[High energy proton therapy for extraocular tumors, neurotrophic keratitis and functional consequence: A series of 3 cases].
High energy proton therapy (HEP) is a form of radiation therapy using protons for extraocular tumors. Its ballistic properties are theoretically advantageous, but the real impact on the surrounding ocular tissues during cerebral and ENT irradiation is poorly documented. We describe three consecutive patients with corneal damage following such irradiation. Post-proton therapy neurotrophic keratitis (NK) is defined as corneal hypo/anesthesia responsible for an alteration of corneal trophicity and graded according to the Mackie classification, in terms of a prospective ophthalmological follow-up protocol for all patients with extraocular tumors treated with HEP. Among 193 patients treated with HEP between 2018 and 2021 for extraocular tumors, three patients developed severe neurotrophic keratitis, i.e. 1.6% of treated patients. According to the Mackie classification, the three patients showed grade 3 NK less than one year after the conclusion of their HEP. These three patients underwent amniotic membrane grafting. They were placed on autologous serum eye drops. Two of the three patients had to be eviscerated. The dose to the cornea was greater than 50 Gray (Gy)_Relative biological effectiveness (RBE) in the three cases. The diagnosis and etiological origin of neurotrophic keratitis are often difficult to establish. In these cases, the imputability of radiation therapy, proton therapy in our cases, in the development of neurotrophic keratitis was plausible based on the dosimetry of the patients, all of whom had anterior tumors with a poor prognosis requiring high tumoricidal doses. Further studies to establish the impact of proton therapy on corneal sensitivity are necessary. However, this feedback and the multidisciplinary management of tumors can help to limit the risk of some complications of radiation therapy. Early diagnosis allows for appropriate management and could possibly minimize the anatomical and functional ocular complications of neurotrophic keratitis.


Comparison of one- and two-dimensional programmes for predicting the state of skin burns.
To understand and accurately predict tissue damage following a burn, bioheat transfer based mathematical models of the skin were developed. First, mathematical equations with multiple factors to represent the different properties of the various layers of the skin were formulated. These equations were then numerically solved using finite-difference (1-D) and finite-element (2-D) analysis. By application of a standard Arrhenius model for damage rate, the extent of burn injury was computed from the transient temperature solution. The study of the thermal efficacy of cooling treatment was done. Numerical results calculated by current 1-D and 2-D models were compared and discussed. Temperature contours were found to be consistent in both one- and two-dimensions. The current finite element code provided some additional precision to previously published models as a mesh independent grid was used to enable more accurate numerical prediction of thermal and injury patterns as they developed during the injury process. The study of thermal efficacy of postburn therapy showed that postburn water-cooling could not effectively reduce the extent of burn. However, low temperatures may inhibit the action of inflammatory mediators, and/or, low-temperatures may depress metabolism or microvascular flow thereby reducing long-term injury. Therefore numerical data obtained in the current study suggest that non-thermal factors must be considered in the calculation of the efficacy of postburn cooling therapy. It is equally important to realize that when dealing with living tissue, any numerical model can provide only an approximate to conditions in actual life.


Mail-out bowel cancer screening: Identifying the behavioural stumbling blocks.
To describe the actions taken by recipients of mail-out faecal occult blood test (FOBT) kits and to identify the points at which progress towards kit completion typically stops. Differences according to gender, age, and screening intention were also examined. 1599 people completed an online survey identifying the actions they took upon receiving an FOBT kit. Latent class analysis was conducted to identify latent subgroups of participants that reported similar actions. Differences between gender, age, and intention status were assessed using non-invariance testing. Four latent subgroups of FOBT invitees were identified: those who complete and return their FOBT kit ('completers'); those who bring the kit into their house but go no further ('ignorers'); those who open the package and read the bowel cancer information materials but go no further ('readers'); and those who read the instructions but do not place the kit near the toilet and do not complete their FOBT kit ('leavers'). Non-completers who intended to use the kit were most likely to be in the 'leavers' class, while those who had no intention were most likely to be in the 'readers' class. Distinct subgroups of non-responders exist among bowel cancer screening invitees, suggesting different behaviour change interventions are needed to facilitate participation. Some invitees, especially those with high participatory intention, are likely to benefit from prompts to take the kit into the toilet, while others, with little participatory intention, often read the invitation materials presenting an opportunity to intervene with health messages.


The probability with which EMS-initiated mutagenic lesions generate mutations in CHO cells.
In this note we distinguish between multiple mutations affecting a given locus which are generated at separate error-prone lesions and multiple independent mutations generated at a single error-prone lesion. We describe a basis for determining the probability with which the latter class of mutations occurs based on the mutant fraction in the progeny and determine an average probability of 0.6 mutations/replication/mutagenic site for those EMS-modified sites which are mutagenic for G6PDH activity in CHO cells.


Potassium iodide in erythema nodosum and other erythematous dermatoses.
Potassium iodide therapy has a history of more than 150 years. It has been tried in many diseases in the past. However, with the development of modern medications indications for potassium iodide therapy are very limited. It is well known that potassium iodide is the drug of choice for sporotrichosis. Subacute nodular migratory panniculitis and erythema nodosum have also been treated successfully with this drug.


