The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys.
The synthetic nonpeptide NOP (nociceptin/orphanin FQ peptide) receptor agonist Ro 64-6198 produces antinociception in rhesus monkeys. In rodents, it has much more variable effects on pain responses, but has response rate-increasing effects on punished operant behavior and decreases drug reward. The aim of this study was to compare Ro 64-6198 with the benzodiazepine diazepam in tests of analgesia, drug self-administration, and response-increasing effects in rhesus monkeys. Ro 64-6198 (0.001-0.01 mg/kg, i.v.) produced antinociception against an acute noxious stimulus (50°C water) in the absence of sedation, whereas diazepam (0.32-3.2 mg/kg, i.v.) did not have analgesic effects without sedation. Diazepam (1.0-5.6 mg/kg, i.v.) and the largest dose of Ro 64-6198 (0.32 mg/kg, i.v.) decreased lever pressing maintained by intravenous self-administration of the mu-opioid agonist, remifentanil, but neither effect could be distinguished from sedative effects. Although neither drug consistently increased responding during nonreinforcement, such effects were observed more frequently following diazepam administration. The effects of Ro 64-6198 on lever pressing were blocked by the NOP-receptor antagonist, J-113397, but not by the benzodiazepine antagonist, flumazenil. These findings suggest that the effects of Ro 64-6198 on operant lever pressing are mediated by NOP receptors and that larger doses are required to impact operant behavior when compared directly with those that produce antinociception. Therefore, the present findings support previous literature suggesting NOP receptors are a viable target for pain management.


Parapatry and niche complementarity of Peruvian Desert geckos (Phyllodactylus): the ambiguous role of competition.
The Sechura Desert of Peru is among the most arid, barren regions of South America. Four species of nocturnal geckos (Phyllodactylus) are parapatric in part of the desert. By comparing niche associations of these species in allopatry and parapatry, I attempt to determine whether the observed parapatric distributions and niche dimension complementarity are related to competition - as is frequently assumed. While parapatry suggests a role for competition, distributional patterns can alternatively be related to adaptations of geckos to different physical environments (sandy desert and rocky foothill) that abut in the study area. Niche complementarity might also be a result of competition, but potentially contradictory evidence suggests that niche complementarity might instead be the result of adaptations developed in allopatry and having no relationship to competition. The ambiguity of these interpretations sets limits on the significance of this kind of evidence: in the absence of attempts to falsify alternative explanations, observations of parapatry or of niche dimension complementarity do not demonstrate conclusively the impact of competition as a force structuring communities.


Effect of age and baseline ASPECTS on outcomes in large-vessel occlusion stroke: results from the HERMES collaboration.
Patient age and baseline Alberta Stroke Program Early CT score (ASPECTS) are both independent predictors of outcome in acute ischemic stroke patients treated with endovascular therapy (EVT). We assessed the combined effect of age and ASEPCTS on clinical outcome in acute ischemic stroke patients with LVO with and without EVT, and EVT treatment effect in different age/ASPECTS subgroups. The HERMES collaboration pooled data of seven randomized controlled trials that tested the efficacy of EVT. Adjusted logistic regression was performed to test for multiplicative interaction of age and ASPECTS with the primary outcome (ordinal mRS) and secondary outcomes (mRS 0-2/0-1/0-3) in the EVT and control arms. Patients were then stratified by age (<75 vs ≥ 75 years) and ASPECTS (0-5/6-7/8-10), and adjusted effect-size estimates for the association of EVT were derived for the six age/ASPECTS subgroups. 1735 patients were included in the analysis. There was no multiplicative interaction between age and ASPECTS on clinical outcomes. In the exploratory subgroup analysis, we found a nominally negative point estimate for the association of EVT with clinical outcome in the ASPECTS 0-5/age ≥75, subgroup (acOR 0.36, 95% CI 0.07 to 1.89). The point estimate for moderate outcome (mRS0-3) nominally favored EVT (aOR 1.24, 95% CI 0.16 to 9.84). In all other subgroups, effect size-estimates consistently favored EVT. There was no multiplicative interaction of age and ASPECTS on clinical outcomes in EVT or control arm patients. Outcomes in patients ≥75 years with ASPECTS 0-5 were poor, irrespective of treatment. Further investigation to define the role of EVT and range of acceptable outcomes in this subgroup is warranted.


Mind the Pulp: Environmental and economic assessment of a sugar beet pulp biorefinery for biobased chemical production.
Sugar beet pulp, a byproduct from sugar beet refining, is used by farmers as fertilizer or sold as animal feed. Both options underestimate the potential of sugar beet pulp as a platform to produce specialty and bulky chemicals as a promising pathway for sustainable biochemicals - mind the pulp. This study proposes a biorefinery concept to produce food additives (pectin-derived oligosaccharides) and bulky chemicals (terephthalic acid). Since the biorefinery has a low technology readiness level (TRL = 1), it is relevant to evaluate the feasibility of this biorefinery concept to provide guidance (at an early stage) on the environmental and economic advantages and limitations. For this purpose, the life cycle assessment and techno-economic assessment frameworks are used to assess the environmental impact and economic performance of the biobased terephthalic acid, respectively. Moreover, environmental impacts are accounted for in economic terms using different monetary valuation methods (environmental prices, Ecovalue12, and Ecotax). The environmental impact of biobased terephthalic acid was higher in most impact categories than the fossil counterpart, depending on the selected allocation approach (mass vs economic). The economic feasibility of the proposed biorefinery is highly dependent on the pectin-derived oligosaccharides market price and the valorization of byproducts (humins and levulinic acid). The selection of the monetary valuation method is critical for monetizing environmental impacts when comparing biobased against fossil-based alternatives.


Associations between XPD Asp312Asn polymorphism and risk of head and neck cancer: a meta-analysis based on 7,122 subjects.
To investigate the association between XPD Asp312Asn polymorphism and head and neck cancer risk through this meta-analysis. We performed a meta-analysis of 9 published case-control studies including 2,670 patients with head and neck cancer and 4,452 controls. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association between XPD Asp312Asn polymorphism and head and neck cancer risk. Overall, no significant association between XPD Asp312Asn polymorphism and head and neck cancer risk was found in this meta-analysis (Asn/Asn vs. Asp/Asp: OR = 0.95, 95%CI = 0.80-1.13, P = 0.550, P(heterogeneity) = 0.126; Asp/Asn vs. Asp/Asp: OR = 1.11, 95%CI = 0.99-1.24, P = 0.065, P(heterogeneity) = 0.663; Asn/Asn+Asp/Asn vs. Asp/Asp: OR = 1.07, 95%CI = 0.97-1.19, P = 0.189, P(heterogeneity) = 0.627; Asn/Asn vs. Asp/Asp+Asp/Asn: OR = 0.87, 95%CI = 0.68-1.10, P = 0.243, P(heterogeneity) = 0.089). In the subgroup analysis by HWE, ethnicity, and study design, there was still no significant association detected in all genetic models. This meta-analysis demonstrates that XPD Asp312Asn polymorphism may not be a risk factor for developing head and neck cancer.


[Efficacy of infliximab combined with surgery in the treatment of perianal fistulizing Crohn disease].
To evaluate the efficacy of infliximab combined with surgery in the treatment of perianal fistulizing Crohn disease (CD). Clinical data of 15 patients with perianal fistulizing CD receiving infliximab combined with surgery in the Affiliated Hospital of Nanjing University of Chinese Medicine from March 2010 to June 2011 were analyzed retrospectively. One week after operation, all the patients received infliximab infusion thrice at weeks 0, 2, and 6. Crohn disease activity index (CDAI), perianal Crohn disease activity index (PDAI), body mass index (BMI), routine blood test and endoscopy were evaluated at week 0, 14. Adverse reactions and healing time were recorded. At week 14, the response rate was 100% with 86.7% (13/15) complete responders. One patient had local improvement and one developed recurrent fistula. The mean healing time was 32.5 (20-45) d. Anorectal stenosis in 4 patients was significantly improved. At week 14, CDAI decreased to 114.0±90.3 from 230.5±97.5 after IFX treatment. PCDAI decreased to 2.8±3.2 from 9.9±3.4, and BMI increased to (21.5±3.0)kg/m(2) from (19.1±3.1)kg/m(2). C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), platelet and neutrophil were significantly decreased from baseline (all P<0.01). Intestinal mucosa healed completely in one patient. There were no serious adverse events except hypokalemia in one patient and severe infusion reaction in another. Infliximab combined with surgery is effective and safe for perianal fistulizing CD.


Plasmic degradation of bovine fibrinogen and non-crosslinked fibrins in solution and in gel form.
1. Analysis of degradation processes of bovine fibrinogen by bovine plasmin using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and a study on the mode of changes of the properties related to clotting of digestion products as a function of time were performed. Gross features and patterns very similar to those which had been reported with human fibrinogen-plasmin systems were obtained. 2. Based on the molecular size of the degradation products and the mode of appearance and disappearance of the degradation products, the processes could tentatively be divided into three stages: stage 1, where fibrinogen (mol. wt 370 000) was degraded to produce fragments X1 (330 000) and X2 (290 000); stage 2, fragment X2 was degraded with appearance of Y (210 000) and D1 (140 000); stage 3, appearance of fragments D1, D2 (110 000), and D3 (100 000) sequentially and E (68 000) with concomitant disappearance of Y. 3. A microseparation method, which is a combination of dansylation and sodium dodecylsulfate-polyacrylamide gel electrophoresis, was devised to analyze the events of stage 1 in detail, and a molecular model for the process was proposed. 4. The plasmic degradation processes of bovine non-cross-linked fibrins in solution and in gel form were compared with that of fibrinogen and it was found that the state of the substrates, fibrins, could cause differences in the degradation patterns. With the former substrate, essentially the same sodium dodecyl sulfate-polyacrylamide gel electrophoretic patterns as those with fibrinogen were obtained. With the latter substrate, however, a distinct difference in the mode of degradation of beta chains was observed.


What neuropsychology tells us about human tool use? The four constraints theory (4CT): mechanics, space, time, and effort.
Our understanding of human tool use comes mainly from neuropsychology, particularly from patients with apraxia or action disorganization syndrome. However, there is no integrative, theoretical framework explaining what these neuropsychological syndromes tell us about the cognitive/neural bases of human tool use. The goal of the present article is to fill this gap, by providing a theoretical framework for the study of human tool use: The Four Constraints Theory (4CT). This theory rests on two basic assumptions. First, everyday tool use activities can be formalized as multiple problem situations consisted of four distinct constraints (mechanics, space, time, and effort). Second, each of these constraints can be solved by the means of a specific process (technical reasoning, semantic reasoning, working memory, and simulation-based decision-making, respectively). Besides presenting neuropsychological evidence for 4CT, this article shall address epistemological, theoretical and methodological issues I will attempt to resolve. This article will discuss how 4CT diverges from current cognitive models about several widespread hypotheses (e.g., notion of routine, direct and automatic activation of tool knowledge, simulation-based tool knowledge).


