proceeds along the anterior wall of the IVC, and mobilization of the pancreas head is completed from the left side. A total of 75 consecutive patients underwent MIPD from April 2016 to July 2022. The median operation times of laparoscopic and robotic procedures were 528 min (356-757 min) and 739 min (492-998 min), respectively. The volume of blood loss during laparoscopic and robotic procedures was 415 g (60-4360 g) and 211 g (17-1950 g), respectively. There was no mortality in any of the cases. Mobilization of the pancreas head and left-sided approach using a caudal view will be a safe and useful technique for MIPD.


Shape change reaction of platelets in protein-free medium: ultramorphology.
Transmission and scanning electron microscopy indicate that rabbit platelets incubated in protein-poor medium retain their reactivity to shape change-inducing agents such as 5-hydroxytryptamine, adenosine-5'-diphosphate and chlorpromazine. Such platelets may be used as models for drug-membrane interactions, e.g. in neuronal cells.


Molecular epidemiology of cystic fibrosis-linked Burkholderia cepacia complex isolates from three national referral centres in Ireland.
Burkholderia cepacia is a Gram-negative bacterium associated with increasing morbidity and mortality and is readily transmitted among infected cystic fibrosis (CF) patients. The B. cepacia complex consists of five distinct subgroups, termed genomovars. A collection of 17 presumptive B. cepacia isolates, obtained from three national CF referral centres located in different geographical regions in Ireland, was studied. The aim of this study was to investigate these isolates using molecular subtyping protocols for evidence of genetic relationships and for the presence of antibiotic resistance-encoding class 1 integron structures. Genomovar classifications were assigned to each isolate based on HaeIII enzyme profiles of their recA locus. Genetic relationships among this collection were also assessed after restriction fragment length polymorphism (RFLP)-mediated analysis of the 16S rDNA locus and DNA amplification fingerprinting (DAF). The surface expression of the cable pilus gene (cblA) may facilitate an early step in the infection process. All isolates were tested by amplification strategies for this marker. Burkholderia cepacia is known to be resistant to several antimicrobial agents. Resistance typing showed that the majority were resistant to three or more common antimicrobial agents. Five of the 17 isolates were resistant to sulphonamide, a characteristic linked with the presence of class 1 integrons. Gene cassettes containing beta-lactamase (oxa) and aminoglycoside acetyltransferase (aac(6')-1a) encoding genes were identified by polymerase chain reaction amplification. Most of the isolates in this study were classified as genomovar III and were indistinguishable based on their corresponding 16S rDNA-RFLP profiles, whilst DAF further subtyped the collection. The cblA marker was identified in 47% of the isolates, many of which clustered in the genomovar III group. Class 1 integrons with recombined gene cassettes containing bla-OXA and aac(6')-1a genes were identified. This study demonstrates the application of molecular methods to investigate B. cepacia, a well-recognized human pathogen, cultured from Irish CF patients. Genomovar III was the most common genomic type identified. DNA fingerprinting further subtyped the latter isolates, facilitating a more detailed description of the molecular epidemiology. Drug resistance in these organisms can be explained, at least in part, by the presence of class 1 integrons. Development of targeted infection control strategies could be facilitated using these applied methods.


Cyclic neutropenia and concomitant IgA nephropathy: a case report.
IgA nephropathy (IgAN) is universally recognized as one of the most common primary glomerular diseases in all ages. Cyclic neutropenia (CN) is a rare haematologic disorder that is associated with mutations of the ELANE gene. The co-occurrence of IgAN and CN is extremely rare. This is the first case report of a patient with IgAN and genetically confirmed CN. We report a case of a 10-year-old boy who presented with recurrent viral upper respiratory tract infections accompanied by several episodes of febrile neutropenia, haematuria, proteinuria and acute kidney injury. Upon first admission, his physical examination was unremarkable. His kidney function was impaired, whereas his urine microscopy showed evidence of macroscopic haematuria and proteinuria. Further workup showed elevated IgA. The renal histology was consistent with mesangial and endocapillary hypercellularity with mild crescentic lesions, while immunofluorescence microscopy showed IgA-positive staining, which was characteristic of IgAN. Moreover, genetic testing confirmed the clinical diagnosis of CN, therefore Granulocyte colony-stimulating factor (G-CSF) was initiated to stabilize the neutrophil count. Regarding proteinuria control, the patient was initially treated with an Angiotensin-converting-enzyme inhibitor for approximately 28 months. However, due to progressive proteinuria (> 1 g/24 h), Corticosteroids (CS) were added for a period of 6 months according to the revised 2021 KDIGO guidelines with favorable outcome. Patients with CN are more susceptible to recurrent viral infections, which can trigger IgAN attacks. In our case CS induced remarkable proteinuria remission. The use of G-CSF contributed to the resolution of severe neutropenic episodes, viral infections and concomitant AKI episodes, contributing to better prognosis of IgAN. Further studies are mandatory to determine whether there is a genetical predisposition for IgAN in children with CN.


Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis.
Survival of adults with acute lymphoblastic leukemia (ALL) is inferior to that of pediatric patients. Strategies to improve the outcome of adult population are warranted. This study aims to evaluate the efficacy and safety of pediatric-inspired regimens given to adolescents and young adults (AYA), usually defined as 16-39 years, with ALL. Systematic review and meta-analysis of comparative trials of AYA patients with ALL given induction chemotherapy with either pediatric-inspired regimens or conventional-adult chemotherapy was conducted. Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. Our search yielded 11 trials, including 2,489 patients. AYA patients given pediatric-inspired regimens had a statistically significant lower all cause mortality rate at 3 years (RR 0.58; 95% CI 0.51-0.67). Complete remission rate after induction chemotherapy and event free survival were superior in the pediatric-inspired regimens arm (RR 1.05; 95% CI 1.01-1.10 and RR 1.66; 95% CI 1.39-1.99, respectively). Relapse rate was also lower in patients given pediatric-inspired regimens (RR 0.51; 95% CI 0.39-0.66) with comparable nonrelapse mortality between the two groups (RR 0.53, 95% CI 0.19-1.48). Pediatric-inspired regimens are superior to conventional-adult chemotherapy in AYA ALL patients. Further randomized controlled studies to investigate this approach in adult ALL patients are warranted.


Imaging the serotonergic system in depression.
Positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow for the in vivo visualisation and measurement of, e.g. the serotonergic system in the brain of depressed patients. Currently, the available ligands permit the investigation of 5-HT2A and 5-HT1A receptors, the serotonin transporter and serotonin synthesis. 5-HT2A receptors have most extensively been investigated and increases, decreases or no differences in ligand binding have been found. Previous treatment and suicidality could be major confounding variables. Tricyclics seem to decrease ligand binding, while SSRIs in most studies increase ligand binding. A few studies have looked at the 5-HT1A receptor and demonstrated decreases in binding. The one study which looked at the effect of an SSRI treatment did not find any effect. The serotonin transporter availability seems to be reduced in depression. Tryptophane depletion studies have demonstrated effects on brain metabolism in serotonin related regions and on 5-HT2A receptors. Finally, serotonin synthesis studies have shown interesting differences between males and females.


Parenteral Nutrition Utilization After Implementation of Multidisciplinary Nutrition Support Team Oversight: A Prospective Cohort Study.
Multidisciplinary nutrition teams can help guide the use of parenteral nutrition (PN), thereby reducing infectious risk, morbidity, and associated costs. Starting in 2007 at Harborview Medical Center, weekly multidisciplinary meetings were established to review all patients receiving PN. This study reports on observed changes in utilization from 2005-2010. All patients who received PN from 2005-2010 were followed prospectively. Clinical data and PN utilization data were recorded. Patients were grouped into cohorts based on exposure to weekly multidisciplinary nutrition team meetings (from 2005-2007 and from 2008-2010). Patients were also stratified by location, primary service, and ultimate disposition. In total, 794 patients were included. After initiation of multidisciplinary nutrition meetings, the rate of patients who started PN decreased by 27% (relative risk [RR], 0.73; 95% confidence interval [CI], 0.63-0.84). A reduction in the number of patients receiving PN was observed in both the intensive care unit (ICU) and on the acute care floor (RR, 0.64; 95% CI, 0.53-0.77 and RR, 0.80; 95% CI, 0.64-0.99, respectively). The rate of patients with short-duration PN use (PN duration of <5 days) declined by 30% in the ICU (RR, 0.70; 95% CI, 0.51-0.97) and by 27% on acute care floors (RR, 0.73; 95% CI, 0.51-1.03). Weekly multidisciplinary review of patients receiving PN was associated with reductions in the number of patients started on PN, total days that patients received PN, and number of patients who had short-duration (<5 days) PN use.


