Anti-cancer activity of doxorubicin-loaded liposomes co-modified with transferrin and folic acid.
Cancer-specific drug delivery represents an attractive approach to prevent undesirable side-effects and increase the accumulation of the drug in the tumor. Surface modification of nanoparticles such as liposomes with targeting moieties specific to the up-regulated receptors on the surface of tumor cells thus represents an effective strategy. Furthermore, since this receptor expression can be heterogeneous, using a dual-combination of targeting moieties may prove advantageous. With this in mind, the anti-cancer activity of PEGylated doxorubicin-loaded liposomes targeted with folic acid (F), transferrin (Tf) or both (F+Tf) was evaluated. The dual-targeted liposomes showed a 7-fold increase in cell association compared to either of the single-ligand targeted ones in human cervical carcinoma (HeLa) cell monolayers. The increased penetration and cell association of the dual-targeted liposomes were also demonstrated using HeLa cell spheroids. The in vitro cytotoxicity of the doxorubicin liposomes (LD) was then evaluated using HeLa and A2780-ADR ovarian carcinoma cell monolayers. In both these cell lines, the (F+Tf) LD showed significantly higher cytotoxic effects than the untargeted, or single-ligand targeted liposomes. In a HeLa xenograft model in nude mice, compared to the untreated group, though the untargeted LD showed 42% tumor growth inhibition, both the (F) LD and (F+Tf) LD showed 75% and 79% tumor growth inhibition respectively. These results thus highlight that though the dual-targeted liposomes represent an effective cytotoxic formulation in the in vitro setting, they were equally effective as the folic acid-targeted liposomes in reducing tumor burden in the more complex in vivo setting in this particular model.


Multidisciplinary aortopathy clinics: A systematic scoping review of the literature and evaluation of patient experiences from a newly started clinic in Norway.
International guidelines recommend hereditary thoracic aortic diseases (HTADs) to be managed in multidisciplinary aorta clinics. To study HTAD patient's experiences with a aortopathy clinic in Norway and to review the literature on aortopathy clinics. (a) A systematic scoping review of research on multidisciplinary clinics for HTADs. (b) A cross-sectional postal questionnaire study to investigate patient experiences with the health-services. Fifty consecutive patients from the aortopathy clinic and 50 controls in usual care were invited to participate. The review identified eight publications on aortopathy clinics. Although the papers were not judged for quality, these showed promising results from such clinics in terms of diagnostics and increased adherence to guideline-directed therapy. The survey constituted thirty-seven (74%) patients and 22 (44%) controls who responded to postal questionnaires. Both groups reported delays in diagnostics and follow-up appointments prior to the start of the clinic. Patients indicated high satisfaction with the aortopathy clinic, whereas controls reported poor coordination of medical follow-up. Individuals in both groups struggled with disease self-management. Norwegian patient experiences found the aortopathy clinic beneficial. According to studies included in the review, disease management in aortopathy clinics may improve patient satisfaction, diagnostics and follow-up. Effect studies may further document the benefits of clinic organization, treatment, cost-efficiency and patient experiences.


Premature acute myocardial infarction in a child with nephrotic syndrome.
We report a case of acute myocardial infarction in a nephrotic child. A 7-year-old boy with a 4-year history of steroid-unresponsive nephrotic syndrome due to mesangial proliferation disease presented with acute vomiting and chest pain. An electrocardiogram showed ST elevation and pathological Q waves in leads consistent with anterior and septal myocardial infarction. Subsequent cardiac catheterization showed no evidence of atherosclerotic coronary artery disease, and thrombotic occlusion of the anterior descending coronary artery was the likely cause of the event. Myocardial scintigraphy showed extensive myocardial damage. The child had no long history of extreme hypercholesterolemia or hypertriglyceridemia. The case suggests that children with long-lasting nephrotic syndrome may be at increased risk for ischemic cardiovascular events, due to hyperlipidemia as well as a hypercoagulability state. The literature is reviewed regarding the relationship between nephrotic syndrome and the incidence of ischemic heart disease.


Percutaneous nephrostomy catheters: drainage flow and retention strength.
To evaluate the impact of percutaneous nephrostomy catheter configuration on drainage flow and retention strength. The Cook nephrostomy 16F (symmetric balloon), Bardex Council 16F (eccentric balloon), Microvasive Flexima 14F (pigtail), and Bardex Malecot 16F (flange) nephrostomy catheters were attached to an artificial renal pelvis (12-in.-round latex balloon). The balloon was subsequently filled with either 60 mL of water or orange juice with pulp, and gravity drainage of this fluid was recorded as flow into a flowmeter. Using a Force Five Model FDV-100 force gauge, the retention strength was tested by measuring the force required to pull the nephrostomy catheter through an 8-mm hole in a 35-mm-thick biologic tissue specimen (bologna). The maximal flow rate using both orange juice and saline was significantly greater for the Cook nephrostomy than for the Microvasive Flexima, Bardex Malecot, and Bardex Council catheters (P < or = 0.016). The average flow rate using saline for the Cook nephrostomy catheter was significantly greater than for all other catheters (P < or = 0.02) and was significantly greater than for the Microvasive Flexima and the Bardex Council catheters (P < or = 0.036) using orange juice. The retention strength was strongest for the Cook nephrostomy catheter (3.41 +/- 0.14 lb) compared with the Bardex Council (1.75 +/- 0.1), Microvasive Flexima (1.35 +/- 0.3), and Bardex Malecot (0.29 +/- 0.03) catheters. In addition, the Microvasive Flexima catheter resulted in greater maceration of the biologic tissue after forceful dislodgement. The results of this study have demonstrated that the Cook nephrostomy catheter combines strong drainage flow and strong retention strength during in vitro testing. Clinical evaluations of the ease of use and patient comfort are warranted.


Liposomal amphotericin-B (AmBisome) for treatment of cutaneous widespread candidosis in an infant with methylmalonic acidaemia.
In a 10-week-old infant with vitamin B12-unresponsive methylmalonic acidaemia, cutaneous candidosis (Candida albicans) progressed rapidly despite topical antifungal treatment. After 1 week of intravenous therapy with liposomal amphotericin-B (AmBisome) the dermatitis disappeared completely and blood cultures were sterile. No side-effects were observed. This is one of the first experiences in the treatment of infants with this new antifungal agent.


An efficient ANFIS-EEBAT approach to estimate effort of Scrum projects.
Software effort estimation is a significant part of software development and project management. The accuracy of effort estimation and scheduling results determines whether a project succeeds or fails. Many studies have focused on improving the accuracy of predicted results, yet accurate estimation of effort has proven to be a challenging task for researchers and practitioners, particularly when it comes to projects that use agile approaches. This work investigates the application of the adaptive neuro-fuzzy inference system (ANFIS) along with the novel Energy-Efficient BAT (EEBAT) technique for effort prediction in the Scrum environment. The proposed ANFIS-EEBAT approach is evaluated using real agile datasets. It provides the best results in all the evaluation criteria used. The proposed approach is also statistically validated using nonparametric tests, and it is found that ANFIS-EEBAT worked best as compared to various state-of-the-art meta-heuristic and machine learning (ML) algorithms such as fireworks, ant lion optimizer (ALO), bat, particle swarm optimization (PSO), and genetic algorithm (GA).


Acute and delayed hypersensitivity reactions to infliximab and adalimumab in a patient with Crohn's disease.
A 61 year old woman with active luminal Crohn's disease was successfully treated with infliximab induction therapy followed by 5 infusions every 8 weeks. However, symptoms returned in the weeks preceding the 7th and 8th infusions. The 9th infusion was therefore given only 4 weeks after the 8th infusion, but an acute severe anaphylactoid reaction occurred immediately after start of the infusion. Anti-infliximab IgG antibody concentration was high (100 U/ml) prior to the 8th infusion and up to 1 year after infliximab discontinuation (81 U/ml). Anti-infliximab IgE antibodies were not found, and the anti-infliximab antibodies did not cross react with adalimumab. One week after the anaphylactoid reaction to infliximab, adalimumab therapy was initiated. Twelve days after the first adalimumab administration (80 mg), a delayed hypersensitivity reaction occurred. This was likely caused by rapidly generated anti-adalimumab IgG antibodies (45 U/ml), as these antibodies appeared to be specific for adalimumab in that infliximab failed to compete with adalimumab/anti-adalimumab antibody binding ex vivo. In conclusion, immunogenicity to infliximab and adalimumab may be associated with both acute anaphylactoid reactions and delayed hypersensitivity reactions. Reactions may be precipitated by newly induced specific anti-drug antibodies rather than by cross-reactivity of previously generated antibodies.


Comparison of transendometrial myomectomy versus conventional myomectomy in cesarean section.
To compare the surgical results of transendometrial myomectomy (TEM) and conventional myomectomy (CM) procedures for fibroid in cesarean section. This retrospective study was conducted with computer-based medical records of patients who underwent myomectomy during cesarean section between January 2013 and March 2019. During the study period, 41 patients underwent transendometrial myomectomy, and 52 patients with had conventional myomectomy. In all patients included in the study, myoma was single, intramural, and localized in the anterior of the uterus. The total duration of surgery was shorter in the TEM group than in the CM group (50,5 ± 10 min vs 63,6 ± 15,2, p = 0,001). There was no difference in terms of length of hospital stay, procedure-related hemoglobin difference, blood transfusion requirement and postoperative fever (respectively, p = 0,65, p = 0,81, p = 0,33 and p = 0,9). Patients who underwent TEM (0.58 ± 0.61) had significantly lower adhesion scores in their subsequent pregnancy compared to patients who underwent CM (1,76 ± 1,1) (p = 0,001). Transendometrial myomectomy technique seems to be more advantageous in selected patients compared to the conventional technique due to the shorter operation time.


Coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice by allosteric mechanisms involving increased GABAA receptor affinity for GABA.
The sedative and anxiolytic-like activity of two coronaridine congeners, (+)-catharanthine and (-)-18-methoxycoronaridine (18-MC), was studied in male and female mice. The underlying molecular mechanism was subsequently determined by fluorescence imaging and radioligand binding experiments. The loss of righting reflex and locomotor activity results showed that both (+)-catharanthine and (-)-18-MC induce sedative effects at doses of 63 and 72 mg/kg in a sex-independent manner. At a lower dose (40 mg/kg), only (-)-18-MC induced anxiolytic-like activity in naïve mice (elevated O-maze test), whereas both congeners were effective in mice under stressful/anxiogenic conditions (light/dark transition test) and in stressed/anxious mice (novelty-suppressed feeding test), where the latter effect lasted for 24 h. Coronaridine congeners did not block pentylenetetrazole-induced anxiogenic-like activity in mice. Considering that pentylenetetrazole inhibits GABAA receptors, this result supports a role for this receptor in the activity mediated by coronaridine congeners. Functional and radioligand binding results showed that coronaridine congeners interact with a site different from that for benzodiazepines, increasing GABAA receptor affinity for GABA. Our study showed that coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice in a sex-independent fashion, likely by a benzodiazepine-independent allosteric mechanism that increases GABAA receptor affinity for GABA.