Altered redox status of coenzyme Q9 reflects mitochondrial electron transport chain deficiencies in Caenorhabditis elegans.
Mitochondrial disorders are often associated with primary or secondary CoQ10 decrease. In clinical practice, Coenzyme Q10 (CoQ10) levels are measured to diagnose deficiencies and to direct and monitor supplemental therapy. CoQ10 is reduced by complex I or II and oxidized by complex III in the mitochondrial respiratory chain. Therefore, the ratio between the reduced (ubiquinol) and oxidized (ubiquinone) CoQ10 may provide clinically significant information in patients with mitochondrial electron transport chain (ETC) defects. Here, we exploit mutants of Caenorhabditis elegans (C. elegans) with defined defects of the ETC to demonstrate an altered redox ratio in Coenzyme Q9 (CoQ9), the native quinone in these organisms. The percentage of reduced CoQ9 is decreased in complex I (gas-1) and complex II (mev-1) deficient animals, consistent with the diminished activity of these complexes that normally reduce CoQ9. As anticipated, reduced CoQ9 is increased in the complex III deficient mutant (isp-1), since the oxidase activity of the complex is severely defective. These data provide proof of principle of our hypothesis that an altered redox status of CoQ may be present in respiratory complex deficiencies. The assessment of CoQ10 redox status in patients with mitochondrial disorders may be a simple and useful tool to uncover and monitor specific respiratory complex defects.


The main obstacle to a malaria vaccine: the malaria parasite.
The challenge to development of a malaria vaccine will be the variability of the sequences of target antigens. We discuss the variability in the T cell epitopes on the circumsporozoite protein of Plasmodium falciparum and the rapid selection of mutants after immunization with a protein from the asexual erythrocytic stage of P. knowlesi.


Synchronous gastric cancer in primary sporadic colorectal cancer patients in Korea.
Colorectal cancer has been reported to be the malignancy most frequently associated with gastric cancer in Korea. The aim of this study was to define the frequency and clinical characteristics of synchronous gastric cancer detected at preoperative esophagogastroduodenoscopy (EGD) in colorectal cancer patients. This prospective study analyzed the EGD results from 1,542 consecutive colorectal cancer patients who underwent surgery from January 2003 to December 2005 at the Center for Colorectal Cancer, National Cancer Center, Korea. Of the 1,542 cases, 1,155 (74.9%) underwent EGD at our center and 387 underwent EGD at other hospitals within 6 months before surgery. Of the 1,542 cases, synchronous gastric cancers were detected in 31 cases (2.0%). Of these 31 cases, 26 had early gastric cancer (EGC; 83.9%) and 5 had advanced gastric cancer. Ten (38.5%) of the 26 EGC cases were managed using endoscopic mucosal resection. Compared to colorectal cancer patients without synchronous gastric cancer, the group of patients with synchronous gastric cancer was older (65.5+/-9.6 vs 58.4+/-11.3 years, p=0.001) and had a greater proportion of males (77.4 vs 59.4%, p=0.043). This study found that 2% of Korean sporadic colorectal cancer patients had synchronous gastric cancer. A preoperative EGD for colorectal cancer patients is likely to greatly assist in the diagnosis of synchronous gastric cancer at an early stage and the implementation of appropriate minimally invasive treatment.


Effects of pneumoperitoneum with or without colostomy on rat colonic anastomotic healing.
Elevated intra-abdominal pressure and colostomy have adverse effects on colonic anastomoses. The aim of the present study was to investigate the effects of laparoscopic colon surgery with and without diverting colostomy on healing of colonic anastomoses in an experimental model. Thirty-six male rats were divided into three equal groups: group 1, control (colonic anastomosis and anaesthesia for 180 min only); group 2, 180 min pneumoperitoneum and colonic anastomosis; and group 3, similar to group 2 with a proximal colostomy. On day 7, bursting pressures, tissue hydroxyproline and nitric oxide concentrations and histopathological inflammation scores were determined and compared. Mean bursting pressures were higher in the control group than the two pneumoperitoneum groups (P=0.0003). Mean tissue hydroxyproline concentrations showed no difference (P>0.05). Mean tissue nitric oxide concentrations were significantly increased in the control group (P=0.0013). Histopathological scores demonstrated increased inflammatory response in group 3 compared to the controls (P=0.0009). Pneumoperitoneum delays collagen maturation and impairs anastomotic strength in the colon. Following pneumoperitoneum, performance of a diverting loop colostomy to protect the anastomosis will not have additional detrimental effects on anastomotic healing.


Evaluation of fine needle aspiration of the male breast for the diagnosis of gynaecomastia.
Fine needle aspiration of the male breast can present problems of diagnosis because the cytological presentation of gynaecomastia can be confused with that of adenocarcinoma. We reviewed breast aspirates from 24 male patients in order to determine the accuracy of cytology as a method of diagnosing gynaecomastia. Discrepancies were observed between the original cytology reports on one hand and the review cytology and biopsies on the other. Of the 24 aspirates from the male breast, the cytology was reported as negative in 16 cases, suspicious in three cases and malignant in five. In four cases of the negative group, a specific diagnosis of gynaecomastia was made. In two of the negative cases the subsequent biopsies revealed adenocarcinoma. Of the five cases reported on the original cytology as adenocarcinoma, two on review showed the features of florid gynaecomastia and this was confirmed on biopsy and three confirmed the initial diagnosis of adenocarcinoma. The cytological features of gynaecomastia which distinguish it from adenocarcinoma are discussed.


TVT versus SPARC: comparison of outcomes for two midurethral tape procedures.
To compare the subjective and objective cure rates in women who underwent either the SPARC or the TVT midurethral sling for the treatment of stress urinary incontinence. This retrospective study included all 122 consecutive women undergoing a TVT or SPARC midurethral sling procedure for objective stress urinary incontinence between January 2000 and March 2003 at the Evanston Continence Center. Primary outcomes were subjective and objective stress incontinence cure rates. Subjects underwent multichannel urodynamics preoperatively and 14 weeks postoperatively, and stress testing at last follow-up. The two groups were compared using univariate and multivariate analyses. Seventy-three subjects underwent a TVT and 49 subjects had a SPARC procedure. There were no statistical differences in demographic factors between the two groups. Subjects undergoing SPARC were more likely to void by Valsalva effort. One hundred and seven women returned for objective postoperative evaluation after surgery. The TVT procedure was associated with higher subjective (86 vs. 60%, P = 0.001) and objective (95 vs. 70%, P < 0.001) stress incontinence cure rates. There was no difference between the TVT and SPARC groups in the resolution of subjective and objective urge urinary incontinence. TVT was associated with a higher stress urinary incontinence cure rate than SPARC in this retrospective study. As new midurethral sling products are introduced, prospective randomized controlled trials should be conducted to evaluate their relative efficacy and safety.


Dissolved organic matter transformations in a freshwater rivermouth.
River-to-lake transitional areas are biogeochemically active ecosystems that can alter the amount and composition of dissolved organic matter (DOM) as it moves through the aquatic continuum. However, few studies have directly measured carbon processing and assessed the carbon budget of freshwater rivermouths. We compiled measurements of dissolved organic carbon (DOC) and DOM in several water column (light and dark) and sediment incubation experiments conducted in the mouth of the Fox river (Fox rivermouth) upstream from Green Bay, Lake Michigan. Despite variation in the direction of DOC fluxes from sediments, we found that the Fox rivermouth was a net sink of DOC where water column DOC mineralization outweighed the release of DOC from sediments at the rivermouth scale. Although we found DOM composition also changed during our experiments, alterations in DOM optical properties were largely independent of the direction of sediment DOC fluxes. We found a consistent decrease in humic-like and fulvic-like terrestrial DOM and a consistent increase in the overall microbial composition of rivermouth DOM during our incubations. Moreover, greater ambient total dissolved phosphorus concentrations were positively associated with the consumption of terrestrial humic-like, microbial protein-like, and more recently derived DOM but had no effect on bulk DOC in the water column. Unexplained variation indicates that other environmental controls and water column processes affect the processing of DOM in this rivermouth. Nonetheless, the Fox rivermouth appears capable of substantial DOM transformation with implications for the composition of DOM entering Lake Michigan. The online version contains supplementary material available at 10.1007/s10533-022-01000-z.


Different iron(II) complexes of bleomycin A2.
By 13C-nmr on iron-bleomycin preparations, an iron-bleomycin-CO complex is found that loses its CO upon standing, as demonstrated using 14CO. Iron-bleomycin, prepared without rigorous exclusion of oxygen, reacts with CO to a stable diamagnetic iron-bleomycin-CO complex.


Biologic premises of combined radiation therapy and chemotherapy in lung cancer.
When radiation is combined with concurrent chemotherapy, independent cell kill and enhancement of tumor response may be expected. On the other hand, spatial cooperation may be the main rationale for sequential combination of the two modalities. Among many new agents being investigated, radiation-activated antitumor prodrugs have a therapeutic potential as a new method to effectively combine radiation and concurrent chemotherapy.


Response from the authors re: Letter to the Editor for our manuscript "The cost of a euploid embryo identified from preimplantation genetic testing for aneuploidy (PGT-A): a counseling tool".


Effect of hexafluoroisopropanol alcohol on the structure of melittin: a molecular dynamics simulation study.
The molecular mechanism by which HFIP stabilizes the alpha-helical structure of peptides is not well understood. In the present study, we use melittin as a model to gain insight into the details of the atomistic interactions of HFIP with the peptide. We have performed extensive comparative molecular dynamics simulations (up to 100 nsec) in the absence and in the presence of HFIP. In agreement with recent NMR experiments, the simulations show rapid loss of tertiary structure in water at pH 2 but much higher helicity in 35% HFIP. The MD simulations also indicate that melittin adopts a highly dynamic global structure in 35% HFIP solution with two alpha-helical segments sampling a wide range of angular orientations. The analysis of the HFIP distribution shows the tendency of HFIP to aggregate around the peptide, increasing the local cosolvent concentration to more than two times that in the bulk concentration. The correlation of local peptide structure with HFIP coating suggests that displacement of water at the peptide surface is the main contribution of HFIP in stabilizing the secondary structure of melittin. Finally, a stabilizing effect promoted by the presence of counter-ions was also observed in the simulations.