Self-Heating-Induced Deterioration of Electromechanical Performance in Polymer-Supported Metal Films for Flexible Electronics.
The retention of electrical performance under the combined conditions of mechanical strain and an electrical current is essential for flexible electronics. Here, we report that even below the critical current density required for electromigration, the electrical current can significantly deteriorate the electromechanical performance of metal film/polymer substrate systems. This leads to a loss of stretchability, and this effect becomes more severe with increasing strain as well as increasing current. The local increase of electrical resistance in the metal film caused by damage, such as localized deformations, cracks, etc., locally raises the temperature of the test sample via Joule heating. This weakens the deformation resistance of the polymer substrate, accelerating the necking instability, and consequently leading to a rapid loss of electrical conductivity with strain. To minimize such a current-induced deterioration of the polymer-supported metal films, we develop and demonstrate the feasibility of two methods that enhance the deformation resistance of the polymer substrate at elevated temperatures: increasing the thickness of the polymer substrate, and utilizing a polymer substrate with a high glass transition temperature.


Oral midazolam and oral butorphanol premedication.
To evaluate the efficacy of oral midazolam and oral butorphanol for their sedative analgesic effects in children. Sixty children, aged 2 to 10 yrs, of ASA physical status I and II, scheduled for surgical procedures of 1 to 2 hrs duration were randomized to one of the two groups. Group I: children received midazolam 0.5 mg/kg orally and Group II: children received butorphanol 0.2 mg/kg orally. Score of the children was assessed every 5 minutes till the induction of anesthesia. Intraoperative and postoperative analgesic requirement was recorded along with postoperative recovery and complications. The groups were identical regarding the patient's characteristics, hemodynamic variables, duration of surgery and awakening time. Less time was required for the onset and time of maximum sedation in the butorphanol group (p<0.05). Sedation scores were similar among the groups at all time intervals, while the scores were higher in the butorphanol group at the time of induction (p<0.05). Less number of children required intraoperative and postoperative rescue analgesia in the butorphanol group (p<0.05). Statistically significant difference was found among the groups in respect to complete amnesia (50% in group I vs 80% I group II, p<0.05) and recollection (40% in group I vs 10% in group II, p<0.05). Oral butorphanol is comparable to oral midazolam in children but analgesia along with sedation is an additional advantage which makes it better than midazolam without a significant increase in side effects.


Differential regulation of G protein subunit expression in mouse oocytes, eggs, and early embryos.
Pertussis toxin ADP-ribosylation and Western blot analysis using G protein-specific antibodies were used to study G protein expression in mouse oocytes, eggs, and early embryos. A pertussis toxin (PT) substrate of about 40 kDa was observed in all stages, but its level was stage dependent. It decreased dramatically between germinal vesicle stage oocytes and unfertilized eggs, remained relatively constant through the early 2-cell stage, and then declined again with each cell division, reaching the lowest level at the 8- to 16-cell stage. Its level, or perhaps that of a different substrate, then increased at the blastocyst stage. Western blot analysis with antisera to the G protein alpha subunit indicated that the decrease between germinal vesicle stage oocytes and unfertilized eggs was less pronounced for the alpha subunit itself than for the PT substrate. Antisera to G protein beta subunit revealed that the difference in the amount of this subunit in germinal vesicle-stage oocytes versus unfertilized eggs was even greater than that of the PT ADP-ribosylation substrate. These results suggest that during oocyte maturation G protein beta gamma levels decline to a greater extent than alpha levels. Additional evidence supporting this hypothesis was obtained by showing that addition of exogenous beta gamma to unfertilized egg preparations increased the amount of PT substrate. These results indicate that G protein subunit expression is differentially regulated during oocyte maturation.


High-velocity power training has similar effects to traditional resistance training for functional performance in older adults: a systematic review.
What is the effect of high-velocity power training (HVPT) compared with traditional resistance training (TRT) on functional performance in older adults? What is the quality of intervention reporting for the relevant literature? Systematic review and meta-analysis of randomised controlled trials. Older adults (aged > 60 years), regardless of health status, baseline functional capacity or residential status. High-velocity power training with the intent to perform the concentric phase as quickly as possible compared with traditional moderate-velocity resistance training performed with a concentric phase of ≥ 2 seconds. Short Physical Performance Battery (SPPB), Timed Up and Go test (TUG), five times sit-to-stand test (5-STS), 30-second sit-to-stand test (30-STS), gait speed tests, static or dynamic balance tests, stair climb tests and walking tests for distance. The quality of intervention reporting was assessed with the Consensus on Exercise Reporting Template (CERT) score. Nineteen trials with 1,055 participants were included in the meta-analysis. Compared with TRT, HVPT had a weak-to-moderate effect on change from baseline scores for the SPPB (SMD 0.27, 95% CI 0.02 to 0.53; low-quality evidence) and TUG (SMD 0.35, 95% CI 0.06 to 0.63; low-quality evidence). The effect of HVPT relative to TRT for other outcomes remained very uncertain. The average CERT score across all trials was 53%, with two trials rated high quality and four rated moderate quality. HVPT had similar effects to TRT for functional performance in older adults, but there is considerable uncertainty in most estimates. HVPT had better effects on the SPPB and TUG, but it is unclear whether the benefit is large enough to be clinically worthwhile.


Risks and Benefits of Removal of the Left Atrial Appendage.
In patients with atrial fibrillation who are unable to take novel oral anticoagulants for stroke prophylaxis due to bleeding risk or other contraindications, left atrial appendage (LAA) occlusion and exclusion devices have shown benefit. In this review, we highlight the risks and benefits associated with LAA removal. LAA, once considered a vestigial organ, has been shown to have physiological, anatomical, and arrhythmogenic properties. Device-related complications such as pericardial effusion, device embolization, device-related thrombus, while uncommon, are still present. With increased operator experience related to appendage occlusion, overall procedural complications have declined. Further refinements in device technology will help decrease complications. While benefits of appendage removal are plenty, procedural complications need to be weighed into the equation when making decisions regarding LAA occlusion.