Evaluation of the abuse potential of AM281, a new synthetic cannabinoid CB1 receptor antagonist.
AM281 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) is a new synthetic cannabinoid CB1 receptor antagonist. Similar to other cannabinoid antagonists, AM281 has been suggested to have therapeutic indications. However, recent reports have suggested that cannabinoid CB1 receptor antagonists may share similar behavioral effects with other drugs of abuse such as cocaine and amphetamine. These reports cast doubts on the safety profile of AM281. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of AM281 through two of the most widely used animal models for assessing the abuse potential of drugs: the conditioned place preference (CPP) and self-administration (SA) tests. Experiments were performed in Sprague-Dawley rats in various dosages [CPP (0.1, 0.5 or 2.5mg/kg), SA (0.005, 0.025 or 0.1mg/kg/infusion)]. We also delved into the consequences of repeated drug exposure on the subsequent response to the drug. Thus, parallel experiments were carried out in rats pretreated with AM281 for 7 or 14 days. Our findings indicated that AM281, at any dose, did not induce CPP and SA in drug-naïve rats. Interestingly, significant CPP (0.5mg/kg of AM281), but not SA, was observed in 14 days pretreated rats. These observations suggest that AM281 per se has no or minimal rewarding and reinforcing properties, but alterations in neuronal functions and behavior due to repeated AM281 exposure may contribute in part to the abuse potential of this drug. In view of this finding, we advocate the careful use, monitoring, and dispensation of AM281.


The kinetic mechanism of the human bifunctional enzyme ATIC (5-amino-4-imidazolecarboxamide ribonucleotide transformylase/inosine 5'-monophosphate cyclohydrolase). A surprising lack of substrate channeling.
5-Amino-4-imidazolecarboxamide ribonucleotide transformylase/IMP cyclohydrolase (ATIC) is a bifunctional protein possessing two enzymatic activities that sequentially catalyze the last two steps in the pathway for de novo synthesis of inosine 5'-monophosphate. This bifunctional enzyme is of particular interest because of its potential as a chemotherapeutic target. Furthermore, these two catalytic activities reside on the same protein throughout all of nature, raising the question of whether there is some kinetic advantage to the bifunctionality. Rapid chemical quench, stopped-flow absorbance, and steady-state kinetic techniques were used to elucidate the complete kinetic mechanism of human ATIC. The kinetic simulation program KINSIM was used to model the kinetic data obtained in this study. The detailed kinetic analysis, in combination with kinetic simulations, provided the following key features of the enzyme reaction pathway. 1) The rate-limiting step in the overall reaction (2.9 +/- 0.4 s(-1)) is likely the release of tetrahydrofolate from the formyltransferase active site or a conformational change associated with tetrahydrofolate release. 2) The rate of the reverse transformylase reaction (6.7 s(-1)) is approximately 2-3-fold faster than the forward rate (2.9 s(-1)), whereas the cyclohydrolase reaction is essentially unidirectional in the forward sense. The cyclohydrolase reaction thus draws the overall bifunctional reaction toward the production of inosine monophosphate. 3) There was no kinetic evidence of substrate channeling of the intermediate, the formylaminoimidazole carboxamide ribonucleotide, between the formyltransferase and the cyclohydrolase active sites.


Overview of chemical genomics and proteomics.
Chemical genetics, genomics, and proteomics have been in existence as distinct offshoots of chemical biology for about 20 years. This review provides a brief definition of each, followed by some examples of how each technology is being used to advance basic research and drug discovery.


Structural plasticity of dendritic spines.
Dendritic spines are small mushroom-like protrusions arising from neurons where most excitatory synapses reside. Their peculiar shape suggests that spines can serve as an autonomous postsynaptic compartment that isolates chemical and electrical signaling. How neuronal activity modifies the morphology of the spine and how these modifications affect synaptic transmission and plasticity are intriguing issues. Indeed, the induction of long-term potentiation (LTP) or depression (LTD) is associated with the enlargement or shrinkage of the spine, respectively. This structural plasticity is mainly controlled by actin filaments, the principal cytoskeletal component of the spine. Here we review the pioneering microscopic studies examining the structural plasticity of spines and propose how changes in actin treadmilling might regulate spine morphology.


Effect of plasma and LPS on respiratory burst of neutrophils in septic patients.
To compare the respiratory burst of neutrophils in sepsis and control patients using lipopolysaccharide (LPS), autologous plasma, and a combination of the two. Prospective, consecutive case study. A 16-bed intensive care unit (ICU) in a university teaching hospital. None. Plasma was obtained from 23 healthy patients scheduled for minor surgery immediately prior to induction of anesthesia (controls) and from 23 ICU patients within 24 h of diagnosis of sepsis or septic shock. Respiratory burst was determined by lucigenin chemiluminescence expressed as mean +/- SEM of peak values of relative light units per neutrophil. There were no significant differences between neutrophils of septic patients and controls for the stimuli saline, phorbol myristate acetate, formyl-methionyl-leucyl-phenylalanine, and LPS alone. Septic patients showed a lower respiratory burst than controls (p < 0.05) under the following stimuli: plasma alone (5911 +/- 803 vs 15,397 +/- 3038) and LPS and plasma combined (13,857 +/- 1537 vs 23,026 +/- 2640). However, when stimulated with plasma after priming with LPS, septic patients elicited a higher value than control subjects (11,373 +/- 1758 vs 5987 +/- 1234, p < 0.05). (1) Some components of the plasma of septic patients may have a profound effect on neutrophil response; (2) plasma as a respiratory burst stimulus differentiates between sepsis and non-sepsis samples better than other common stimuli; (3) precautions must be taken when using plasma together with LPS because of the different response depending on whether LPS-priming precedes the plasma stimulus or both are introduced simultaneously and whether septic or nonseptic plasma is used.


Presence of Archaea in dental caries biofilms.
Although the prevalence and functions associated with members of Bacteria are well known in dental caries, the role of Archaea in cariogenic biofilms has not been studied yet. To detect the presence of Archaea in dental caries, a triplicate of carious dentine samples and duplicate of supragingival biofilms were collected, total microbial DNA was extracted and the composition of the microbiota was investigated. Total DNA was submitted to 16S rRNA gene amplification using universal prokaryotic primers; amplicons were sequenced by high-throughput DNA sequencing. As a second strategy to detect Archaea, a representative sample of caries was chosen and other PCR reactions were performed using specific primers targeting the archaeal 16S rRNA gene; amplicons were cloned and sequenced. Annotation of sequences was performed using SILVA database and the relative abundance of genus level OTUs was calculated. The high-throughput sequencing method detected archaeal sequences in all samples (identified as group I.1c of the phylum Thaumarchaeota), although in a very low abundance (≤0.03 % of the total sequences). For the second strategy, 14 archaeal clones were detected, with an OTU affiliated to Methanocella clade, and another one affiliated to group I.1b of the phylum Thaumarchaeota. Archaeal sequences were detected in dental caries and biofilms from surfaces without caries lesions. DNA sequences of Thaumarchaeota were also identified, showing that overall archaeal diversity in the human oral cavity could be currently underestimated and not restricted to methanogens.


An extension of the meaning making model using data from Chinese cancer patients: The moderating effect of resilience.
Meaning making refers to the process of integrating the appraised meaning of a traumatic event into one's global belief system to reduce cognitive discrepancy. Park and Folkman (1997) proposed the renowned "meaning-making model," which was a major contribution to trauma research from a positive psychology viewpoint. This concept is important for understanding the trauma of cancer patients, as searching for meaning is fairly common after a cancer diagnosis. However, the original model did not incorporate individual differences in resilience, which might account for the fact that research on this model has produced contradictory results. This study recruited 146 Chinese cancer patients and used different scales to measure each stage of the meaning-making process, resilience, posttraumatic growth (PTG), and anxiety/depression symptoms. A follow-up study was conducted after 6 months. A structural equation model was constructed; meaning discrepancy triggered meaning making, predicted changes in situational and global beliefs, and ultimately resulted in better mental health outcomes. The moderating effect of resilience was noteworthy; the indirect effect of meaning making on the relationship between meaning discrepancy (Time 1 [T1]) and mental health outcomes (Time 2 [T2]) was significant in the low resilience group, but nonsignificant in the high resilience group. These results suggest that the effects of meaning-making processes may differ based on individual factors, such as resilience. (PsycINFO Database Record


Reducing attentional capture of emotion by broadening attention: increased global attention reduces early electrophysiological responses to negative stimuli.
Decades of research has shown the influence of emotion on attentional capture, and more recently, the influence of emotion on neurophysiological processes related to attentional capture. The current research tested whether some of the earliest neurophysiological underpinnings of emotive attentional processes can be influenced by attentional manipulations of broadening versus narrowing. Previous research has shown that negative affects high in motivational intensity (e.g., disgust, fear) cause a relative narrowing of attentional scope (Gable and Harmon-Jones, 2010a; Easterbrook, 1959). Because of the strong link between motivation and attention, attentional scope should also influence the attentional capture of negative stimuli. The current study manipulated a local attentional scope or global attentional scope, then measured attentional capture towards disgust and neutral pictures using the N1 event-related potential component. Results revealed that a manipulated global attentional scope reduced N1 amplitude towards disgust pictures compared to a manipulated local attentional scope.