Medial Open Wedge High tibial Osteotomy (MOWHTO) does not relevantly alter patellar kinematics: a cadaveric study.
The purpose of this study was to quantify the influence of medial open wedge high tibial osteotomy on patellar kinematics using optical computer navigation, as anterior knee pain infrequently occurs postoperatively and the reason is still being unknown. Ten medial open wedge high tibial osteotomies at supratuberosity level in 5 full body specimens were performed. The effect of the surgical procedure on patellar kinematics, measured at 5 and 10 degrees of leg alignment correction angle, was analyzed and compared to native patellar kinematics during passive motion-regarding patella shift, tilt, epicondylar distance and rotation. Linear mixed models were used for statistical analysis, a two-sided p value of ≤ 0.05 was considered statistically significant. Tilt behavior, medial shift and epicondylar distance did not show a significant difference regarding natural patellar kinematics at both osteotomy levels. Both osteotomy correction angles showed a significant less external rotation of the patella (p < 0.001, respectively) compared to natural kinematics. Except less external rotation of the patella, medial open wedge high tibial osteotomy does not seem to relevantly alter patellar alignment during passive motion. Future clinical studies have to prove the effect of MOWHTO on patellar kinematics measured in this experimental setup, especially regarding its influence on anterior knee pain.


Thyrotropin-induced hyperthyroidism: evidence for a common progenitor stem cell.
A 36-year-old woman with hyperthyroidism, elevated blood thyroid-stimulating hormone (TSH) and alpha-subunit levels, amenorrhea, hyperprolactinemia and no evidence of acromegaly, was found to have a pituitary adenoma containing TSH, alpha-subunit and growth hormone by immunohistochemistry. Preoperative testing revealed elevated TSH and alpha-subunit with no response to thyrotropin-releasing hormone (TRH) but a normal response in prolactin to TRH. Culture of the pituitary cells showed release of TSH, alpha-subunit and prolactin. In vitro, TRH failed to cause TSH discharge; however, it increased prolactin concentrations in the culture medium. Triiodothyronine, added to the pituitary cell culture, resulted in no inhibition of TSH and prolactin discharge. By electron microscopy, the adenoma cells showed features of thyrotrophs. However, some adenoma cells contained fibrous bodies characteristic of some growth hormone cell tumors and acidophil stem cell adenomas, suggesting that the adenoma originated in a common progenitor cell.


Encouragement of cervical cancer screening via an evolutionary theoretical approach: A randomized controlled study in Japan.
The introduction of an evolutionary perspective into public health research has received attention in recent years. We aimed to examine the effects of messages that target the fundamental human motive of kin care (i.e., childbirth and parenting) on cervical cancer screening recommendations, based on an evolutionary theoretical approach. A randomized controlled study was conducted in Japan. Female participants (n = 969) were randomly assigned either to a group that received an intervention message that targeted the fundamental motive of kin care (recommending cervical cancer screening for future childbearing), or that targeted the fundamental motive of disease avoidance, or a control message. Intention to obtain cervical cancer screening was assessed both before and after reading the messages. A one-way ANOVA with Tukey's or Games-Howell test was conducted. Each of the intervention message targeting the fundamental motive of kin care and of the message targeting disease avoidance significantly increased intention to obtain cervical cancer screening versus a control message (M = 0.76 vs. M = 0.17, p < 0.001; M = 0.74 vs. M = 0.17, p < 0.001, respectively). A message that targeted the fundamental motive of kin care was as effective as one targeting the fundamental motive of disease avoidance. Health professionals should add messages that target the fundamental motive of kin care to their repertoire to encourage cervical cancer screening among women who wish future childbirth and parenting (e.g., "Delayed detection of cervical cancer may prevent your future childbirth and parenting. So let's obtain cervical cancer screening regularly for your future childbirth and parenting.").


Factors Associated With Abducens Nerve Palsy in Patients Undergoing Surgery for Petroclival Meningiomas.
During the surgical resection of petroclival meningiomas, preserving the cranial nerves is crucial. The abducens nerve is particularly vulnerable during surgery. However, the preoperative risk factors and postoperative prognosis of abducens nerve palsy (ANP) are poorly understood. We retrospectively analyzed 70 patients who underwent surgery for petroclival meningiomas between May 2010 and December 2019, divided into gross-total resection (GTR) and subtotal resection (STR) groups. The relationship of preoperative clinical factors with the incidence and recovery of postoperative ANP was analyzed. Postoperative ANP was observed in 23 patients (32.9%). Multivariable logistic regression revealed that the tumor-to-cerebellar peduncle T2 imaging intensity index (TCTI) (P < 0.001) and internal auditory canal invasion (P = 0.033) contributed to postoperative ANP. GTR was achieved in 37 patients (52.9%), and 10 (27.0%) of them showed ANP. STR was achieved in 33 patients (47.1%), and 13 (39.4%) of them showed ANP. Recovery from ANP took a median of 6.6 months (range, 4.5-20.3 months). At 6 months after the operation, recovery of the abducens nerve function was observed in 16 patients (69.0%); of whom, 4 (40.0%) were in the GTR group and 12 (92.3%) were in the STR group (P = 0.025). TCTI and internal auditory canal invasion were the risk factors for postoperative ANP. Although intentional STR did not prevent ANP immediately after the operation, recovery of the abducens nerve function after surgery was observed more frequently in the STR group than in the GTR group.


Brain circuits in panic disorder.
This paper reviews the pathophysiology of panic disorder (PD), within the context of newly described "fear circuitries," which have been well characterized in preclinical models. Substantial advances in the neurosciences have made it possible for clinical neuroscientists to refine our understanding of the pathophysiology of PD and the mechanisms of currently effective treatment. These advances have in turn helped generate testable hypotheses for future neurobiological and psychopharmacologic research. Perturbation of mutual modulation ("cross talk") between key brain transmitter systems (serotonin, norepinephrine, gamma-aminobutyric acid, corticotropin-releasing factor, and others) may underlie the pathogenesis of panic-anxiety. Restoration of normal homeostasis may be an important therapeutic component of antipanic therapy and may provide information about underlying neurocircuits. Neuroimaging, an important new tool, has already begun to bridge the gap between the preclinical and clinical neurosciences through confirmation of hypothesized dysfunction of the complex human prefrontal cortex and its subcortical components. In higher species, such as humans, dysfunction of cortical inhibition or excessive cortical activation of caudal limbic structures is postulated to lead to activation of the phylogenetically conserved amygdalofugal pathways. Consistent with probable subtypes of PD, overlapping theoretical models of panic neurocircuitries are proposed, including ventilatory dysregulation, which is coupled with neurovascular instability in a critical area of the panic neurocircuitry--the amygdalohippocampus. Neuroimaging appears a critical tool in guiding further elaboration of the interaction of cortical and subcortical components of the panic neurocircuitry, whereas challenge studies appear crucial in gathering further information regarding brain stem dysfunction.


Structure-activity relationship studies and bioactivity evaluation of 1,2,3-triazole containing analogues as a selective sphingosine kinase-2 inhibitors.
Sphingosine kinase (SphK) is primarily responsible for the production of Sphingosine-1-phosphate (S1P) that plays an important role in many biological and pathobiological processes including cancer, inflammation, neurological and cardiovascular disorders. Most research has focused on developing inhibitors of SphK1 rather than inhibitors of the other isoform SphK2 which has great importance in several pathophysiologic pathways. Exploration of new analogues for improving the potency and selectivity of SphK2 inhibitors is critical. We now have designed, synthesized, and evaluated eighteen new 1,2,3-triazole analogues for their SphK2 inhibitory activity using a ADP-Glo kinase assay, and explored their in vivo anti-tumor bioactivity. Several compounds including 21c, 21e, 21g, 25e-h, 29a-c have high selectivity for SphK2 over SphK1; compound 21g displayed the highest potency with an IC50 value of 0.23 μM. In addition, three compounds 21a, 21b, and 25b have high anti-tumor activity against U-251 MG human glioblastoma cells. Molecular modeling study was performed to elucidate the polar head group and 1,2,3-triazole pharmacophore impact on the SphK2 selectivity.


Characterizing key attributes of COVID-19 transmission dynamics in China's original outbreak: Model-based estimations.
A novel coronavirus strain, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. This study aims to characterize key attributes of SARS-CoV-2 epidemiology as the infection emerged in China. An age-stratified mathematical model was constructed to describe transmission dynamics and estimate age-specific differences in biological susceptibility to infection, age-assortativeness in transmission mixing, and transition in rate of infectious contacts (and reproduction number R 0) following introduction of mass interventions. The model estimated the infectious contact rate in early epidemic at 0.59 contacts/day (95% uncertainty interval-UI = 0.48-0.71). Relative to those 60-69 years, susceptibility was 0.06 in those ≤19 years, 0.34 in 20-29 years, 0.57 in 30-39 years, 0.69 in 40-49 years, 0.79 in 50-59 years, 0.94 in 70-79 years, and 0.88 in ≥80 years. Assortativeness in transmission mixing by age was limited at 0.004 (95% UI = 0.002-0.008). R 0 rapidly declined from 2.1 (95% UI = 1.8-2.4) to 0.06 (95% UI = 0.05-0.07) following interventions' onset. Age appears to be a principal factor in explaining the transmission patterns in China. The biological susceptibility to infection seems limited among children but high among those >50 years. There was no evidence for differential contact mixing by age.


Should patients with acute myeloid leukemia treated with venetoclax-based regimens receive antifungal prophylaxis?
Invasive fungal disease (IFD) is a major complication in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy, and the use of anti-mold prophylaxis is considered standard of care. On the other hand, the use of anti-mold prophylaxis in AML patients receiving less-intensive venetoclax-based regimens is not well established, basically because the incidence of IFD may not be high enough to justify primary antifungal prophylaxis. Furthermore, dose adjustments in venetoclax are needed because of drug interactions with azoles. Finally, the use of azoles is associated with toxicity, including liver, gastrointestinal and cardiac (QT prolongation) toxicity. In a setting of low incidence of invasive fungal disease, the number needed to harm would be higher than the number needed to treat. In this paper we review the risk factors for IFD in AML patients receiving intensive chemotherapeutic regimens, the incidence and risk factors for IFD in patients receiving hypomethylating agents alone, and in patients receiving less-intensive venetoclax-based regimens. We also discuss potential problems with the concomitant use of azoles, and present our perspective on how to manage AML patients receiving venetoclax-based regimens without primary antifungal prophylaxis.