Fibroblasts from skin biopsies as a tool for biomarker discovery in Parkinson׳s disease.
Parkinson׳s disease (PD) is a complex disease and the current interest and focus of scientific research is both investigating the variety of causes that underlie PD pathogenesis, and identifying reliable biomarkers to diagnose and monitor the progression of pathology. Investigation on pathogenic mechanisms in peripheral cells, such as fibroblasts derived from patients with sporadic PD and age/gender matched controls, might generate deeper understanding of the deficits affecting dopaminergic neurons and, possibly, new tools applicable to clinical practice. The chronic and slow progressing nature of PD may result from subtle yet persistent alterations in biological mechanisms, which might be undetectable in basal, unchallenged conditions. Unlike body fluids, dermal fibroblasts can be exposed to different challenges while in culture and can therefore generate information about the dynamic cellular responses to exogenous stressors. These studies may ultimately generate indicators highlighting the biological defects intrinsic to PD. In fact, fibroblasts from idiopathic PD patients' exhibit deficits typically sustaining the neurodegenerative process of PD, such as increased susceptibility to rotenone as well as deficits in protein homeostasis and mitochondrial bioenergetics Fibroblasts therefore represent a powerful and minimally invasive tool to investigate PD pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease.


Correlation of Lead Poisoning and Intelligence Status of School Children in a Southern Nigerian Urban City.
Lead is a heavy metal of utmost public health significance in Nigeria. It is a known neurotoxin that impairs neurotransmission and brain function resulting in cognitive and motor deficits. Ingestion of lead contaminated food or water is the major route of exposure to lead manifesting as neurologic symptoms which can interfere with the intelligence of school children. To correlate the Intelligence quotient scores with the blood lead levels of primary school children in Southern Nigeria. The study was a descriptive cross-sectional study amongst primary school pupils, conducted in Asaba, the capital of Delta state, Nigeria. Goodenough-Harris "Draw a Person Test" validated by Ebigbo and Izuora in Enugu, Nigeria was used to assess the intelligence of the pupils while blood lead levels was measured with Flame Atomic Absorption Spectrophotometer (FAAS). Three hundred and twenty subjects were recruited. Seventy-one subjects did not have lead poisoning (22%) while two hundred and forty-nine subjects had lead poisoning (77.8%). Mild, moderate and severe level lead poisoning constituted 22.5% (56/249), 28.1% (70/249) and 49.4% (123/249) respectively. Seventy percent (225) subjects had optimal IQ while 95 subjects had sub-optimal IQ and mean IQ score was 92.9 ± 25.1. There was no association and correlation between IQ status and levels of lead poisoning. A significant proportion of school children had optimal level of intelligence despite the high prevalence of lead poisoning seen among them. There was no association or correlation between different levels of childhood lead poisoning and Intelligence quotient status.


Nonfenestrated extracardiac total cavopulmonary connection in 132 consecutive patients.
The study was conducted to assess the need for fenestration for completion of a total cavopulmonary connection (TCPC) with the most recent modification of an extracardiac conduit. The extracardiac approach was introduced to our institution in January 1999. Between June 2000 and June 2006, 132 consecutive patients were treated without a fenestration. At the time of TCPC, the median age was 31 months (range, 16 251), with 93 patients (70%) being younger than 48 months. Median patient weight was 12.5 kg (range, 9 to 66 kg). A previous partial cavopulmonary connection (PCPC) was accomplished in 117 patients (88.6%), without additional pulmonary blood flow. Thirty-day-mortality was 1.5%. Median time to extubation was 14 hours (range, 3 hours to 126 days). Initial pulmonary artery pressure value was 16.5 +/- 2.2 mm Hg, and 13.1 +/- 1.8 after extubation. Median drainage requirement was 4 days (range, 1 to 45), and median duration of hospitalization was 20 days (range, 5 to 128). Thirty-one (24%) required repeat drainage insertion. No subsequent fenestration was performed, and at hospital discharge no significant repeat effusions were observed. Multiple covariate logistic regression revealed longer time interval from PCPC to extracardiac TCPC (p = 0.006) as a significant predictor of pleural drainage lasting longer than 4 days, and older age at the time of extracardiac TCPC (p = 0.040) as a risk factor for hospitalization more than 20 days. Higher pulmonary artery pressure 3 hours postoperatively was a significant predictor for both outcome variables in the multivariate model (p = 0.013, p = 0.001). In general, an extracardiac TCPC can be performed without fenestration. Early staging of patients with functional single ventricle physiology may be one of the keys for these findings.


Fibroblast growth factor receptor fusions in cancer: opportunities and challenges.
Fibroblast growth factors (FGFs) and their receptors (FGFRs) play critical roles in many biological processes and developmental functions. Chromosomal translocation of FGFRs result in the formation of chimeric FGFR fusion proteins, which often cause aberrant signaling leading to the development and progression of human cancer. Due to the high recurrence rate and carcinogenicity, oncogenic FGFR gene fusions have been identified as promising therapeutic targets. Erdafitinib and pemigatinib, two FGFR selective inhibitors targeting FGFR fusions, have been approved by the U.S. Food and Drug Administration (FDA) to treat patients with urothelial cancer and cholangiocarcinoma, respectively. Futibatinib, a third-generation FGFR inhibitor, is under phase III clinical trials in patients with FGFR gene rearrangements. Herein, we review the current understanding of the FGF/FGFRs system and the oncogenic effect of FGFR fusions, summarize promising inhibitors under clinical development for patients with FGFR fusions, and highlight the challenges in this field.


Opening of Cx43-formed hemichannels mediates the Ca2+ signaling associated with endothelial cell migration.
Endothelial cell migration is a key process in angiogenesis. Progress of endothelial cell migration is orchestrated by coordinated generation of Ca2+ signals through a mechanism organized in caveolar microdomains. Connexins (Cx) play a central role in coordination of endothelial cell function, directly by cell-to-cell communication via gap junction and, indirectly, by the release of autocrine/paracrine signals through Cx-formed hemichannels. However, Cx hemichannels are also permeable to Ca2+ and Cx43 can be associated with caveolin-1, a structural protein of caveolae. We proposed that endothelial cell migration relies on Cx43 hemichannel opening. Here we show a novel mechanism of Ca2+ signaling in endothelial cell migration. The Ca2+ signaling that mediates endothelial cell migration and the subsequent tubular structure formation depended on Cx43 hemichannel opening and is associated with the translocation of Cx43 with caveolae to the rear part of the cells. These findings indicate that Cx43 hemichannels play a central role in endothelial cell migration and provide new therapeutic targets for the control of deregulated angiogenesis in pathological conditions such as cancer.


Plasma catecholamine and cortisol concentrations during acceleration stress.
Serial changes in catecholamine (CA) and cortisol (Col) concentrations of human subjects exposed to acceleration stress with the vector in the head-foot direction (+ 5Gz for 1 min) were determined using a newly designed continuous blood sampling system. The results demonstrated that the time course changes in noradrenaline (NA), adrenaline (A) and Col concentrations were quite different from each other during and after the Gz exposure. The NA remained relatively unchanged during the exposure, and showed a marked increase at the end of the exposure, peaking at about 110 s after the end of the exposure. The A showed a gradual increase from the start of the exposure and continued to rise during and after the exposure. Its maximal peak was also found at about 110 s after the exposure. The A showed a sevenfold increase, while NA showed only about a threefold increase as high as pre-exposure levels. The more rapid and greater magnitude of increase in A concentration during exposure may have reflected the larger emotional stress and strenuous physical activities involved in the Gz exposure. Heart rate showed a rapid increase upon exposure and remained significantly increased during the exposure; it then showed a transient fall immediately after the exposure, despite the increase in CA. An interesting observation was a decrease in Col during the Gz exposure. A plausible explanation would appear to be the result of an enhanced rate of Col removal from the plasma. From these observations, the importance of serial determination of hormonal excretion during Gz stress for the precise analysis of hormonal response to Gz stress was confirmed.


Chemokine (C-C motif) ligand 2 and coronary artery disease: Tissue expression of functional and atypical receptors.
Chemokines, particularly chemokine (C-C- motif) ligand 2 (CCL2), control leukocyte migration into the wall of the artery and regulate the traffic of inflammatory cells. CCL2 is bound to functional receptors (CCR2), but also to atypical chemokine receptors (ACKRs), which do not induce cell migration but can modify chemokine gradients. Whether atherosclerosis alters CCL2 function by influencing the expression of these receptors remains unknown. In a necropsy study, we used immunohistochemistry to explore where and to what extent CCL2 and related receptors are present in diseased arteries that caused the death of men with coronary artery disease compared with unaffected arteries. CCL2 was marginally detected in normal arteries but was more frequently found in the intima. The expression of CCL2 and related receptors was significantly increased in diseased arteries with relative differences among the artery layers. The highest relative increases were those of CCL2 and ACKR1. CCL2 expression was associated with a significant predictive value of atherosclerosis. Findings suggest the need for further insight into receptor specificity or activity and the interplay among chemokines. CCL2-associated conventional and atypical receptors are overexpressed in atherosclerotic arteries, and these may suggest new potential therapeutic targets to locally modify the overall anti-inflammatory response.


Sentinel lymph node biopsy for gastrointestinal cancers.
Sentinel lymph node biopsy (SLNB) in gastrointestinal-(GI)-tract cancer is not yet of clinical relevance. Nevertheless, the results in the upper GI-tract promise to be helpful to individualize the indication for surgical therapy. SLNB in colon cancer still fails to show high validity to predict the nodal status, but may be helpful to clarify the prognostic role of micrometastases/isolated tumor cells. In anal cancer SLNB is able to guide the indication for groin irradiation.


Evaluation of Transforming Growth Factor-β1 and Interleukin-35 Serum Levels in Patients with Placenta Accreta.
Placenta accreta is a pregnancy-related disorder with extreme trophoblast invasion and the adherence of the placenta to the uterine wall. This study aimed to investigate the serum level of transforming growth factor-beta 1 (TGF-β1) and interleukin (IL)-35 in patients with placenta accreta. Thirty-one women with placenta accreta and 57 healthy pregnant women were enrolled. The serum levels of TGF-β1 and IL-35 were measured using the enzyme-linked immunosorbent assay method. The serum levels of both TGF-β and IL-35 were significantly higher in the placenta accreta group compared with the group of healthy women (1082.48 pg/mL vs 497.33 pg/mL and 4541.14 pg/mL vs 1306.04 pg/mL; P <.001, respectively). Moreover, the level of TGF-β1 positively correlated with the IL-35 level but other factors such as age, gestations, live births, and abortions did not correlate with IL-35 and TGF-β1 levels. The serum levels of IL-35 and TGF-β1 may contribute to the pathogenesis of placenta accreta and could be considered as potential targets in clinical and diagnostic approaches.