Compensatory mechanisms and the type of injury determine the fate of cells with impaired macroautophagy.
The relationship between the degradative process of autophagy and cellular death pathways remains unclear. Macroautophagy may potentially function to prevent or promote cell death, and both effects have been reported in studies of cells with a block in macroautophagy. To better delineate the function of macroautophagy in cell death, we contrasted the responses to death stimuli in wild-type and atg5(-/-) murine embryonic fibroblasts. We have reported that a knockout of the critical macroautophagy gene ATG5 sensitizes cells to death receptor ligand-induced death from Fas and tumor necrosis factor-alpha. Death occurs by caspase-dependent apoptosis resulting from activation of the mitochondrial death pathway. In contrast, atg5(-/-) cells are more resistant to death induced by oxidative stress from menadione or UV light. This resistance was associated with an upregulation of chaperone-mediated autophagy. Inhibition of this form of autophagy sensitizes cells to death from menadione, suggesting that the compensatory upregulation of chaperone-mediated autophagy, and not the loss of macroautophagy, prevents death from menadione. These findings demonstrate that the effects of a loss of macroautophagy on the cellular death response differ depending on the mechanism of cellular injury and the compensatory changes in other forms of autophagy.


Frequency and power dependence of ultrasonic degassing.
We investigated the time variation of ultrasonic degassing for air-saturated water and degassed water with a sample volume of 100 mL at frequencies of 22, 43, 129, 209, 305, 400, 514, 1018, and 1960 kHz and ultrasonic power of 15 W. Ultrasonic degassing was evaluated by dissolved oxygen concentration. Ultrasonic degassing was also investigated at a frequency of 1018 kHz and ultrasonic powers of 5, 10, 15, and 20 W. The dissolved oxygen concentration varied with the ultrasonic irradiation time and became constant after prolonged ultrasonic irradiation. The constant dissolved oxygen concentration value depended on the frequency and ultrasonic power but not the initial dissolved oxygen concentration. The degassing rate at 101.3 kPa was higher in the frequency range of 200 kHz to 1 MHz. The frequency dependence of the degassing rate was almost the same as that of the sonochemical efficiency obtained by the potassium iodide (KI) method. Ultrasonic degassing in the frequency range of 22-1960 kHz was also investigated under reduced pressure of 5 kPa. Degassing was accelerated when ultrasonic irradiation was applied under reduced pressure. However, under a reduced pressure of 5 kPa, the lower the frequencies, the higher is the degassing rate. The sonochemical reaction rate was examined by the KI method for varying dissolved air concentrations before ultrasonic irradiation. Cavitation did not occur when the initial dissolved oxygen concentration was less than 2 mg·L-1. Therefore, the lower limit of ultrasonic degassing under 101.3 kPa equals 2 mg·L-1 dissolved oxygen concentration. A model equation for the time variation of dissolved oxygen concentration due to ultrasonic irradiation was developed, and the degassing mechanism was discussed.


The diurnal time course of net photosynthesis of soybean leaves: Analysis with a physiologically based steady-state photosynthesis model.
A physiologically based steady-state model of whole leaf photosynthesis (WHOLEPHOT) is used to analyze observed net photosynthesis daily time courses of soybean, Glycine max (L.) Merr., leaves. Observations during two time periods of the 1978 growing season are analyzed and compared. After adjustment of the model for soybean, net photosynthesis rates are calculated with the model in response to measured incident light intensity, leaf temperature, air carbon dioxide concentration, and leaf diffusion resistance. The steady-state calculations closely approximate observed net photosynthesis. Results of the comparison reveal a decrease in photosynthetic capacity in leaves sampled during the second time period, which is associated with decreasing ability of leaves to respond to light intensity and internal air space carbon dioxide concentration, increasing mesophyll resistance, and increasing stomatal resistance.


Refractory Fetal Supraventricular Tachycardia with Hydrops Successfully Converted by Intraperitoneal Flecainide in the Fetus: A Case Report.
Supraventricular tachycardia is the most common fetal tachyarrhythmia and if persistent often associated with fetal hydrops which can cause intrauterine and neonatal death. We present a case of early second trimester supraventricular tachycardia in a hydropic fetus, initially refractory to transplacental treatment. The supraventricular tachycardia was successfully treated when supplemented with intraperitoneal flecainide in the fetus.


Vitamin B12 produced by Cetobacterium somerae improves host resistance against pathogen infection through strengthening the interactions within gut microbiota.
Pathogen infections seriously affect host health, and the use of antibiotics increases the risk of the emergence of drug-resistant bacteria and also increases environmental and health safety risks. Probiotics have received much attention for their excellent ability to prevent pathogen infections. Particularly, explaining mechanism of action of probiotics against pathogen infections is important for more efficient and rational use of probiotics and the maintenance of host health. Here, we describe the impacts of probiotic on host resistance to pathogen infections. Our findings revealed that (I) the protective effect of oral supplementation with B. velezensis against Aeromonas hydrophila infection was dependent on gut microbiota, specially the anaerobic indigenous gut microbe Cetobacterium; (II) Cetobacterium was a sensor of health, especially for fish infected with pathogenic bacteria; (III) the genome resolved the ability of Cetobacterium somerae CS2105-BJ to synthesize vitamin B12 de novo, while in vivo and in vitro metabolism assays also showed the ability of Cetobacterium somerae CS2105-BJ to produce vitamin B12; (IV) the addition of vitamin B12 significantly altered the gut redox status and the gut microbiome structure and function, and then improved the stability of the gut microbial ecological network, and enhanced the gut barrier tight junctions to prevent the pathogen infection. Collectively, this study found that the effect of probiotics in enhancing host resistance to pathogen infections depended on function of B12 produced by an anaerobic indigenous gut microbe, Cetobacterium. Furthermore, as a gut microbial regulator, B12 exhibited the ability to strengthen the interactions within gut microbiota and gut barrier tight junctions, thereby improving host resistance against pathogen infection. Video Abstract.