The Use of Botulinum Toxin for Treatment of Depression.
A series of clinical studies have shown that botulinum toxin can treat major depression. Subjects suffering from unipolar depression may experience a quick, strong, and sustained improvement in the symptoms of depression after a single glabellar treatment with botulinum toxin.Preliminary data suggest that botulinum toxin therapy may also be effective in the treatment of other mental disorders characterized by an excess of negative emotions, such as borderline personality disorder.The mood-lifting effect of botulinum toxin therapy is probably mediated by the interruption of a proprioceptive feedback loop from the facial musculature to the emotional brain.


Simultaneous nitrification and denitrification by Pseudomonas sp. Y-5 in a high nitrogen environment.
Pseudomonas sp. Y-5, a strain with simultaneous nitrification and denitrification (SND) capacity, was isolated from the Wuhan Municipal Sewage Treatment Plant. This strain could rapidly remove high concentrations of inorganic nitrogen. Specifically, Pseudomonas sp. Y-5 removed 103 mg/L of NH4+-N in 24 h without nitrate or nitrite accumulation when NH4+-N was its sole nitrogen source. The NH4+-N removal efficiency (RE) was 97.26%, and the average removal rate (RR) was 4.30 mg/L/h. Strain Y-5 also removed NO3--N and NO2--N even in aerobic conditions, with average RRs of 4.39 and 4.23 mg/L/h, respectively, and REs of up to 99.34% and 95.81% within 24 h. When cultured in SND medium (SNDM-1), strain Y-5 achieved an NH4+-N RE of up to 97.80% and a total nitrogen (TN) RE of 93.01%, whereas NO3--N was fully depleted in 48 h. Interestingly, high nitrite concentrations did not inhibit the nitrification capacity of Y-5 when grown in SNDM-2, the RE of NH4+-N and TN reached 96.29% and 94.26%, respectively, and nitrite was consumed completely. Strain Y-5 also adapted well to high concentrations of ammonia (~401.68 mg NH4+-N/L) or organic nitrogen (~315.12 mg TN/L). Our results suggested that Pseudomonas sp. Y-5 achieved efficient simultaneous nitrification and denitrification, thus demonstrating its potential applicability in the treatment of nitrogen-polluted wastewater.


New fundamental evidence of non-classical structure in the combination of natural concepts.
We recently performed cognitive experiments on conjunctions and negations of two concepts with the aim of investigating the combination problem of concepts. Our experiments confirmed the deviations (conceptual vagueness, underextension, overextension etc.) from the rules of classical (fuzzy) logic and probability theory observed by several scholars in concept theory, while our data were successfully modelled in a quantum-theoretic framework developed by ourselves. In this paper, we isolate a new, very stable and systematic pattern of violation of classicality that occurs in concept combinations. In addition, the strength and regularity of this non-classical effect leads us to believe that it occurs at a more fundamental level than the deviations observed up to now. It is our opinion that we have identified a deep non-classical mechanism determining not only how concepts are combined but, rather, how they are formed. We show that this effect can be faithfully modelled in a two-sector Fock space structure, and that it can be exactly explained by assuming that human thought is the superposition of two processes, a 'logical reasoning', guided by 'logic', and a 'conceptual reasoning', guided by 'emergence', and that the latter generally prevails over the former. All these findings provide new fundamental support to our quantum-theoretic approach to human cognition.


[Epidural anesthesia: indications and limitations (author's transl)].
The effectiveness and indications for epidural anesthesia have progressed in the last two decades. Better techniques, new long-acting local anesthetics, and better understanding of pathophysiologic changes after epidural block made this technique widely used and rather safe. Nowadays, limitations of epidural block include the absolute and relative contraindications, the lack of pharmacologic and pathophysiologic knowledge, and insufficient techniques and equipment. In experienced hands, epidural block is one of the safest techniques for surgical anesthesia.


Sorghum-Waste-Derived High-Surface Area KOH-Activated Porous Carbon for Highly Efficient Methylene Blue and Pb(II) Removal.
With the development of the environment and human society, the removal of metal ions and dyes in wastewater treatment remains an urgent problem to solve. In this work, two biomass carbon adsorbents were synthesized by a KOH activation and carbonization route using sorghum stem and root as carbon precursors. In comparison with the samples without KOH activation, the pore structure of the KOH-activated carbon has been dramatically improved. The findings show that the specific surface areas of the adsorbents by sorghum stem (S1) and sorghum root (R1) were 948.6 and 168.1 m2 g-1, respectively. Meanwhile, the abundant OH- and COO- groups on the surface of these adsorbents endow them with negative polarity, thereby exhibiting excellent adsorption performance for removing methylene blue (MB) and Pb(II) from wastewater. The adsorption amount and removal rate of S1 were 98.1 mg g-1 and 98.08%, respectively, for MB, whereas those of R1 were 197.6 mg g-1 and 98.82% for the Pb(II) ion, respectively. Our findings offer an invaluable insight into designing and synthesizing a highly efficient sustainable adsorbent to remove MB and Pb(II) based on biomass agricultural waste.


Acute normovolemic hemodilution is safe in neurosurgery.
To determine the safety of acute normovolemic hemodilution (ANH) for patients undergoing neurosurgical procedures. A group of 100 patients undergoing neurosurgical procedures was assigned prospectively to receive ANH. A group of 47 patients who underwent craniotomy for aneurysm clipping and standard anesthetic management was used as a control. Procedures conducted under ANH were performed without significant variations in physiologic parameters. Compared with controls, intraoperative blood loss, operative time, incidence and grade of complications, and length of hospital stay were similar between the two groups. Although the ANH group showed a difference in prothrombin levels before and after hemodilution procedures, the levels were still considered within physiologic parameters. Platelet counts and partial thromboplastin time (PTT) levels indicated no significant variations in either group. During the ANH procedure, a considerable reduction of brain oxygen extraction was observed in individuals with worse preoperative neurologic status (P < 0.05), indicating potential benefit. Among patients with cerebral aneurysm, patients with good initial clinical grades had better clinical results as indicated by Glasgow Outcome Scale scores (P < 0.02). ANH is a safe procedure for patients undergoing neurosurgical procedures. Further studies are necessary to confirm the improvement in brain oxygen extraction and the clinical impact. Nonetheless, patients undergoing aneurysm clipping with good clinical grades seem to profit from ANH.


Understanding the surgeon's behaviour during robot-assisted surgery: protocol for the qualitative Behav'Robot study.
Robot-assisted surgery is spreading worldwide, accounting for more than 1.2 million procedures in 2019. Data are sparse in the literature regarding the surgeon's mechanisms that mediate risk-taking during a procedure, especially robot-assisted. This study aims to describe and understand the behaviour of the surgeons during robot-assisted surgery and the change in their behaviour with increasing experience in using the robot. This is a qualitative study using semistructured interviews with surgeons who perform robot-assisted surgery. An interview guide comprising open questions will be used to ensure that the points to be discussed are systematically addressed during each interview (ie, (1) difference in behaviour and preparation of the surgeon between a standard procedure and a robot-assisted procedure; (2) the influence of proprioceptive modifications, gain in stability and cognitive biases, inherent in the use of a surgical robot and (3) the intrinsic effect of the learning curve on the behaviour of the surgeons. After transcription, interviews will be analysed with the help of NVivo software, using thematic analysis. Since this project examines professional practices in the field of social and human sciences, ethics committee was not required in accordance with current French legislation (Decree no 2017-884, 9 May 2017). Consent from the surgeons is implied by the fact that the interviews are voluntary. Surgeons will nonetheless be informed that they are free to interrupt the interview at any time.Results will be presented in peer-reviewed national and international congresses and submitted to peer-reviewed journals for publication. The communication and publication of the results will be placed under the responsibility of the principal investigator and publications will be prepared in compliance with the ICMJE uniform requirements for manuscripts. NCT04869995.


