Relationships of salivary cortisol and melatonin rhythms to sleep quality, emotion, and fatigue levels in patients with newly diagnosed lung cancer.
After being diagnosed with lung cancer, patients often experience sleep disturbance, anxiety, depression, and fatigue. These symptoms may occur because of changes in neurotransmitter secretion caused by tumors. This study investigated the correlation of cortisol and melatonin rhythms with sleep quality, anxiety, depression, and fatigue levels in patients with newly diagnosed lung cancer. We conducted a case-control study and recruited 40 patients with newly diagnosed lung cancer and 40 healthy adults. The patient group had a lower salivary melatonin level and flatter slope (p < 0.001 and p < 0.001), higher salivary cortisol level and steeper slope (p < 0.001 and p < 0.001), higher sleep disturbance level (p = 0.004), and higher depression level (p < 0.001). The multivariate linear regression analysis indicated that the cortisol slope (p = 0.005) and fatigue score (p = 0.032) predicted the sleep quality score (p = 0.011). Overall, the patients with newly diagnosed lung cancer had poorer sleep quality, higher depression levels, lower salivary melatonin levels, higher cortisol levels, and flatter melatonin and cortisol slopes than did the controls. The fatigue level and cortisol slope significantly predicted sleep quality. Therefore, the assessment of cortisol and melatonin rhythms and levels could provide crucial information that may be beneficial for managing symptoms in patients with newly diagnosed lung cancer.


[Level of total injury severity as a possible parameter for evaluation of height in fatal falls].
The injuries caused by high falls from over the seventh floor are considered mostly fatal. It is possible to survive the high fall from over 30 metres at landing on the surface of high deformity (snow or water). The Injury Severity Score (ISS) due to a high fall is influenced by the height from which the body has fallen, then, the body and surface features, and finally, the manner of body impact on to the surface. The aim of the study was determining the possibility of the height estimation that caused the fatality of the impact, considering the severity of injury expressed by ISS. A retrospective autopsy study was done on the materials of Institute of Forensic Medicine in Belgrade, during a twenty-year period: 1981-2000. The autopsy records were analyzed together with clinical medical data, of the deadly injured due to high falls on to a solid surface. ISS value was determined in each case. The height of fall was determined on the basis of police reports, i.e. death scene analysis. The results were done statistically (linear correlation). The sample included 660 cases: 469 males (71%) and 191 females (29%). The average age of the examined sample was 44.66 (SD=6.62). The number of 290 cases (44%) were accidental deaths, while 370 were suicidal ones (56%). Only few injured due to high falls up to 7 metres had ISS value below 26. Deaths in these cases were caused by complications of the injuries. The ISS value in the injured rose with the height from which the victim had fallen: ISS was 25 in all falls over 7 metres of height. In all cases were severe, critical injuries of one organic system (mostly severe head injuries). According to the analysis of our sample, we concluded that it was not possible to determine the precise height of fatal falls only on the basis of the injury severity score estimation by ISS. This determination, approximate one, was possible only in falls on to a solid surface up to 30 metres. The same determination was not possible by the analysis of the time of survival. It is obvious that determining the height of fall is more possible by types and combinations of single injuries which are, single or combined with other injuries, characteristic for single mechanisms of primary body contact with the solid surface depending on the height of fall.


Deep Margins Melanoma: How Deep Is Deep Enough?
Wide excision (WE) to muscular fascia for invasive melanoma is common practice but excision to subcutaneous tissue may be adequate. We evaluated practice patterns regarding depth of biopsy and excision as well as risks for recurrence. Retrospective review of patients with pT1-4 melanoma (cN0) treated with WE at a single institution was performed. Patient factors were evaluated. Biopsy and excision techniques were compared to pathology and reviewed for recurrence. 385 patients from 2006 to 2020 were included. Lesions were on the extremity (n = 189), head/neck (n = 48), trunk (n = 148). Biopsy techniques included shave (n = 330), excisional (n = 36), punch (n = 10), incisional (n = 9). Deep biopsy margins were positive for IM/melanoma in situ in 139 patients. WE specimens were taken to muscular fascia (n = 218) or mid/deep fat (n = 144). 51 patients had recurrent disease or a new primary lesion: locoregional (n = 31), distant (3), or new lesions (n = 17). Patient characteristics associated with recurrence include older age and female gender. Tumor characteristics associated with recurrence include lesions located on the trunk, superficial spreading melanoma, ulceration, perineural invasion, and clinical T and P stage. Patients that recurred were more likely to have WE taken to or including muscular fascia. Biopsy type, deep margin on biopsy, and depth of dissection was not associated with recurrence.


Interleukin 2 binding molecule distinct from the Tac protein: analysis of its role in formation of high-affinity receptors.
Interleukin 2 (IL-2) receptors on activated T cells exist in high- and low-affinity configurations, both of which share a ligand-binding component known as the Tac protein. Although almost all binding of IL-2 to such cells was inhibited by an antibody to Tac, the predominant component of binding on the natural killer (NK)-like cell line YT was resistant to this reagent. The ligand-binding component on YT cells also differed from Tac in its affinity constant (Kd approximately 8.2 X 10(-10) M vs. Kd approximately equal to 1.1 X 10(-8) M for low-affinity Tac sites) and in its susceptibility to inhibition by certain antibodies to IL-2. When the YT cells were stimulated in a manner that induced expression of the Tac protein, the IL-2 binding sites were converted to a high-affinity configuration (Kd approximately 1.8 X 10(-11) M). Thus, the original binding component on unstimulated YT cells appeared to combine with Tac and IL-2 to produce a high-affinity receptor complex. Use of bifunctional crosslinking agents following ligand binding to unstimulated YT cells yielded covalent IL-2-receptor complexes of 83 and 90 kDa. These complexes were similar in size to those derived from high-affinity receptors on activated T cells and shared a similar fragmentation pattern upon proteolysis. These results demonstrate the existence of a second IL-2 binding component in addition to the Tac protein and suggest that this component combines with Tac and IL-2 to form high-affinity receptor sites.


Soy affects trabecular microarchitecture and favorably alters select bone-specific gene expressions in a male rat model of osteoporosis.
We have recently reported that soy isoflavones particularly when provided in the context of soy protein are capable of preventing loss of bone mineral density due to orchidectomy in F344 rats. We hypothesize, that soy isoflavones also exert beneficial effects on bone microstructural properties, in part, by enhancing bone formation. Therefore, in the present study, we examined the dose-dependent effects of soy isoflavones on femoral bone microarchitectural properties and select bone-specific gene expressions in the same rat model. Seventy-two, 13-month old rats were either orchidectomized (ORX; 5 groups) or sham-operated (Sham; 1 group) and immediately placed on dietary treatments for 180 days. Four of the ORX groups were fed either casein- or soy protein-based diets each with one of two doses of isoflavones either 600 or 1200 mg/kg diet. Rats in the remaining ORX control and Sham groups were fed a control casein-based diet. Soy protein at the high isoflavone dose, and to a lesser extent with the lower dose, reduced the magnitude of the ORX-induced decreases in trabecular bone volume (BV/TV) and trabecular number (Th.N) and increase in trabecular separation (Tb.Sp) at the femoral neck site. These modulations of trabecular microstructural properties by isoflavones may be due to increased mRNA levels of alkaline phosphatase (ALP), collagen type I (COL), and osteocalcin (OC), which are associated with enhanced bone formation. These findings confirm our earlier observations that the modest bone protective effects of soy isoflavones are due to increased rate of bone formation.


Physically and Chemically Compartmentalized Polymersomes for Programmed Delivery and Biological Applications.
Multicompartment polymersomes (MCPs) refer to polymersomes that not only contain one single compartment, either in the membrane or in the internal cavity, but also mimic the compartmentalized structure of living cells, attracting much attention in programmed delivery and biological applications. The investigation of MCPs may promote the application of soft nanomaterials in biomedicine. This Review seeks to highlight the recent advances of the design principles, synthetic strategies, and biomedical applications of MCPs. The compartmentalization types including chemical, physical, and hybrid compartmentalization are discussed. Subsequently, the design and controlled synthesis of MCPs by the self-assembly of amphiphilic polymers, double emulsification, coprecipitation, microfluidics and particle assembly, etc. are summarized. Furthermore, the diverse applications of MCPs in programmed delivery of various cargoes and biological applications including cancer therapy, antimicrobials, and regulation of blood glucose levels are highlighted. Finally, future perspectives of MCPs from the aspects of controlled synthesis and applications are proposed.


Catalytic Alkene Carboaminations Enabled by Oxidative Proton-Coupled Electron Transfer.
Here we describe a dual catalyst system comprised of an iridium photocatalyst and weak phosphate base that is capable of both selectively homolyzing the N-H bonds of N-arylamides (bond dissociation free energies ∼ 100 kcal/mol) via concerted proton-coupled electron transfer (PCET) and mediating efficient carboamination reactions of the resulting amidyl radicals. This manner of PCET activation, which finds its basis in numerous biological redox processes, enables the formal homolysis of a stronger amide N-H bond in the presence of weaker allylic C-H bonds, a selectivity that is uncommon in conventional molecular H atom acceptors. Moreover, this transformation affords access to a broad range of structurally complex heterocycles from simple amide starting materials. The design, synthetic scope, and mechanistic evaluation of the PCET process are described.