The effect of rutin-N-mustard on the survival of NK/Ly ascites tumour-bearing mice.
A newly synthetized rutin derivative, rutin-N-mustard, showed a marked antiproliferative effect on NK/Ly ascites tumour cells in vivo. When administered i.p. or i.v., this compound increased the survival time of the animals, but oral administration had no such effect. The drug was not able to kill the tumour cells, since the chromium release from the rutin-N-mustard-treated tumour cells was the same as in the case of the controls. Tumour growth was completely inhibited in the animals when the cells were pretreated with 100 mg/kg rutin-N-mustard before transplantation. The results also showed that rutin-N-mustard has little effect on the xenogenization of NK/Ly tumour cells. We presume that the antiproliferative action of rutin-N-mustard is due to its alkylating activity.


A pediatric case of critical illness polyneuropathy: clinical and pathological findings.
Critical illness polyneuropathy (CIP) is a sensorimotor polyneuropathy recognized in adult intensive care patients with sepsis and multiple organ dysfunction and only a few cases have been reported in children. Here we report a 13-year-old Japanese boy with CIP that developed during the course of encephalopathy. Two months after the onset of encephalopathy, he developed tetraplegia although consciousness had already recovered. Deep tendon reflex was absent. MRI of the brain and spinal cord was normal and no abnormality in the cerebrospinal fluid was detected. Motor and sensory nerve conduction velocities of the lower limbs and somatosensory evoked potential could not be detected. The motor activity subsequently showed gradual recovery, although standing and walking could not be achieved. Sural nerve biopsy performed 3 years after the onset showed severe reduction of the number of myelinated large-diameter fibers, thin myelin in almost all fibers and cluster formation of myelinated small-diameter fibers, indicating primary axonal degeneration with regeneration. We report here for the first time the neuropathological changes in peripheral nerves during the chronic stage of CIP in children.


Polynucleotide phosphorylase and the T3SS.
Low temperatures as well as encounters with host phagocytes are two stresses that have been relatively well studied in many species of bacteria. The exoribonuclease polynucleotide phosphorylase (PNPase) has previously been shown to be required by several species of bacteria, including Yersinia, for low-temperature growth. We have shown that PNPase also enhances the ability of Yersinia to withstand the killing activities of murine macrophages. We have gone on to show that PNPase is required for the optimal functioning of Yersinia's type three secretion system (T3SS), an organelle that injects effector proteins directly into host cells. Surprisingly, the PNPase-mediated effect on T3SS activity is independent of PNPase's ribonuclease activity and instead requires only its S1 RNA-binding domain. In stark contrast, the catalytic activity of PNPase is strictly required for enhanced growth at low temperature. Preliminary experiments suggest that the RNA-binding interface of the S1 domain is critical for its T3SS-enhancing activity. Our findings indicate that PNPase plays versatile roles in promoting Yersinia's survival in response to stressful conditions.


CXCL14 enhances insulin-dependent glucose uptake in adipocytes and is related to high-fat diet-induced obesity.
Accumulating evidence suggests an association between obesity and adipose tissue inflammation. Chemokines are involved in the regulation of inflammation status. Chemokine (C-X-C motif) ligand 14 (CXCL14) is known to be a chemoattractant for monocyte and dendritic cells. Recently, it was reported that CXCL14-deficient mice show resistance to high-fat diet-induced obesity. In this study, we identified CXCL14 as a growth hormone (GH)-induced gene in HepG2 hepatoma cells. Substantial in vivo expression of CXCL14 was detected in the adipose tissue and liver. Its expression and secretion were strikingly increased by insulin administration and high-fat diet. Intriguingly, incubation of 3T3-L1 adipocytes with CXCL14 stimulated insulin-dependent glucose uptake. Further, this effect was associated with enhanced insulin signaling. CXCL14 enhanced the insulin-induced tyrosine phosphorylation of insulin receptors and insulin receptor substrate-1. These results suggest that CXCL14 plays a causal role in high-fat diet-induced obesity.


An angiotensin receptor blocker reduces the risk of congestive heart failure in elderly hypertensive patients with renal insufficiency.
We examined the efficacy of candesartan in reducing cardiovascular events in hypertensive patients with coexisting chronic kidney disease and cardiovascular diseases. This open-label, prospective study was conducted from 1999 to 2002, and 141 hypertensive subjects 60 to 75 years old with non-diabetic chronic renal insufficiency were enrolled. Before randomization of the patients, we examined their past medical history and found that 69 patients had been hospitalized due to myocardial infarction (MI) or stroke. Therefore, the patients were divided into 2 groups, one with previous histories of MI or stroke and the other with no previous history of Ml or stroke. The patients were randomized to receive either the angiotensin receptor blocker candesartan or conventional treatment. The mean duration of follow-up was 3.1 +/- 0.4 years. The primary outcome was a primary cardiovascular event (MI, stroke, or heart failure) verified by hospitalization. At the end of the study, in the patients with past history of cardiovascular diseases, blood pressure was reduced from 146.4 +/- 7.2/79.2 +/- 5.1 to 34.4 +/- 6.1/72.3 +/- 4.0 mmHg in the candesartan group and from 145.3 +/- 5.1/80.1 +/- 3.8 to 133.4 +/- 5.8/73.8 +/- 4.2 mmHg in the conventional treatment group. In the patients without past history of cardiovascular diseases, blood pressure was reduced from 143.2 +/- 4.3/78.3 +/- 4.8 to 133.8 +/- 5.3/ 73.1 +/- 3.8 mmHg in the candesartan group and from 143.9 +/- 6.8/78.1 +/- 4.2 to 132.6 +/- 5.4/74.5 +/- 4.4 mmHg in the conventional treatment group at the end of the study. There were no significant differences between the candesartan group and the conventional treatment group in the reduction of blood pressures. Among patients with a past history of cardiovascular disease, the serum creatinine concentration increased from 1.49 +/- 0.38 to 1.58 +/- 0.42 by candesartan treatment and from 1.50 +/- 0.32 to 1.89 +/- 0.37 by conventional treatment. On the other hand, in patients with no past history of cardiovascular disease, the serum creatinine concentration increased from 1.44 +/- 0.42 to 1.46 +/- 0.40 by candesartan treatment and from 1.46 +/- 0.44 to 1.51 +/- 0.38 by conventional treatment. Although, there was no significant difference in the incidence of cardiovascular events between the 2 groups with the candesartan-based and conventional-based antihypertensive treatment, in patients without cardiovascular events (12/36 vs. 7/34: these figures indicate events per total participated persons per 3 years; following figures are the same as this), treatment with candesartan reduced the incidence of cardiovascular events in the patients with past history of cardiovascular diseases (20/33 vs. 32/ 38). In particular, candesartan-based treatment reduced the incidence of congestive heart failure by 66.4% in these patients. In conclusion, this prospective, open-labeled randomized study suggests that 1) previous history of cardiovascular diseases is a major risk factor for cardiovascular events; and 2) candesartan is effective for reduction of cardiovascular events in hypertensive patients with coexisting chronic kidney disease and cardiovascular diseases, especially for prevention of congestive heart failure.


Vaginal and Penile Microbiome Associations With Herpes Simplex Virus Type 2 in Women and Their Male Sex Partners.
We determined how the vaginal and penile microbiomes contribute to herpes simplex virus type 2 (HSV-2) serostatus within sexual partnerships. Microbiomes were characterized in cervicovaginal lavage and penile meatal swab specimens through high-throughput 16s ribosomal RNA gene amplicon sequencing. HSV-2 antibody was detected in serum specimens. We modeled vaginal and penile taxa and covariates contributing to HSV-2 status in women and men using bivariate probit analysis. Among 231 couples, HSV-2 was detected in both partners in 78 couples (33.8%), in the woman only in 52 (22.5%),in the man only in 27 (11.7%), and in neither in 74 (32.0%). Among the women (median age, 22 years) 10.9% had human immunodeficiency virus (HIV), and 21.4% had Bacterial vaginosis. Among men (median age, 26 years), 11.8% had HIV, and 55.0% circumcised. In an analysis with adjustment for sociodemographics and Bacterial vaginosis, enrichment of vaginal Gardnerella vaginalis and Lactobacillus iners was associated with increased likelihood of HSV-2 in both partners. Penile taxa (including Ureaplasma and Aerococcus) were associated with HSV-2 in women. We demonstrate that penile taxa are associated with HSV-2 in female partners, and vaginal taxa are associated with HSV-2 in male partners. Our findings suggest that couples-level joint consideration of genital microbiome and sexually transmitted infection or related outcomes could lead to new avenues for prevention.


Determination of drugs in biological samples by thin-layer chromatography-tandem mass spectrometry.
In this work thin-layer chromatography-tandem mass spectrometry (TLC-MS-MS) allowed detection and confirmation of caffeine and nicotine in human urine and of butorphanol, betamethasone, and clenbuterol in equine urine. In most cases of trace analysis of labile compounds the drugs could not be identified unless they were developed on a TLC plate, scraped from the plate and the TLC scrape eluted with a suitable organic solvent prior to MS-MS. Usually a sample prepared in this way still had several components in it, but was sufficiently cleaned up to allow collision-induced dissociation (CID) experiments to unequivocally identify the drug. In contrast, trace levels of labile drugs could not be identified by CID experiments either directly from the raw urine extracts or by thermally desorbing them from the TLC scrape.


Selective tetramodal bladder-preservation therapy, incorporating induction chemoradiotherapy and consolidative partial cystectomy with pelvic lymph node dissection for muscle-invasive bladder cancer: oncological and functional outcomes of 107 patients.
To evaluate the oncological and functional outcomes associated with selective tetramodal bladder-sparing therapy, comprising maximal transurethral resection of bladder tumour (TURBT), induction chemoradiotherapy (CRT), and consolidative partial cystectomy (PC) with pelvic lymph node dissection (PLND). In the present study, 154 patients with non-metastatic muscle-invasive bladder cancer (MIBC), prospectively enrolled in the tetramodal bladder-preservation protocol, were analysed. After TURBT and induction CRT, patients showing complete remission were offered consolidative PC with PLND for the achievement of bladder preservation. Pathological response to induction CRT was evaluated using PC specimens. Oncological and functional outcomes after bladder preservation were evaluated using the following endpoints: MIBC-recurrence-free survival (RFS); cancer-specific survival (CSS); overall survival (OS), and cross-sectional assessments of preserved bladder function and quality of life (QoL) including uroflowmetry, bladder diary, International Prostate Symptom Score, Overactive Bladder Symptom Score and the 36-item Short-Form Health Survey (SF-36) score. The median follow-up period was 48 months. Complete MIBC remission was achieved in 121 patients (79%) after CRT, and 107 patients (69%) completed the tetramodal bladder-preservation protocol comprising consolidative PC with PLND. Pathological examination in these 107 patients revealed residual invasive cancer (≥pT1) that was surgically removed in 11 patients (10%) and lymph node metastases in two patients (2%). The 5-year MIBC-RFS, CSS and OS rates in the 107 patients who completed the protocol were 97%, 93% and 91%, respectively. As for preserved bladder function, the median maximum voided volume, post-void residual urine volume, and nighttime frequency were 350 mL, 25 mL, and two voids, respectively. In the SF-36, patients had favourable scores, equivalent to the age-matched references in all the QoL scales. Selective tetramodal bladder-preservation therapy, incorporating consolidative PC with PLND, yielded favourable oncological and functional outcomes in patients with MIBC. Consolidative PC may have contributed to the low rate of MIBC recurrence in patients treated according to this protocol.