Outcomes of Patients with Severe Aortic Stenosis and Left Ventricular Obstruction Undergoing Transcatheter Aortic Valve Implantation.
Scarce data exist on clinical features and prognosis of patients with severe aortic stenosis (AS), concomitant with left ventricular obstruction (LVO). We aimed to evaluate the prevalence, characteristics, and outcomes in patients with severe AS and LVO undergoing transcatheter aortic valve implantation (TAVI). Consecutive patients with severe AS undergoing TAVI between January 2013 to December 2017 at our institution were included. Significant LVO was defined as resting peak left ventricular (LV) systolic gradient ≥30 mm Hg on pre-TAVI echocardiography. We analyzed the primary composite outcome of all-cause mortality and rehospitalization for heart failure (HHF) at 1-year in patients with LVO and those without LVO in the overall and propensity-matched populations. Among 1,729 patients who underwent TAVI, significant LVO was observed in 31 (1.8%) patients. This group was more likely to be female, had smaller aortic annulus and LV cavity, and received a smaller size of the transcatheter heart valve. The most common phenotype of LV hypertrophy causing LVO was concentric LV hypertrophy (58%), and mid-LV obstruction was more common than LV outflow tract obstruction (77% vs 23%, respectively). After adjustment for baseline differences, the primary outcome was not significantly different between patients with LVO and those without LVO (15% vs 16%, respectively; hazard ratio: 0.83; 95% confidence interval: 0.19 to 3.72; p = 0.809). In conclusion, in patients undergoing TAVI, concomitant LVO was relatively uncommon and occurred more often at mid-LV. The presence of pre-TAVI LVO was not associated with worse outcomes defined as increase all-cause mortality or HHF at 1-year.


[Mechanical circulatory support systems : When and how much protection does a PCI need?]
The interventional treatment of high-risk patients remains challenging and has a high potential for improvement despite all technical innovations. Mechanical circulatory support (MCS) systems can be meaningful depending on the clinical situation, although a clear study situation for this is so far lacking. Multivessel coronary disease and a high SYNTAX score combined with impaired ventricular function is a possible predictor combination for the use of MCS that justifies the higher risk of complications.


Relationship of renin-angiotensin-aldosterone system polymorphisms and phenotypes to mortality in Chinese coronary atherosclerosis patients.
We performed a large, long-term cohort study to evaluate the association of renin-angiotensin-aldosterone system gene polymorphisms and baseline phenotypes to all-cause mortality among patients with angiographically confirmed coronary atherosclerosis. The study included 1075 subjects who underwent coronary angiography. Patients were genotyped for eight polymorphisms (rs4343, rs5186, rs5182, rs5049, rs5051, rs699, rs4762, and rs1799998), and their baseline plasma angiotensin II and aldosterone levels were measured. The interval between baseline and follow-up time-points ranged from 6.39 to 9.59 years. The results of multivariate regression analysis further indicated that high baseline angiotensin II levels (1.226 (1.024-1.468), p = 0.027) were independently associated with all-cause death. Therefore, we found that an increased baseline plasma angiotensin II level was associated with higher long-term all-cause mortality, even after correcting for established cardiovascular risk factors.


Fake News, Defamation, Online Reviews, and Their Potential Devastating Consequences for Aesthetic Plastic Surgeons.
Anecdotal evidence of the exposure and vulnerability of aesthetic plastic surgeons to fake news and online defamation by a minority of vociferous patients has been accruing over the past 10 to 20 years and lurks, hidden like an iceberg, beneath our specialty. Because of acute embarrassment, it is rarely, if ever, discussed in public, and the true extent of the underlying problem remains unknown. The authors sought to accurately document the true magnitude of defamation in British aesthetic plastic surgery. An anonymous online survey was distributed to all full members of the British Association of Aesthetic Plastic Surgeons in the summer of 2020. Forty-six percent of full British Association of Aesthetic Plastic Surgeons members responded. Over one-half had experienced denigration of their professional reputation; the most common medium reported was digital defamation. Over three-quarters of the respondents had been the subject of patient blackmail in an attempt to refund professional fees, and, most distressingly, almost one-third stated that the incident had significantly impacted their mental well-being. The majority had found help from their professional bodies to be significantly lacking. These findings reveal a torment among aesthetic plastic surgeons that has not, to the authors' knowledge, been previously recognized and requires urgent attention by professional organizations.