Neurological and cognitive recovery following abstinence from petrol sniffing.
Anecdotal observations suggest that neurological impairments associated with petrol (gasoline) sniffing resolve with abstinence, although these effects have not been proven empirically. Severe exposure to leaded petrol may induce a lead encephalopathy that extends beyond any acute intoxication and requires emergency hospital treatment. Previously, in chronic petrol sniffers, we showed neurological, saccadic, and cognitive abnormalities that were more severe in petrol sniffers with a history of hospitalization for lead encephalopathy, and that correlated with blood lead levels and the length of time of sniffing petrol. Ex-petrol sniffers showed a qualitatively similar but quantitatively less severe pattern of impairment. Petrol sniffing was stopped completely in one of the study communities by modifying social, occupational, and recreational opportunities. After 2 years, we obtained biochemical and neurobehavioral (neurological, saccade, and cognitive) data from all available participants of the earlier study including 10 nonsniffers and 29 chronic petrol sniffers, with six of these individuals previously receiving hospital treatment for lead encephalopathy. Here, we report that blood lead was reduced and that neurobehavioral impairments improved, and in many cases normalized completely. The most severe petrol-related neurobehavioral impairment was observed among individuals who had longer histories of abuse and higher blood lead levels, and among petrol sniffers with a history of lead encephalopathy. Those with the greatest extent of neurobehavioral impairment showed the greatest degree of improvement with abstinence, but were less likely to recover completely. This is the first direct evidence that neurological and cognitive impairment from chronic petrol sniffing ameliorates with abstinence and may recover completely.


[Expression of DNMT3b in human bladder cancer tissue and its correlation with clinical prognosis].
To investigate the expression of DNMT3b in human bladder cancer tissues and its correlation with postoperative survival of patients with bladder cancer. Thirty-eight pairs of surgically resected human bladder cancer tissues and adjacent bladder tissues were detected by immunohistochemistry for DNMT3b expression, and the correlations of DNMT3b expression level were analyzed with the patients'age, gender, pathological grade, tumor size, T stage, lymph node metastasis and TNM stages. Kaplan-Meier survival analysis was performed to assess the effect of DNMT3b expression on survival outcomes of the patients. High DNMT3b protein expression was detected in 63.16% of the bladder cancer tissues and in 13.16% of the adjacent tissues (P < 0.05). The expression level of DNMT3b was associated with the pathological grade (P=0.002), tumor size (P < 0.001), T stage (P < 0.001), lymphatic metastasis (P=0.039) and TNM stage (P < 0.001), but not with gender or age of the patients. Multivariate logistic regression analysis showed that the protein expression level of DNMT3b was correlated with tumor size (P=0.008) and TNM grades of the tumor (P=0.042). Kaplan-Meier analysis showed that the patients with a high DNMT3b expression had a significantly shorter overall survival than those with a low DNMT3b expression (P=0.021). DNMT3b overexpression in bladder cancer is closely related to such clinicopathological factors as pathological grade, tumor size, T stage, lymphatic metastasis, and TNM stage and a shorter overall survival of the patients, suggesting the potential value of DNMT3b as a prognostic marker and a new therapeutic target for bladder cancer.


Albinos who bleed (Hermansky-Pudlak syndrome). The Gypsy's Warning?
Attention is drawn to the uncommon autosomal recessive Hermansky-Pudlak syndrome, because of the very material risk of unexpected death in this triad of albinism, platelet deficiency, and failure of 'ceroid' metabolism, which appears to have been overlooked in ophthalmic literature. A possible Scottish case is described.


Phylogenomics of Xanthomonas field strains infecting pepper and tomato reveals diversity in effector repertoires and identifies determinants of host specificity.
Bacterial spot disease of pepper and tomato is caused by four distinct Xanthomonas species and is a severely limiting factor on fruit yield in these crops. The genetic diversity and the type III effector repertoires of a large sampling of field strains for this disease have yet to be explored on a genomic scale, limiting our understanding of pathogen evolution in an agricultural setting. Genomes of 67 Xanthomonas euvesicatoria (Xe), Xanthomonas perforans (Xp), and Xanthomonas gardneri (Xg) strains isolated from diseased pepper and tomato fields in the southeastern and midwestern United States were sequenced in order to determine the genetic diversity in field strains. Type III effector repertoires were computationally predicted for each strain, and multiple methods of constructing phylogenies were employed to understand better the genetic relationship of strains in the collection. A division in the Xp population was detected based on core genome phylogeny, supporting a model whereby the host-range expansion of Xp field strains on pepper is due, in part, to a loss of the effector AvrBsT. Xp-host compatibility was further studied with the observation that a double deletion of AvrBsT and XopQ allows a host range expansion for Nicotiana benthamiana. Extensive sampling of field strains and an improved understanding of effector content will aid in efforts to design disease resistance strategies targeted against highly conserved core effectors.


Infectious Pseudoaneurysm of the Internal Carotid Artery in a Child Secondary to Parapharyngeal Abscess.
Infectious pseudoaneurysm is a rare condition characterized by arterial wall dilation, usually due to an adjacent infectious focus. We present an 8-year-old male with a 3-day history of progressive, severe headache 2 weeks after treatment for a parapharyngeal abscess. Computed tomography revealed a left internal carotid artery (ICA) pseudoaneurysm inferior to the skull base and a small parapharyngeal abscess inferior to the pseudoaneurysm. The patient was admitted for intravenous antibiotic treatment and underwent transfemoral endovascular coil occlusion of the cervical ICA pseudoaneurysm without complications. We discuss the presentation and management of rare vascular complications of parapharyngeal abscesses involving major arteries of the neck and the role of neurointerventional embolization in these cases.


Electro-acupuncture for irritable bowel syndrome patients: study protocol for a single-blinded randomized sham-controlled clinical trial.
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders in clinical practice. IBS diagnosis is based on symptoms defined by abdominal pain or discomfort associated with defecation or changes in bowel habits. Gut-brain interaction caused by stress or depressive emotion is one of the essential pathologies. Acupuncture has been used for the treatment of internal medicine, including digestive disorders and depressive disorders in Chinese medicine. This study aims to determine whether electro-acupuncture could have significant benefits than sham acupuncture for IBS. This is a single-blinded randomized sham-controlled clinical trial with two arms. A total of 120 IBS patients will be recruited. After a 2-week run-in period, eligible subjects will be randomly assigned to one of two arms, acupuncture (AC) arm and sham acupuncture (SAC) arm. Each eligible subject will go through a 2-week run-in-period, 6-week treatment period, and 6-week follow-up period. Five visits in total were scheduled for each subject in week 0, week 2, week 5, week 8, and week 14. The outcomes would be measured with (1) IBS-SSS, (2) Hamilton Depression Rating Scale (HAMD-17), (3) Clinical Global Impression-Severity (CGI-S), (4) Self-Rating Depression Scale (SDS), and (5) IBS Quality of Life (IBS-QoL). The study will compare electro-acupuncture with sham acupuncture to explore the feasibility of electro-acupuncture in improving IBS symptoms. ClinicalTrials.gov NCT04387383 . Registered on 13 May 2020.


Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock.
Recent evidence has emerged that peroxisome proliferator-activated receptor alpha (PPARalpha), which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPARalpha influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPARalpha in peripheral clocks.


Innately shorter vegetation periods in North American species explain native-non-native phenological asymmetries.
The length of the vegetation period (LVP), which is the time between leaf-out and leaf senescence, affects numerous ecosystem functions, including biogeochemical cycles and interspecific interactions. The evolutionary mechanisms determining LVP, however, are poorly understood, and thus, it is unknown whether innate LVPs differ between eastern North American (ENA), European and East Asian species. Here we monitored LVP in 2014-2015 in 396 Northern Hemisphere woody species grown in a common garden. We found that ENA species, under the same conditions, have three weeks (11%) shorter vegetation periods than their European and East Asian relatives, because their leaves flushed 9 ± 4 and 13 ± 4 days later and senesced 9 ± 4 and 11 ± 4 days earlier. LVPs of species introduced from Eurasia into ENA are therefore longer than those of native species, suggesting that the spread of non-natives might alter seasonal forest productivity in ENA. LVP between naturalized invasive and non-invasive species, however, did not differ, rejecting the common assumption that longer leaf presentation generally fosters invasive success. A likely explanation for the shorter LVP of ENA species is that region's uniquely high inter-annual temperature variation. These results highlight the footprint of regional climate history, which will affect forest response to climate change.


Correlation between cocaine prices and purity with trends in emergency department visits in a major metropolitan area.
Illicit drug use not only causes acute and chronic adverse health outcomes but also results in a significant burden to health care providers. The objective of this study is to examine the relationship between cocaine prices and purity with emergency department (ED) visits for the Chicago-Naperville-Joliet metropolitan area. Our primary outcome was number of cocaine-related ED visits per quarter provided by the Drug Abuse Warning Network. The predictor variables of cocaine purity and price were provided by the System to Retrieve Information from Drug Evidence database. Autoregressive integrated moving average (ARIMA) regressions were used to estimate the effects of cocaine price and purity on cocaine-related ED visits. Although cocaine prices did not change substantially over time, cocaine purity decreased by over 30 % between 2006 and 2010. ARIMA regression results suggest that cocaine-related ED visits were not significantly associated with powder or crack cocaine prices; however, a decrease in powder cocaine purity was associated with 2,081 fewer ED visits overall from 2007 to 2010. The cocaine trade continues to be a major public health and law enforcement threat to large metropolitan cities like Chicago. Regular monitoring of cocaine purity levels may provide early warning of impending changes in cocaine-related ED visits for law enforcement and health care providers.


Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia.
Diverse metabolic changes are induced by various driver oncogenes during the onset and progression of leukemia. By upregulating glycolysis, cancer cells acquire a proliferative advantage over normal hematopoietic cells; in addition, these changes in energy metabolism contribute to anticancer drug resistance. Because leukemia cells proliferate by consuming glucose as an energy source, an alternative nutrient source is essential when glucose levels in bone marrow are insufficient. We profiled sugar metabolism in leukemia cells and found that mannose is an energy source for glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway. Leukemia cells express high levels of phosphomannose isomerase (PMI), which mobilizes mannose to glycolysis; consequently, even mannose in the blood can be used as an energy source for glycolysis. Conversely, suppression of PMI expression or a mannose load exceeding the processing capacity of PMI inhibited transcription of genes related to mitochondrial metabolism and the TCA cycle, therefore suppressing the growth of leukemia cells. High PMI expression was also a poor prognostic factor for acute myeloid leukemia. Our findings reveal a new mechanism for glucose starvation resistance in leukemia. Furthermore, the combination of PMI suppression and mannose loading has potential as a novel treatment for driver oncogene-independent leukemia.