The anatomical location of the flexor hallucis brevis as it pertains to implant arthroplasty.
Hallux limitus/rigidus is a painful arthritic condition affecting the first metatarsophalangeal joint that can be treated by implant arthroplasty, which, ultimately, may cause loss of the anatomical insertion points of the flexor hallucis brevis muscle. Preparation of the base involves resection of bone, thus compromising the insertion of the flexor hallucis brevis muscle. We dissected 54 fresh-frozen cadaveric specimens and quantitatively measured the distalmost insertion point of the medial and lateral heads of the flexor hallucis brevis muscle. These measurements were performed for both heads. The measurements were performed three times by three separate examiners. In addition, taking into consideration the anatomical construct of the articular surface of the base of the proximal phalanx of the hallux, another measurement was performed to note the concavity using 44 of the specimens. Again, these measurements were performed three times by three separate investigators. The mean length from the base of the proximal phalanx to the distalmost insertion of the medial and lateral heads of the flexor hallucis brevis muscle was found to be 7 mm. This study provides precise anatomical data that can be used by foot and ankle surgeons when considering the use of implant arthroplasty for the treatment of hallux limitus/rigidus and the ability to maintain the insertion point of the flexor hallucis brevis muscle.


Delayed post-operative use of 5-fluorouracil as an adjunct in medically uncontrolled open angle glaucoma.
The current study was performed to evaluate the efficacy and safety of late post-operative use of subconjunctival 5-fluorouracil (5-FU) with ocular massage (OM) after trabeculectomy with or without intraoperative mitomycin C (MMC) in patients with medically uncontrolled primary open angle glaucoma (POAG). Initial trabeculectomy was performed in 60 eyes of 60 consecutive patients with medically uncontrolled POAG. Thirty eyes (group 1) were randomly assigned to intraoperative MMC (0.2 mg/ml for 3 min) and 30 (group 2) were randomised to standard trabeculectomy. During the first 3 months post-operatively OM and subconjunctival injections of 5-FU (5 mg in 0.5 ml of balanced salt solution) were performed in both groups every time the clinical evaluation suggested imminent bleb failure. Suture lysis was not performed in any patient. Follow-up ranged from 14 to 53 months (mean 30.17, SD 9.23) in trabeculectomy + MMC treated eyes and from 6 to 54 months (mean 27.37, SD 10.83) in trabeculectomy treated eyes. During the first 3 months of follow-up OM and subconjunctival injections of 5-FU were performed in 14 cases in group 1 and in 18 cases in group 2 (p = NS). A positive response to OM was obtained in 14 of 14 eyes and in 14 of 18 eyes in group 1 and in group 2, respectively (p = 0.042). The difference in post-operative mean IOP between the two groups was statistically significant at each time interval studied (p < 0.001). Success (complete or qualified) was achieved in 50 of 60 eyes (83.33%): 28 (93.3%) in the trabeculectomy + MMC treated group and 22 (73.3%) in the trabeculectomy treated group (p = 0.039). Among the complications seen, the incidence of bleb fibrosis was higher in group 2 (p = 0.0026). By means of post-operative treatment four nonrandomised subgroups were identified: intraoperative MMC + post-operative 5-FU, intraoperative MMC + no post-operative 5-FU, no intraoperative MMC + post-operative 5-FU, no intraoperative MMC + no post-operative 5-FU. The eyes treated with intraoperative MMC and post-operative 5-FU had a better long-term (48 months) cumulative probability of success (100%); treatment with intraoperative MMC or post-operative 5-FU alone was followed by a success rate of 87.1% and 72.2%, respectively. The cumulative probability of success after only trabeculectomy was 56% (p < 0.05). One case of hypotony maculopathy was found in the subgroup treated only with intraoperative MMC. This study confirms the effectiveness and relative safety of delayed post-operative 5-FU treatment in patients with clinical evidence of bleb failure. Only when OM had caused a lowering of IOP were late subconjunctival injections of 5-FU followed by good control of IOP. The use of intraoperative MMC may ensure a greater IOP decrease after OM.


Transport Characteristics of Interfacial Charge in SiC Semiconductor-Epoxy Resin Packaging Materials.
The silicon carbide (SiC) wide bandgap (WBG) semiconductor power device has been widely applied for its excellent properties. However, the charge accumulated in the interface of SiC semiconductor-related insulation packaging may lead to serious material performance degradation and failure, threatening the reliability and operation life of power devices. In this research, interface charge accumulation characteristics of SiC-epoxy resin double-layered material were investigated, and space charge injection, transport, and accumulation mechanisms, as well as the related temperature effect for the SiC-epoxy resin under polarization and depolarization conditions, were studied by the pulsed electro-acoustic (PEA) technique. The results show that a charge peak appears between the SiC-epoxy resin interface, which shows the same polarity as the SiC side electrode. Charge injects from the SiC electrode, transports along with the SiC semiconductor bulk due to the high mobility, and is blocked by the interface barrier. In addition, under high temperature and high electrical stress conditions, obvious charge accumulation occurs inside the epoxy resin bulk, which was captured by the deep traps. The charge accumulation of the SiC-insulation packaging material can influence the operation of the power device and should attract more attention.


Subcutaneous cystic granuloma caused by Phialophora verrucosa.
A case of subcutaneous cystic granuloma caused by Phialophora verrucosa was reported. The patient was 21-year-old Japanese female with systemic lupus erythematosus (SLE) who had received prolonged steroid therapy. P. verrucosa has occasionally been isolated from patients as one of etiological agents of chromomycosis. There have been, however, no paper published to report an isolation of this fungus from subcutaneous cyst or abscess of a patient. This case is the first report of subcutaneous cystic granuloma induced clinically by P. verrucosa.


Capsule Commentary on Misra-Hebert et al., Implementing Team-Based Primary Care Models: A Mixed-Methods Comparative Case Study in a Large, Integrated Health Care System.


RETINAL DETACHMENT IN EYES WITH BOSTON TYPE 1 KERATOPROSTHESIS: Surgical Techniques and Mid-Term Outcomes.
To evaluate the mid-term outcomes of pars plana vitrectomy performed for retinal detachment (RD) repair after Boston Type 1 keratoprosthesis (KPro) implantation. Retrospective review of medical records of KPro implanted at the Stein Eye Institute presenting with RD and treated by pars plana vitrectomy. Functional success was defined as a postoperative visual acuity maintained within 2 Snellen lines of the corrected distance visual acuity measured before the development of the RD (baseline) and anatomical success as an attached retina after the pars plana vitrectomy. Kaplan-Meyer survival analyses were performed. Among the 224 KPro performed, 28 (15.2%) RD were identified; of which, 21 (9.4%) were included. The mean follow-up was 42.5 ± 27.3 months. Vitreoretinal proliferation was present in 18 of 21 eyes (85.7%). Surgical techniques were adapted to the complex anterior segment anatomy of KPro eyes. Anatomical success was achieved in 18 of 21 eyes (85.7%). Functional success occurred in 17 of 21 eyes (81.0%), and 5 of 21 eyes (23.8%) reached 20/400 or better visual acuity at the final follow-up. The KPro was retained in 11 in 21 eyes (52.4%). The retention rate decreased from 94.7% at 1 year to 53.5% at 5 years. The most frequent complications were retroprosthetic membrane (47.6%) and corneal melt (23.8%). Modified pars plana vitrectomy techniques resulted in relatively good mid-term anatomical, functional, and retention rate outcomes, given the severity of RD at presentation and the numerous preoperative comorbidities of KPro eyes.


Highlights from a workshop on opportunities for cancer prevention during preadolescence and adolescence.
In an effort to explore opportunities for cancer prevention during preadolescence and adolescence, the Cancer Prevention Across the Lifespan workgroup within the Division of Cancer Prevention and Control at the Centers for Disease Control and Prevention (CDC) convened an informal panel of experts for a 2-day workshop August 9-10, 2011. In this report, we provide highlights from the workshop. A central theme of the workshop was that preadolescence and adolescence are times of unique susceptibility and vulnerability within the lifespan. Participants discussed the evidence linking exposures during adolescence (e.g., risky behaviors, chemicals, medical imaging procedures) and subsequent cancer risk during adulthood. Participants also discussed potential opportunities to intervene on risk factors for cancer at multiple levels during adolescence, the importance of more focused approaches to adequately address health disparities, and the ongoing need for transdisciplinary and translational prevention research. Future opportunities for the CDC include further leveraging surveillance data from sources such as the National Health and Nutrition Examination Survey, the Youth Risk Behavior Surveillance System, and the National Children's Study and continuing to build on collaborations with other federal agencies and with national, state, and local organizations. Many ideas and insights generated during the workshop will be put into action as CDC continues to explore opportunities for cancer prevention during youth and across the lifespan.


A population-based study of the effect of pregnancy history on risk of stillbirth.
To examine the effect of pregnancy history on the risk of stillbirth. In a population-based cross-sectional study, data were reviewed from all women aged at least 20 years with singleton pregnancies in Finland between 2000 and 2010. The primary outcome-stillbirth-was defined as fetal death after 22 gestational weeks or death of a fetus weighing at least 500 g. Among 604 047 singleton pregnancies, the prevalence of stillbirth was 3.17 per 1000 deliveries. Prevalence was lowest for multiparous women without previous pregnancy loss after adjusting for major pregnancy complications associated with stillbirth (placenta previa, placental abruption, and pre-eclampsia) and other confounders. Relative to these women, stillbirth prevalence was higher among multiparous women with previous spontaneous abortion and/or stillbirth (adjusted odds ratio [aOR] 1.20, 95% confidence interval [CI] 1.05-1.36), nulliparous women with no previous pregnancy loss (aOR 1.23, 95% CI 1.10-1.38), and nulliparous women with prior spontaneous abortion (aOR 1.43, 95% CI 1.18-1.74). Previous pregnancy loss was found to be an independent risk factor for stillbirth, irrespective of the number of prior deliveries.