Femoral neck fractures following surface replacement.
A femoral neck fracture following surface replacement of the hip has been studied and five potential causes of failure were noted. These consisted of; removal of a hip nail during surgery, use of a too small femoral cup, initial reaming in varus, notching of the femoral neck, and failure to completely seat the cup.


Is attention deficit hyperactivity disorder increasing among girls in the US? Trends in diagnosis and the prescribing of stimulants.
To use a single national data source to discern trends in the prevalence of office-based visits resulting in a diagnosis of attention deficit hyperactivity disorder (ADHD) among girls, and trends in the prescribing of stimulant pharmacotherapy (including methylphenidate) for its treatment in the US. Data from the US National Ambulatory Medical Care Survey were utilised for this analysis. The number and rate of office-based physician visits resulting in a diagnosis of ADHD (International Classification of Diseases, 9th Revision, Clinical Modification code 314.00 or 314.01) were discerned from the beginning of 1990 to the end of 1998, for children aged 5 to 18 years. Gender-specific trend analyses were conducted using four time intervals: 1991 to 1992, 1993 to 1994, 1995 to 1996, and 1997 to 1998. The estimated number of office-based visits documenting a diagnosis of ADHD among children increased from 947 208 in 1990 to 3 234 180 in 1998. The rate of office-based visits documenting a diagnosis of ADHD among children increased from 19.4 per 1000 of the US population aged 5 to 18 years in 1990 to 59.0 per 1000 in 1998, a 3-fold increase (p < 0.05). The annualised mean number of office-based visits documenting a diagnosis of ADHD among girls tripled between 1991 to 1992 and 1997 to 1998 (from 296 389 to 886 798), whereas the number for boys increased 2.2-fold (from 1 006 243 to 2 200 021). The US population-adjusted rate of office-based visits documenting a diagnosis of ADHD among girls increased 2.7-fold between 1991 to 1992 and 1997 to 1998 (from 12.3 per 1000 girls to 33.4 per 1000; p < 0.05), whereas the rate among boys doubled (from 39.5 per 1000 boys to 78.7 per 1000; p < 0.05). Documentation of a diagnosis of ADHD and the prescribing of stimulant pharmacotherapy increased 2.8-fold for girls, from 7.5 per 1000 girls in 1991 to 1992 to 21.1 per 1000 in 1997 to 1998 (p < 0.05), as compared with a 2.2-fold increase among boys (from 25.5 per 1000 boys to 57.0 per 1000; p < 0.05). Over the time frame 1990 to 1998, the rate of ADHD as well as the prescribing of stimulant medications for its treatment increased significantly among children aged 5 to 18 years. Between 1991 to 1992 and 1997 to 1998, the increased rate of diagnosis of ADHD among girls contributed to the overall upward trend. The rapidly increasing rate of ADHD among girls, and the prolonged nature of the disorder, represent significant public health problems. There exists a need for additional research examining both the aetiology and treatment of ADHD by gender.


Treatment of congenital nephrogenic diabetes insipidus by hydrochlorothiazide and cyclooxygenase-2 inhibitor.
A 1-month-old male infant presented with failure to thrive, polyuria, and severe hypernatremic dehydration. Based on family history, lack of response to vasopressin, and normal sonography of the urinary system, the diagnosis of congenital nephrogenic diabetes insipidus (cNDI) was established. The infant responded well to indomethacin in combination with hydrochlorothiazide (HCTZ), but quickly developed gastrointestinal bleeding. The substitution of indomethacin by amiloride and later by tolmetin was found to be ineffective. Treatment with HCTZ (3 mg/kg per day) and rofecoxib (1 mg/kg per day, both divided into three doses) combined with a low-salt formula resulted in a dramatic decrease in urinary free water losses. No side effects of the combination were noted. At age 8.5 months, the infant demonstrated catch-up growth and normal neurodevelopmental milestones. We conclude that the combination HCTZ/cyclooxygenase-2 inhibitor could be successfully used to treat infantile cNDI.


Successful desensitization of methylphenidate-induced rash.
Methylphenidate is a cornerstone of attention-deficit/hyperactivity disorder (ADHD) treatment. Cutaneous adverse reactions resulting from methylphenidate may prohibit its usage. We sought a way to continue this therapy in a patient who developed a rash twice following methylphenidate administration. In a desensitization protocol, methylphenidate was given in increasing doses, 30 minutes apart, over 10 days, until the therapeutic dose was reached and was continued regularly thereafter. No adverse reactions developed during the desensitization period or during the 6- month follow-up. In nonlife threatening cutaneous adverse reactions to methylphenidate, a desensitization protocol may enable the continued, safe administration of this drug.


Cell-division inhibitors: new insights for future antibiotics.
The growing problem of antibiotic resistance has been exacerbated by the use of new drugs that are merely variants of older overused antibiotics. While it is naive to expect to restrain the spread of resistance without controlling antibacterial usage, the desperate need for drugs with novel targets has been recognized by health organizations, industry and academia alike. The wealth of knowledge available about the bacterial cell-division pathway has aided target-driven approaches to identify novel inhibitors. Here, we discuss the therapeutic potential of inhibiting bacterial cell division, and review the progress made in this exciting new area of antibacterial discovery.


Comparison of glenoid inclination angle using different clinical imaging modalities.
The β-angle, formed by the intersection of a line on the floor of the supraspinatus fossa and glenoid fossa line, has been described as a reliable measurement tool in the clinical setting to analyze glenoid inclination on the anteroposterior (AP) view of the shoulder. The purpose of this study was to compare the accuracy of the β-angle measurement using different imaging modalities with a validated 3-dimensional (3D) software tool. The β-angle was measured on AP radiographs, unformatted 2-dimensional (2D) computed tomography (CT) scan, and reformatted 2D CT scan in the scapular plane for 51 shoulders of 49 patients undergoing primary total shoulder arthroplasty. Comparison to the glenoid inclination angle calculated by the 3D software was performed. The β-angle measured on reformatted CT scan was found to be the most accurate measurement method, with a mean difference of 1° (standard deviation [SD], 0.5°) with respect to 3D measurement. On AP radiographs, the β-angle was not as accurate, with a mean difference of 3° (SD, 0.7°; P < .006). The β-angle on unformatted 2D CT scan was not a reliable method to measure glenoid inclination, with a mean difference of 10° (SD, 0.9°; P < .0001). The β-angle measured with 2D CT scan formatted in the scapular plane was the most accurate method for measuring glenoid inclination. The β-angle on the AP radiograph is less accurate and reliable. Measurement of the β-angle on an unformatted 2D CT scan is not an acceptable method to determine glenoid inclination.


The antitumour effect of doxycycline on a T-cell leukaemia in the rat.
Previous studies showed that T-lymphoid cells are permeable to the tetracyclines, whereas B-lymphoid and erythroid cells are not. The tetracyclines impair mitochondrial protein synthesis if they have access to cells. Inhibition of mitochondrial protein synthesis during a number of cell cycles results, as a consequence, in proliferation arrest. The tetracyclines can therefore be considered as cytostatics. In the present study the effect of prolonged treatment with doxycycline on the growth of a T-cell type leukaemia of the rat was investigated. It is shown that doxycycline treatment inhibits not only tumour cell proliferation, but leads moreover to complete tumour eradication. The way by which the latter is achieved depends on the doxycycline concentration and, surprisingly, on the stage of tumour progression at which doxycycline administration is started. As, because of the permeability barrier, the proliferation of erythroid and B-lymphoid cells is not affected by the tetracyclines, the tetracyclines may provide a tool without serious side-effects in the therapy of T-type tumours.


Blockade of bepridil on IA and IK in acutely isolated hippocampal CA1 neurons.
The effects of bepridil, an antianginal agent with antiarrhythmic action, on voltage-dependent K+ currents in the CA1 pyramidal neurons acutely isolated from rat hippocampus were studied by means of whole-cell patch clamp techniques. Current recordings were made in the presence of TTX to block Na+ current. Depolarizing test pulses activated two components of outward K+ currents: a rapidly activating and inactivating component, IA; and a delayed component, IK. Results showed that bepridil reduced the amplitude of IA and IK, and exerted its inhibitory action in time- and dose-dependent manner. Half-blocking concentrations (IC50) of bepridil on IA and IK were 17.8 microM and 1.7 microM, respectively. 10 microM bepridil suppressed IA and IK by 46.7% and 77.1% at +30 mV of depolarization, respectively. When IK was activated nearly uncontaminated with IA by holding at -50 mV, 10 microM bepridil inhibited IK by 71.6% at +30 mV of depolarization; 10 microM bepridil positively shifted the voltage-dependent of activation curves of IA and IK 12.1 mV and 28.7 mV, respectively. These results suggested that blockade on K+ currents by bepridil is preferential for IK, and contributes to the protection brain against ischemic damage.


Humoral IgG antibodies to oral microbiota in a population at risk for root-surface caries.
Mutans streptococci have been strongly implicated in the initiation of dental caries on coronal surfaces. Their role in development of root-surface caries is less clear. The etiologic agents of both types of dental caries are likely to elicit systemic immune responses. The objective of the present study, therefore, was to study the association of clinical variables of disease with humoral IgG antibodies to nine oral micro-organisms in 314 adult subjects, aged 45-65 years, who were at risk for root-surface caries. Antibody activity to Streptococcus mutans strain Ingbritt, S. mutans/S. sobrinus GTFs, S. faecalis strain 19433, Actinomyces viscosus strain WVU 626, Actinomyces naeslundii strain 12, Lactobacillus casei, Actinobacillus actinomycetemcomitans strain Y4, Porphyromonas gingivalis strain 381, Eikenella corrodens strain 1073, and Wolinella recta strain 371 was measured by ELISA. Pearson correlation coefficients among log10 antibody levels within subjects revealed marked positive correlations among subgingival bacteria, generally weak positive correlations among supragingival micro-organisms, and no correlations between elements of the supragingival battery with the subgingival battery. IgG antibody levels to mutans streptococcal antigens were significantly correlated with subject DMF scores (r = 0.23; p less than 0.0001). No significant correlation was seen between DMF scores and antibody to any other supragingival micro-organism tested. Further relationships between levels of S. mutans antibody and individual clinical variables were analyzed by step-wise multiple linear regression, resulting in a model that was highly significant (p = 0.0001), with an r2 = 0.14. Numbers of missing teeth, coronal caries, root-surface caries, and root-surface restorations were each positively associated with antibody levels to mutans streptococci.(ABSTRACT TRUNCATED AT 250 WORDS)


Lymphokine-activated killer cell lysis of human neuroblastoma cells: a model for purging tumor cells from bone marrow.
Evidence is presented that neuroblastoma tumor cells in host bone marrow is susceptible to autologous lymphokine-activated killer cells (LAK). Thus, immunologic purging of bone marrow with LAK may be considered as a tool in the arsenal of bone marrow purging-for autologous bone marrow transplantation.