Root-knot nematodes demonstrate temporal variation in host penetration.
Root-knot nematodes (RKN; Meloidogyne spp.) are obligate plant parasites that require constant communication with their host to establish and maintain specialized feeding cells. The intimacy of this interaction likely requires constant monitoring of host biology and behavior. As plant processes follow tightly regulated circadian and diurnal patterns, RKN may use similar cues to regulate aspects of this symbiosis. We interrogated RKN biology within the context of host diurnal rhythms throughout nematode development. At 24-hr post-inoculation, RKN penetrated host roots significantly more when inoculated during the night compared to the day. We excluded the possibility that this phenomenon is due to nematode perception of light penetrating the soil, as an identical phenomenon is observed under inverted light conditions. Additionally, when plants were allowed to equilibrate and adjust their light-driven clock under constant light conditions, the temporal variation in nematode penetration was abolished. This phenomenon is not present during earlier nematode developmental stages as egg hatch and infective juvenile mobility did not follow rhythmic patterns and are not affected by light. Taken together, it appears nematode host seeking and penetration are at least partially influenced by daily changes in plant root signaling and light does not have a direct effect on RKN developmental stages. Understanding the role and origin of circadian and diurnal rhythms in the plant-nematode interaction underscores the importance of exploiting basal plant biology to develop novel control methods for these pathogens. Root-knot nematodes (RKN; Meloidogyne spp.) are obligate plant parasites that require constant communication with their host to establish and maintain specialized feeding cells. The intimacy of this interaction likely requires constant monitoring of host biology and behavior. As plant processes follow tightly regulated circadian and diurnal patterns, RKN may use similar cues to regulate aspects of this symbiosis. We interrogated RKN biology within the context of host diurnal rhythms throughout nematode development. At 24-hr post-inoculation, RKN penetrated host roots significantly more when inoculated during the night compared to the day. We excluded the possibility that this phenomenon is due to nematode perception of light penetrating the soil, as an identical phenomenon is observed under inverted light conditions. Additionally, when plants were allowed to equilibrate and adjust their light-driven clock under constant light conditions, the temporal variation in nematode penetration was abolished. This phenomenon is not present during earlier nematode developmental stages as egg hatch and infective juvenile mobility did not follow rhythmic patterns and are not affected by light. Taken together, it appears nematode host seeking and penetration are at least partially influenced by daily changes in plant root signaling and light does not have a direct effect on RKN developmental stages. Understanding the role and origin of circadian and diurnal rhythms in the plant–nematode interaction underscores the importance of exploiting basal plant biology to develop novel control methods for these pathogens.


Prognostic factors for poor outcomes in patients with severe COVID-19 treated with remdesivir plus dexamethasone in Taiwan.
Coronavirus disease-2019 (COVID-19) remains a global public health concern, and remdesivir plus dexamethasone combination therapy is suggested for patients with severe disease. However, the factors associated with poor outcomes in these patients remain unclear. We identified the factors associated with poor outcomes in Taiwanese patients with severe COVID-19 treated with remdesivir plus dexamethasone. Adults with severe COVID-19 (oxygen saturation <94% on room air or requiring supplemental oxygen) treated with remdesivir and dexamethasone were identified between 1 May and 31 July 2021. The main outcomes were 14-day non-recovery, 28-day mortality, and progression to respiratory failure requiring invasive mechanical ventilation or death in initially non-ventilated patients. The prognostic factors associated with poor outcomes were analyzed by multivariate logistic regression and Cox regression. Of the 110 patients treated with remdesivir and dexamethasone, 57 (51.8%) recovered within 14 days and 6 (5.5%) died within 28 days. Of the 89 initially non-ventilated patients, 12 (13.5%) progressed to respiratory failure or death. Charlson Comorbidity Index, SOFA score, and admission to remdesivir treatment interval were associated with 14-day non-recovery. C-reactive protein level was associated with 28-day mortality. Pneumonia Severity Index and admission to remdesivir treatment interval were associated with progression to respiratory failure requiring invasive mechanical ventilation or death in initially non-ventilated patients. High disease severity on admission and delayed initiation of remdesivir therapy were associated with poor outcomes in COVID-19 patients treated with remdesivir and dexamethasone.


The haplotype of the CACNA1B gene associated with cerebral infarction in a Japanese population.
Cerebral infarction (CI) is thought to be a multifactorial disease that is affected by several environmental factors and genetic variants. N-type voltage-gated calcium channels (VGCCs), which are expressed primarily in the neurons, have various roles in neuronal functions and are especially involved with neurotransmitter release at the sympathetic nerve terminals. We considered the α1B subunit of the N-type voltage-gated calcium channel (CACNA1B) to be representative of the general characteristics of this channel type. The aim of the present study was to assess the association of the human CACNA1B gene with the occurrence of CI via a haplotype-based case-control study that used single nucleotide polymorphisms (SNPs) from the Japanese population. A total of 165 CI patients and 314 controls were enrolled in the case-controlled studies that examined three SNPs of the human CACNA1B gene (rs7042521, rs11137351, rs10780199). There were significant differences between the CI and control groups for the overall distribution of the genotypes and the presence of the recessive rs10780199. Multiple logistic regression analyses revealed that even after adjusting for confounding factors (odds ratio: 1.716), the frequencies of the A/G and G/G genotypes of rs10780199 in the CI group were significantly higher than those observed in the control group (p = 0.021). Furthermore, the C-C-G and G-G-G haplotypes of rs7042521-rs11137351-rs10780199 were significantly more frequent in the CI group than in the control group (p = 0.024 and p < 0.000). In conclusion, significant differences were noted between the CI and control patients for the specific SNPs and haplotypes in the CACNA1B gene. The results indicate that these polymorphisms and haplotypes might be genetic markers for CI.


Bone mineral density in 15- to 21-year-old eumenorrheic and amenorrheic subjects.
The purposes of this study were to compare the lumbar spine bone mineral density of eumenorrheic and amenorrheic white subjects aged 15 to 21 years, and to describe the femoral neck bone mineral density in the eumenorrheic subjects. Twenty-eight eumenorrheic females had lumbar bone mineral density (mean +/- SD) of 1.213 +/- 0.117 g/cm2, and femoral neck bone mineral density of 1.032 +/- 0.092 g/cm2 measured with dual energy x-ray absorptiometry. Bone mineral density at neither site was related to age, energy intake, or calcium intake. Femoral neck bone mineral density was related to energy expenditure. Body composition was measured with total body electrical conductivity, and bone mineral density at both sites was related to body weight as much as fat-free mass. Eight amenorrheic subjects had a lumbar spine bone mineral density of 1.057 +/- 0.113 g/cm2, which was lower than in the eumenorrheic group. However, when controlling for weight, this difference was not significant. Peak lumbar and femoral neck bone mineral density may be reached at midadolescence.


Gait outcomes after additional backward walking training in patients with stroke: a randomized controlled trial.
To examine the effectiveness of additional backward walking training on gait outcome of patients post stroke. Randomized controlled trial. Medical centre. Twenty-five subjects with stroke, who were lower extremity Brunnstrom motor recovery stage at 3 or 4 and were able to walk 11 m with or without a walking aid or orthosis, randomly allocated to two groups, control (n = 12) and experimental (n = 13). Subjects in both groups participated in 40 min of conventional training programme three times a week for three weeks. Subjects in experimental group received additional 30 min of backward walking training for three weeks at a frequency of three times per week. Gait was measured using the Stride Analyzer. Gait parameters of interest were walking speed, cadence, stride length, gait cycle and symmetry index. Measures were made at baseline before commencement of training (pre-training) and at the end of the three-week training period (post-training). After a three-week training period, subjects in experimental group showed more improvement than those in control group for walking speed (change score: 8.60 +/- 6.95 versus 3.65 +/- 2.92, p-value = 0.032), stride length (change score: 0.090 +/- 0.076 versus -0.0064 +/- 0.078, p-value = 0.006), and symmetry index (change score: 44.07 +/- 53.29 versus 5.30 +/- 13.91, p-value = 0.018). This study demonstrated that asymmetric gait pattern in patients post stroke could be improved from receiving additional backward walking therapy.


Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS.
To study the effect of rifampicin on the pharmacokinetics of fluconazole and on clinical outcomes of fluconazole treatment in patients with AIDS-related cryptococcal meningitis. Forty Thai patients with AIDS and cryptococcal meningitis, of whom 20 had been receiving oral rifampicin for at least 2 weeks to treat tuberculosis. Patients were treated for cryptococcal meningitis with amphotericin 0.7 mg/kg/day for 14 days followed by fluconazole 400 mg/day, which was reduced to 200 mg/day once culture of cerebrospinal fluid (CSF) became negative. Patients with tuberculosis received oral rifampicin 600 mg/day at night. Blood samples were collected from the first 12 patients in each group and pharmacokinetic parameters for fluconazole were calculated. CSF samples were collected by lumbar puncture and monitored for eradication of Cryptococcus neoformans. Concomitant administration of rifampicin with fluconazole resulted in significant changes in the pharmacokinetic parameters of fluconazole, including a 39% increase in elimination rate constant, 28% shorter elimination half-life, 22% decrease in area under the concentration-time curve, 17% decrease in maximum concentration and 30% increase in clearance (p < 0.05). Different fluconazole regimens did not affect the extent of change in the elimination rate constant. Although serum concentrations of fluconazole during the time that patients received rifampicin concomitantly with fluconazole 200 mg/day were generally lower than the minimum inhibitory concentration for C. neoformans, there were no significant differences in clinical outcomes between the two groups to date (p = 0.792). Coadministration of rifampicin with fluconazole caused significant changes in the pharmacokinetic parameters of fluconazole. Long-term monitoring for recurrence rates of cryptococcal meningitis is required to assess the clinical significance of this interaction.