Mitral valve aneurysm: clinical features, echocardiographic-pathologic correlations.
Aneurysm of the mitral valve occurs most commonly in association with infective endocarditis of the aortic valve. The probable mechanism of its formation is destruction of the aortic valve which results in a regurgitant jet that strikes the anterior leaflet of the mitral valve, creating a secondary site of infection leading to the development of an aneurysm. Perforation of these aneurysms may occur, resulting in mitral regurgitation and pulmonary edema from a ventricle already volume overloaded from aortic regurgitation. This report describes the clinical and echocardiographic-pathologic findings in five patients with pathologically proven aneurysm of the mitral valve. There are no clinical features that appear specific for this abnormality. The two-dimensional echocardiographic feature that is helpful in the diagnosis is a bulge of the mitral valve leaflet toward the left atrium that persists throughout the cardiac cycle. Preoperative diagnosis is important because a mitral valve aneurysm may produce serious complications and is frequently overlooked during surgery. Repair of the aneurysm may be feasible; otherwise, valve replacement becomes necessary. Careful two-dimensional echocardiographic examination should be done in patients with left-sided infective endocarditis to detect an aneurysm of the mitral valve.


Analysis of the p53 gene mutations in acute myelogenous leukemia: the p53 gene mutations associated with a deletion of chromosome 17.
In order to determine the relevance of the p53 tumor suppressor gene mutations in acute myelogenous leukemia (AML), we analyzed the p53 gene in genomic DNA of 18 unselected cases of AML by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing. We detected three cases (16.7%) with the p53 gene mutations showing only the mutant alleles; the high incidence in cases with loss of a whole chromosome 17 (two of three) contrasted with the low incidence in cases without abnormalities of chromosome 17 (one of 15). These cases containing the mutations of the p53 gene showed a poor prognosis. Although we analyzed a rather small series of patients, these findings suggest that the p53 gene mutations might be involved in the progression and prognosis of at least some cases of AML.


Odorant concentration and receptor potential in olfactory sensory neurons.
The first step of olfactory transduction consists of the interaction of odorant molecules with receptor proteins. This interaction can be described either as a single-step reaction (binding only) or as a double-step one (binding and activation). The number of bound or activated receptors is analyzed as a function of the external concentration of odorant molecules in two models of the neuron environment. In one model the odorant molecules can freely access and leave the vicinity of receptors, whereas in the other a real perireceptor space, partly isolated from the external environment is considered. The steady state and time variable responses to the stimulus are investigated.


Papillary thyroid microcarcinoma co-exists with Hashimoto's thyroiditis: Is strain elastography still useful?
To study the performance of strain elastography in differentiating papillary thyroid microcarcinoma (PTMC) combined with Hashimoto's thyroiditis (HT), conventional ultrasound scan (US) and strain elastography (SE) were performed on 558 nodules smaller than 10 mm by one examiner before surgeries. Serum concentrations of thyroid peroxidase antibody (TPO-Ab) (normal range: 0-60 U/ml) were measured. Continuous variables were analyzed by independent t test. Receiver operating characteristics (ROC) curve analysis was applied to calculate the cut-off values of strain ratio (SR) and elastography score (ES). The comparison of AUCs is performed by Z test. 482 nodules were diagnosed as PTMC and there were 181 nodules co-existed with HT. SR measurements were lower in PTMC co-existed with HT when comparing to those without HT. (7.292±6.581 vs 11.319±13.155, p<0.000). Taking the data from all of the 558 nodules, the best cut-off of diagnosing PTMC was SR>2.58. When taking the data from 181 PTMC with HT, the best cut-off was SR>2.10. The diagnostic value of SR>2.1 were higher than ES>3, conventional US and combining US and SE (z=3.595, 4.876, 4.420, p<0.001), but cut-off of SR>2.1 did not show significant enhancement of diagnostic value compared to SR>2.58 (z=0.439, p=0.8903>0.001) in PTMC with HT. There is a negative relation between SR and titer of TPO-Ab (r=-0.650, p<0.0001). PTMC with high TPO-Ab (>1000) titer presented lower SR (5.972±4.118 vs 8.379±9.172, p=0.009). Although SR measurements were lower in nodules co-existed with HT when comparing those without HT, using a regular ES and cut-off of SR measurement would not influence the diagnosing performance. SE is still very useful for diagnosing PTMC with HT. PTMC with high TPO-Ab titer might require a lower cut-off of SR.


Levels and determinants of breast and cervical cancer screening uptake in HIV-infected women compared with the general population in France.
Cancer is a growing concern for HIV-infected people, and screening plays a major role in alleviating the burden it causes. We sought to investigate the levels and determinants of breast cancer screening (BCS) and cervical cancer screening (CCS) in HIV-infected women as compared with the general population. The Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS)-Vespa2 study was conducted in 2011 in a national representative sample of 3022 HIV-infected hospital out-patients in France. The rates and correlates of BCS and CCS among HIV-infected women were compared with those in the general population using multivariate Poisson regression models. The BCS rate during the 2 years preceding the survey interview was 80.7% among HIV-infected women vs. 89.1% in the general population (P = 0.146). The CCS rate during the preceding 3 years was 88.1% among HIV-infected women vs. 83.1% in the general population (P = 0.021). During the preceding year, the CCS rate among HIV-infected women was 76.5%. The barriers to BCS and CCS were a low educational level [BCS: adjusted prevalence rate ratio 0.88; 95% confidence interval (CI) 0.80-0.97; CCS: adjusted prevalence rate ratio 0.91; 95% CI 0.83-0.99], not having supplementary health insurance (CCS: adjusted prevalence rate ratio 0.92; 95% CI 0.86-0.98), an irregular gynaecological follow-up (BCS: adjusted prevalence rate ratio 0.77; 95% CI 0.64-0.92; CCS: adjusted prevalence rate ratio 0.72; 95% CI 0.64-0.81) and a low CD4 count (BCS: adjusted prevalence rate ratio 0.83; 95% CI 0.71-0.97; CCS: adjusted prevalence rate ratio 0.78; 95% CI 0.63-0.98). The disparities in CCS uptake in terms of age, employment and gynaecological follow-up were less pronounced among HIV-infected women than in the general population. BCS and CCS uptake was not lower among HIV-infected women than in the general population, but CCS was suboptimal. Specificities in the profile of barriers to screening emerged.


The Measurement of Whole-Body Glucose Homeostasis in Mice.
The resident immune cells (e.g., macrophages) present in major metabolic tissues, such as adipose and liver tissues, play crucial roles in respective tissue homeostasis through cross talk with metabolic tissues, and consequently in metabolic homeostasis at the systemic level, and their dysregulation contributes to metabolic dysregulation at large, as well as many associated diseases. Moreover, the cross talk between different resident immune cells and metabolic tissues is not limited to an intra-organ level but also includes interorgan cross talk, as they work in a coordinated manner throughout the body, such as in adipose tissue, skeletal muscle, and liver. Thus, it is important to determine the impact of altered immune functions on metabolic homeostasis and vice versa, to enhance our knowledge of immunometabolic biology. Glucose and insulin tolerance tests are simple methods that enable the measurement and analysis of the overall glucose homeostasis at the systemic level. Here we describe the process of performing metabolic tests for glucose homeostasis in mice, as mouse models are often used for defining the mechanistic underpinnings of physiology and pathophysiology related to immunometabolism, and in preclinical studies.


A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody.
A novel myelin antigen has been defined by a mouse monoclonal antibody (8-18C5) raised against rat cerebellar glycoproteins. By immunohistochemistry, the antigen was detected in white matter tracts of the central nervous system, but was absent from peripheral myelin. Western blotting followed by immunostaining revealed that the antigen was a glycoprotein of Mr 51 000 daltons which was degraded on storage to cross-reacting products of 20-26 000 daltons. Antigen was detected in central but not peripheral nervous system samples. Products of identical Mr were obtained by affinity chromatography of iodinated cerebellar glycoproteins on a column of immobilised 8-18C5.