Overcoming language barriers in community-based research with refugee and migrant populations: options for using bilingual workers.
Although the challenges of working with culturally and linguistically diverse groups can lead to the exclusion of some communities from research studies, cost effective strategies to encourage access and promote cross-cultural linkages between researchers and ethnic minority participants are essential to ensure their views are heard and their health needs identified. Using bilingual research assistants is one means to achieve this. In a study exploring alcohol and other drug service use by migrant women in Western Australia, bilingual workers were used to assist with participant recruitment and administration of a survey to 268 women who spoke more than 40 different languages. Professional interpreters, bilingual students, bilingual overseas-trained health professionals and community sector bilingual workers were used throughout the research project. For the initial qualitative phase, professional interpreters were used to conduct interviews and focus group sessions, however scheduling conflicts, inflexibility, their inability to help with recruitment and the expense prompted exploration of alternative options for interview interpreting in the quantitative component of the study. Bilingual mature-age students on work placement and overseas-trained health professionals provided good entry into their different community networks and successfully recruited and interviewed participants, often in languages with limited interpreter access. Although both groups required training and supervision, overseas-trained health professionals often had existing research skills, as well as understanding of key issues such as confidentiality and referral processes. Strategies to minimise social desirability bias and the need to set boundaries were discussed during regular debriefing sessions. Having a number of workers recruiting participants also helped minimise the potential for selection bias. The practical and educational experience gained by the bilingual workers was regarded as capacity building and a potentially valuable community resource for future health research projects. The use of bilingual workers was key to the feasibility and success of the project. The most successful outcomes occurred with students and overseas-trained health professionals who had good community networks for recruitment and the required linguistic skills. By describing the advantages and disadvantages encountered when working with bilingual workers, we offer practical insights to assist other researchers working with linguistically diverse groups.


Two-dimensional-strain echocardiography in intensive care unit patients: A prospective, observational study.
Two-dimensional-strain echocardiography (2D-strain) is a promising technique for the early detection of myocardial dysfunction. Our study was aimed to assess its feasibility in the intensive care unit (ICU). Our secondary goal was to determine if 2D-strain could predict the patient's outcome. Conventional echocardiography and 2D-strain were performed on 64 consecutive patients admitted to our ICU. Using 2D-strain, the longitudinal deformation of the left ventricle was assessed. Feasibility of 2D-strain, diagnosis performance, and 28-day mortality prediction were determined. 2D-strain measurements could be performed in 77% of our patients. All 2D-strain variables related to ventricular performance were significantly impaired in the patients who died compared with those who survived. Strain global medium was the only independent echocardiographic variable predictor of 28-day mortality rate (odds ratio 0.60; 95% confidence interval 0.43-0.80, p = 0.002). 2D-strain measurement is feasible in ICU patients, enabling identifying early left ventricle dysfunction. Strain global medium is an independent predictor of 28-day mortality. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:368-374, 2016.


Effect of gender on atrial fibrillation ablation outcomes using a propensity score-matched analysis.
Previous studies have shown that women with atrial fibrillation (AF) have a higher incidence of recurrence and non-pulmonary vein (non-PV) triggers. However, there remains an incomplete understanding of the impact of gender on AF ablation strategies and outcomes. The purpose of this study was to evaluate the impact of gender on AF ablation outcomes. We analyzed 1568 AF ablations in 1412 patients (34% female) performed at a single tertiary care center between January 2013 and July 2021. Patients were followed for at least 6 months (mean 34 months) for detection of AF recurrence, complications, and emergency department visits/hospitalizations. The effect was assessed by multivariate logistic regression analysis using propensity score matching (PSM). Mean age was 64 years, and mean body mass index (BMI) was 31 kg/m2. Seventy-seven percent of patients underwent de novo ablations. Twenty-seven percent of patients had persistent AF, with a recurrence rate of 37%. There was no difference in AF recurrence when stratified by gender (hazard ratio [HR] 1.15; 95% confidence interval [CI] 0.92-1.43; P >.05) and age. After PSM gender 1:1 (criteria: age, type of AF, hypertension, diabetes mellitus, and BMI; n = 888 patients), there was no difference in AF recurrence or procedure-related complications. Having a history of persistent AF (HR 1.54; 95% CI 1.18-1.99; P = .001) predisposed to recurrence of AF. Persistent AF (HR 2.99; 95% CI 1.94-4.78; P <.001) and age >70 years (HR 1.03; 95% CI 1.02-1.05; P <.001) were associated with the need for additional substrate modification with no difference based on gender. There was no difference in overall safety or efficacy outcomes between genders after AF ablation.


[Right iliac fossa pain and Alvarado Score].
Unsuspected or undiagnosed acute appendicitis could progress to a perforation or could lead to the removal of a normal appendix. using a clinical score system as a diagnostic tool for this pathology and can decrease negative appendectomies. Prospective and protocolized study. National Clinicas Hospital. Córdoba. Argentina. Between May 2007 and June 2007 224 patients were studied of which 117 were male and 107 were female with a mean age of 26.65 years. An Alvarado score was performed on all patients on admission. Based on the clinical evidence and a second assessment with the Alvarado Score, surgical exploration was decided in 207 patients. The remaining 17 were excluded due to other pathology. The diagnosis of acute appendicitis was confirmed by surgical finding and histopathological studies. In the surgical findings it was shown that 189 (91%) patients had acute appendicitis. There was no surgical mortality. As regards morbidity, 3.86% had medical and 27% had surgical complications. The histopathology reports showed a normal caecal appendix in 18. Whereas the incidence of negative appendicectomy was about 8.69%. The use of the Alvarado Score together with the surgical and histopathology findings confirmed it was sensitive from 6 points for the diagnosis of acute appendicitis.


Knockout of the abundant Trichomonas vaginalis hydrogenosomal membrane protein TvHMP23 increases hydrogenosome size but induces no compensatory up-regulation of paralogous copies.
The Trichomonas vaginalis genome encodes up to 60000 genes, many of which stem from genome duplication events. Paralogous copies thus accompany most T. vaginalis genes, a phenomenon that limits genetic manipulation. We characterized one of the parasite's most abundant hydrogenosomal membrane proteins, TvHMP23, which is phylogenetically distinct from canonical metabolite carriers, and which localizes to the inner hydrogenosomal membrane as shown through sub-organellar fractionation and protease protection assays. Knockout of Tvhmp23 through insertion of the selectable neomycin marker led to a size increase of hydrogenosomes, the first knockout-induced phenotypes reported for Trichomonas, but no growth impairment. The transcriptional response of its four paralogous copies then analyzed revealed that they are not up-regulated, and hence do not compensate for the Tvhmp23 knockout.


Intrinsic reward circuit connectivity profiles underlying symptom and quality of life outcomes following antidepressant medication: a report from the iSPOT-D trial.
There is a critical need to better understand the neural basis of antidepressant medication (ADM) response with respect to both symptom alleviation and quality of life (QoL) in major depressive disorder (MDD). Reward neurocircuitry has been implicated in QoL, the neural basis of MDD, and the mechanisms of ADM response. Yet, we do not know whether change in reward neurocircuitry as a function of ADM is associated with change in symptoms and QoL. To address this gap in knowledge, we analyzed data from 128 patients with MDD who participated in the iSPOT-D trial and were assessed with functional neuroimaging pre- and post-ADM treatment (randomized to sertraline, venlafaxine-XR, or escitalopram). 58 matched healthy controls were scanned at the same time points. We quantified functional connectivity (FC) of reward neurocircuitry using nucleus accumbens (NAc) seed regions of interest, and then characterized how changes in FC relate to symptom response (primary outcome) and QoL response (secondary outcome). Symptom responders showed an increase in NAc-dorsal anterior cingulate cortex (ACC) FC relative to non-responders (p < 0.001) which was associated with improvement in physical QoL (p < 0.0003), and a decrease in NAc-inferior parietal lobule FC relative to controls (p < 0.001). QoL response was characterized by increases in FC between NAc-ventral ACC for environmental, NAc-thalamus for physical, and NAc-paracingulate gyrus for social domains (p < 0.001). Symptom responders to sertraline were distinguished by a decrease in NAc-insula FC (p < 0.001) and to venlafaxine-XR by an increase in NAc-inferior temporal gyrus FC (p < 0.005). Findings suggest that change in reward neurocircuitry may underlie differential ADM response profiles with respect to symptoms and QoL in depression.


Could treatment of autonomic dysfunction in early and prodromal Parkinson's disease slow disease progression?
A recently published study by Ma et al. (Ma J, Dou K, Liu R, Liao Y, Yuan Z, Xie A. Front Aging Neurosci 14: 898149, 2022) investigated the 5-year longitudinal association between sleep disorders and depression in early and prodromal Parkinson's disease (PD). Not surprisingly, sleep disorders were associated with higher depression scores among patients with PD but, interestingly, autonomic dysfunction was revealed as a mediator between the two. This mini-review highlights these findings with an emphasis on the proposed benefit of autonomic dysfunction regulation and early intervention in prodromal PD.


Pre- or postoperative radiotherapy for soft tissue sarcomas.
Sarcomas are rare tumours arising from mesenchymal tissue. A multimodal management in an expert centre combining surgery and radiotherapy is the current standard of care for localized soft-tissue sarcomas of the extremities, to enable limb-sparing strategies. The delivery of pre- radiotherapy or postoperative radiotherapy offers similar local control and survival rates but the toxicity profile is quite different: preoperative radiotherapy increases the risk of wound complications and postoperative radiotherapy affects long-term functional outcomes. While postoperative radiotherapy has long been the rule, especially in Europe, technical improvements with image-guided- and intensity-modulated radiotherapy associated with a better management of postoperative wounds has tended to change practices with more frequent preoperative radiotherapy. More recently the possibilities of a hypofractionated regimen or potentiation by nanoparticles to increase the therapeutic index plead in favour of a preoperative delivery of radiotherapy. The aim of this paper is to report pros and cons of pre- and post-operative radiotherapy for soft-tissue sarcomas.