Career Development From Adolescence Through Emerging Adulthood Insights From Information Technology Occupations.
Career development theories suggest that social-contextual experiences are influential in individuals' career interests, aspirations, and skill development and may be a source of gender and ethnic differences in certain career fields. In this mixed methods study, we examine the supportive and obstructive career-related experiences of 13 men and 13 women (modal age 25). Interviews focused primarily on the pathway toward or away from an information technology (IT) career. Thematic coding indicated that parents were mostly supportive, while experiences in school and work occasionally made individuals reconsider their career plans. Social influences often changed developmentally as participants entered full-time jobs. Gendered participation in IT was often attributed to women's perception that it is a male-oriented field.


New pituitary oncogenes.
Pituitary tumors are common monoclonal neoplasms which cause considerable morbidity and mortality. Several molecular events underlying pituitary tumorigenesis have been elucidated in recent years, but no tumor marker has clearly emerged which assists clinical and therapeutic decisions. Activating mutations and loss of inactivating mutations, together with hypothalamic hormones, circulating hormones, growth factors and cytokines cooperatively ensure the inexorable expansion of the initial mutated pituitary cell clone. This review describes new developments in our understanding of the molecular mechanisms involved in the pathogenesis of pituitary tumors. The availability of molecular probes will allow the early prediction of tumor behavior, identify targets for designing subcellular pituitary tumor therapy and provide novel approaches to pituitary tumor management.


Mental imagery of self-location during spontaneous and active self-other interactions: an electrical neuroimaging study.
Substantial data from the cognitive neurosciences point to the importance of bodily processing for the development of a comprehensive theory of the self. A key aspect of the bodily self is self-location, the experience that the self is localized at a specific position in space within one's bodily borders (embodied self-location). Although the neural mechanisms of self-location have been studied by manipulating the spatial location of one's visual perspective during mental imagery, such experiments were conducted in constrained, explicit, and unecological contexts such as explicit instructions in a prone/seated position, although most human interactions occur spontaneously while standing/walking. Using a motor paradigm, we investigated the behavioral and neural mechanisms of spontaneous self-location and mental body transformations during active human interaction. Using own-body imagery using spontaneous and explicit changes in self-location in standing participants, we report that spontaneous interactions with an avatar are neurally indistinguishable from explicit own-body transformation with disembodied self-location but differ from explicit own-body transformation with embodied self-location at 400-600 ms after stimulus onset. We discuss these findings with respect to the neural mechanisms of perspective-taking and self-location in spontaneous human interaction.


ED-DEL: Development of a change package and toolkit for delirium in the emergency department.
Delirium is a common and deadly problem in the emergency department affecting up to 30% of older adult patients. The 2013 Geriatric Emergency Department guidelines were developed to address the unique needs of the growing older population and identified delirium as a high priority area. The emergency department (ED) environment presents unique challenges for the identification and management of delirium, including patient crowding, time pressures, competing priorities, variable patient acuity, and limitations in available patient information. Accordingly, protocols developed for inpatient units may not be appropriate for use in the ED setting. We created a Delirium Change Package and Toolkit in the Emergency Department (ED-DEL) to provide protocols and guidance for implementing a delirium program in the ED setting. This article describes the multistep process by which the ED-DEL program was created and the key components of the program. Our ultimate goal is to create a resource that can be disseminated widely and used to improve delirium identification, prevention, and management in older adults in the ED.


Intraocular Injection of ES Cell-Derived Neural Progenitors Improve Visual Function in Retinal Ganglion Cell-Depleted Mouse Models.
Retinal ganglion cell (RGC) transplantation is a promising strategy to restore visual function resulting from irreversible RGC degeneration occurring in glaucoma or inherited optic neuropathies. We previously demonstrated FGF2 induced differentiation of mouse embryonic stem cells (ESC) to RGC lineage, capable of retinal ganglion cell layer (GCL) integration upon transplantation. Here, we evaluated possible improvement of visual function by transplantation of ES cell derived neural progenitors in RGC depleted glaucoma mice models. ESC derived neural progenitors (ES-NP) were transplanted into N-Methyl-D-Aspartate (NMDA) injected, RGC-ablated mouse models and a pre-clinical glaucoma mouse model (DBA/2J) having sustained higher intra ocular pressure (IOP). Visual acuity and functional integration was evaluated by behavioral experiments and immunohistochemistry, respectively. GFP-expressing ES-NPs transplanted in NMDA-injected RGC-depleted mice differentiated into RGC lineage and possibly integrating into GCL. An improvement in visual acuity was observed after 2 months of transplantation, when compared to the pre-transplantation values. Expression of c-Fos in the transplanted cells, upon light induction, further suggests functional integration into the host retinal circuitry. However, the transplanted cells did not send axonal projections into optic nerve. Transplantation experiments in DBA/2J mouse showed no significant improvement in visual functions, possibly due to both host and transplanted retinal cell death which could be due to an inherent high IOP. We showed that, ES NPs transplanted into the retina of RGC-ablated mouse models could survive, differentiate to RGC lineage, and possibly integrate into GCL to improve visual function. However, for the survival of transplanted cells in glaucoma, strategies to control the IOP are warranted.


Medium-chain, triglyceride-containing lipid emulsions increase human neutrophil beta2 integrin expression, adhesion, and degranulation.
To test the hypothesis that lipid emulsions with different triglyceride structures have distinct immunomodulatory properties, we analyzed human neutrophil adhesion and degranulation after lipid incubation. Neutrophils, isolated from the blood of 10 healthy volunteers, were incubated in medium or physiologic (2.5 mmol/L) emulsions containing long-chain (LCT), medium-chain (MCT), mixed LCT/MCT, or structured (SL) triglycerides. Expression of adhesion molecules and degranulation markers was evaluated by flow cytometry. Also, functional adhesion was investigated by means of a flow cytometric assay using fluorescent beads coated with the integrin ligand intercellular adhesion molecule (ICAM)-1. Although LCT and SL had no effect, LCT/MCT significantly increased expression of the beta2 integrins lymphocyte-function-associated antigen 1 (+18%), macrophage antigen 1 (+387%), p150,95 (+82%), and (alphaDbeta2 (+230%). Degranulation marker expression for azurophilic (CD63, +210%) and specific granules (CD66b, +370%) also significantly increased, whereas L-selectin (CD62L, -70%) decreased. The effects of LCT/MCT were mimicked by the MCT emulsion. ICAM-1 adhesion (% beads bound) was increased by LCT/MCT (34% +/- 4%), whereas LCT (19% +/-3%) and SL (20% +/- 2%) had no effect compared with medium (17% +/- 3%). LCT/MCT and MCT, contrary to LCT and SL emulsions, increased neutrophil beta2 integrin expression, adhesion, and degranulation. Apart from other emulsion constituents, triglyceride chain length might therefore be a key feature in the interaction of lipid emulsions and the phagocyte immune system.


Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. However, only few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Here, we aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. SIRT3 expression was downregulated in high glycolytic and proliferative HCC cells of human patients, xenograft model and HCC cell lines. Moreover, SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phosphorylated retinoblastoma protein in HCC. Notably, combined treatment with sorafenib and PD0332991 showed an enhancement of the anti-tumor effect in HCC cells. Our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be useful for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.


[Studies on sialidase and esterase in influenza viruses].
The main contributions of the author and collaborators about sialidase (EC 220.127.116.11) of influenza virus types A and B and O-acetylesterase (EC 188.8.131.52) of type C are summarized. After a short introduction on the topic, the negative results obtained by the author on inhibitors are commented. Then, the peculiarities of the three procedures assayed, based on the NADH determination as a measurement for the sialidase activity, are discussed. The spectrofluorimetric measurement of NADH concentration is a more sensitive and convenient procedure than that by spectrophotometry, although it is less sensitive than that based on bioluminiscence. Sialidase activity is generally higher in influenza virus type A than in type B; however, some differences have been found between the three sub-types A analysed. Furthermore, thermal stability and stability against changes in the pH values are higher for influenza virus from ducks, followed by those from humans and, finally, by those from pigs. O-acetylesterase of influenza virus type C shows a broad specificity; it acts on O-acetyl-containing compounds which may not be sialic acids. It seems that this enzyme might contribute to facilitate the action of sialidase of influenza virus types A and B. The peculiarities of influenza virus type C suggest to include this type as a new genus in the future classification of viruses.


First-Onset Psychosis After COVID-19 Infection: A Systematic Review of the Literature.
The COVID-19 pandemic has been an inciting factor for a wide variety of neuropsychiatric symptoms, including first-episode psychosis (FEP). The aim of this systematic review was to summarize the current literature on COVID-19 associated postviral FEP. A systematic review was completed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and identified 81 articles that met inclusion criteria. Articles included case reports, case series, and cohort studies with postviral FEP occurring outside the setting of delirium, demonstrating a broad range of symptoms. This systematic review shows that postviral FEP associated with COVID-19 follows a pattern similar to psychosis associated with other viral infections and is an important consideration when building a differential for FEP when delirium has been ruled out. Better understanding of postviral FEP associated with COVID-19 and other viral illnesses may help clarify aspects of underlying pathophysiology of psychotic symptoms broadly.


Serodiagnosis of parasitic diseases.
In this review on serodiagnosis of parasitic diseases, antibody detection, antigen detection, use of monoclonal antibodies in parasitic serodiagnosis, molecular biological technology, and skin tests are discussed. The focus at the Centers for Disease Control on developing improved antigens, a truly quantitative FAST-enzyme-linked immunosorbent assay, and the very specific immunoblot assays for antibody detection is highlighted. The last two assays are suitable for field studies. Identification of patient response in terms of immunoglobulin class or immunoglobulin G subclass isotypes or both is discussed. Immunoglobulin isotypes may asist in defining the stage of some diseases. In other instances, use of a particular anti-isotype conjugate may increase the specificity of the assay. Monoclonal antibodies have played important roles in antigen purification and identification, in competitive antibody assays with increased sensitivity and specificity, and in assays for antigen detection in serum, body fluids, or excreta. Molecular biological technology has allowed significant advances in the production of defined parasitic serodiagnostic antigens.