Development of three-dimensional semi-solid hydrogel matrices for ratiometric fluorescence sensing of Amyloid β peptide and imaging in SH-SY5 cells: Improvement of point of care diagnosis of Alzheimer's disease biomarker.
Alzheimer's is a neurodegenerative disease with high morbidity and mortality in the elderly, so, detection of its biomarker for definite diagnosis of Alzheimer's in the early stage of disease is a challenge. Amyloid beta peptide (Aβ) chosen as an Alzheimer's biomarker. Here, we developed novel, semi-solid, three-dimensional hydrogel matrices for ratiometric fluorescence detection of Aβ. This assay's great performance stems from the employment of a hybrid conjugate composed of Rhodamine B (RB), Carbon dots (CDs), and an Aβ probe entrapped in Polyvinyl alcohol (PVA), and then detection of fluorescence resonance energy transfer (FRET) that occurs in the presence of AuNP/target-Aβ, as a result of hybridization. The RB-CDs' fluorescence (at 582 nm and 675 nm under 430 nm excitation) is quenched in the presence of AuNPs, while the ratio of fluorescence (I582/I675) is increased by the addition of Aβ target, and shows a linear relationship in the range of 75 pM-250 nM, with a detection limit of 0.5 pM. Furthermore, the assay possesses strong selectivity for Aβ compared to other proteins, and different quantities of a human serum sample successfully analyzed with excellent sensitivity, satisfactory precision, and reliability. Due to distribution of Aβ in SH-SY5 human neuroblastoma cells, extending this UV-Vis-NIR full-range responsive CDs bio-probe to imaging of Aβ in cells. In both fixed and living SH-SY5 cells, the nanoprobe delivers a clear signal to the Aβ target. Because of its high sensitivity, selectivity, biocompatibility and affordability, this nanoprobe is a good option for early Alzheimer's disease diagnosis.


The Collicular-Pulvinar-Amygdala Axis and Adult-Onset Idiopathic Focal Dystonias.
Adult-onset idiopathic focal dystonias (AOIFD) are the most common type of dystonia. It has varied expression including multiple motor (depending on body part affected) and non-motor symptoms (psychiatric, cognitive and sensory). The motor symptoms are usually the main reason for presentation and are most often treated with botulinum toxin. However, non-motor symptoms are the main predictors of quality of life and should be addressed appropriately, as well as treating the motor disorder. Rather than considering AOIFD as a movement disorder, a syndromic approach should be taken, one that accommodates all the symptoms. Dysfunction of the collicular-pulvinar-amygdala axis, with the superior colliculus as a central node, can explain the diverse expression of this syndrome.


Genetic and molecular characterization of H9N2 and H5 avian influenza viruses from live poultry markets in Zhejiang Province, eastern China.
Live poultry markets (LPMs) are a key source of reassorted avian influenza viruses (AIVs) because of the density of terrestrial and aquatic poultry and the frequency of AIV infection. H9N2 viruses are prevalent in terrestrial poultry throughout Asia and have been isolated from poultry outbreaks worldwide. They infect both avian and mammalian species and may be significant donors of genetic material to emerging human pathogens. LPMs in Zhejiang Province were surveyed from 2013-2014 for AIVs. Three hundred seventy-four (374) AIV strains were isolated from 3,328 samples. Whole-genome sequencing and phylogenetic analyses were performed. We identified a novel H9N2 virus genotype that had undergone reassortment with gene segments from Qa/HK/G1/97-like, Ck/BJ/1/94-like, and Dk/HK/Y439/97-like viruses. Phylogenetic analyses suggested the H9N2 viruses had undergone reassortments with other AIV subtypes. The results also suggested that two different clades (2.3.2 and 126.96.36.199) of H5 viruses were co-circulating in Zhejiang Province. Given that reassorted H5 AIVs were detected in geese and ducks, it is possible that apparently healthy birds contribute to emerging H5 AIVs. Continued surveillance is required in poultry in eastern China.


Vibrational behavior of the phosphates ions in dittmarite-type compounds M'M''PO4.H2O (M'=K+, NH4+; M''=Mn2+, Co2+, Ni2+).
The IR and Raman spectra of the isostructural M'M''PO4.H2O compounds (M'=K+, NH4+; M''=Mn2+, Co2+, Ni2+) are reported and discussed with respect to the normal vibrations of the PO(4)3- ions. The vibrational behavior of PO4(3-) is in agreement with its low site symmetry Cs in the lattices-the symmetric nu1 and nu2 modes are activated in the IR spectra and the degeneration of the asymmetric nu3 and nu4 modes is lifted. A relatively large unit-cell group splitting is observed for nu1 in both the IR and Raman spectra and for nu3 in Raman spectra. It has been established that the mean wavenumbers of the P-O stretches (nuPO) are not affected by the M2+ ions present, but they are lower for the NH4-series than for the K-one (predominant influence of both the smaller repulsion potential and the hydrogen bonds in the NH4-lattices over the influence of the M+-O interactions). The extent of the energetic distortion of the PO(4)3- ions has been estimated based on the spectroscopic data for the site group splitting of the asymmetric modes (Deltanu3 and Deltanu4), the separation between the highest and the lowest wavenumbered P-O stretches (Deltanumax) and the intensity of nu1 in the IR spectra. The data provide an evidence that the PO4(3-) ions in KM''PO4.H2O are more distorted regarding the P-O bond lengths than those in NH4M''PO4.H2O, but their angular distortion is the same in both series. The trends for the energetic distortion of the phosphate ions found from the spectroscopic data correspond to the data for their geometric distortion deduced from the values of the distortion indices DI(PO) and DI(OPO).


Organic zinc supplementation in early-lactation dairy cows and its effects on zinc content and distribution in milk and cheese.
This study investigated the effects of organic zinc (Zn) supplementation in early-lactation dairy cows on Zn content and distribution in raw milk and mozzarella cheese. Thirty-four multiparous dairy cows in early lactation were randomly assigned to 2 groups: basal diet (control; CON) and basal diet supplemented with a Zn AA complex (CZ). After feeding the diets for 8 wk, raw milk was collected for manufacturing mozzarella cheese. Total Zn content and Zn distribution in raw milk and cheese were determined by atomic absorption spectrophotometry. Results showed that milk fat content was significantly increased in the CZ group compared with the CON group. No significant differences in fat, protein, and moisture contents of cheese were observed between the 2 groups. Zinc contents in milk (4.25 vs. 3.85 mg/L) and cheese (38.65 vs. 27.20 mg/kg) were significantly higher in the CZ group than in the CON group. Little Zn was lost in stretch water (<0.04 mg/L) and brine (<0.01 mg/L) during the cheese-making process. Most of the Zn was detected in casein (87.3% vs. 88.4%) of the raw milk, and then in the whey (10.6% vs. 9.88%) and fat (2.07% vs. 1.77%). Organic Zn supplementation in early-lactation cows increased Zn content in raw milk and mozzarella cheese, and Zn remained stable during cheese making.