Emerging therapies in cancer metabolism.
Metabolic reprogramming in cancer is not only a biological hallmark but also reveals treatment vulnerabilities. Numerous metabolic molecules have shown promise as treatment targets to impede tumor progression in preclinical studies, with some advancing to clinical trials. However, the intricacy and adaptability of metabolic networks hinder the effectiveness of metabolic therapies. This review summarizes the metabolic targets for cancer treatment and provides an overview of the current status of clinical trials targeting cancer metabolism. Additionally, we decipher crucial factors that limit the efficacy of metabolism-based therapies and propose future directions. With advances in integrating multi-omics, single-cell, and spatial technologies, as well as the ability to track metabolic adaptation more precisely and dynamically, clinicians can personalize metabolic therapies for improved cancer treatment.


Improving influenza virus backbones by including terminal regions of MDCK-adapted strains on hemagglutinin and neuraminidase gene segments.
Reverse genetics approaches can simplify and accelerate the process of vaccine manufacturing by combining the desired genome segments encoding the surface glycoproteins from influenza strains with genome segments (backbone segments) encoding internal and non-structural proteins from high-growth strains. We have developed three optimized high-growth backbones for use in producing vaccine seed viruses for group A influenza strains. Here we show that we can further enhance the productivity of our three optimized backbones by using chimeric hemagglutinin (HA) and neuraminidase (NA) genome segments containing terminal regions (non-coding regions (NCRs) and coding regions for the signal peptide (SP), transmembrane domain (TMD), and cytoplasmic tail (CT)) from two MDCK-adapted high growth strains (PR8x and Hes) and the sequences encoding the ectodomains of the A/Brisbane/10/2010 (H1N1) HA and NA proteins. Viruses in which both the HA and NA genome segments had the high-growth terminal regions produced higher HA yields than viruses that contained one WT and one chimeric HA or NA genome segment. Studies on our best-performing backbone indicated that the increases in HA yield were also reflected in an increase in HA content in partially purified preparations. Our results show that the use of chimeric HA and NA segments with high-growth backbones is a viable strategy that could improve influenza vaccine manufacturing. Possible mechanisms for the enhancement of HA yield are discussed.


Inflammation and immune activation are associated with risk of Mycobacterium tuberculosis infection in BCG-vaccinated infants.
Tuberculosis vaccine development is hindered by the lack of validated immune correlates of protection. Exploring immune correlates of risk of disease and/or infection in prospective samples can inform this field. We investigate whether previously identified immune correlates of risk of TB disease also associate with increased risk of M.tb infection in BCG-vaccinated South African infants, who became infected with M.tb during 2-3 years of follow-up. M.tb infection is defined by conversion to positive reactivity in the QuantiFERON test. We demonstrate that inflammation and immune activation are associated with risk of M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently infected with M.tb, and this is coupled with upregulated gene expression of immunoglobulin-associated genes and type-I interferon. Plasma levels of IFN-[Formula: see text]2, TNF-[Formula: see text], CXCL10 (IP-10) and complement C2 are also higher in infants that were subsequently infected with M.tb.


Red cell distribution width and neutrophil-lymphocyte ratio in rheumatoid arthritis.
Red cell distribution width (RDW) and neutrophil-lymphocyte ratio (NLR) are potential low-cost markers for detecting rheumatoid arthritis (RA) disease activity, but evidence on their accuracy for this purpose is conflicting. We aimed to determine the relationship between these and the Disease Activity Score of 28 joints (DAS-28) among Filipino RA patients, and to evaluate their ability to discriminate between patients with active RA and those in remission. This was a cross-sectional study done through a 7-year review of medical records of 134 adult patients with RA in a tertiary government hospital. Correlations were analyzed using Spearman analysis, and the receiver operating characteristic (ROC) curve was used to derive the sensitivity, specificity, and optimal cut-off values of RDW and NLR. Most patients were females with a mean disease duration of 7 years. Eighty-one percent (81%) had active disease using DAS-28 ESR. A weak positive correlation was found between NLR and DAS-28 and between NLR and ESR, but RDW did not correlate with either DAS-28 or ESR. The ROC analysis showed that in the differentiation of active RA and inactive RA, both RDW (area under the curve [AUC] 0.516, cut-off of ≥ 14.2% with 55.6% sensitivity and 42.3% specificity) and NLR (AUC 0.629, cut-off of ≥ 2.32 with 54.6% sensitivity and 76.9% specificity) had poor performance. NLR, but not RDW, was positively but weakly correlated with DAS-28 and ESR, making it a helpful marker of disease activity and inflammation in RA. Both NLR and RDW had low sensitivity and specificity for active RA and may not be useful in detecting disease activity.


Synergistic effect of organic-inorganic hybrid monomer and polyhedral oligomeric silsesquioxanes in a boronate affinity monolithic capillary/chip for enrichment of glycoproteins.
A boronate affinity monolith with improved affinity and selectivity for glycoproteins was prepared starting from two monomers. The first is 3-aminopropyltriethoxysilane-methacrylic acid (APTES-MAA), and the other is a polyhedral oligomeric silsesquioxane (POSS) monomer. In the next step, 3-(acrylamido)benzeneboronic acid was adopted as boronate affinity ligand, and ethylene glycol dimethacrylate as the crosslinker, and iso-propanol and octanol as binary porogens. The synergistic effect of APTES-MAA and POSS warrants good affinity and selectivity for glycoproteins, which results in a number of attractive features including (a) a wide operation pH range (from 5 to 8); (b) higher enrichment factors ranging from 19.3 to 20.6; (c) greater recoveries of glycoproteins between 95.8 and 107.1%; (d) lower relative standard deviations of ≤4.2%. Compared to the corresponding APTES-MAA/POSS-free monolith, the new boronate material had 1.7-fold increased glycoprotein recovery from complex samples. Glycoproteins in 500-fold diluted serum samples can be enriched by the boronate monolith. Graphical abstractSchematic representation of the preparation of 3-aminopropyltriethoxysilane-methacrylic acid/polyhedral oligomeric silsesquioxanes boronate affinity monolith. This sorbent exhibits high selectivity and wide pH operation range for capturing glycopeptides.


Lack of awareness despite complex visual processing: Evidence from event-related potentials in a case of selective metamorphopsia.
Visual awareness is thought to result from integration of low- and high-level processing; instances of integration failure provide a crucial window into the cognitive and neural bases of awareness. We present neurophysiological evidence of complex cognitive processing in the absence of awareness, raising questions about the conditions necessary for visual awareness. We describe an individual with a neurodegenerative disease who exhibits impaired visual awareness for the digits 2 to 9, and stimuli presented in close proximity to these digits, due to perceptual distortion. We identified robust event-related potential responses indicating 1) face detection with the N170 component and 2) task-dependent target-word detection with the P3b component, despite no awareness of the presence of faces or target words. These data force us to reconsider the relationship between neural processing and visual awareness; even stimuli processed by a workspace-like cognitive system can remain inaccessible to awareness. We discuss how this finding challenges and constrains theories of visual awareness.


Histiocytic lymphoma simulating lepromatous leprosy--a case report.
Histiocytic lymphomas are known to begin with skin lesions and remain localised to the skin for months or years before visceral involvement becomes evident. We report a case of nodular histiocytic lymphoma with clinical features simulating lepromatous leprosy.


Vitamin D increases IGF-I and insulin levels in experimental diabetic rats.
Previous studies have found that IGF-I may play an important role in glucose metabolism. The aim of this study is to examine the effect of vitamin D intake on the serum levels of glucose, insulin, and IGF-I in experimental diabetic rats. A total of 24 male Sprague-Dawley rats aged six to seven months, with an average weight of 300±30g, were randomly divided into three groups (eight rats per group). The first group served as control and the other two groups received an intraperitoneal injection of 45mg/kg streptozotocin (STZ) to develop diabetes. Then groups were treated for four weeks either with placebo or vitamin D (two injections of 20,000IU/kg). At the end of the experiment, two injection of vitamin D were found to result in a significant increase in plasma cholecalciferol, which could improve hyperglycaemia and hypoinsulinemia in diabetic rats. HbA1c concentration had a slight and insignificant decrease following vitamin D intake. In addition, a significant decline was observed in the serum IGF-I level of STZ-treated rats in comparison to the controls, which was compensated in the vitamin D group. The serum vitamin D concentration was positively correlated to the changes in IGF-I level by Pearson test. These data showed for the first time that vitamin D intake could significantly improve fasting plasma glucose, insulin, and IGF-I in an experimental type 1 diabetes model.


Effectiveness of reducing the risk of eating-related problems using the German school-based intervention program, "Torera", for preadolescent boys and girls.
Representative surveys indicate that eating disorders are an increasing problem, especially among (pre)adolescents. We assessed the effects of a German school-based primary prevention program ("Torera") for seventh graders. Torera especially relates to pathological eating behavior in the realm of bulimia nervosa or binge eating disorder. The program is built upon two previously evaluated modules for sixth graders with a gender-specific adaption. The coeducational intervention involves nine manual-guided lessons touching a wide range of eating-related problems. Twenty-two Thuringian secondary schools (n = 256 boys and 277 girls, aged 11-13 years at baseline) participated in a trial with 2 control groups (untreated and pretreated) with pre-post assessment. Primary outcomes were conspicuous eating behavior and body self-esteem, measured by standardized questionnaires (SCOFF, EAT-26D, and FBeK). Girls and students at risk showed significant improvement with small (d = 0.35) to medium (d = 0.66) effect sizes on eating behavior, significantly mediated by body self-esteem. Boys only improved with respect to eating attitudes, revealing a small effect size (d = 0.35). With relatively low implementation costs (about <euro>2.50 per student), Torera provides an efficient model for reducing risky eating behavior and strengthening body self-esteem without negative side effects. To improve the effectiveness of the intervention, further research efforts focusing on at-risk groups (secondary prevention) and structural actions for prevention (e.g., offering healthy school catering) are needed.


The effects of stature, age, gender, and posture preferences on preferred joint angles after real driving.
Few studies have investigated preferred driving posture involving real-world driving. For this purpose, seven preferred joint angles of 127 participants were recorded three times from sagittal plane photographs after a short, standardized drive on public roads. Participants' individual driving posture preferences were determined using a word-based questionnaire. The inter- and intraindividual joint angle differences were calculated and some significant effects of stature, age, and gender on these joint angle differences were found. Additionally, significant correlations were found between posture preferences and joint angles, except for the lower extremities. The results show that the factors stature, age, gender, and posture preferences have influence on the preferred joint angles. However, other human-, vehicle-, and context-related factors also seem relevant and should be considered in future studies. The results provide important field-based knowledge for an application-oriented understanding of driving posture and for the human-centered design process of future vehicle interior research and development.