Positron lifetimes of bare and hydrogenated zirconium vacancies in cubic yttria-stabilized zirconia: an ab initio study.
Recent studies by positron-annihilation spectroscopy (PAS) in single-crystal and nanostructured yttria-stabilized zirconia (YSZ) revealed extensive positron trapping at vacancy-type point defects and other structural imperfections. The present work reports first principles calculations of formation energies and positron lifetimes of Zr vacancies in 10.3 mol% cubic YSZ. The lifetime calculations are based on two-component density-functional theory within the local-density approximation for the electron-positron correlation energy. Gradient-correction effects were also examined. Zr monovacancies were found to be potent trapping sites for positrons with large binding energies and lifetimes in excess of 220 ps. A strong dependency of the lifetimes on the Zr site and local coordination number was observed, a consequence of the structural disorder of the stabilized lattice. In contrast, oxygen vacancies did not act as attractive centers for positrons, either as single defects or as nearest neighbors to seven-fold coordinated Zr vacancies. Defect association of the Zr vacancies with hydrogen led to stable ([Formula: see text]-H) complexes with hydrogen bound to oxygen ions which are nearest neighbors to the vacancies. The negatively-charged ([Formula: see text]-H) defects were also found to trap positrons with corresponding lifetimes strongly dependent upon the hydrogen content within the complex.


An electropolymerized molecularly imprinted polymer for selective carnosine sensing with impedimetric capacity.
A chemosensor with a molecularly imprinted polymer (MIP) film as the recognition unit selective to a carnosine biomarker was molecularly engineered, devised and fabricated. The molecular structure of the pre-polymerization complex of the carnosine template with the carboxy and 18-crown-6 ether derivatives of bis(2,2'-bithien-5-yl)methane functional monomers was thermodynamically optimized by density functional theory (DFT) at the B3LYP/6-31g(d) level. The calculated high negative Gibbs free energy change, ΔG = -227.4 kJ mol-1, indicated the formation of a very stable complex. The solution of this complex was prepared and used for deposition of the MIP films on a Pt disk electrode or an Au electrode of the quartz crystal resonator by potentiodynamic electropolymerization. Subsequently, the carnosine template was extracted from the MIPs with 0.1 M NaOH, as confirmed by the differential pulse voltammetry (DPV), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy measurements. For carnosine sensing, impedimetric capacity (IC) measurements were performed under flow-injection analysis (FIA) conditions resulting in the limit of detection of 20 μM (at S/N = 3). This limit implied the readiness of the chemosensor for carnosine determination in clinical samples. Due to multiple modes of carnosine binding to MIP recognition sites, the IC chemosensor was found to be more selective to carnosine than to its common interferences including anserine, carcinine and histidine. Advantageously, the imprinting factor, determined by piezoelectric microgravimetry (PM), was high equaling 14.9.


Inhibition of Soluble Tumor Necrosis Factor Prevents Chemically Induced Carcinogenesis in Mice.
TNF is a potent promoter of carcinogenesis and potentially important target for cancer prevention. TNF is produced as functionally distinct transmembrane and soluble molecules (tmTNF and sTNF, respectively), but their individual roles in carcinogenesis are unexplored. We investigated the participation of tmTNF and sTNF in chemically induced carcinogenesis in mice. We found that injection of XPro1595, a dominant-negative TNF biologic (DN-TNF) and specific antagonist of sTNF, decreased tumor incidence and growth, and prolonged survival of 3-methylcholanthrene (MCA)-injected mice. Similar results were obtained following the exclusion of both TNF forms by either TNF-receptor 2-Fc fusion protein (TNFR2-Fc) treatment or TNF gene deletion. In addition, gene deletion of TNFR1, which is preferentially triggered by sTNF, was temporarily blocked, whereas gene deletion of TNFR2, which is preferentially triggered by tmTNF, enhanced MCA-induced carcinogenesis. Concomitantly with carcinogenesis induction, MCA increased circulating IL1α, accumulation of myeloid-derived suppressor cells (MDSC), STAT3 phosphorylation, and immunosuppression in the spleen. In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2. These findings reveal that sTNF is both an essential promoter of carcinogenesis and a pivotal regulator of MDSCs, and indicate that sTNF could be a significant target for cancer prevention and therapy. Cancer Immunol Res; 4(5); 441-51. ©2016 AACR.


New Setting of Neurally Adjusted Ventilatory Assist during Noninvasive Ventilation through a Helmet.
Compared to pneumatically controlled pressure support (PSP), neurally adjusted ventilatory assist (NAVA) was proved to improve patient-ventilator interactions, while not affecting comfort, diaphragm electrical activity (EAdi), and arterial blood gases (ABGs). This study compares neurally controlled pressure support (PSN) with PSP and NAVA, delivered through two different helmets, in hypoxemic patients receiving noninvasive ventilation for prevention of extubation failure. Fifteen patients underwent three (PSP, NAVA, and PSN) 30-min trials in random order with both helmets. Positive end-expiratory pressure was always set at 10 cm H2O. In PSP, the inspiratory support was set at 10 cm H2O above positive end-expiratory pressure. NAVA was adjusted to match peak EAdi (EAdipeak) during PSP. In PSN, the NAVA level was set at maximum matching the pressure delivered during PSP by limiting the upper pressure. The authors assessed patient comfort, EAdipeak, rates of pressurization (i.e., airway pressure-time product [PTP] of the first 300 and 500 ms after the initiation of patient effort, indexed to the ideal pressure-time products), and measured ABGs. PSN significantly increased comfort to (median [25 to 75% interquartile range]) 8 [7 to 8] and 9 [8 to 9] with standard and new helmets, respectively, as opposed to both PSP (5 [5 to 6] and 7 [6 to 7]) and NAVA (6 [5 to 7] and 7 [6 to 8]; P < 0.01 for all comparisons). Regardless of the interface, PSN also decreased EAdipeak (P < 0.01), while increasing PTP of the first 300 ms from the onset of patient effort, indexed to the ideal PTP (P < 0.01) and PTP of the first 500 ms from the onset of patient effort, indexed to the ideal PTP (P < 0.001). ABGs were not different among trials. When delivering noninvasive ventilation by helmet, compared to PSP and NAVA, PSN improves comfort and patient-ventilator interactions, while not ABGs. (Anesthesiology 2016; 125:1181-9).


Identification of new cell size control genes in S. cerevisiae.
Cell size homeostasis is a conserved attribute in many eukaryotic species involving a tight regulation between the processes of growth and proliferation. In budding yeast S. cerevisiae, growth to a "critical cell size" must be achieved before a cell can progress past START and commit to cell division. Numerous studies have shown that progression past START is actively regulated by cell size control genes, many of which have implications in cell cycle control and cancer. Two initial screens identified genes that strongly modulate cell size in yeast. Since a second generation yeast gene knockout collection has been generated, we screened an additional 779 yeast knockouts containing 435 new ORFs (~7% of the yeast genome) to supplement previous cell size screens. Upon completion, 10 new strong size mutants were identified: nine in log-phase cells and one in saturation-phase cells, and 97% of the yeast genome has now been screened for cell size mutations. The majority of the logarithmic phase size mutants have functions associated with translation further implicating the central role of growth control in the cell division process. Genetic analyses suggest ECM9 is directly associated with the START transition. Further, the small (whi) mutants mrpl49Δ and cbs1Δ are dependent on CLN3 for cell size effects. In depth analyses of new size mutants may facilitate a better understanding of the processes that govern cell size homeostasis.


Getting some insight into the home care nursing service in Croatia.
Croatia, as the other Western societies are facing with the increasing share of the population over 65 years and consequently with more care-dependant people. Community living and care, including home care, is stimulating not just because of efficiency of care but also because of the peopleis preferences that home is a place of emotional and physical associations, memories and comfort. The aim of the study was to see if there is lack or surplus of Home care nursing services within the health care system. Data from the Croatian Health Insurance Fond Data base were analysed. The results of this research indicated that the number of inhabitants per one home nurse and physiotherapist contracted by the Croatian Health Insurance Fond was below the defined Standard. The average number of inhabitants per one home care nurse contracted by the CHIF for 2013 was 3373.9 compared to 3500 defined by the Standard. There was found also the huge regional differences in their distributions. The average number of contracted home physiotherapists for the same year was 9805.2 in comparison to the Standard, which was setup at the level of 15000 inhabitants per one physiotherapist.


Second harmonic echocardiography and spontaneous contrast during implantation of a left ventricular assist device.
Implantable mechanical left ventricular assist devices (LVADs) are used as a bridge or alternative to heart transplantation. Peroperative transesophageal echocardiography is commonly applied during implantation. Significant air embolism may occur as a result of air leakage at connections and anastomoses when LV filling becomes inadequate, and this must be prevented. Early suspicion and detection of air is mandatory to avoid negative circulatory effects. We hypothesized that monitoring of heart chamber size and occurrence of single air bubbles using second harmonic imaging (SHI) echocardiography may prevent risk for significant air embolism. After implantation of the LVAD in 10 calves, invasive hemodynamic monitoring and epicardial SHI were performed while increasing pump speed. Air bubbles in the ascending aorta were monitored and the left heart visualized for off-line dimensional analysis. Detection of air bubbles in the ascending aorta preceded their appearance in the left ventricle. They occurred exclusively but not always after a decrease in left atrial (LA) size. Decrease in LA pressure did not predict bubble detection or reduction in LA size. We conclude that SHI detects spontaneous ultrasound contrast during implantation of a LVAD and that a decrease in LA size is a warning that air embolism is imminent.