The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women.
Few studies have systematically determined whether the response to cocaine in human females is related to hormonal fluctuations at different phases of the menstrual cycle. To investigate the responses to repeated doses of smoked cocaine in women during two phases of the menstrual cycle using a within-subject design. Eleven non-treatment seeking female cocaine smokers were administered smoked cocaine during the follicular and mid-luteal phases of the menstrual cycle. The order of menstrual cycle phase was counterbalanced across women and the order of cocaine doses was randomized. During each phase, there were four cocaine administration sessions. During each session, participants could smoke up to six doses of cocaine (either 0, 6, 12, or 25 mg cocaine base, depending on the session) at 14-min intervals. The number of cocaine doses administered did not vary between the follicular and luteal phases. After cocaine administration, heart rate and several ratings - such as "good drug effect", "high", "stimulated", and "drug quality ratings" - were increased more during the follicular phase than the luteal phase, although, for some measures, these effects varied based on the cocaine dose. Further, dysphoric mood during the luteal phase was improved after cocaine administration. These results indicate that the cardiovascular and subjective effects of repeated doses of smoked cocaine are complex and vary as a function of menstrual cycle phase and cocaine dose.


Ultrasonic Exfoliation of Hydrophobic and Hydrophilic Metal-Organic Frameworks To Form Nanosheets.
The modular structure of metal-organic framework nanosheets (MONs) provides a convenient route to creating two-dimensional materials with readily tuneable surface properties. Here, the liquid exfoliation of two closely related layered metal-organic frameworks functionalised with either methoxy-propyl (1) or pentyl (2) pendent groups intended to bestow either hydrophilic or hydrophobic character to the resulting nanosheets is reported. Exfoliation of the two materials in a range of different solvents highlighted significant differences in their dispersion properties, as well as their molecular and nanoscopic structures. Exchange or loss of solvent was found to occur at the labile axial position of the paddle-wheel based MONs and DFT calculations indicated that intramolecular coordination by the oxygen of the methoxy-propyl pendant groups may take place. The nanoscopic dimensions of the MONs were further tuned by varying the exfoliation conditions and through "liquid cascade centrifugation". Aqueous suspensions of the nanosheets were used as sensors to detect aromatic heterocycles with clear differences in binding behaviour observed and quantified.


Displacement of three dental implants into the maxillary sinus in two patients. Report of two cases.
Reconstruction of the posterior edentulous maxilla with dental implants has become a popular practice worldwide. However, the poor bone quality and quantity in this area is sometimes related with complications. Dental implant displacement into the maxillary sinus is a rare complication. In the present paper, we present two patients with three implants displaced into the maxillary sinus. The implants were removed soon after their displacement, using the classic intraoral approach, through the anterior wall of the maxillary sinus. The operation was performed under local anesthesia for both of the patients. The postoperative course was uneventful for both of the patients without any wound dehiscence. Recovery remained uneventful, without any signs of postoperative sinusitis. Implant displacement into the maxillary sinus is of rare occurrence and usually related to inadequate bone quality and quantity. Dental implants into the maxillary sinus usually act as foreign bodies and should be removed, to avoid the development of sinus complications. Removal of dental implants from the maxillary sinus can be performed either with functional endoscopic sinus surgery, or with intraoral operation through the anterior maxillary wall especially in fresh cases and in the presence of oroantral communication.


NK cell receptors and their MHC class I ligands in host response to cytomegalovirus: insights from the mouse genome.
The complex interaction between natural killer (NK) cells and cytomegalovirus is a paradigm of the co-evolution between genomes of large DNA viruses and their host immune systems. Both human and mouse cytomegalovirus posses numerous mechanisms to avoid NK cell detection. Linkage studies, positional cloning and functional studies in mice and cells, have led to the identification of key genes governing resistance to cytomegalovirus, including various NK cell activating receptors of major histocompatibility complex (MHC) class I. These receptors, however, seem to require either viral or host MHC class I molecules to operate recognition and elimination of the cytomegalovirus-infected cell leading to host resistance. Here we will review the genes and molecules involved in these mechanisms while contrasting their function with that of other NK cell receptors. Activating receptors of MHC class I may represent a window of therapeutic intervention during human infection with viruses, of which cytomegalovirus remains an important health threat.


Postpartum thyroiditis.
Postpartum thyroiditis (PPT) is a syndrome of transient thyroid dysfunction occurring in the first postpartum year. A thyrotoxic phase may be brief and unnoticed before a more long-lasting hypothyroid phase occurs. The incidence is variably reported, ranging from 1.9% to 16.7%, perhaps reflecting racial or geographical differences in the distribution of genetic or environmental risk factors such as the titre of thyroid antibodies and the dietary intake of iodine. The syndrome is an autoimmune disorder, strongly associated with the presence of thyroid microsomal antibody in serum. The thyrotoxic phase may be distinguished from Graves' disease by the finding of low, rather than high, uptake of radioactive iodine or technetium in the thyroid. Screening may be valuable in women with other autoimmune disorders such as Type 1 diabetes mellitus. Treatment should be tailored to the symptoms. Significant thyrotoxic problems should be managed with beta-blocking agents, but severe hypothyroid symptoms should be treated with the short-term replacement thyroxine. A small proportion of affected women will remain permanently hypothyroid. There is also a significant risk of recurrent disease after a subsequent pregnancy.