Intra- and interhemispheric number priming: evidence for rapid integration of magnitude information between hemispheres.
In the present study we investigated whether the corpus callosum exerts an inhibitory or an integrative influence on hemispheric communication of magnitude information by presenting prime-target pairs to the same or opposite hemispheres (intra- and interhemispheric number priming trials). During the experiment, subjects were asked to compare the targets with a fixed reference number and classify them as small or large. The prime stimulus was irrelevant for the task. To examine the interhemispheric communication of magnitude under present task conditions, we made use of a new presentation technique with filler items, thereby eliminating the latency benefit for intrahemispheric priming trials observed in previous studies. The results of this experiment showed equal priming effects for both intra- and interhemispheric priming conditions: stimuli were reacted to faster when the numerical distance between prime and target was smaller (i.e., quantity priming) and when both prime and target required the same response (i.e., response priming). This is in line with the idea of a rapid integration of magnitude information between hemispheres.


Studies on a high molecular weight luteinizing hormone release stimulating factor of the ovine pineal gland.
Former work has shown that crude extracts of ovine pineal glands probably exert a stimulating activity on the release of gonadotropins of anterior pituitaries in vitro. By aqueous extraction followed by ultrafiltration through anisotropic membranes high Mr (above 100,000 daltons) fractions were obtained, which exhibit a stimulating effect on the levels of gonadotropins in the medium of either cultured pituitary cells or anterior hemipituitaries in short-term culture. Partial purification of a pineal luteinizing hormone release stimulating factor was accomplished by Sephadex G-150 filtration with a biopotency of 226 +/- 23 micrograms LH-RP-1 equivalents per mg protein and without an affinity for binding to anti-LHRH or anti-LH antibodies. The present data substantiate that high Mr forms, slightly heavier than authentic pituitary LH (Mr 23,000 daltons) and therefore not identical to the hypothalamic decapeptide LH-RH, represent ovine pineal factors which can increase the concentration of LH in the medium of cultured anterior pituitaries, but does not influence the secretion of prolactin in vitro.


Higher Rates of Residual Postoperative Instability after Anterior Cruciate Ligament Reconstruction in Female Patients: A Systematic Review of Level II Studies.
To compare revision rates and residual postoperative instability after anterior cruciate ligament (ACL) reconstruction based on biological sex. A systematic review was conducted according to the 2020 PRISMA guidelines. PubMed, Embase, MEDLINE, and Cochrane library databases were queried from database inception through October 2022. Level I and II prospectively-enrolling human clinical studies that compared revision rates and physical examination of postoperative stability after ACL reconstruction between male and female patients were included. Outcomes were stratified by patient sex and quantitatively compared using a χ2 test. Study quality was assessed using the MINORS criteria. Four studies consisting of 406 patients (50% males) with a mean age of 25 years (range, 13.9-62 years) were identified. Mean follow-up time was 34.4 months (range, 22-60 months). Hamstring tendon autografts were used in 62% of ACL reconstructions in males and in 65% of ACL reconstructions in females, whereas bone-patellar tendon-bone autografts were used in 38% and 35% of procedures in males and females, respectively. A residual positive Lachman test result was more frequently reported among females compared to males (5.8% vs 0.6%; P = 0.03). No significant difference in revision rates or residual pivot-shift on examination was observed between males and females (P = 0.38 and P = 0.08, respectively). Female patients undergoing ACL reconstruction have higher reported rates of residual anterior instability with Lachman than male patients. However, no sex-based differences were identified with residual pivot-shift on examination or rate of revision ACL surgery. II; Systematic Review of level II studies.


Retracted: Magnetic Resonance Image Compilation Was Used in Conjunction with Prostate PI-RADS v2.1 Score Has Diagnostic Relevance for Benign and Malignant Prostate Lesions.
[This retracts the article DOI: 10.1155/2022/3613540.].


Effect of diaphragm manual release versus conventional breathing exercises and prone positioning on physical functional performance in women with COVID-19: A randomized trial.
Manual therapy has recently gained much interest in managing COVID-19 patients. This study aimed to mainly compare the effect of diaphragm manual release to the effect of conventional breathing exercises and prone positioning on physical functional performance in women with COVID-19. Forty COVID-19 women patients completed this study. They were randomly assigned to two groups. Group A received diaphragm manual release, and group B received conventional breathing exercises and prone positioning. Both groups received pharmacological treatment. Inclusion criteria were moderate COVID-19 illness, women patients, and ages from 35 to 45 years. The outcome measures were 6-min walk distance (6MWD), chest expansion, Barthel index (BI), oxygen saturation, fatigue Assessment Scale (FAS), and Medical Research Council (MRC) dyspnea scale. Both groups showed significant improvements in all outcome measures compared to the baseline (p < 0.001). Compared to group B, group A showed more significant improvements in the 6MWD (MD, 22.75 m; 95% CI, 15.21 to 30.29; p < 0.001), chest expansion (MD, 0.80 cm; 95% CI, 0.46 to 1.14; p < 0.001), BI (MD, 9.50; 95% CI, 5.69 to 13.31; p < 0.001), the O2 saturation (MD, 1.3%; 95% CI, 0.71 to 1.89; p < 0.001), the FAS (MD, -4.70; 95% CI, -6.69 to -2.71; p < 0.001), and dyspnea severity assessed by the MRC dyspnea scale (p = 0.013) post-intervention. Combined with pharmacological treatment, diaphragm manual release could be superior to conventional breathing exercises and prone positioning in improving physical functional performance, chest expansion, daily living activities, O2 saturation, and measures of fatigue and dyspnea in middle-aged women with moderate COVID-19 illness. Pan African Clinical Trial Registry (PACTR), retrospective, PACTR202302877569441.


Greater Lateral Femorotibial Cartilage Loss in Osteoarthritis Initiative Participants With Incident Total Knee Arthroplasty: A Prospective Cohort Study.
To explore whether baseline to 12-month followup change in femorotibial cartilage thickness differs between subjects who received a total knee arthroplasty (TKA) between 24 and 60 months from those without TKA (non-TKA). In this prospective cohort study, 531 right knees from Osteoarthritis Initiative participants with definite radiographic knee osteoarthritis (Kellgren/Lawrence [K/L] grades 2-4) were studied. Segmentation was applied to coronal fast low-angle shot magnetic resonance images, to quantitatively determine cartilage thickness in 16 femorotibial subregions. Unadjusted P values (t-tests) and P values adjusted for age, baseline body mass index (BMI), K/L grade, and sex (generalized estimating equation models) were used to evaluate differences in longitudinal 1-year rates of cartilage thickness between TKAs and non-TKAs, with total knee arthroplasty status as fixed effect. Of the 531 participants (mean ± SD ages 63 ± 9 years, BMI 30 ± 4.8 kg/m(2)), 40 received a femorotibial TKA within 4 years. At baseline, TKAs had thinner medial and lateral femorotibial cartilage (-15%; P < 0.001) than non-TKAs. Longitudinal cartilage thickness change was significantly greater in TKAs than in non-TKAs in the total femorotibial joint (area under the curve [AUC] 0.64), the lateral compartment (AUC 0.66), both tibiae (AUC ≥ 0.61), and the first 9 (of 16) ordered values of subregion change (AUC 0.64-0.69). Discrimination was stronger for TKAs that occurred at 24 and 36 months (n = 18) than for those at 48 and 60 months (n = 22). Knees with incident TKA displayed smaller baseline cartilage thickness and greater lateral as well as location-independent ordered value femorotibial cartilage loss than non-TKAs. Discrimination of cartilage loss was greater for TKAs occurring within 2 years after the measurement than for those occurring later.


Assessment of early harvest in the prevention of aflatoxins in peanuts during drought stress conditions.
The present study aimed to evaluate the effectiveness of early harvest in preventing aflatoxins in peanuts under drought-stress conditions. A field experiment was conducted on the 2018-2019 and 2019-2020 growing seasons in a greenhouse with an irrigation system to induce three drought stress conditions: no stress, mild, and severe stress. In addition, three harvest dates were proposed: two weeks earlier, one week earlier, and ideal harvest time. The mean peanut yield was 2634 kg/ha, considering the two growing seasons, and the drought stress conditions and harvest dates did not influence significantly. The shelling percentage was significantly higher in samples harvested at ideal harvest (77.7 %) than two weeks earlier (76.2 %) and was not influenced by drought stress conditions. Although a low mean percentage of grains with insect damage was identified, this percentage was statistically higher under severe stress (0.4 %) compared to no-stress conditions (0.2 %). The soil contamination ranged from 2.52 × 103 to 1.64 × 104 CFU/g of Aspergillus section Flavi, and the drought stress resulted in significantly higher concentrations in mild and severe stressed samples. A. section Flavi was found to infect all the peanut kernel samples. The drought stress resulted in higher percentages of A. section Flavi infections in samples from mild and severe stress conditions. The harvest date did not influence the soil and peanut kernel occurrence of A. section Flavi. A total of 435 and 796 strains of A. section Flavi were isolated from soil and peanut kernels, respectively. The potential of aflatoxin production by soil isolates was 31, 44, and 25 % for aflatoxin non-producers, aflatoxin B producers, and aflatoxin B and G producers, respectively, while in peanut kernel isolates were 44, 44, and 12 %. Three different A. section Flavi species were identified from peanut kernels: A. flavus, A. parasiticus, and A. pseudocaelatus. The mean aflatoxin concentration in peanut kernels was 42, 316, and 695.5 μg/kg in samples under no stress, mild stress, and severe stress conditions, respectively. Considering the harvest time, the mean aflatoxin concentration was 9.9, 334.3, and 614.2 μg/kg in samples harvested two weeks earlier, one week earlier, and in ideal harvest, respectively. In conclusion, the early harvest proved to be a viable, cost-free alternative for controlling aflatoxin in the peanut pre-harvest, resulting in a safer product and a better quality for sale and economic gain.


Human updating of visual motion direction during head rotations.
Previous studies have demonstrated that human subjects update the location of visual targets for saccades after head and body movements and in the absence of visual feedback. This phenomenon is known as spatial updating. Here we investigated whether a similar mechanism exists for the perception of motion direction. We recorded eye positions in three dimensions and behavioral responses in seven subjects during a motion task in two different conditions: when the subject's head remained stationary and when subjects rotated their heads around an anteroposterior axis (head tilt). We demonstrated that after head-tilt subjects updated the direction of saccades made in the perceived stimulus direction (direction of motion updating), the amount of updating varied across subjects and stimulus directions, the amount of motion direction updating was highly correlated with the amount of spatial updating during a memory-guided saccade task, subjects updated the stimulus direction during a two-alternative forced-choice direction discrimination task in the absence of saccadic eye movements (perceptual updating), perceptual updating was more accurate than motion direction updating involving saccades, and subjects updated motion direction similarly during active and passive head rotation. These results demonstrate the existence of an updating mechanism for the perception of motion direction in the human brain that operates during active and passive head rotations and that resembles the one of spatial updating. Such a mechanism operates during different tasks involving different motor and perceptual skills (saccade and motion direction discrimination) with different degrees of accuracy.