Association of core-binding factor β with the malignant phenotype of prostate and ovarian cancer cells.
Core binding factor (CBF) is a transcription factor complex that plays roles in development, stem-cell homeostasis, and human disease. CBF is a heterodimer composed of one of three DNA-binding RUNX proteins plus the non-DNA-binding protein, CBFβ. Recent studies have showed that the RUNX factors exhibit complex expression patterns in prostate, breast, and ovarian cancers, and CBF has been implicated in the control of cancer-related genes. However, the biologic roles of CBF in solid tumors have not been fully elucidated. To test whether CBF is required for the malignant phenotype of various epithelial cancers, we used lentiviral delivery of CBFβ-specific shRNA to significantly decrease CBFβ expression in two prostate cancer cell lines (PPC1 and PC-3) and the SKOV-3 ovarian cancer cell line. We found that knockdown of CBFβ significantly inhibited anchorage independent growth of each cell line. Further, CBFβ knockdown in PPC1 cells suppressed xenograft tumor growth compared to controls. Mice injected with SKOV-3 ovarian cancer cells knocked-down for CBFβ exhibited a survival time similar to control mice. However, human cells recovered from the ascites fluid of these mice showed CBFβ expression levels similar to those from mice injected with control SKOV-3 cells, suggesting that CBFβ knockdown is incompatible with tumor cell growth. Gene expression profiling of CBFβ knockdown cells revealed significant changes in expression in genes involved in various developmental and cell signaling pathways. These data collectively suggest that CBFβ is required for malignancy in some human cancers.


Application of an in vitro infection model and simulation for reevaluation of fluoroquinolone breakpoints for Salmonella enterica serotype typhi.
Salmonella enterica serotype Typhi and nontyphoidal Salmonella remain major causes of morbidity and mortality worldwide. Ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol no longer provide reliable coverage of Salmonella, and fluoroquinoloes have emerged as first-line treatment options. Due to mounting evidence of decreased in vitro susceptibility and diminished clinical response to fluoroquinolone therapy, it has been suggested that the NCCLS breakpoints for the salmonellae be reevaluated. We utilized an in vitro infection model to determine which pharmacokinetic-pharmacodynamic (PK-PD) measure was most closely linked to fluoroquinolone activity against salmonellae and the magnitude that was predictive of efficacy. Monte Carlo simulation was utilized to determine the probability of attaining potential susceptibility breakpoints for three fluoroquinolones. The free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio was the PK-PD measure most predictive of efficacy, and a ratio of 105 corresponded to 90% of maximal activity. Simulation results suggested susceptible breakpoints of 0.12 microg/ml for ciprofloxacin and gatifloxacin and 0.25 microg/ml for levofloxacin. These proposed breakpoints correspond to the MIC separating the wild-type susceptible organism population from those strains possessing single-step mutations in the quinolone resistance-determining region. These results that integrate PK-PD measures and fluoroquinolone MIC distributions in the genetic context of examined Salmonella isolates clearly demonstrate that the prudent use of a lower susceptibility breakpoint minimizes the probability of clinical failure or delayed response in fluoroquinolone-treated patients.


Acute Toxicity of Eight Aqueous Film-Forming Foams to 14 Aquatic Species.
Researchers have developed numerous per- and polyfluoroalkyl substances (PFAS)-free aqueous film-forming foam (AFFF) formulations to replace PFAS-containing AFFF used for fire suppression. As part of the Department of Defense's Strategic Environmental Research and Development Program (SERDP), we examined the direct lethal effects of seven PFAS-free AFFF and a PFAS-containing AFFF on 14 aquatic species using a series of lethal concentration (LC50) tests. We assessed the LC10, LC50, and LC90 values using log-logistic and logit analyses. Across all aquatic species tested, we discovered that exposure to at least one PFAS-free AFFF was more or as toxic as exposure to the PFAS-containing AFFF. For most cases, National Foam Avio F3 Green KHC 3% and Buckeye Platinum Plus C6MILSPEC 3% were the most and least toxic formulations, respectively. Moreover, we found consistency among results from multiple experiments using the same minnow species (Pimephales promelas) and among closely related taxa (e.g., daphnids, amphibians). Lastly, the LC50 values for AFFF formulations trended lower for tested marine species as compared to those of freshwater species. These results dramatically increase the current knowledge on the potentially toxic effects of AFFF but also highlight the need for additional research and the development of new PFAS-free AFFF that are more "ecologically friendly" than those containing persistent PFAS.


Galbanic acid from Ferula szowitsiana enhanced the antibacterial activity of penicillin G and cephalexin against Staphylococcus aureus.
In this study the enhancement effect of Ferula szowitsiana roots' acetone extract on the antibacterial activity of penicillin G and cephalexin was evaluated against Staphylococcus aureus. Disk diffusion and broth dilution methods were used to determine the antibacterial activity of these antibiotics in the absence and presence of plant extract and its various fractions separated by TLC plate. The active component of plant extract involved in enhancement of penicillin G's and cephalexin's activities had Rf=0.336 on a TLC plate. The spectral data ((1)H-, (13)C-NMR) of this compound revealed that this compound was 7-[6-(beta-carboxyethyl)-5-isopropylidene-1,2-dimethylcyclo-hexylmethoxy]coumarin (galbanic acid), previously isolated from Ferula assa-foetida. In the presence of sub-inhibitory concentration of galbanic acid (100 microg/ml) the MIC of penicillin G for S. aureus decreased from 64 to 1 (a sixteen four-fold decrease) and for cephalexin from 128 to 1 microg/ml (a one hundred twenty eight-fold decrease). The highest fold decrease in MIC was observed for cephalexin in combination of galbanic acid against test strain. These results signify that the low concentration of galbanic acid (100 microg/ml) potentiates the antimicrobial action of penicillin G and cephalexin suggesting a possible utilization of these compounds in combination therapy against S. aureus.


Alterations in gp37 Expand the Host Range of a T4-Like Phage.
The use of phages as antibacterial agents is limited by their generally narrow host ranges. The aim of this study was to make a T4-like phage, WG01, obtain the host range of another T4-like phage, QL01, by replacing its host-determinant gene region with that of QL01. This process triggered a direct expansion of the WG01 host range. The offspring of WG01 obtained the host ranges of both QL01 and WG01, as well as the ability to infect eight additional host bacteria in comparison to the wild-type strains. WQD had the widest host range; therefore, the corresponding fragments, named QD, could be used for constructing a homologous sequence library. Moreover, after a sequencing analysis of gene 37, we identified two different mechanisms responsible for the expanded host range: (i) the first generation of WG01 formed chimeras without mutations, and (ii) the second generation of WG01 mutants formed from the chimeras. The expansion of the host range indicated that regions other than the C-terminal region may indirectly change the receptor specificity by altering the supportive capacity of the binding site. Additionally, we also found the novel means by which subsequent generations expanded their host ranges, namely, by exchanging gene 37 to acquire a wider temperature range for lysis. The method developed in this work offers a quick way to change or expand the host range of a phage. Future clinical applications for screening phages against a given clinical isolate could be achieved after acquiring more suitable homologous sequences.IMPORTANCE T4-like phages have been established as safe in numerous phage therapy applications. The primary drawbacks to the use of phages as therapeutic agents include their highly specific host ranges. Thus, changing or expanding the host range of T4-like phages is beneficial for selecting phages for phage therapy. In this study, the host range of the T4-like phage WG01 was expanded using genetic manipulation. The WG01 derivatives acquired a novel means of expanding their host ranges by acquiring a wider temperature range for lysis. A region was located that had the potential to be used as a sequence region for homologous sequence recombination.


An effector phenotype of CD8+ T cells at the junction epithelium during clinical quiescence of herpes simplex virus 2 infection.
Herpes simplex virus 2 infection is characterized by cycles of viral quiescence and reactivation. CD8(+) T cells persist at the site of viral reactivation, at the genital dermal-epidermal junction contiguous to neuronal endings of sensory neurons, for several months after herpes lesion resolution. To evaluate whether these resident CD8(+) T cells frequently encounter HSV antigen even during times of asymptomatic viral infection, we analyzed the transcriptional output of CD8(+) T cells captured by laser microdissection from human genital skin biopsy specimens during the clinically quiescent period of 8 weeks after lesion resolution. These CD8(+) T cells expressed a characteristic set of genes distinct from those of three separate control cell populations, and network and pathway analyses revealed that these T cells significantly upregulated antiviral genes such as GZMB, PRF1, INFG, IL-32, and LTA, carbohydrate and lipid metabolism-related genes such as GLUT-1, and chemotaxis and recruitment genes such as CCL5 and CCR1, suggesting a possible feedback mechanism for the recruitment of CD8(+) T cells to the site of infection. Many of these transcripts are known to have half-lives of <48 h, suggesting that cognate antigen is released frequently into the mucosa and that resident CD8(+) T cells act as functional effectors in controlling viral spread.


The development of pyramidal neurons after eye opening in the visual cortex of hooded rats: a quantitative study.
Dendritic maturation of pyramidal neurons in layers III and V of the rat visual cortex was quantified in rapid Golgi-stained tissue from socially housed hooded rats at ages 15, 30, and 60 days. A complex pattern of changes emerged. Dendritic branching analyses revealed that in layer III both bifurcating and terminal basilar branches increased in length over the sampled days. Likewise, total dendritic length increased in the layer III basilar dendritic tree between 15 and 30 days of age and peaked at 30 days of age in the layer III apical oblique branches. No changes in dendritic length were observed in layer V pyramidal neurons. Neither layer III nor layer V neurons exhibited any changes in the number of basilar or apical oblique branches over the time period studied. Dendritic spine density increased on terminal basilar branches in both cell populations between 15 and 30 days. There also was an increase in spine density on the layer V pyramidal apical shaft between 15 and 30 days, while on layer III bifurcating basilar branches, spine density fell between 30 and 60 days. These data indicate that while dendrites may continue to grow longer, pyramidal neurons do not on average generate additional branches after day 15. However, the pattern of spine density is still changing between 15 and 60 days of age. Thus no single developmental pattern holds for all cell populations or even across areas of the dendritic field within a population.