A new ultrasonic apparatus for ophthalmology using manuel compound scanning.
A new ultrasonic equipment for ophthalmological diagnosis has been developed. Manual compound scanning using water immersion made acurate representation of cross-section of the orbital structure possible. A large, focused transducer brought resolution and sensitivity. Gray scale display of the ultrasonogram increased information concerning intensity of echoes. Ultrasonograms of retinoblastoma, vitreous hemorrhage, melanocytoma, optic disc coloboma and unilateral exophthalmos are presented.


Facial paralysis following blunt head injury.
Schirmer's test is not a reliable test to localize the level of facial nerve damage. From our results of Schirmer's test (greater than 30%), 53.3 per cent of the cases had facial nerve damage below the geniculate ganglion. Conservative treatment is recommended for delayed palsy.


Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only.
Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. ALL treatment using chemotherapy-only protocols. This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. β values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: β = 55.54; SE = 25.55; P = .03; right cerebellum: β = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: β = 82.71; SE = 31.04; P = .009; right cerebellum: β = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (β = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (β = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction. These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.


Medication management strategy for older people with polypharmacy in general practice: a qualitative study on prescribing behaviour in primary care.
For older patients with polypharmacy, medication management is a process of careful deliberation that needs periodic adjustment based on treatment effects and changing conditions. Because of the heterogeneity of the patient group, and limited applicability of current guidelines, it is difficult for GPs to build up a routine. To gain insight into GPs' medication management strategies for patients with polypharmacy, and to explore the GPs' perspectives and needs on decision-making support to facilitate this medication management. Two focus group meetings with Dutch GPs, discussing four clinical vignettes of patients with multimorbidity and polypharmacy. Questions about medication management of the vignettes were answered individually; the strategy chosen in each case was discussed in plenary. Analysis followed a Framework approach. In total, 12 GPs described a similar strategy regarding the patients' medication management: defining treatment goals; determining primary goals; and adjusting medications based on the treatment effect, GPs' and patients' preferences, and patient characteristics. There was variation in the execution of this strategy between the GPs. The GPs would like to discuss their choices with other professionals and they valued structured medication reviews with the patient, as well as quick and practical support tools that work on demand. To facilitate decision making, a more extensive and structured collaboration between healthcare professionals is desired, as well as support to execute structured medication reviews with eligible patients, and some on-demand tools for individual consultations.


Development and validation of polyamines metabolism-associated gene signatures to predict prognosis and immunotherapy response in lung adenocarcinoma.
Polyamines metabolism is closely related to tumor development and progression, as well as tumor microenvironment (TME). In this study, we focused on exploring whether polyamines metabolism-associated genes would provide prognosis and immunotherapy response prediction in lung adenocarcinoma (LUAD). The expression profile data of polyamines metabolism-associated genes were acquired from the Cancer Genome Atlas (TCGA) database. Utilizing the least absolute shrinkage and selection operator (LASSO) algorithm, we created a risk score model according to polyamines metabolism-associated gene signatures. Meanwhile, an independent cohort (GSE72094) was employed to validate this model. Through the univariate and multivariate Cox regression analyses, the independent prognostic factors were identified. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect their expression in LUAD cells. By consensus clustering analysis, polyamines metabolism-associated subgroups were determined in LUAD patients, with differential gene expression, prognosis, and immune characteristics analyses explored. A total of 59 polyamines metabolism genes were collected for this study, of which 14 genes were identified for the construction of risk score model using LASSO method. High- and low- risk groups of LUAD patients in TCGA cohort were distinguished via this model, and high-risk group presented dismal clinical outcomes. The same prognostic prediction of this model had been also validated in GSE72094 cohort. Meanwhile, three independent prognostic factors (PSMC6, SMOX, SMS) were determined for constructing the nomogram, and they were all upregulated in LUAD cells. In addition, two distinct subgroups (C1 and C2) were identified in LUAD patients. Comparing the two subgroups, 291 differentially expressed genes (DEGs) were acquired, mainly enriching in organelle fission, nuclear division, and cell cycle. Comparing to C1 subgroup, the patients in C2 subgroup had favorable clinical outcomes, increased immune cells infiltration, and effective immunotherapy response. This study identified polyamines metabolism-associated gene signatures for predicting the patients' survival, and they were also linked to immune cells infiltration and immunotherapy response in LUAD patients.


Sister chromatid exchanges induced by tertiary butyl hydroquinone in bone marrow cells of mice.
Tertiary butyl hydroquinone (TBHQ)--a phenolic antioxidant, was evaluated by assessing the induction of sister chromatid exchanges (SCEs) in bone marrow metaphase cells of mice. Six concentrations, 0.5, 2, 20, 50, 100, and 200 mg/kg, of TBHQ were injected intraperitoneally. A positive dose-response effect in the SCE frequency was observed using the Cochran-Armitage trend test. Two mg/kg of TBHQ was found to be the minimum effective dose. Study of the cell-cycle kinetics showed a delay in cell cycle induced by the higher concentrations of TBHQ. Thus, TBHQ was found to be a DNA damage-inducing agent and also a cytotoxic chemical in vivo in mice.