ZC3H13 reduced DUOX1-mediated ferroptosis in laryngeal squamous cell carcinoma cells through m6A-dependent modification.
Laryngeal squamous cell carcinoma (LSCC) is the second most common head and neck cancer. To identify the link between ferroptosis and LSCC, we targeted the dual oxidase 1 (DUOX1) gene. This study aimed to reveal the intrinsic mechanism by which the DUOX1-zinc-finger CCCH domain-containing protein 13 (ZC3H13) ferroptosis axis affected the LSCC process. GEPIA was used to investigate the expression of DUOX1 in LSCC, and the expression levels of DUOX1 and ZC3H13 were manipulated by overexpression and RNA interference. MTT assay was used to detect cell proliferation. Chromatin immunoprecipitation (CHIP) detected the binding of DUOX1 and ZC3H13, and ROS assessment and intracellular Fe2+ content determination were performed to examine the ferroptosis. MeRIP was used to analyze the m6A methylation of DUOX1. Ferroptosis-related proteins were detected by qRT-PCR. DUOX1 was found to be poorly expressed in LSCC cells, low DUOX1 level promoted LSCC cell proliferation, and low ZC3H13 level decreased LSCC cell proliferation. Besides, there was an interaction between DUOX1 and ZC3H13. DUOX1 could inhibit the expression levels of ferroptosis-related genes GPX4 and F1H1 in LSCC cells DUOX1 inhibited the expression levels of ROS and ferroptosis-related genes GPX4 and F1H1 and increased intracellular iron content in LSCC cells, but ZC3H13 reversed this phenomenon by inhibiting DUOX1 gene through m6A methylation modification. ZC3H13 reduced DUOX1-mediated ferroptosis in LSCC cells through m6A-dependent modification. The regulatory pathway of DUOX1 and ferroptosis are potential targets for designing diagnostic and combination therapeutic strategies for LSCC patients.


Treatment of heart block due to sarcoid heart disease.
The role of glucocorticosteroid therapy for myocardial sarcoidosis is not well defined. This report shows the effect of prednisone therapy on atrioventricular (AV) conduction in a patient with myocardial sarcoidosis and AV block. On three separate occasions AV block was documented prior to prednisone therapy. On the first two occasions the patient had first and second degree AV block which by His bundle electrogram initially was shown to be in the AV node. On the third occasion the patient developed complete heart block. On each occasion treatment with prednisone resulted in improved AV conduction. The results indicate that prednisone therapy can be beneficial in the treatment of AV block due to myocardial sarcoidosis.


Familial occurrence of lumbar spondylolysis and spondylolisthesis.
In a Finnish kindred consisting of 192 descendants from two marriages of a male ancestor born in 1868, the lumbar spines of 105 of the 170 living members were X-rayed. Spondylolysis was found in 22 individuals. In addition, six of them had spondylolisthesis, four had spina bifida occulta, and two had a transitional lumbar/sacral vertebra. Seven members of the kindred without spondylolysis had spina bifida occulta and 10 had transitional lumbar vertebrae. The pedigree is consistent with autosomal dominant inheritance and incomplete (about 75%) penetrance for spondylolysis. It raises the question of a common aetiology for several congenital disturbances in the formation of lumbar vertebrae and possibly supports the concept of variable expressivity of a "spondylolysis gene".


Operating one-handed: emergency treatment of Jehovah's Witnesses.
An elderly woman was brought to the emergency room (ER) hypotensive in a confused mental state from what turned out at exploration to be a ruptured splenic artery aneurysm. You are in the operating room, and the anesthesiologist has just hung the first unit of blood but has not started infusion when the ER calls. The patient and her husband were visiting their children and live in another state. Her husband, an elder in a Jehovah's Witness congregation, arrived and is adamant that she have no transfusions. Her blood pressure is dangerously low. It is being maintained by a high-dose Levophed (leave-um dead) drip and continues to slip. You have avoided operating on Jehovah's Witness patients because of the added unnecessary risk they pose. Your assistant is of like mind. What is the best ethical course at this time?


Greater post-exercise hypotension in healthy young untrained men after exercising in a hot compared to a temperate environment.
This research examined the effects of exercising in a hot compared to a temperate environment on post-exercise hemodynamics in untrained men. We hypothesized exercise in a hot compared to a temperate environment would elicit greater post-exercise hypotension, and this would be attributable to higher cutaneous vascular conductance and sweat loss, and lower heart rate variability (HRV) and cardiac baroreflex sensitivity (cBRS). In a randomized counterbalanced order, 12 untrained healthy men completed two trials involving 40-min leg-cycling exercise at either 23 °C (CON) or 35 °C (HOT). Post-exercise participants rested supine for 60 min at 23 °C whilst hemodynamic and thermoregulatory measurements were assessed. Post-exercise hypotension was greater after exercising in a hot than a temperate environment as indicated by a lower mean arterial pressure at 60 min recovery (CON 83 ± 5 mmHg, HOT 78 ± 5 mmHg, Mean difference [95% confidence interval], -5 [-8, -3] mmHg). Throughout recovery, cutaneous vascular conductance was higher, and cBRS and HRV were lower after exercising in a hot than in a temperate environment (P < 0.05). Sweat loss was greater on HOT than on CON (P < 0.001). Post-exercise hypotension after exercising in the hot environment was associated with sweat loss (r = 0.66, P = 0.02), and changes in cutaneous vascular conductance (r = 0.64, P = 0.03), and HRV (Root mean square of the successive difference in R-R interval [RMSSD]) r=0.75, P = 0.01 and and log high frequency [HF] r=0.66, P = 0.02), but not cBRS (all, r ≤ 0.2, P > 0.05). Post-exercise hypotension was greater after exercise in a hot compared to a temperate environment and may be partially explained by greater sweat loss and cutaneous vascular conductance, and lower HRV.


Platinum replica electron microscopy: Imaging the cytoskeleton globally and locally.
Structural studies reveal how smaller components of a system work together as a whole. However, combining high resolution of details with full coverage of the whole is challenging. In cell biology, light microscopy can image many cells in their entirety, but at a lower resolution, whereas electron microscopy affords very high resolution, but usually at the expense of the sample size and coverage. Structural analyses of the cytoskeleton are especially demanding, because cytoskeletal networks are unresolvable by light microscopy due to their density and intricacy, whereas their proper preservation is a challenge for electron microscopy. Platinum replica electron microscopy can uniquely bridge the gap between the "comfort zones" of light and electron microscopy by allowing high resolution imaging of the cytoskeleton throughout the entire cell and in many cells in the population. This review describes the principles and applications of platinum replica electron microscopy for studies of the cytoskeleton.


glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins.
Genomic DNA closely related in sequence to lin-12, a gene that specifies certain cell fates during C. elegans development, was isolated from a C. elegans library by low stringency hybridization. DNA sequencing of genomic and cDNA clones predicts the new sequence to encode an integral membrane protein that shares three repeated amino acid sequence motifs with the lin-12 product and the Drosophila Notch product: an epidermal growth factor-like motif, the "lin-12/Notch Repeat," and a motif present in two yeast gene products that have cell cycle dependent functions. Austin and Kimble (see accompanying paper) present evidence that this sequence corresponds to glp-1, a gene implicated in cell-cell interactions distinct from those involving lin-12. Possible implications of the predicted structure of the glp-1 product with respect to these cell-cell interactions are discussed.


Slow conformational changes in MutS and DNA direct ordered transitions between mismatch search, recognition and signaling of DNA repair.
MutS functions in mismatch repair (MMR) to scan DNA for errors, identify a target site and trigger subsequent events in the pathway leading to error removal and DNA re-synthesis. These actions, enabled by the ATPase activity of MutS, are now beginning to be analyzed from the perspective of the protein itself. This study provides the first ensemble transient kinetic data on MutS conformational dynamics as it works with DNA and ATP in MMR. Using a combination of fluorescence probes (on Thermus aquaticus MutS and DNA) and signals (intensity, anisotropy and resonance energy transfer), we have monitored the timing of key conformational changes in MutS that are coupled to mismatch binding and recognition, ATP binding and hydrolysis, as well as sliding clamp formation and signaling of repair. Significant findings include (a) a slow step that follows weak initial interaction between MutS and DNA, in which concerted conformational changes in both macromolecules control mismatch recognition, and (b) rapid, binary switching of MutS conformations that is concerted with ATP binding and hydrolysis and (c) is stalled after mismatch recognition to control formation of the ATP-bound MutS sliding clamp. These rate-limiting pre- and post-mismatch recognition events outline the mechanism of action of MutS on DNA during initiation of MMR.