Two Auxinic Herbicides Affect Brassica napus Plant Hormone Levels and Induce Molecular Changes in Transcription.
With the introduction of the new auxinic herbicide halauxifen-methyl into the oilseed rape (Brassica napus) market, there is a need to understand how this new molecule interacts with indigenous plant hormones (e.g., IAA) in terms of crop response. The aim of this study was to investigate the molecular background by using different growth conditions under which three different auxinic herbicides were administered. These were halauxifen-methyl (Hal), alone and together with aminopyralid (AP) as well as picloram (Pic). Three different hormone classes were determined, free and conjugated indole-3-acetic acid (IAA), aminocyclopropane carboxylic acid (ACC) as a precursor for ethylene, and abscisic acid (ABA) at two different temperatures and growth stages as well as over time (2-168 h after treatment). At 15 °C growth temperature, the effect was more pronounced than at 9 °C, and generally, the younger leaves independent of the developmental stage showed a larger effect on the alterations of hormones. IAA and ACC showed reproducible alterations after auxinic herbicide treatments over time, while ABA did not. Finally, a transcriptome analysis after treatment with two auxinic herbicides, Hal and Pic, showed different expression patterns. Hal treatment leads to the upregulation of auxin and hormone responses at 48 h and 96 h. Pic treatment induced the hormone/auxin response already after 2 h, and this continued for the other time points. The more detailed analysis of the auxin response in the datasets indicate a role for GH3 genes and genes encoding auxin efflux proteins. The upregulation of the GH3 genes correlates with the increase in conjugated IAA at the same time points and treatments. Also, genes for were found that confirm the upregulation of the ethylene pathway.


Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats.
To investigate the role of extrinsic influences on the survival and growth of axotomized retinal ganglion cells (RGCs) in the mature mammalian CNS, both optic nerves (ONs) of adult rats were transected intraorbitally and, on one side, replaced by an autologous segment of peripheral nerve (PN) that had been left unconnected distally. The survival of RGCs and the regrowth of their cut axons into the PN grafts were assessed using morphometric techniques, neuroanatomic tracers, and immunologic cell markers to identify and count RGCs at times ranging from 15 d to 9 months. It was observed that (1) in the absence of a PN graft, more than 90% of the RGCs died by 1 month after axotomy; (2) between 1 and 3 months after axotomy, survival of RGCs in the PN-grafted retinas was enhanced 2-4-fold; (3) nearly 20% of the surviving RGCs regrew lengthy axons into the grafts; and (4) although the density of surviving RGCs in PN-grafted retinas decreased significantly between 1 and 3 months after axotomy, the densities of RGCs with axons extending into the graft remained relatively stable. These results confirm that in the adult rat retina, neuronal death is a major effect of axotomy near the cell soma. Although such lesions lead to the degeneration of many RGCs, we show that extrinsic influences introduced by the apposition of a PN segment at the time of severing the ON can rescue a substantial number of these neurons. Because the enhanced survival of many axotomized RGCs in the PN-grafted retinas appears to be limited to the first few weeks after injury, while those of RGCs that regenerate axons into the grafts do not show a parallel decline, it is possible that, in these experiments, neuronal viability depends on a spectrum of differently timed influences that may include the early diffusion of critical molecules arising from the graft and the subsequent establishment of more complex interactions with graft components.


Evaluation of timolol in chronic open-angle glaucoma. Once a day vs twice a day.
Regimens of once-a-day or twice-a-day 0.25% timolol ophthalmic solution were compared for efficacy and tolerability in a four-week study of 41 patients with chronic open-angle glaucoma and elevated, untreated intraocular pressure. Significant reductions in IOP relative to untreated baseline values were achieved within a range of 18% to 25%. No significant between-group differences were noted, although the twice-a-day group had somewhat lower IOPs at each evaluation point and the once-a-day group had somewhat fewer subjective symptoms of local irritation. A statistically significant decrease from baseline in mean pulse rate was noted in the twice-a-day treatment group after two weeks; no clinically significant or serious adverse reactions occurred in any patient. Both once-daily and twice-daily administrations of 0.25% timolol ophthalmic solution were found to be effective and well tolerated in the population studied.


Hepatitis C knowledge among primary care residents: is our teaching adequate for the times?
Increasingly, primary care (PC) physicians will be the first to encounter patients with hepatitis C virus (HCV) infection. To determine opinions and practices of PC residents regarding HCV. We administered a one-page questionnaire to 180 PC residents at five U.S. training programs. Respondents were distributed equally across postgraduate year, 83% were U.S. graduates, and 44% had seen >11 (HCV) patients in the past year. Residents tested for HCV in persons with: increased transaminases (83%), history of blood transfusion (46%), multiple tattoos (57%), +ANCA (16%), and alcohol abuse (31%). Sixteen percent of respondents tested all patients. Forty-one percent would vaccinate HCV patients for hepatitis A and 65% for hepatitis B while only 19% and 78% knew the respective vaccination schedules. Although no vaccine is available, 66% recommended vaccination for HCV. Only 37% and 29%, respectively, reported HCV genotype 1 as most common and most resistant to treatment. Fifty-three percent recommend liver biopsy before treating HCV. Only 52% reported alpha-interferon (IFN) with ribavirin as initial treatment for HCV while 28% recommend ribavirin or lamivudine alone or combinations of IFN and lamivudine or amantadine. As contraindications to treatment, 33% reported AIDS with PCP infection, 19% coronary artery disease, and 19% suicidal ideation. Sixty-nine percent felt that there was insufficient information on HCV. Many PC residents lack adequate knowledge of recommended guidelines for the management of HCV. Many test for HCV in inappropriate situations, are unclear regarding available vaccines and their administration, and are uncertain about current treatment. Education of PC residents on guidelines for detection and management of HCV must be improved.


Evidence that the human pathogenic fungus Cryptococcus neoformans var. grubii may have evolved in Africa.
Most of the species of fungi that cause disease in mammals, including Cryptococcus neoformans var. grubii (serotype A), are exogenous and non-contagious. Cryptococcus neoformans var. grubii is associated worldwide with avian and arboreal habitats. This airborne, opportunistic pathogen is profoundly neurotropic and the leading cause of fungal meningitis. Patients with HIV/AIDS have been ravaged by cryptococcosis--an estimated one million new cases occur each year, and mortality approaches 50%. Using phylogenetic and population genetic analyses, we present evidence that C. neoformans var. grubii may have evolved from a diverse population in southern Africa. Our ecological studies support the hypothesis that a few of these strains acquired a new environmental reservoir, the excreta of feral pigeons (Columba livia), and were globally dispersed by the migration of birds and humans. This investigation also discovered a novel arboreal reservoir for highly diverse strains of C. neoformans var. grubii that are restricted to southern Africa, the mopane tree (Colophospermum mopane). This finding may have significant public health implications because these primal strains have optimal potential for evolution and because mopane trees contribute to the local economy as a source of timber, folkloric remedies and the edible mopane worm.


Severe Urinary Retention Resulting in Extreme Post-obstructive Diuresis and Decompressive Hematuria.
Post-obstructive diuresis and decompressive hematuria are rare but potentially serious complications of severe urinary retention. This is a case report of a 73-year-old patient with undiagnosed severe large-volume urinary retention who developed extreme cases of both complications after presenting with progressive weight gain, lower extremity edema, worsening dyspnea, and new-onset urinary incontinence. Upon further evaluation, the patient was determined to have acute renal failure, bilateral hydroureteronephrosis, a severely distended urinary bladder, and an enlarged prostate. Foley catheterization produced 5.9 L of urinary output with initial placement. He required prolonged hospitalization for hemodynamic monitoring requiring fluid resuscitation, serial electrolyte monitoring requiring repletion, acute blood loss anemia requiring four units of red blood cell transfusion, continuous bladder irrigation, three cystoscopies under anesthesia, and intravesicular fibrinolysis inhibitor instillations. This case illustrates an extreme severity of post-obstructive diuresis and decompressive hematuria in chronic urinary retention that has not been previously described in the literature.


A five-year comparative study of calcium hydroxide-glutaraldehyde pulpotomies versus calcium hydroxide pulpotomies in young permanent molars.
Twenty children with twenty cariously exposed first permanent molars treated with either calcium hydroxide-glutaraldehyde or calcium hydroxide pulpotomies, were followed up clinically and radiographically for a period of five years. Overall success rates obtained at the end of the follow up period were higher with calcium hydroxide-glutaraldehyde pulpotomies (100%) than with calcium hydroxide pulpotomies (80%).


A systematic review examining the relationship between cytokines and cachexia in incurable cancer.
Cancer cachexia is an unmet clinical need that affects more than 50% of patients with cancer. The systemic inflammatory response, which is mediated by a network of cytokines, has an established role in the genesis and maintenance of cancer as well as in cachexia; yet, the specific role of the cytokine milieu in cachexia requires elucidation. This systematic review aims to examine the relationship between cytokines and the cachexia syndrome in patients with incurable cancer. The databases MEDLINE, EMBASE, CINAHL, CENTRAL, PsycINFO, and Web of Science were searched for studies published between 01/01/2004 and 06/01/2020. Included studies measured cytokines and their relationship with cachexia and related symptoms/signs in adults with incurable cancer. After title screening (n = 5202), the abstracts (n = 1264) and the full-text studies (n = 322) were reviewed independently by two authors. The quality assessment of the selected papers was conducted using the modified Downs and Black checklist. Overall, 1277 patients with incurable cancer and 155 healthy controls were analysed in the 17 eligible studies. The mean age of the patients was 64 ± 15 (mean ± standard deviation). Only 34% of included participants were female. The included studies were assessed as moderate-quality to high-quality evidence (mean quality score: 7.8; range: 5-10). A total of 31 cytokines were examined in this review, of which interleukin-6 (IL-6, 14 studies) and tumour necrosis factor-α (TNF-α, 12 studies) were the most common. The definitions of cachexia and the weight-loss thresholds were highly variable across studies. Although the data could not be meta-analysed due to the high degree of methodological heterogeneity, the findings were discussed in a systematic manner. IL-6, TNF-α, and IL-8 were greater in cachectic patients compared with healthy individuals. Also, IL-6 levels were higher in cachectic participants as opposed to non-cachectic patients. Leptin, interferon-γ, IL-1β, IL-10, adiponectin, and ghrelin did not demonstrate any significant difference between groups when individuals with cancer cachexia were compared against non-cachectic patients or healthy participants. These findings suggest that a network of cytokines, commonly IL-6, TNF-α, and IL-8, are associated with the development of cachexia. Yet, this relationship is not proven to be causative and future studies should opt for longitudinal designs with consistent methodological approaches, as well as adequate techniques for analysing and reporting the results.