Costs of falls in an ageing population: a nationwide study from the Netherlands (2007-2009).
Falls are a common mechanism of injury in the older population, putting an increasing demand on scarce healthcare resources. The objective of this study was to determine healthcare costs due to falls in the older population. An incidence-based cost model was used to estimate the annual healthcare costs and costs per case spent on fall-related injuries in patients ≥ 65 years, The Netherlands (2007-2009). Costs were subdivided by age, gender, nature of injury, and type of resource use. In the period 2007-2009, each year 3% of all persons aged ≥ 65 years visited the Emergency Department due to a fall incident. Related medical costs were estimated at €675.4 million annually. Fractures led to 80% (€540 million) of the fall-related healthcare costs. The mean costs per fall were €9370, and were higher for women (€9990) than men (€7510) and increased with age (from €3900 at ages 65-69 years to €14,600 at ages ≥ 85 year). Persons ≥ 80 years accounted for 47% of all fall-related Emergency Department visits, and 66% of total costs. The costs of long-term care at home and in nursing homes showed the largest age-related increases and accounted together for 54% of the fall-related costs in older people. Fall-related injuries are leading to a high healthcare consumption and related healthcare costs, which increases with age. Programmes to prevent falls and fractures should be further implemented in order to reduce costs due to falls in the older population and to avoid that healthcare systems become overburdened.


Limited impact of Delta variant's mutations in the effectiveness of neutralization conferred by natural infection or COVID-19 vaccines in a Latino population.
The SARS-CoV-2 pandemic has impacted public health systems all over the world. The Delta variant seems to possess enhanced transmissibility, but no clear evidence suggests it has increased virulence. Our data shows that pre-exposed individuals had similar neutralizing activity against the authentic COVID-19 strain and the Delta and Epsilon variants. After one vaccine dose, the neutralization capacity expands to all tested variants. Healthy vaccinated individuals showed a limited breadth of neutralization. One vaccine dose induced similar neutralizing antibodies against the Delta compared to the authentic strain. However, even after two doses, this capacity only expanded to the Epsilon variant.


Maximum aerobic capacity of underground coal miners in India.
Miners fitness test was assessed in terms of determination of maximum aerobic capacity by an indirect method following a standard step test protocol before going down to mine by taking into consideration of heart rates (Telemetric recording) and oxygen consumption of the subjects (Oxylog-II) during exercise at different working rates. Maximal heart rate was derived as 220-age. Coal miners reported a maximum aerobic capacity within a range of 35-38.3 mL/kg/min. It also revealed that oldest miners (50-59 yrs) had a lowest maximal oxygen uptake (34.2 ± 3.38 mL/kg/min) compared to (42.4 ± 2.03 mL/kg/min) compared to (42.4 ± 2.03 mL/kg/min) the youngest group (20-29 yrs). It was found to be negatively correlated with age (r = -0.55 and -0.33 for younger and older groups respectively) and directly associated with the body weight of the subjects (r = 0.57 - 0.68, P ≤ 0.001). Carriers showed maximum cardio respiratory capacity compared to other miners. Indian miners VO(2 max) was found to be lower both compared to their abroad mining counterparts and various other non-mining occupational working groups in India.


Biofilm-forming associated genotypic and phenotypic characteristics of Staphylococcus spp. isolated from animals and air.
Biological monitoring is performed to detect and analyze microorganisms that have continuously made an effort to survive in the environment. Of such microorganisms, Staphylococcus spp. is considered a common cause of nosocomial and environmental infections., Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs) are required for the adhesion and biofilm formation of Staphylococci. Thirty-six and thirty-five Staphylococci isolated from animals and air, respectively, were analyzed. Biofilm formation and ten MSCRAMM genes were investigated using Congo red agar, tissue culture plate methods, and PCR. Airborne isolates were shown to have higher adherence and stronger biofilm formation than those from animals. The prevalence of MSCRAMM genes from air isolates was also higher than those from animals. Of the genes, eno was mainly associated with biofilm formation in both animals and airborne isolates (P<0.05). Moreover, the rate of airborne isolates harboring the eno gene was higher than in animal isolates. These results indicated that analysis of MSCRAMM genes with a phenotypic assay might be a helpful bacterial control system for the environment.


[Preliminary study of the effects of propolis in the treatment of chronic gingivitis and oral ulceration].
Since many years ago are known curative effects of propolis on different lesions due, mainly, to more than 30 biologically active elements isolated from it. It is a wordly accepted opinion that propolis is one of the most useful substances elaborated by bees. Despite it, its use in our country is relatively recent. Several investigators, specially in Matanzas, study curative effects of propolis in the field of human and animal medicine. In other countries it has been used in stomalogy, but we have no knowledge about its therapeutical effects in the periodontal disease or its effectiveness in oral ulcers. Therefore, a therapeutical form has been elaborated, which is provisionally called Propolan, for the treatment of two entities: chronic gingivitis and stomatitis of different etiology. The clinical cases supporting effectiveness found with the treatment applied in our setting are presented.


John Darwall, MD (1796-1833): the short yet productive life of a Birmingham practitioner.
This paper summarizes the life and work of John Darwall, a Birmingham physician whose work helped develop several fields of medicine, including occupational health, medical journalism and paediatrics.


Do clinical and paraclinical findings have the power to predict critical conditions of injured patients after traumatic injury resuscitation? Using data mining artificial intelligence.
The triage and initial care of injured patients and a subsequent right level of care is paramount for an overall outcome after traumatic injury. Early recognition of patients is an important case of such decision-making with risk of worse prognosis. This article is to answer if clinical and paraclinical signs can predict the critical conditions of injured patients after traumatic injury resuscitation. The study included 1107 trauma patients, 16 years and older. The patients were trauma victims of Levels I and II triage and admitted to the Rajaee (Emtiaz) Trauma Hospital, Shiraz, in 2014-2015. The cross-industry process for data mining methodology and modeling was used for assessing the best early clinical and paraclinical variables to predict the patients' prognosis. Five modeling methods including the support vector machine, K-nearest neighbor algorithms, Bagging and Adaboost, and the neural network were compared by some evaluation criteria. Learning algorithms can predict the deterioration of injured patients by monitoring the Bagging and SVM models with 99% accuracy. The most-fitted variables were Glasgow Coma Scale score, base deficit, and diastolic blood pressure especially after initial resuscitation in the algorithms for overall outcome predictions. Data mining could help in triage, initial treatment, and further decision-making for outcome measures in trauma patients. Clinical and paraclinical variables after resuscitation could predict short-term outcomes much better than variables on arrival. With artificial intelligence modeling system, diastolic blood pressure after resuscitation has a greater association with predicting early mortality rather than systolic blood pressure after resuscitation. Artificial intelligence monitoring may have a role in trauma care and should be further investigated.


Novel Gerota-edge-sling technique facilitates retroperitoneal robot-assisted partial nephrectomy: a comparative study.
Retroperitoneal robotic partial nephrectomy is markedly restricted by limited space and visual field. We introduced a novel Gerota-edge-sling (GES) technique with self-designed traction devices to overcome these defects by attaching Gerota fascia to abdominal wall, and comparatively evaluated its utilization with routine technique. A retrospective analysis was performed for consecutive patients who underwent routine (control group) or GES assisted (GES group) retroperitoneal robotic partial nephrectomy for localized renal tumors in our hospital between March 2018 and June 2020. Clinical data of perioperative outcomes and complications were collected and compared. Comparison of outcomes between anterior versus posterior tumor subgroups was also conducted. Linear regression analysis was used to define the relationship between dissection time and perinephric fat status in each group. Totally 103 patients were included, 48 in control and 55 in GES group respectively. All the procedures were completed successfully without conversion or positive surgical margin. GES group had significantly decreased console time (91 ± 36 min vs. 117 ± 41 min, p < 0.01) and dissection time (67 ± 35 min vs. 93 ± 38 min, p < 0.01) than control, while ischemia time, blood loss, and nephrometry score comparable between them. No major postoperative complications occurred. Dissection time of GES group was notably shorter than that of control in both anterior/posterior subgroups. Only in control group, dissection time was positively associated with perinephric fat status. The GES technique acting as an adjunct to robotic arms with space-sparing feature, notably improves surgical exposure and facilitates dissection in retroperitoneal partial nephrectomy, while having great feasibility, efficacy and safety.


Statin therapy and sex hormones.
Current guidelines recommend statin therapy for all adult patients with coronary artery disease irrespective of sex. Over recent years, some concerns have been raised concerning the effects of statins on endogenous steroid hormones synthesis. The aim of this review was to summarize the effects of statins on endogenous sex hormones in order to clarify their role and safety in different clinical settings. Results suggest that HMG-CoA inhibitors may slightly impair adrenal and/or gonadal steroid hormone production. In men, statins do not cause any clinically-relevant harmful effects on erectile function and spermatogenesis and, in women, statins have beneficial effects in treatment of polycystic ovary syndrome (PCOS). Additional research is needed to provide specific clinical recommendations concerning this topic.


Renal dysfunction among rheumatoid arthritis patients: A retrospective cohort study.
Rheumatoid arthritis (RA) is a common rheumatological disease which can involve a variety of different renal manifestations. This may be explained by disease effect itself or by medications used for treatment that may lead to renal dysfunction and its complications.We aimed to identify the prevalence and factors that played a role in renal dysfunction among RA Jordanian patients. 285 patients with RA visiting outpatient clinic between March 2016 and March 2017 were included in a retrospective study design. Age, gender, comorbidities, duration of the disease, medications and laboratory results were gathered and scoring of RA activity was done. Data gathered from the 285 patients showed a female predominance with 88.4% female and 11.6% male. The average disease duration was 6.7 years. Age, DM, HTN, and serum CRP were associated with worse renal function on univariate analysis. 44 patients (18.8%) presented with microscopic hematuria, 16 (6.9%) with proteinuria and only 5 (2.1%) patients presented with both microscopic hematuria and proteinuria. Patients with eGFR <60 ml/min had longer disease duration with a mean of 11 years (±7.7) in comparison to 6.4 years (±6.1) for those with eGFR>90 ml/min (P = 0.001). Renal dysfunction is not common in RA Jordanian population and has variable presentations. Age and the duration of illness play a major role in the progression of CKD if present. Future prospective studies evaluating renal biopsies in RA patients are needed.