Proton radiotherapy as a treatment strategy to increase survival in locally advanced pancreatic cancer in the body and tail: a retrospective study.
Long-term outcomes and prognostic factors of proton radiotherapy for locally advanced pancreatic cancer (LAPC) in the body and tail are still unknown. The aim of this study was to determine the prognostic factors after proton radiotherapy in a large group of patients with LAPC in the body and tail. The medical records of 200 patients with LAPC in the body and tail who underwent proton radiotherapy between February 2009 and January 2021 at the Hyogo Ion Beam Medical Center were retrospectively reviewed to identify prognostic factors that contribute to long-term survival. The overall survival rate at 1- and 2-year after PT was 69.6% and 35.4% with a median overall survival of 18.4 months. The 1- and 2-year local progression-free, and progression-free survival rates were 84.3% and 68.0%, and 44.3% and 19.4%, respectively. In multivariate analysis, superior mesenteric artery (SMA) invasion (SMA only invasion vs. celiac artery only invasion; P = 0.049: SMA and celiac artery invasion vs. celiac artery only invasion; P = 0.017), carbohydrate antigen 19-9 (CA 19-9) level ≥ 231.9 U/mL (P = 0.001), anterior peripancreatic invasion (P = 0.006), and incomplete scheduled concurrent chemotherapy (P = 0.009) were statistically significant prognostic factors for overall survival. There was no significant difference in local progression-free survival; however, distant metastasis-free survival was statistically worse in patients with prognostic factors than in those without. Proton radiotherapy for LAPC in the body and tail may be a valuable multidisciplinary treatment option. Patients with SMA invasion, higher pre-proton radiotherapy serum CA 19-9 level, anterior peripancreatic invasion, or incomplete scheduled concurrent chemotherapy had worse overall survival because of worse distant metastasis-free survival, suggesting that distant metastases have a significant impact on overall survival in such patients. Retrospectively registered.


Rapid Soft Tissue Approximation and Repair using Laser-activated Silk Nanosealants.
Tissue approximation and repair have been conventionally performed with sutures and staples, but these means are inherently traumatic. Tissue approximation using laser-responsive nanomaterials can lead to rapid tissue sealing and repair, and is an attractive alternative to existing clinical methods. Here, we demonstrate the use of laser-activated nanosealants (LANS) with gold nanorods (GNRs) embedded in silk fibroin polypeptide matrices. The adaptability of LANS for sealing soft tissues is demonstrated using two different modalities: insoluble thin films for internal, intestinal tissue repair, and semi-soluble pastes for external repair, shown by skin repair in live mice. Laser repaired intestinal tissue held over seven times more fluid pressure than sutured intestine and also prevented bacterial leakage. Skin incisions in mice closed using LANS' showed indication of increased mechanical strength and faster repair compared to suturing. Laser-activated silk-GNR nanosealants rapidly seal soft-tissue tears and show high promise for tissue approximation and repair in trauma and routine surgery.


Emergency evaluation of head injuries in the elderly.
The first hour after head injury in the elderly is the most critical. Airway obstruction and impaired cardiovascular reflex mechanisms are the major initial problems. A patient with an extracerebral hematoma may need emergency trephination. You must look for the specific clinical indications or use a CAT scan to identify surgically accessible lesions.


EGFR mRNA is upregulated, but somatic mutations of the gene are hardly found in renal cell carcinoma in Japanese patients.
Heterozygous somatic mutations of epidermal growth factor receptor (EGFR) in exons 18, 19, and 21 were recently reported to be associated with response to gefitinib in patients having nonsmall cell lung cancer. Such mutations are more frequently found among Japanese than Europeans. In this work, the frequency of mutations was investigated in renal cell carcinoma (RCC) samples obtained from Japanese subjects to examine the potential of gefitinib as a therapeutic agent for RCC. Nineteen patients with RCC, who gave written informed consent, were enrolled in this study. mRNA expression levels of EGFR were measured in RCC and its adjacent noncancerous renal tissue via the real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. Somatic mutations were determined using genomic DNA extracted from RCC by direct sequencing method. mRNA expression was confirmed to be about 19 times higher in RCC than in adjacent noncancerous renal tissues, but no such mutations were detected in both. Results from this study do not support the validity of further clinical trials on gefitinib for RCC with genotyping even in Japanese patients, although EGFR plays a key role in tumor progression.


Iron deficiency--facts and fallacies.
Iron deficiency occurs in all strata of society, is primarily a result of postnatal feeding practices and not due to congenital deficiencies of iron, can be prevented by appropriate dietary guidance, and, when present, produces important nonhematologic manifestations.


Chiral solitons in a coupled double Peierls chain.
Chiral edge states are the hallmark of two- and three-dimensional topological materials, but their one-dimensional (1D) analog has not yet been found. We report that the 1D topological edge states, solitons, of the charge density wave system of indium atomic wires self-assembled on a silicon surface have chirality. The system is described by a coupled double Peierls-dimerized atomic chain, where the interchain coupling induces dynamical sublattice symmetry breaking. This changes its topological symmetry from Z₂× Z₂to Z₄ and endows solitons with a chiral degree of freedom. Chiral solitons can produce quantized charge transport across the chain that is topologically protected and controllable by the soliton's chirality. Individual right- and left-chiral solitons in indium wires are directly identified by scanning tunneling microscopy.


FR255734, a humanized, Fc-Silent, Anti-CD28 antibody, improves psoriasis in the SCID mouse-psoriasis xenograft model.
In psoriasis, CD28/B7 costimulatory molecules are well characterized. Here, using the severe combined immunodeficient (SCID) mouse-psoriasis xenograft model, we report therapeutic efficacy of a humanized anti-CD28 monoclonal antibody (FR255734; Astellas Pharmaceuticals Inc., Tokyo, Japan). Transplanted psoriasis plaques on the SCID mouse were treated weekly for 4 weeks with intraperitoneal injections of FR255734 at 10, 3, and 1-mg kg(-1) doses. Groups treated with doses of 10 and 3 mg kg(-1) had significant thinning of the epidermis and reduced HLA-DR-positive lymphocytic infiltrates. The length of the rete pegs changed from 415.2+/-59.6 to 231.4+/-40.4 microm (P<0.005) in the 10-mg kg(-1) group, and from 323.4+/-69.6 to 237.5+/-73.6 microm in the 3-mg kg(-1) group (P=0.002). Positive controls treated with CTLA4-Ig and cyclosporine had significant histological improvement, whereas plaques treated with saline and isotype controls (human and mouse IgG2) remained unchanged. In vitro studies have shown that FR255734 effectively blocked T-cell proliferation and proinflammatory cytokine production. These observations warrant studies to evaluate the efficacy of FR255734 in human autoimmune diseases.


Serum levels of anti-PF4 IgG after AZD1222 (ChAdOx1 nCoV-19) vaccination.
Rare cases of thrombosis with thrombocytopenia syndrome (TTS) have been reported after AZD1222. Anti-platelet factor-4 (PF4) antibodies were observed in patients following presentation of TTS, however it is unclear if AZD1222 was responsible for inducing production of anti-PF4. Paired samples (baseline and day-15) from a phase 3 trial of AZD1222 vs placebo were analyzed for anti-PF4 levels; 19/1727 (1.1%, AZD1222) vs 7/857 (0.8%, placebo) participants were anti-PF4-IgG-negative at baseline but had moderate Day-15 levels (P = 0.676) and 0/35 and 1/20 (5.0%) had moderate levels at baseline but high Day-15 levels. These data indicate that AZD1222 does not induce a clinically relevant general increase in anti-PF4 IgG.


FOXP1, an estrogen-inducible transcription factor, modulates cell proliferation in breast cancer cells and 5-year recurrence-free survival of patients with tamoxifen-treated breast cancer.
Breast cancer is primarily a hormone-dependent tumor that can be regulated by the status of steroid hormones, including estrogen and progesterone. Forkhead box P1 (FOXP1) is a member of the forkhead box transcription factor family and has been reported to be associated with various types of tumors. In the present study, we investigated the expression of FOXP1 in 133 human invasive breast cancers, obtained by core biopsy, by immunohistochemical analysis. Nuclear immunoreactivity of FOXP1 was detected in 89 cases (67%) and correlated positively with tumor grade and hormone receptor status, including estrogen receptor alpha (ERα) and progesterone receptor, and negatively with pathological tumor size. In ERα-positive MCF-7 breast cancer cells, we demonstrated that FOXP1 mRNA was upregulated by estrogen and increased ERα recruitment to ER binding sites identified by ChIP-on-chip analysis within the FOXP1 gene region. We also demonstrated that proliferation of MCF-7 cells was increased by exogenously transfected FOXP1 and decreased by FOXP1-specific siRNA. Furthermore, FOXP1 enhanced estrogen response element-driven transcription in MCF-7 cells. Finally, FOXP1 immunoreactivity was significantly elevated in relapse-free breast cancer patients treated with tamoxifen. These results suggest that FOXP1 plays an important role in proliferation of breast cancer cells by modulating estrogen signaling and that FOXP1 immunoreactivity could be associated with the estrogen dependency of clinical breast cancers, which may predict favorable prognosis in the patients treated with tamoxifen.