Quasiparticle mass enhancement and temperature dependence of the electronic structure of ferromagnetic SrRuO3 thin films.
We report high-resolution angle-resolved photoemission studies of epitaxial thin films of the correlated 4d transition metal oxide ferromagnet SrRuO(3). The Fermi surface in the ferromagnetic state consists of well-defined Landau quasiparticles exhibiting strong coupling to low-energy bosonic modes which contributes to the large effective masses observed by transport and thermodynamic measurements. Upon warming the material through its Curie temperature, we observe a substantial decrease in quasiparticle coherence but negligible changes in the ferromagnetic exchange splitting, suggesting that local moments play an important role in the ferromagnetism in SrRuO(3).


A motif in the 5'untranslated region of messenger RNAs regulates protein synthesis in a S6 kinase-dependent manner.
The 5' untranslated regions (UTRs) in messenger RNAs (mRNAs) play an important role in the regulation of protein synthesis. We had previously identified a group of mRNAs that includes human semaphorin 7A (SEMA7A) whose translation is upregulated by the Erk/p90S6K pathway in human eosinophils, with a potential negative impact in asthma and airway inflammation. In the current study, we aimed to find a common 5'UTR regulatory cis-element, and determine its impact on protein synthesis. We identified a common and conserved 5'UTR motif GGCTG-[(C/G)T(C/G)]n-GCC that was present in this group of mRNAs. Mutations of the first two GG bases in this motif in SEMA7A 5'UTR led to a complete loss of S6K activity dependence for maximal translation. In conclusion, the newly identified 5'UTR motif present in SEMA7A has a critical role in regulating S6K-dependent protein synthesis.


Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infection.
Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gram-negative bacteria, including carbapenem-resistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 ml/min, and it is adjusted for patients with <60 ml/min or ≥120 ml/min CrCL. A population pharmacokinetic (PK) model was constructed using 3,427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors, including infection sites and mechanical ventilation, were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT>MIC was >90% against MICs of ≤4 μg/ml for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients, including the patients with augmented renal function, ventilation, and/or severe illness.


Differential cellular expression of galectin family mRNAs in the epithelial cells of the mouse digestive tract.
Galectin is an animal lectin that recognizes beta-galactosides of glycoconjugates and is abundant in the gut. This study revealed the cellular expression of galectin subtypes throughout the mouse digestive tract by in situ hybridization. Signals for five subtypes (galectin-2, -3, -4/6, and -7) were detected exclusively in the epithelia. In the glandular stomach, galectin-2 and -4/6 were predominantly expressed from gastric pits to neck of gastric glands, where mucous cells were the main cellular sources. The small intestine exhibited intense, maturation-associated expressions of galectin-2, -3, and -4/6 mRNAs. Galectin-2 was intensely expressed from crypts to the base of villi, whereas transcripts of galectin-3 gathered at villous tips. Signals for galectin-4/6 were most intense at the lower half of villi. Galectin-2 was also expressed in goblet cells of the small intestine but not in those of the large intestine. In the large intestine, galectin-4/6 predominated, and the upper half of crypts simultaneously contained transcripts of galectin-3. Stratified epithelium from the lip to forestomach and anus intensely expressed galectin-7 with weak expressions of galectin-3. Because galectins in the digestive tract may be multi-functional, information on their cell/stage-specific expression contributes to a better understanding of the functions and pathological involvements of galectins.


[Cancer mortality trends in Brazilian state capitals, 1980-2004].
Cancer mortality rates began to decline in developed countries in the 1990s, but their behavior in developing countries is less well-known. An earlier study on cancer mortality in Brazil showed a declining mortality trend for cancer as a whole. however the quality of data results raised some criticism t. The population of state capitals comprises about a quarter of the total Brazilian population and for these cities mortality data available have a better quality than for the entire country, enabling analyses of trends in cancer rates based on more accurate data. Mortality and population data were collected from government databases (SIM/DATASUS and IBGE, respectively). Age-adjusted (world standard) and age-specific mortality rates were calculated for both genders . Linear regression was used to investigate changes in trends. For all cancers as a whole mortality rates declined throughout the study period for both men and women (-4.6% and -10.5%, respectively). For both genders , the cancer that decreased most was stomach cancer. Among men, lung cancer death rates presented a slight reduction, while prostate cancer rates increased. Among women, "uterus, site unspecified' presented a downward trend, while lung cancer rates increased. The trend for breast cancer remained stable, and cervix uterus rates showed a slight increase at the end of the period. As already seen in developed countries, all cancer mortality rates tended to decline in Brazilian state capitals over the period 1980-2004, a tendency largely due to a decline in stomach cancer death rates for both genders.


Profiles of mental health help seeking among Australian adolescent males.
Adolescent males are at increased risk of mental illness and are reluctant to engage in treatment. This study aims to identify subgroups of help-seeking intentions among a sample of Australian male adolescents. A sample of 1038 male adolescent sport participants in Australia (age M = 14.69 years, SD = 1.35) reported help-seeking intentions from ten sources and from 'no one'. Latent profile analysis was conducted based on these 11 items. Identified profiles were then compared across mental health measures. Four latent profiles were identified: Low general help-seekers (10.5%), Moderate general help-seekers (46.8%), High general help-seekers (25.5%), High family and friends help-seekers (17.2%). Low, Moderate, and High general help-seekers had uniformly low, moderate, and high intentions to seek help from all sources, respectively. High family and friends help-seekers reported high endorsement of intentions to seek help from intimate partners, friends, parents, and other relatives, but low intentions for other sources. Low general help-seekers had lower intentions to seek help from parents compared to all other profiles. They also had significantly lower perceived family support and higher psychological distress. Low general help-seekers were particularly reluctant to seek help from all sources and at high risk of experiencing psychological difficulties. Their distinct profile offers potential to identify this high-risk group through the use of ratings on the parent help-seeking intentions item. Further research should investigate the predictive utility of this item on help-seeking and mental health, and should consider the influence of masculinity and previous experiences of help-seeking.


Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of hypoxia-inducible factor-1alpha signaling.
Exposure to hypoxia triggers a variety of adverse effects in the brain that arise from metabolic stress and induce neuron apoptosis. Overexpression of the hypoxia-inducible factor-1alpha (HIF-1alpha) is believed to be a major candidate in orchestrating the cell's defense against stress. To test the impact of HIF-1alpha on apoptosis during chronic hypoxia in vivo, we examined the protective effect of modulating the nitric oxide (NO)/cGMP pathway by sildenafil, a selective inhibitor of phosphodiesterase-5 (PDE-5). Male ICR/CD-1 mice were divided into 3 groups (n = 6/group): normoxic (21% O(2)), hypoxic (9.5% O(2)), and hypoxic with sildenafil (1.4-mg/kg intraperitoneal injections daily). At the end of the 8-day treatment period, the mice were euthanized and cerebral cortex biopsies were harvested for analyses. We found that sildenafil: (1) did not significantly alter the hypoxia-induced weight loss and hemoglobin increase, but did augment plasma nitrates+nitrites and the tissue content of cGMP and phosphorylated (P) NO synthase III; (2) reversed the hypoxia-induced neuron apoptosis (terminal deoxynucleotidyl transferase positivity and double-staining immunofluorescence, P = 0.009), presumably through increased bcl-2/Bax (P = 0.0005); and (3) did not affect HIF-1alpha, but rather blunted the hypoxia-induced increase in P-ERK1/2 (P = 0.0002) and P-p38 (P = 0.004). We conclude that upregulating the NO/cGMP pathway by PDE-5 inhibition during hypoxia reduces neuron apoptosis, regardless of HIF-1alpha, through an interaction involving ERK1/2 and p38.


Differences in neural stem cell identity and differentiation capacity drive divergent regenerative outcomes in lizards and salamanders.
While lizards and salamanders both exhibit the ability to regenerate amputated tails, the outcomes achieved by each are markedly different. Salamanders, such as Ambystoma mexicanum, regenerate nearly identical copies of original tails. Regenerated lizard tails, however, exhibit important morphological differences compared with originals. Some of these differences concern dorsoventral patterning of regenerated skeletal and spinal cord tissues; regenerated salamander tail tissues exhibit dorsoventral patterning, while regrown lizard tissues do not. Additionally, regenerated lizard tails lack characteristically roof plate-associated structures, such as dorsal root ganglia. We hypothesized that differences in neural stem cells (NSCs) found in the ependyma of regenerated spinal cords account for these divergent regenerative outcomes. Through a combination of immunofluorescent staining, RT-PCR, hedgehog regulation, and transcriptome analysis, we analyzed NSC-dependent tail regeneration. Both salamander and lizard Sox2+ NSCs form neurospheres in culture. While salamander neurospheres exhibit default roof plate identity, lizard neurospheres exhibit default floor plate. Hedgehog signaling regulates dorsalization/ventralization of salamander, but not lizard, NSCs. Examination of NSC differentiation potential in vitro showed that salamander NSCs are capable of neural differentiation into multiple lineages, whereas lizard NSCs are not, which was confirmed by in vivo spinal cord transplantations. Finally, salamander NSCs xenogeneically transplanted into regenerating lizard tail spinal cords were influenced by native lizard NSC hedgehog signals, which favored salamander NSC floor plate differentiation. These findings suggest that NSCs in regenerated lizard and salamander spinal cords are distinct cell populations, and these differences contribute to the vastly different outcomes observed in tail regeneration.