Design, synthesis, and characterization of mesogenic amine-capped nematic gold nanoparticles with surface-enhanced plasmonic resonances.
The use of the liquid-crystalline state to control the assembly of large (>5 nm) gold nanoparticles (NPs) is of considerable interest because of the promise of novel metamaterial properties of such systems. Here we report on a new approach for the preparation of large nematic gold NPs using a bifunctional capping agent that enables control over the particle size and serves as a linkage for subsequent functionalization with mesogenic groups. Properties of the NPs were characterized by HRTEM, NMR, DSC, TGA, UV/vis, OPM, and XRD studies. The results confirmed the formation of a stable nematic mesophase above 37.5 °C for NPs in the 6-11 nm size range.


Multidrug resistance protein 1 silencing in osteosarcoma and chondrosarcoma cell lines.
The poor response of metastatic osteo- and chondrosarcomas to chemotherapy could be the result of multidrug resistance (MDR), which may be overcome through the use of small interfering RNA (siRNA). However, several methodologic questions remain unresolved. To test the toxicity of three commonly used siRNA transfection reagents and apply the least toxic reagent to investigate the siRNA-induced MDR1 mRNA knockdown. The toxicity of TransIT-TKO, Lipofectamine 2000, and X-tremeGENE siRNA transfection reagents was investigated on osteosarcoma (MG-63) and chondrosarcoma (SW1353) cell lines. The toxicity was measured at 4 and 24 hours using a MTT toxicity assay. The least toxic transfection reagent was applied to investigate the siRNA-induced MDR1 mRNA knockdown effect using qRT-PCR. Furthermore, five housekeeping genes were assessed in the BestKeeper software to obtain mRNA expression normalization. Lipofectamine 2000 was the least toxic transfection reagent, reducing the cell viability only in chondrosarcoma 24 hours following exposure to the highest dose. In contrast, TransIT-TKO and X-tremeGENE transfection reagents displayed a significant reduction in cell viability in both chondrosarcoma after 4 hours and in osteosarcoma after 24 hours. Significant MDR1 mRNA silencing of over 80% was achieved in osteo- and chondrosarcoma using Lipofectamine at a final siRNA concentration of 25 nM. No significant dose response was observed in knockdown efficiency in either Lipofectamine or siRNA concentration. Lipofectamine 2000 was the least toxic transfection reagent in osteo- and chondrosarcoma. Successful siRNA-induced MDR1 mRNA silencing of over 80% was achieved.


Renal Denervation: A New Approach to an Old Problem.
Renal sympathetic hyperactivity is associated with hypertension. Renal denervation is an interventional approach to selectively denervate the renal sympathetic fibers. The reduction of systolic and diastolic blood pressure in patients with resistant hypertension has been demonstrated in the Symplicity HTN-1 and HTN-2 trials. Before the patient undergoes an interventional procedure, causes of secondary hypertension or pseudoresistance must be excluded.


Alternative splicing caused by lentiviral integration in the human genome.
Gene transfer vectors derived from murine oncoretroviruses or human lentiviruses are widely used in human gene therapy. Integration of these vectors in the human genome may, however, have genotoxic effects, caused by deregulation of gene expression at the transcriptional or posttranscriptional level. In particular, integration of lentiviral vectors within transcribed genes has a significant potential to affect their expression by interfering with splicing and polyadenylation of primary transcripts. Aberrant splicing is caused by the usage of both constitutive and cryptic splice sites located in the retroviral backbone as well as in the gene expression cassettes. We describe a set of simple methods that allow the identification of chimeric transcripts generated by the insertion of a lentiviral vector within genes and the evaluation of their relative abundance. Identification of the splice sites, either constitutive or cryptic, that are frequently used by the cell splicing machinery within a given vector provides a useful resource to attempt recoding of the vector with the objective of reducing its potential genotoxicity in a clinical context.


Use of the single-item Patient Global Impression-Severity scale as a self-reported assessment of insomnia severity.
We evaluated a single-item Patient Global Impression-Severity (PGI-S) scale for assessing insomnia severity during the clinical development programme for suvorexant. The analyses used data from two randomised, double-blind, placebo-controlled, 3-month, Phase III clinical trials of suvorexant in patients with Diagnostic and Statistical Manual of Mental Disorders IV criteria insomnia. Patients assessed insomnia severity during the previous week using the PGI-S, a one-item questionnaire containing six response options ranging from 0 (none) to 5 (very severe), at baseline and at Week 2, and Months 1, 2, and 3 after randomisation. The seven-item Insomnia Severity Index (ISI) and other subjective and objective assessments were also completed by patients. PGI-S responses were compared primarily with the ISI using descriptive statistics and correlations. The PGI-S demonstrated favourable measurement characteristics (validity, reliability, responsiveness and sensitivity). PGI-S scores decreased from baseline to Month 3 in a similar pattern to the ISI total score, and the Spearman correlation coefficient between PGI-S and the ISI was .73. An improvement of ≥2 points on the PGI-S defined a treatment responder, based on comparison to the ISI definition of a responder (improvement of ≥6 points). Our present findings suggest that the PGI-S is a simple but valid, reliable, responsive, sensitive, and meaningful patient-reported assessment of insomnia severity. The PGI-S may be particularly useful as a companion outcome to sleep monitoring using wearable sleep devices or smartphones in at-home settings.


Benzimidazole Derivatives as New Potential NLRP3 Inflammasome Inhibitors That Provide Neuroprotection in a Rodent Model of Neurodegeneration and Memory Impairment [Retraction].
[This retracts the article DOI: 10.2147/JIR.S351913.].


The association of white matter hyperintensities with motoric cognitive risk syndrome.
The motoric cognitive risk syndrome (MCR) was characterized by slow gait and subjective cognitive complaints. MCR was associated with brain structural changes. However, the association between white matter hyperintensities (WMH) and MCR was unclear and the aim of this study was to examine this association. The study participants were 1227 older adults (mean age: 72.0 ± 6.0 yrs, women: 52.6%). We collected magnetic resonance imaging (MRI) data to assess WMH. To assess MCR, data on gait speed and subjective cognitive complaints were collected. Demographical and medical data was collected as covariates. Among participants, the proportion of MCR was 5.0% (n = 61) and severe WMH was 16.8% (n = 206). From logistic regression analysis, severe WMH associated with MCR even when adjusted for covariates (odds ratio 2.18 [95% confidential interval 1.15-4.16], p = 0.017). This association was observed in subgroups stratified by the participants' characteristics: higher age, not having fall history, not obesity, not being physical inactivity and not having depressive symptom. Our findings revealed that vascular pathophysiological changes in the brain were associated with MCR. The association was pronounced by several factors. Further evaluation was required to clarify pathophysiology of MCR.


Fasle-positive macroscopic appearance of blood cultures in sorbitol-containing hypertonic medium.
Inability to rely on macroscopic examination as an aid in identifying positive blood cultures was encountered when a hypertonic medium containing sorbitol was tested in a comparative study with an isotonic blood culture medium.


Encysted spermatic cord hydroceles: a report of three cases in adults and a review of the literature.
A hydrocele of the spermatic cord, which results from aberrant closure of the processus vaginalis, is an asymptomatic entity detected incidentally on computed tomography (CT)scans performed for other clinical indications. There are two variations of a spermatic cord hydrocele: the "encysted" variety that does not communicate with the peritoneal cavity, and the "funicular" variety that does communicate with the peritoneal cavity. The encysted type can be confused with an inguinal mass (lymphadenopathy, hernias), and also primary tumors of the cord. We reviewed CT scans for all three adults and ultrasound images for one patient. Confirmation of spermatic cord hydrocele was made by surgery in one case, and CT and follow-up CT in two cases. Our findings indicate that a mass of the spermatic cord, showing fluid attenuation by CT and an avascular,anechoic appearance with sound transmission by ultrasound in an otherwise asymptomatic patient or even in those with an underlying malignancy, should prompt the radiologist to consider the diagnosis of spermatic cord hydrocele. This may eliminate the need for unnecessary, highly invasive procedures such as biopsy or surgical exploration.


Saline inflatable prostheses: 14 years' experience.
This article presents the author's experience with saline implants from 1977 through 1991. One thousand ninety-one women underwent cosmetic breast augmentation during that period. The accumulated surgical data represents the collective practice of the author during that period. From 1977 through 1981 all implants were placed in the submammary position. From 1982 through 1991 all implants were placed in the subpectoral position. The author reviews his experience including complications and results. The data supports the conclusion that saline implants are an effective, viable alternative to gel-filled implants for cosmetic breast augmentation.


Effect of stride frequency on metabolic costs and rating of perceived exertion during walking in water.
We investigated the effect of stride frequency (SF) on metabolic costs and rating of perceived exertion (RPE) during walking in water and on dry land. Eleven male subjects walked on a treadmill on dry land and on an underwater treadmill at their preferred SF (PSF) and walked at an SF which was lower and higher than the PSF (i.e., PSF ± 5, 10, and 15 strides min(-1)). Walking speed was kept constant at each subject's preferred walking speed in water and on dry land. Oxygen uptake, heart rate, RPE, PSF and preferred walking speeds were measured. Metabolic costs and RPE were significantly higher when walking at low and high SF conditions than when walking at the PSF condition both in water and on dry land (P<0.05). Additionally, the high SF condition produced significantly higher metabolic costs and RPE than the equivalent low SF condition during walking in water (P<0.01). Furthermore, metabolic costs, RPE, PSF, and the preferred walking speed were significantly lower in water than on dry land when walking at the PSF (P<0.05). These observations indicate that a change in SF influences metabolic costs and RPE during walking in water.


Technical tip: Dorsal transmetatarsal approach to intermetatarsal and deep plantar lesions.
Synovial and chondromatous lesions can extend dorsally, intermetatarsally and deep into the vault of the longitudinal and transverse plantar arches of the foot. The lesions may prove difficult to excise even with combined approaches. Two cases where a transmetatarsal approach by excision of the base of the third metatarsal enabled successful complete excision of the lesions are presented. Level V, expert opinion.


Accommodating Protein Dynamics in the Modeling of Chemical Crosslinks.
Chemical crosslinking can identify the neighborhood relationships between specific amino-acid residues in proteins. The interpretation of crosslinking data is typically performed using single, static atomic structures. However, proteins are dynamic, undergoing motions spanning from local fluctuations of individual residues to global motions of protein assemblies. Here we demonstrate that failure to explicitly accommodate dynamics when interpreting crosslinks structurally can lead to considerable errors. We present a method and associated software, DynamXL, which is able to account directly for flexibility in the context of crosslinking modeling. Our benchmarking on a large dataset of model structures demonstrates significantly improved rationalization of experimental crosslinking data, and enhanced performance in a protein-protein docking protocol. These advances will provide a considerable increase in the structural insights attainable using chemical crosslinking coupled to mass spectrometry.