[Effect and safety of 10-day decitabine-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation in 31 patients with acute myeloid leukemia/myelodysplastic syndrome].
Objective: To investigate the early effect and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a 10-day decitabine-containing conditioning regimen in the treatment of acute myeloid leukemia (AML) /myelodysplastic syndrome (MDS) . Methods: From April 2021 to May 2022, 31 AML/MDS patients who received allo-HSCT with a 10-day decitabine-containing conditioning regimen were analyzed. Results: AML (n=10), MDS-AML (n=6), CMML-AML (n=1), and MDS (n=14) were identified in 31 patients, 16 males, and 15 females, with a median age of 41 (20-55) yr. Neutrophils and platelets were successfully implanted in 31 patients (100%), with a median implantation duration of 12 (9-30) and 14 (9-42) days, respectively. During the preconditioning period, 16 patients (51.6%) developed oral mucositis, with 15 cases of Ⅰ/Ⅱ grade (48.4%) and one case of Ⅲ grade (3.2%). After transplantation, 13 patients (41.9%) developed CMV viremia, six patients (19.4%) developed hemorrhagic cystitis, and four patients (12.9%) developed a local infection. The median time of acute graft versus host disease (aGVHD) following transplantation was 33 (12-111) days. The cumulative incidence of aGVHD and Ⅲ/Ⅳ grade aGVHD was 41.9% (95% CI 26.9%-61.0%) and 22.9% (95% CI 13.5%-47.5%), respectively. There was no severe cGVHD, and mild and moderate chronic GVHD (cGVHD) incidence was 23.5% (95% CI 12.1%-43.6%). As of November 30, 2022, only one of the 31 patients had relapsed, with a 1-yr cumulative relapse rate (CIR) of 3.2% (95% CI 0.5%-20.7%). There was only one relapse patient death and no non-relapse deaths. The 1-yr overall survival (OS) and disease-free survival (DFS) rates were 92.9% (95% CI 80.3%-100%) and 96.8% (95% CI 90.8%-100%), respectively. Conclusions: A 10-day decitabine-containing conditioning regimen for allo-HSCT reduced relapse and was safe and feasible in treating AML/MDS.


In-target production of [13N]ammonia: target design, products, and operating parameters.
[13N]Ammonia, commonly used in PET, has been prepared in good yield in the target. Up to 800 mCi of radiopharmaceutical was obtained by in-line processing of the irradiated water. Relatively low hydrogen pressure was used to control the target chemistry. Target designs and the product dependence on beam dose, dose rate and pressure are reported. Ethanol as a target additive was also investigated. Hydrogen and ethanol together were more effective than either alone at high beam dose. Parameters are reported for production needs from single doses to synthetic applications. An incidental method for production of [13N]nitrogen gas is also reported.


Recombinase-mediated cassette exchange-based screening of a CRISPR/Cas9 library for enhanced recombinant protein production in human embryonic kidney cells: Improving resistance to hyperosmotic stress.
Targeted engineering of mammalian cells has been widely attempted to ensure the efficient production of therapeutic proteins with proper quality during bioprocesses. However, the identification of novel targets for cell engineering is labor-intensive and has not yet been fully substantiated. Here, we established a CRISPR/Cas9 library screening platform in human embryonic kidney (HEK293) cells based on guide RNA integration mediated by recombinase-mediated cassette exchange (RMCE) to interrogate gene function in a high-throughput manner. This platform was further advanced using a nuclear localization signal-tagged recombinase that increased RMCE efficiency by 4.8-fold. Using this platform, we identified putative target genes, such as CDK8, GAS2L1, and GSPT1, and their perturbation confers resistance to hyperosmotic stress that inhibits cell growth and induces apoptosis. Knockout of these genes in monoclonal antibody (mAb)-producing recombinant HEK293 (rHEK293) cells enhanced resistance to hyperosmotic stress-induced apoptosis, resulting in enhanced mAb production. In particular, GSPT1-knockout yielded 2.3-fold increase in maximum mAb concentration in fed-batch culture where hyperosmotic stress naturally occurs due to nutrient feeding. Taken together, this streamlined screening platform allows the identification of novel targets associated with hyperosmotic stress, enabling the development of stress-resistant cells producing recombinant proteins.


Treatment of chiasmatic/hypothalamic gliomas of childhood with chemotherapy: an update.
Chiasmatic/hypothalamic gliomas (CHG) of childhood may cause progressive neurological and visual deterioration. Radiotherapy results in at least transient stabilization of tumor growth in most patients but may also have adverse long-term effects, especially in young children. Since 1977, children with progressive CHG under 5 years of age at diagnosis have been treated with combination chemotherapy (actinomycin D and vincristine) without radiotherapy. Twenty-four patients, a median of 1.6 years of age at diagnosis, have been treated and followed for a median of 4.3 years (range, 0.3-10 years). All patients are alive. Nine have developed radiographic or clinical progression, occurring a median of 3 years (range, 2-6.5 years) after initiation of treatment. Fifteen of 24 (62.5%) have remained free of progressive disease and have received no other therapy. Tumor shrinkage was documented in 9 of 24 patients but did not clearly relate to long-term outcome. Full-scale intelligence quotient (IQ) obtained a median of 3.5 years after diagnosis in patients who received only chemotherapy was a mean of 103 (range 84-133). We conclude that chemotherapy can significantly delay the need for radiotherapy in children with CHG and such a delay may be beneficial regarding long-term outcome.


Artificial intelligence and radiomics in nuclear medicine: potentials and challenges.
Artificial intelligence involves a wide range of smart techniques that are applicable to medical services including nuclear medicine. Recent advances in computer power, availability of accumulated digital archives containing large amount of patient images, and records bring new opportunities for the implementation of artificial techniques in nuclear medicine. As a subset of artificial intelligence, machine learning is an emerging tool that possibly perform many clinical tasks. Nuclear medicine community needs to adapt to this fast approaching smart era, to exploit the opportunities and tackle the problems associated with artificial intelligence tools. It is aimed in this editorial to outline the potentials and challenges of artificial intelligence applications in nuclear medicine.


Carbon nitride photocatalyzes regioselective aminium radical addition to the carbonyl bond and yields N-fused pyrroles.
Addition of N-centered radicals to C=C bonds or insertion into C-H bonds is well represented in the literature. These reactions have a tremendous significance, because they afford polyfunctionalized organic molecules. Despite the tetrahydroisoquinoline (THIQ) moiety widely occurring in natural biologically active compounds, N-unsubstituted THIQs as a source of N-centered radicals are not studied. Herein, we report a photocatalytic reaction between tetrahydroisoquinoline and chalcones that gives N-fused pyrroles-1,3-disubstituted-5,6-dihydropyrrolo[2,1-a]isoquinolines (DHPIQ). The mechanism includes at least two photocatalytic events in one pot: (1) C-N bond formation; (2) C-C bond formation. In this process potassium poly(heptazine imide) is used as a visible light active heterogeneous and recyclable photocatalyst. Fifteen N-fused pyrroles are reported with 65-90% isolated yield. DHPIQs are characterized by UV-vis and fluorescence spectroscopy, while the fluorescence quantum efficiency of fluorinated DHPIQs reaches 24%.


Mutational analysis of human BLyS in patients with common variable immunodeficiency.
BLyS, a TNF family member, is crucial for B cell proliferation and differentiation by acting through its three receptors, TACI, BCMA and BAFF-R. The knock out model for BLyS is characterized by an immunological phenotype reminiscent of the human phenotype of common variable immunodeficiency (CVID). CVID is characterized by a defective B cell compartment, evidencing the putative importance of BLyS in its pathogenesis. On the contrary, the transgenic model for BLys is characterized by autoimmune manifestations, underlying its role in B cell regulation. In fact, mutations in TACI, one of the three BLyS receptors, are associated with CVID. Based on these facts, we hypothesized that BLyS could be a candidate gene for CVID. We screened 78 patients with CVID using DHPLC and direct sequencing: No disease causing mutations were identified. A novel heterozygous single nucleotide polymorphism (SNP) was found in exon 1 of one individual, however this SNP (G189A) does not lead to an amino acid substitution.