(8-Hy-droxy-6-meth-oxy-1-oxo-1H-isochromen-3-yl)methyl formate: a supra-molecular framework.
In the title compound, C12H10O6, an intra-molecular O-H⋯O hydrogen bond forms an S(6) ring motif. The mol-ecule is essentially planar with an r.m.s. deviation of 0.051 Å for all non-H atoms. In the crystal mol-ecules are linked by C-H⋯O hydrogen bonds and a C-H⋯π inter-action, forming a supra-molecular framework.


New Insights into Cold Shock Proteins Effects in Human Cancer: Correlation with Susceptibility, Prognosis and Therapeutical Perspectives.
The microenvironment of the tumor cells is central to its phenotypic modification. One of the essential elements of this milieu is thermal regulation. An augment in local temperature has been reported to augment the tumor cell's responsiveness to chemoand radiation treatment. Cold shock proteins are RNA/DNA binding proteins identified by the existence of one or more cold shock domains. In humans, the best studied components of this group of proteins are called Y-box binding proteins, such as Y-box binding protein-1 (YB-1), but several other proteins have been recognized. Biological functions of these proteins extend from the control of transcription, translation and splicing to the regulation of exosomal RNA content. Several findings correlate an altered cold shock protein expression profile with tumor diseases. In this review we summarize the data for a causative participation of cold shock proteins in cancer onset and diffusion. Furthermore, the possible use of cold shock proteins for diagnostics, prognosis, and as targets for cancer treatment is exposed.


[Early childhood intervention from a distance-opportunities and challenges in supporting psychosocially stressed families in the COVID-19 pandemic].
As of spring 2020, contact-restricting measures were necessary to contain the incidence of infection with the SARS-CoV‑2 virus in Germany. However, these restrictions posed particular challenges to families, especially families in high-stress situations. This paper examines how the COVID-19 pandemic affected the life of families and if long-term support in the context of early childhood intervention could be continued. The following analyses are based on qualitative research with psychosocially stressed mothers of young children, two surveys of health professionals who provide long-term support to families in early childhood intervention, and a survey of municipal actors who are responsible for the management and implementation of early childhood intervention in German communities.During the pandemic, families in high-stress conditions report existential fears and general overstrain. Intrafamilial conflicts seem to increase. Home visits in the context of long-term psychosocial support were initially primarily replaced by phone calls, video calls or other forms of "support from a distance." During the course of the pandemic, many professionals have begun conducting home visiting again, but several elements of support from a distance continue to be used as a supplement.Due to the pandemic-related additional burdens on the families who were accompanied by early childhood intervention, the continuation of support was even more important than it already was. Having been tested by necessity during the pandemic, several formats of support from a distance may have the potential to complement the usual assistance provided by health professionals in early childhood intervention and thus contribute to its quality development push.


Erratum to: Comparative ileal amino acid digestibility and growth performance in growing pigs fed different level of canola meal.
[This corrects the article DOI: 10.1186/s40781-015-0055-3.].


Staurosporine potentiates platelet activating factor stimulated phospholipase C activity in rabbit platelets but does not block desensitization by platelet activating factor.
The possible involvement of protein kinase C activation in regulating PAF-stimulated PLC activity was studied in rabbit platelets. PAF (100 nM for 5 seconds) stimulated incorporation of 32P into proteins and caused [3H]InsP3 levels to increase about 260% of control. These responses were compared after platelets were pretreated with either PAF, phorbol 12-myristate 13-acetate (PMA) or staurosporine and also after pretreatments with staurosporine followed by PAF or PMA. Pretreating platelets with staurosporine potentiated PAF-stimulated [3H]InsP3 levels by 54% and blocked protein phosphorylation. Pretreatments with PAF and PMA caused PAF-stimulated [3H]InsP3 levels to decrease to 115 and 136%, respectively. Staurosporine pretreatment blocked the decrease caused by the PMA pretreatment but not that by PAF. This study demonstrates that PAF-stimulated PLC activity is negatively affected by protein kinase C (PKC) activation and that inhibition of PKC activity did not prevent desensitization of PLC by PAF.


The Biophysics of Lymphatic Transport: Engineering Tools and Immunological Consequences.
Lymphatic vessels mediate fluid flows that affect antigen distribution and delivery, lymph node stromal remodeling, and cell-cell interactions, to thus regulate immune activation. Here we review the functional role of lymphatic transport and lymph node biomechanics in immunity. We present experimental tools that enable quantitative analysis of lymphatic transport and lymph node dynamics in vitro and in vivo. Finally, we discuss the current understanding for how changes in lymphatic transport and lymph node biomechanics contribute to pathogenesis of conditions including cancer, aging, neurodegeneration, and infection.


An improved method for isolation of specific antibodies by affinity chromatography; application to an antiserum to testosterone.
The specificity of polyclonal antibodies for use in immunoassay procedures can be improved by purification on affinity columns. The standard procedure involves immunoabsorption of the specific antibody populations on the insolubilized antigen, followed by desorption from the latter. However, the desorption process usually results in antibody damage and loss of antibody titer. We therefore designed an affinity chromatography procedure involving immunoabsorption of the main cross-reacting antibody fractions instead of the specific ones, eliminating thereby the desorption step. We exemplify the procedure with the purification of an anti-testosterone antibody.


Prenatal diagnosis of fetal cerebral abnormalities by ultrasonography and magnetic resonance imaging.
We found magnetic resonance imaging (MRI) of the fetal brain to be effective in confirming or denying diagnosis of fetal cerebral defects when ultrasonography was inconclusive or incomplete. In this paper we describe 31 cases in which ultrasonographic evidence of fetal brain defects was verified by MRI. MRI was performed after curarization of the fetus. In 21 cases, ultrasonographic evidence was confirmed by histological study of the fetus or postnatal radiological examination. In 10 cases, ultrasonographic diagnosis was denied by MRI and healthy infants were born. In one case of cerebral toxoplasmosis, ultrasonography detected periventricular calcifications but MRI was normal. In 20 cases MRI ascertained or further documented the ultrasonographic findings. However in 4 of these 20 cases autopsy of the fetus was required to determine the exact nature of the lesion.


Corneal thickness and morphology after orthokeratology of six-month lens wear among young Malay adults.
Menicon Z night orthokeratology (OK) lenses was introduced in Malaysia in 2015 and to date there is no report on its effects on the cornea. The objective of this study was to examine short term changes in corneal thickness and morphology of endothelial cells in young Malay adults after wearing Menicon Z night OK lenses. Corneal thickness was measured at the central and mid-peripheral locations of 20 participants aged 22.45±1.19 years using Tomey SP-3000 A-scan ultrasonography. Endothelial images of the central and peripheral locations captured using Tomey EM-3000 specular microscope were noted. Corneal thickness, endothelial cell density (ECD), coefficient of variation in cell size (CV), and hexagonality (HEX) at baseline, 24 hours, three months and six months after treatment were noted and analysed using repeated measure analysis of variance. Central corneal thickness decreased significantly over a three-month period (p=0.001) and stabilised thereafter. There were no significant changes in thickness in all peripheral areas measured (p>0.05), and in ECD, CV and HEX after the six-month period (p>0.05). The current study showed that significant thinning of central cornea and none at the mid-periphery. OK lens wear with Menicon Z night lenses had no effects on corneal morphology over the six month period.


[Diagnostic, therapeutic, and prognostic aspects of typhoid intestinal perforations in Dapaong, Togo].
This study's aim is to describe the diagnostic, therapeutic, and prognostic aspects of typhoid intestinal perforations (TIP) at the Dapaong regional hospital (Togo). This retrospective study covered all patients with such perforations seen and managed in the Dapaong regional hospital's general surgery department during the 3-year period of 2009-2011. There were 110 patients with TIP during the study period, and they accounted for 67.9% of the patients treated for generalized peritonitis (162 cases). Their mean age was 10.2 years. The sex-ratio was 1.4. A single perforation was present for 69 patients (62.7%) and multiple perforations for the other 41 (37.3%). Sixty (54.5%) patients underwent simple closure, 36 (32.8%) had an ileal resection and enteroanastomosis, and 14 (12.7%) had loop or double-barrelled ileostomy. The postoperative course was complicated in 26 cases (23.6%), most often by surgical site infection, seen in 19 patients (17.3%). Overall, 23 patients died during the postoperative period, for a mortality rate of 20.9%. Typhoid intestinal perforations are the most common cause of generalized peritonitis at the Dapaong regional hospital. Most patients have only a single perforation, which is repaired by excision-suture. Their morbidity and mortality rate are high.


Bidirectional regulation of desmosome hyperadhesion by keratin isotypes and desmosomal components.
Desmosomes are intercellular junctions which mediate cohesion and communication in tissues exposed to mechanical strain by tethering the intermediate filament cytoskeleton to the plasma membrane. While mature desmosomes are characterized by a hyperadhesive, Ca2+-independent state, they transiently loose this state during wound healing, pathogenesis and tissue regeneration. The mechanisms controlling the hyperadhesive state remain incompletely understood. Here, we show that upon Ca2+-induced keratinocyte differentiation, expression of keratin 17 (K17) prevents the formation of stable and hyperadhesive desmosomes, accompanied by a significant reduction of desmoplakin (DP), plakophilin-1 (PKP1), desmoglein-1 (Dsg1) and -3 (Dsg3) at intercellular cell borders. Atomic force microscopy revealed that both increased binding strength of desmoglein-3 molecules and amount of desmoglein-3 oligomers, known hallmarks of hyperadhesion, were reduced in K17- compared to K14-expressing cells. Importantly, overexpression of Dsg3 or DPII enhanced their localization at intercellular cell borders and increased the formation of Dsg3 oligomers, resulting in stable, hyperadhesive desmosomes despite the presence of K17. Notably, PKP1 was enriched in these desmosomes. Quantitative image analysis revealed that DPII overexpression contributed to desmosome hyperadhesion by increasing the abundance of K5/K17-positive keratin filaments in the proximity of desmosomes enriched in desmoglein-3. Thus, our data show that hyperadhesion can result from recruitment of keratin isotypes K5/K17 to desmosomes or from enhanced expression of DP and Dsg3 irrespective of keratin composition. The notion that hyperadhesive desmosomes failed to form in the absence of keratins underscores the essential role of keratins and suggest bidirectional control mechanisms at several levels.