Construction and evaluation of a flow injection micro-analyser based on urethane-acrylate resin.
A flow injection micro-analyser with an integrated injection device and photometric detection is described. Channels measuring 205-295 microm depth by 265-290 microm maximum width were manufactured by deep UV lithography on two layers of urethane-acrylate oligomers-based photoresist. Hypodermic syringe needles (450 microm diameter) were connected to the channels for introduction of solutions into the system. Plastic optical fibres were connected to the ends of a 5.0 mm long channel, in order to conduct the light from and to a homemade photometer. The device has a total volume of 7.0 microL and three different sample volumes (0.09, 0.22 and 0.30 microL) can be inserted into the system by choosing the appropriate loop of the hydrodynamic injection approach. The micro-analyser, designed as a single line manifold, was evaluated by determining chloride in waters (mercuric thiocyanate method), and chromium (VI) in wastewater and total chromium in metallic alloys (diphenylcarbazide method). For chloride determination two micro-pumps were employed to impel the solutions, while for chromium determination this task was performed by a conventional peristaltic pump. The results obtained in all determinations did not differ significantly from the reference methods at a confidence level of 95%. In the chloride determination, a flow rate of 50 microL min(-1) was used, providing a sample frequency of 45 injection h(-1), generating ca. 0.7 mg of Hg(II) after an 8-h working day (ca. 20 mL of solution). This result suggests the potential of the micro-analyser towards the reduction of waste, following the philosophy of Green Chemistry.


Androgenic alteration in pathways of C19-steroid metabolism by cultured rat granulosa cells.
Pretreatment of rat granulosa cells with androgens altered the subsequent metabolism of [4-14C]testosterone in vitro. In cells pretreated with testosterone or 5 alpha-dihydrotestosterone, the accumulation of radiolabeled 5 alpha-androstane-3 alpha, 17 beta-diol decreased by 40% and 36%, respectively, when compared with control, while the levels of androstenedione increased by 64% and 54%, respectively. For comparison, pretreatment with 0.5 microM 17 beta-estradiol failed to affect the level of radioactivity incorporated into all three major metabolites. In other experiments, granulosa cells were incubated in the presence of 0.5 microM [4-14C]dihydrotestosterone. While 5 alpha-androstane-3 alpha, 17 beta-diol was decreased slightly by pretreatment with testosterone or 5 alpha-dihydrotestosterone, radiolabeled androsterone was increased significantly. These data suggest a possible modulatory action of androgens on ovarian 17 beta-hydroxysteroid dehydrogenase and/or 5 alpha-reductase activity.


Establishment of T-cell clones recognizing difference in H-2K antigen and inducing graft-versus-host disease.
From the spleen cells of C57BL/6 (B6) mice, T-cell clones were established which responded to mutant H-2K antigen of B6. B-H-2bml (Hz1) mice. One clone and its subclones were maintained in culture medium containing lower concentration (2.5%) of IL-2 (culture supernatant of rat spleen cells stimulated with concanavalin A). They were shown to have a capability to induce graft-versus-host reaction in (B6 X Hz1)F1 recipients as well as to exert cytotoxicity against concanavalin-A-activated spleen cells of Hz1 mice and also their kidney fibroblasts. They lacked cytotoxicity against syngeneic and also third-party Con-A-stimulated spleen cells. These reactive clones were Thy-1.2 and Lyt-2 positive and Lyt-1 negative. On the other hand, clones which were maintained in culture medium containing higher concentration (20%) of IL-2 were devoid of activities in vivo as well as in vitro. These clones were Thy-1.2 positive but Lyt-1.2 and Lyt-2.2 negative.


Mechanism of ER Stress and Inflammation for Hepatic Insulin Resistance in Obesity.
Obesity is a major risk factor in the development of hepatic insulin resistance, which is characterized by an impairment of insulin ability to inhibit glucose output. Although the underlying mechanism for the link between obesity and insulin resistance in the liver is unclear, it has been widely reported and suggested that hepatic endoplasmic reticulum (ER) stress and inflammation induced by obesity lead to the development of hepatic insulin resistance and gluconeogenesis. This review addresses the aspects of ER stress and inflammation currently understood to be involved in metabolic disease, including their role in obesity, hepatic insulin resistance, and hyperglycemia.


The three-dimensional structure of 3, 3', 5'-trichloro-4-methoxybiphenyl, a "coplanar" polychlorinated biphenyl (PCB) derivative.
The crystal structure of a "coplanar" polychlorinated biphenyl (PCB) derivative, 4-methoxy-3, 3', 5'-trichlorobiphenyl (C13H9Cl3O), is described. The torsion angle of the title compound is 41.31(07) degrees, which is in good agreement with the calculated torsion angle of 38.2 degrees in aqueous solution.


A rat brain cDNA encodes enzymatically active GABA transaminase and provides a molecular probe for GABA-catabolizing cells.
cDNAs encoding gamma-aminobutyric acid aminotransferase (GABA-T) were isolated from a lambda ZAP rat hippocampal cDNA expression library by two independent cloning methods, immunological screening with an antimouse GABA-T antibody and plaque hybridization with a GABA-T cDNA probe derived by polymerase chain reaction. We have produced enzymatically active GABA-T from a rat brain cDNA containing the full-length GABA-T coding region. Our rat brain GABA-T cDNAs hybridize to mRNAs in brain and peripheral tissues, including liver, kidney, and testis. We have also detected GABA-T mRNA in GABAergic cells of rat cerebellar cortex by in situ hybridization. Our rat brain GABA-T probe hybridizes to Purkinje, basket, stellate, and Golgi II cells, the same GABAergic neurons previously shown to contain glutamate decarboxylase GAD65 and GAD67.


Conformation-Selective Self-Assembly of Pd6 Trifacial Molecular Barrels Using a Tetrapyridyl Ligand.
A conformationally flexible tetrapyridyl ligand L was assembled separately with three cis-blocked 90° PdII acceptors (M1, M2, and M3) containing different blocking diamines. Surprisingly, different conformations of the donor L were arrested by the acceptors depending on the nature of the blocking amine, leading to the formation of isomeric Pd6 barrels (B1, B2, and B3). B2 and B3 with larger windows have been used to encapsulate polyaromatic hydrocarbons.


Molar incisor hypomineralization: a questionnaire inventory of its occurrence in member countries of the European Academy of Paediatric Dentistry (EAPD).
The objectives were to find out whether hypomineralized permanent first molars and incisors, known as Molar Incisor Hypomineralization (MIH), occurs all over Europe, whether its prevalence in each country is known and whether or not it is considered to be a clinical problem. Clinical photos of MIH and a five-item questionnaire were sent to members of the European Academy of Paediatric Dentistry (EAPD). A total of 59 questionnaires were sent to members in 31 countries. After one month a reminder was sent to non-responders. Fifty-four dentists (92%) in 30 countries (97%) returned the questionnaire. MIH was stated to occur in all but one country (the Czech Republic). Nearly all the responders (97%) stated that they were familiar with the clinical appearance of MIH and a majority saw it as a clinical problem. Furthermore, a large majority of the responders (90%) considered it important to map the prevalence of MIH in European countries as such data are available to only a limited extent. Paediatric dentists in Europe are aware of MIH and the majority consider it to be a clinical problem. Only limited data are available on the prevalence of MIH. Comparable and representative prevalence studies are therefore urgently needed to gain more knowledge about the magnitude of MIH and related clinical problems.


Nuclear receptor mRNA expression by HBV in human hepatoblastoma cell lines.
Recent studies have implicated nuclear receptors (NRs) in the development of hepatocarcinogenesis. We assumed that hepatitis B virus (HBV) alters the expression of NRs and coregulators, and compared the gene expression profiling for 84 NRs and related genes between HpeG2.2.15, which secretes complete HBV virion, and HepG2 by real-time RT-PCR with SyBr green. Forty (47.6%) genes were upregulated 2-fold or greater, and only 5 (5.9%) were downregulated 2-fold or more, in HepG2.2.15 compared to HepG2. These results suggest that HBV affects NRs and their related signal transduction, and that they play important roles in viral replication and HBV-related hepatocarcinogenesis.


Degradative activity of granzyme A on skeletal muscle proteins in vitro: a possible molecular mechanism for muscle fiber damage in polymyositis.
The importance of cytotoxic T lymphocytes (CTLs) in the autoimmune inflammatory myopathies, especially polymyositis (PM), has been emphasized. We have studied the degradative activity of granzyme A, a cytotoxic molecule with trypsin-like specificity in CTL granules, on several muscle proteins in vitro. Our study reveals that granzyme A hydrolyzes dystrophin, myosin, and nebulin, but not laminin, alpha-actinin, vinculin, and connectin in vitro. Among these proteins, nebulin is more susceptible to proteolysis, followed by dystrophin, myosin heavy chain, and myosin light chains, in that order. This result implies an important role of granzyme A in CTL-mediated muscle fiber damage in PM.


Impact of vaccine protection against multiple HPV types on the cost-effectiveness of cervical screening.
Cross-protection against non-HPV16/18 types and the emergence of broad spectrum vaccines protecting against multiple HPV types will influence the cost-effectiveness of future screening. To assess this influence we used an individual-based simulation model describing the relation between 14 HPV types and cervical disease, allowing the occurrence of multiple type infections. Screening scenarios for vaccinated women were evaluated, firstly for HPV16/18 vaccination with partial cross-protection against HPV 31, 33, 45 and 58 and secondly, for broad spectrum vaccination against 5-13 HPV types. The vaccine-induced incidence reduction of type-specific infection was varied from 0 to 95% in the cross-protection setting and set at 100% in the setting of broad spectrum vaccines. Scenarios of either cytology or HPV DNA screening were considered under varying lifetime number of screening rounds. At a cost-effectiveness threshold of €20,000/QALY, four times HPV DNA screening between 30 and 60 years was the selected scenario in addition to HPV16/18 vaccination, whether or not cross-protection was conferred (€6707 and €9994/QALY, respectively). In the absence of cross-protection, a fifth screening round might be considered (ICER €22,967/QALY). In addition to broad spectrum vaccination, one screen during lifetime was cost-effective up to an 11-valent vaccine. If the vaccine-induced type-specific incidence reduction was lowered to 99%, one screen during lifetime was cost-effective even in addition to 13-valent vaccination. In conclusion, in a cohort of HPV16/18 vaccinated women, four rounds of HPV DNA screening is cost-effective. One screen during lifetime remains cost-effective in addition to broad spectrum vaccination offering protection against many high-risk HPV types.