Automated selection of beam orientations and segmented intensity-modulated radiotherapy (IMRT) for treatment of oesophagus tumors.
For some treatment sites, there is evidence in the literature that five to nine equi-angular input beam directions are enough for generating IMRT plans. For oesophagus cancer, there is a report showing that going from four to nine beams may even result in lower quality plans. In this paper, our previously published algorithm for automated beam angle selection (Cycle) has been extended to include segmented IMRT. For oesophagus cancer patients, we have investigated whether automated orientation selection from a large number of equi-angular input beam directions (up to thirty-six) for IMRT optimisation can result in improved lung sparing. CT-data from five oesophagus patients treated recently in our institute were used for this study. For a prescribed mean PTV dose of 55 Gy, Cycle was used in an iterative procedure to minimise the mean lung dose under the following hard constraints: standard deviation for PTV dose inhomogeneity 2% (1,1 Gy), maximum spinal cord dose 45 Gy. Conformal radiotherapy (CFRT) and IMRT plans for a standard four field oesophagus beam configuration were compared with IMRT plans generated by automated selection from nine or thirty-six equi-angular input beam orientations. Comparisons were also made with dose distributions generated with our commercial treatment planning system (TPS), and with observations in the literature. Using Cycle, automated orientation selection from nine or thirty-six input beam directions resulted in improved lung sparing compared to the four field set-ups. Compared to selection from nine input orientations, selection from thirty-six directions did always result in lower mean lung doses, sometimes with even fewer non-zero weight beams. On average only seven beams with a non-zero weight were enough for obtaining the lowest mean lung dose, yielding clinically feasible plans even in case of thirty-six input directions for the optimisation process. With our commercial TPS we observed the same contra-intuitive, unfavourable results as reported in the literature; nine field equi-angular IMRT plans had substantially higher mean lung doses than plans for the conventional four field set-ups. For all cases, the Cycle plans generated from nine equi-angular input directions were superior compared to similar plans generated with our commercial TPS. For the studied oesophagus cancer patients the best plans for IMRT were obtained with Cycle, using automated beam orientation selection from thirty-six input beam directions. The lowest mean lung doses could be obtained with, on average, a selection of only seven beams with non-zero weight.


[Study of hyperacusis at a tinnitus unit].
Description of the epidemiological and clinical characteristics of hyperacusis in a tinnitus clinic unit. Transversal descriptive. Two hundred and fifty patients referred to our Tinnitus Unit a Teaching Hospital, between January 1999 and December 2000. Questionnaires to evaluate hyperacusis and tinnitus interference in life quality. Epidemiological and audiological data as well as tinnitus characteristics in hyperacustic patients are reported. Sixty three percent of the patients showed hyperacusis according to sound threshold level. Hearing loss was present in 83%. Discomfort with background noise was referred in 54% of cases and 52% avoided at least one daily activity because of this discomfort. Tinnitus in hyperacusis population showed a disability level of 47% using the Tinnitus Handicap Inventory (THI). A physiopathological relation between tinnitus and hyperacusis could be explained by the high prevalence of both symptoms in the same population. It is necessary to agree in the criteria to define hyperacusis as well as for the evaluation of its effect in quality of life. The tinnitus retraining therapy (TRT) is the more accepted hyperacusis treatment approach in the literature.


Chronic treatment with anesthetic propofol attenuates β-amyloid protein levels in brain tissues of aged mice.
Alzheimer's disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of β-amyloid protein (Aβ) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on Aβ levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced Aβ (Aβ40 and Aβ42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of β-site amyloid precursor protein cleaving enzyme (the enzyme for Aβ generation), and increased the levels of neprilysin (the enzyme for Aβ degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain Aβ levels potentially via decreasing brain levels of β-site amyloid precursor protein cleaving enzyme, thus decreasing Aβ generation; and via increasing brain neprilysin levels, thus increasing Aβ degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research.


Enhancement by food of canrenone bioavailability from spironolactone.
The influence of food intake on the bioavailability of canrenone, the major and active metabolite of spironolactone, was explored in 8 healthy male volunteers. Spironolactone was administered as a single oral dose of 100 mg, both in the fasting state and together with a standardized breakfast. Numerous venous blood samples were taken from 30 min to 96 hr after ingestion of the drug, and the plasma concentrations of canrenone were determined by spectrofluorometry. The results indicate that more canrenone enters the general circulation when spironolactone in ingested together with a meal.


Ecce Homo: Moving past labels to lives.
We report a contemporary individual who died with advanced holoprosencephaly (HPE) to encourage recognition of rare diseases (RDs), especially congenital conditions in archaeological samples. We also explore the range of conditions associated with hydrocephalus in support of nuanced interpretations of this disease. The skeleton of a 17-year-old male who died with clinically diagnosed HPE, along with an age and sex matched comparative sample of 6 individuals who suffered accidental death and who were normal. We observed and measured all remains using standard osteological methods. The clinical records for Ecce Homo were scrutinized; his family was interviewed, and his skull was X-rayed. The morphology and morphometry of Ecce Homo's skeleton display irregularities along the cranial midline and the postcranial skeleton consistent with anomalies derived from HPE as well as related congenital disorders and physical anomalies. We have reported HPE here and developed a differential diagnosis with closely related conditions. Likewise we relate the information generated in the clinical history and interviews with the family of Ecce Homo to facilitate an understanding of the social context. This case is exceptional in providing information from the life context of a contemporary individual who suffered from a rare disease (HPE), with skeletal remains could be studied extensively. The differential diagnosis is useful in identifying HPE and other closely related conditions. This is a single example with clinical intervention. Future osteological research should occur on other cases of HPE; molecular studies may offer further clarity.


The summer skin check.
Skin cancer is a major public health problem in Australia and represents a substantial health cost. General practitioners provide the majority of care to patients with skin cancer, so becoming familiar with the clinical features and management of these tumours is important. To provide a pictorial essay on the common types of benign and malignant skin lesions encountered in general practice, and briefly describe key clinical features, differential diagnosis and management options. Examination for skin cancer should be considered in the general practice setting for all patients over the age of 40 years, particularly the elderly. A proper skin check requires a systematic approach and ideally an entire consultation should be set aside for this purpose. However, clinical examination conducted for other purposes provides an opportunity for screening and early detection of skin cancer.


Manipulating Reduction Potentials in an Artificial Safranin Cofactor.
Safranines hold great promise as artificial flavin-like electron transfer cofactors with tunable properties. We report the design and chemical synthesis of the p-methoxy derivative of safranine O using a new synthetic route based on the Ulmann condensation. Spectroelectrochemical comparison of the purified parent safranine and this derivative demonstrates that the modification increases its two-electron reduction potential by 125 mV, or 5.75 kcal/mol. This modification also causes redshifts in the absorbance and fluorescence spectra of the cofactor, suggesting that it may find future utility in arrayed sensor applications.


Cytokines, JAK-STAT Signaling and Radiation-Induced DNA Repair in Solid Tumors: Novel Opportunities for Radiation Therapy.
A number of solid tumors are treated with radiation therapy (RT) as a curative modality. At the same time, for certain types of cancers the applicable doses of RT are not high enough to result in a successful eradication of cancer cells. This is often caused by limited pharmacological tools and strategies to selectively sensitize tumors to RT while simultaneously sparing normal tissues from RT. We present an outline of a novel strategy for RT sensitization of solid tumors utilizing Jak inhibitors. Here, recently published pre-clinical data are reviewed which demonstrate the promising role of Jak inhibition in sensitization of tumors to RT. A wide number of currently approved Jak inhibitors for non-malignant conditions are summarized including Jak inhibitors currently in clinical development. Finally, intersection between Jak/Stat and the levels of serum cytokines are presented and discussed as they relate to susceptibility to RT.


Frequency dependence of acoustic parameters of freshly excised tissues of Sprague Dawley rats.
A modified version of the pulse echo technique was used to measure the velocity of propagation and attenuation of ultrasound in excised tissue of young-adult Sprague-Dawley rats. The measurements were made at ultrasonic frequencies of 1.0, 2.25, 5.0, 7.5 and 10.0 MHz. The temperature of the tissues was monitored continuously to within +/- 0.1 degrees C of the ambient temperature. The acoustic parameters were measured in the liver, kidney, cardiac muscle and gastrocnemius muscle. All measurements were carried out in the near field region of the ultrasonic beam. It was observed that the velocity of propagation in tissues showed a slight dispersion with frequency. The attenuation in tissues increased with increasing frequency.