Survival rate and ultrastructure of vitrified bovine in vitro and in vivo developed embryos.
The capacity of different vitrification media and methods was tested onto in vivo and in vitro produced bovine morula/blastocysts and their ultrastructure and survival studied post-thawing. Two vitrification solutions were finally selected, named 40 ES (40% ethylene glycol in PBS containing 0.5 M sucrose) and 35 EFS (composed of 35% (v/v) ethylene glycol in PBS containing 0.5 M/l sucrose and 30% (w/v) Ficoll 70). The straws were either precooled or not precooled in nitrogen vapour, plunged and stored in LN2 for 10-25 days, and then thawed in a 20 degrees C waterbath. The content of the straws was rediluted in 1M sucrose solution in PBS and later cocultured with BOEC for 48 h. The overall survival rates for in vitro and in vivo embryos were 36% (12 of 33) and 20% (3 of 15) after 24 h and 21% (7 of 33) and 33% (5 of 15) after 48 h. The survival rates for precooled embryos were significantly higher than for not precooled (48% vs 13% after 24 h and 44% vs 4% after 48 h) when tested across vitrification media. The in vitro-produced embryos presented an ultrastructure similar to the pre-freeze state, irrespective of the vitrification media used. The in vivo developed embryos showed a rather modified post-thaw ultrastructure, with clear signs of osmotic changes at both the trophoblastic and embryonic cells. The results indicated that in vitro and in vivo developed bovine embryos can survive vitrification using ethylene glycol as a cryoprotectant.


Effect of bacterial volatiles on the mycelial growth of mushrooms.
Bacteria play an important role in the life cycle of fungi by influencing positively or negatively morphological features, mycelial growth and/or fruiting body induction. However, little is known about the underlying mechanisms and their species-dependence, especially among fungi of the phylum Basidiomycota. Hence, we analyzed the effects of seven bacterial isolates, that were previously obtained from Pleurotus ostreatus HK35, on the mycelial growth of P. ostreatus HK35, Pleurotus eryngii DSMZ 8264, Pleurotus sapidus DSMZ 8266, Pleurotus citrinopileatus DSMZ 5341, Cyclocybe aegerita AAE-3, Lentinula edodes CBS 389.89 and Kuehneromyces mutabilis DSMZ 1013 during eight days. Notably, the bacterial isolates only showed significant mycelial growth-promoting effects when co-cultivated on Petri dishes with Pleurotus species, except for P. citrinopileatus. In particular, Paenibacillus peoriae strain M48F induced remarkably the mycelial growth in P. ostreatus (∼47 %), P. eryngii (∼32 %) and P. sapidus (∼27 %) during the early cultivation stages, but with ongoing cultivation this strain inhibited the growth of all fungi. To investigate the impact of bacterial volatile organic compounds (VOCs) on the mycelial growth, P. ostreatus and P. eryngii were co-cultivated with the bacteria on bi-plates. No growth inhibition on bi-plates was observed while bacterial isolates and mycelia were separated by a physical barrier, assuring that late mycelial growth inhibition was not caused by bacterial volatile compounds. VOCs from strain M48F induced the strongest growth of P. ostreatus (∼50 %) and P. eryngii (∼20 %) mycelia compared to controls. Furthermore, we analyzed the VOCs of strain M48F alone and in combination with P. ostreatus, P. eryngii, P. sapidus and L. edodes using bi-plates and SPME-GC-MS. Strain M48F triggered the formation of β-bisabolene when co-cultivated with P. ostreatus or P. eryngii, which may indicate a fungal defense reaction. Additionally, 2,5-diisopropylpyrazine dominated the volatilome of strain M48F on all eight sampling days. In samples of strain M48F, alone and co-cultivated with L. edodes, the amount of 2,5-diisopropylpyrazine remained quite constant. In contrast, the quantity of this substance declined substantially in co-cultures with P. ostreatus. Interestingly, 2,5-diisopropylpyrazine enhanced P. ostreatus mycelial growth significantly although the growth-promoting effect was not as pronounced as during co-cultivation with strain M48F. Our results show that the mycelial growth-promoting effects of bacteria are remarkably species-dependent, and that bacterial VOCs such as 2,5-diisopropylpyrazine can enhance mycelial growth.


Long- and short-term history effects in a spiking network model of statistical learning.
The statistical structure of the environment is often important when making decisions. There are multiple theories of how the brain represents statistical structure. One such theory states that neural activity spontaneously samples from probability distributions. In other words, the network spends more time in states which encode high-probability stimuli. Starting from the neural assembly, increasingly thought of to be the building block for computation in the brain, we focus on how arbitrary prior knowledge about the external world can both be learned and spontaneously recollected. We present a model based upon learning the inverse of the cumulative distribution function. Learning is entirely unsupervised using biophysical neurons and biologically plausible learning rules. We show how this prior knowledge can then be accessed to compute expectations and signal surprise in downstream networks. Sensory history effects emerge from the model as a consequence of ongoing learning.


Geometrical factors influencing muscle force development. I. The effect of filament spacing upon axial forces.
The influence of geometry on the force and stiffness measured during muscle contraction at different sarcomere lengths is examined by using three specific models of muscle cross-bridge geometry which are based upon the double-hinge model of H. E. Huxley (Science [Wash. D.C.]. 1969, 164:1356-1366) extended to three dimensions. The force generated during muscle contraction depends upon the orientation of the individual cross-bridge force vectors and the distribution of the cross-bridges between various states. For the simplest models, in which filament separation has no effect upon cross-bridge distribution, it is shown that changes in force vectors accompanying changes in myofilament separation between sarcomere lengths 2.0 and 3.65 microgram in an intact frog skeletal muscle fiber have only a small effect upon axial force. The simplest models, therefore, produce a total axial force proportional to the overlap between the actin and myosin filaments and independent of filament separation. However, the analysis shows that it is possible to find assumptions that produce a cross-bridge model in which the axial force is not independent of filament spacing. It is also shown that for some modes of attachment of subfragment-1 (S1) to actin the azimuthal location of the actin site is important in determining the axial force. A mode of S1 attachment to actin similar to that deduced by Moore et al. (J. Mol. Biol., 1970, 50:279-294), however, exhibits rather constant cross-bridge behavior over a wide range of actin site location.


Clinical Outcomes of Umbilical Cord Blood Transplantation Using Ex Vivo Expansion: A Systematic Review and Meta-Analysis of Controlled Studies.
Greater use of umbilical cord blood (UCB) for hematopoietic cell transplantation (HCT) is limited by the number of cells in banked units. Ex vivo culture strategies have been increasingly evaluated in controlled studies, but their impact on transplantation-related outcomes remains uncertain owing to the small patient numbers in these studies, necessitating an updated systematic review and meta-analysis. A systematic literature search was conducted using the MEDLINE, Embase, and Cochrane databases to March 18, 2022. Nine cohort-controlled phase I to III trials were identified, and data of 1146 patients undergoing umbilical cord blood transplantation (UCBT) were analyzed (308 ex vivo expanded and 838 unmanipulated controls). Expansion strategies involved cytokine cocktails plus the addition of small molecules (UM171, nicotinamide [NiCord], copper chelation, Notch ligand, or Stem regenin-1 [SR-1]) and coculture with mesenchymal stromal cells in a single-unit transplant strategy (5 studies) or a double-unit transplant strategy with 1 unmanipulated unit (4 studies). The included trials reported a median ex vivo expansion of CD34+ cells from 28-fold to 330-fold. Eight of the 9 studies demonstrated a significantly faster time to initial neutrophil and platelet engraftment using expanded cells compared with controls. Studies using UM171 and NiCord in single-unit UCBT and SR-1 or NiCord double-unit UCBT demonstrated long-term donor chimerism of the expanded unit at 100 days to 36 months post-transplantation in all single-unit recipients and in 35% to 78% of double-unit recipients. Our meta-analysis revealed a lower risk of death at the study endpoint in patients who received ex vivo expanded grafts (odds ratio [OR], .66; 95% confidence interval [CI], .47 to .95; P = .02), while the risk of grade II-IV acute graft-versus-host disease was unchanged (OR, .79; 95% CI, .58 to 1.08; P = .14). This review indicates that UCBT following ex vivo expansion can accelerate initial engraftment. Durable donor chimerism can be achieved after transplanting cord blood units expanded using NiCord, UM171, or SR-1; however, long term outcomes remain unclear. Larger studies with longer-term outcomes are needed to better understand the merits of specific expansion strategies on survival.


The effect of different organic solvents in liposome properties produced in a periodic disturbance mixer: Transcutol®, a potential organic solvent replacement.
Liposomes are versatile particles used in the biomedical field as drug delivery systems (DDS). Liposome production using micromixers have shown to yield nanoparticles for DDS in a single step with a controllable size by changing flow conditions. Nonetheless, other factors such as the organic solvent, play a crucial role in the liposome formation process. Furthermore, drug solubility and toxicity are pivotal when deciding which organic solvent to choose. In this work, liposomes were produced in a periodic disturbance mixer (PDM). We investigated three conventional organic solvents: ethanol, methanol, and isopropanol as well as Transcutol®. We assessed the organic solvent influence on liposome characteristics (size, size distribution and zeta potential). Among the four organic solvents, Transcutol® yielded the smallest liposomes, which ranged from 80 nm to 160 nm. Moreover, a more in-depth investigation showed that Transcutol® produced smaller or similar-sized particles under different temperature and lipid concentration conditions, compared with ethanol. Furthermore, we proved that particles zeta potential was not influenced by the organic solvent, production temperature, or lipid concentration. This work results show that Transcutol® could replace the conventional alcohol-based solvents and can potentially avoid filtration steps due to its low toxicity. Therefore, the present approach is appealing for DDS development.


3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties.
A protein fraction containing gamma-butyrobetaine hydroxylase (sp.act. 1.54 mU/mg) was isolated from the rat liver by differential precipitation with ammonium sulphate. 3-(2,2,2-Trimethylhydrazinium)propionate (THP), a noncompetitive enzyme inhibitor, when administered orally to rats for 10 days (150 mg/kg) elicited a reduction in myocardial free carnitine and long-chain acyl carnitine content by 63.7 and 74.3%, respectively. This reduction in free carnitine concentration causes a suppression of the free fatty acid oxidation, as measured by the production of 14CO2 and ketone bodies. The inhibition of fatty acid oxidation is particularly manifest when their metabolism is stimulated by feeding a fat-rich diet to the animals or in fasting rats. The inhibition of fatty acid metabolism at the stage of activation (acyl carnitine formation) can account for the cardioprotective effect of THP, which is assessed by its ability to prevent a decrease in ATP level and myocardial energy charge as well as to prevent a rise in creatine phosphokinase and lactic dehydrogenase (myocardium-specific isozyme) activity in rat blood serum in response to isoproterenol and epinephrine. Regulation of the carnitine-dependent fatty acid metabolism in ischaemia is a pathogenetically justified approach to pharmacological treatment of ischaemic myocardium. In its biochemical mechanism, THP significally distinguishes itself from other known inhibitors of fatty acid oxidation.