Periorbital melasma: Hierarchical cluster analysis of clinical features in Asian patients.
Studies have shown melasma lesions to be distributed across the face in centrofacial, malar, and mandibular patterns. Meanwhile, however, melasma lesions of the periorbital area have yet to be thoroughly described. We analyzed normal and ultraviolet light-exposed photographs of patients with melasma. The periorbital melasma lesions were measured according to anatomical reference points and a hierarchical cluster analysis was performed. The periorbital melasma lesions showed clinical features of fine and homogenous melasma pigmentation, involving both the upper and lower eyelids that extended to other anatomical sites with a darker and coarser appearance. The hierarchical cluster analysis indicated that patients with periorbital melasma can be categorized into two clusters according to the surface anatomy of the face. Significant differences between cluster 1 and cluster 2 were found in lateral distance and inferolateral distance, but not in medial distance and superior distance. Comparing the two clusters, patients in cluster 2 were found to be significantly older and more commonly accompanied by melasma lesions of the temple and medial cheek. Our hierarchical cluster analysis of periorbital melasma lesions demonstrated that Asian patients with periorbital melasma can be categorized into two clusters according to the surface anatomy of the face.


[Sisomicin sulfate: its efficacy in the treatment of urologic infections].
The authors explain the good results (80%) obtained with a new antibiotic belonging to the aminoglucoside group, the Sisomycin sulphate. Due to its active kidney excretion, its beneficial bactericide effect on Gram-positive and negative germs and its excellent tolerance, the author advises its use in infectious urological pathologies.


Lateral differences in the detection of stereoscopic depth.
The experiment investigated the hemifield differences in stereoscopic depth perception. Random dot stereograms (Julesz figures) producing the experience of a square appearing in front or behind the fixation plane were used as stimuli. The patterns in depth were exposed either in the left or in the right side of the stereograms for 30 msec. Three different magnitudes of depth were used. The results showed a higher amount of correct detections of depth in the left visual field than in the right visual field. The effects of direction and magnitude of depth were also significant. The hypothesis referring the observed results to the right hemisphere superiority in stereoscopic depth perception is discussed.


Beta-D-Glucan Levels With Use of an Anti-adhesion Barrier Film in Pediatric Living Donor Liver Transplantation.
Serum beta-D-glucan (BDG) levels may increase with anti-adhesion barrier film (ABF) use during pediatric living donor liver transplantation (LDLT). It may affect detection of fungal infections after LDLT. We evaluate BDG levels after pediatric LDLT. Pediatric patients who received an ABF during LDLT were included. Patients who may have had fungal infections prior to LDLT were excluded. One sheet of ABF was placed in the peritoneum during abdominal closure. Serum BDG levels before transplantation and on postoperative days (PODs) 1, 4, 7, 14, 21, and 28 and peritoneal fluid BDG levels on PODs 1 and 7 were measured. Sixteen patients received an ABF during LDLT. Median age at transplant was 1.9 years (range, 6-11 years). Median body weight was 12.6 kg (range, 6.8-39 kg). Indications for LDLT were biliary atresia (n = 10) and other (n = 5). Prior to transplantation, the mean serum BDG level was 3.8 pg/mL. Mean Serum BDG levels were 18.1, 38.3, 5.3, 3.8, 3.3, and 3.3 pg/mL on PODs 1, 4, 7, 14, 21, and 28, respectively. Mean peritoneal fluid BDG levels were 485.9 and 240.4 pg/mL on PODs 1 and 7, respectively. No clinical fungal infections were observed. BDG levels were high in serum and peritoneal fluid after pediatric LDLT. Serum BDG levels normalized after POD 7. Careful interpretation of BDG levels until POD 7 is needed when an ABF has been used.


Cation-Disordered Lithium-Excess Li-Fe-Ti Oxide Cathode Materials for Enhanced Li-Ion Storage.
Cation-disordered Li-excess lithium-transition metal (Li-TM) oxides designed based on the percolation theory are regarded as a promising new type of high-performance cathode material for Li-ion batteries. Herein, cation-disordered rocksalt-type Li-Fe-Ti oxides of Li0.89Fe0.44Ti0.45O2, Li1.18Fe0.34Ti0.45O2, and Li1.24Fe0.38Ti0.38O2 with different Li-to-transition metal ratios (Li/TM = 1, 1.49, or 1.63) are investigated to understand the effect of a Li excess on the electrochemical Li-ion storage properties. The Li excess leads to local structural fluctuations of the as-prepared Li-Fe-Ti oxides, contributing to the formation of 0-TM diffusion channels for rapid Li-ion migration. The as-prepared Li-excess Li-Fe-Ti oxide cathodes (Li/TM = 1.49 and Li/TM = 1.63) deliver a higher reversible capacity of over 220 mAh g-1 and a better rate capability compared to the Li/TM = 1 electrode, which possesses a maximum discharge capacity of only about 165 mAh g-1. The redox reactions of Fe2+/Fe3+ and O2-/O22- achieve the main capacity of the Li-excess Li-Fe-Ti oxide cathodes during cycling, as supported by 57Fe Mössbauer spectroscopy, O 1s X-ray photoelectron spectroscopy, and O K-edge soft X-ray absorption spectroscopy.


Outcomes of Biologic Use in Asian Compared with Non-Hispanic White Adult Psoriasis Patients from the CorEvitas Psoriasis Registry.
Real-world data are limited comparing Asian and White patients with psoriasis using biologic therapy. This study compared the 6-month effectiveness of biologic therapy between Asian and White plaque patients with psoriasis in the CorEvitas Psoriasis Registry. Analyses included biologic initiations and 6-month follow-up visits from self-identified Asian (n = 293) and White (n = 2314) patients in the USA/Canada (4/2015-4/2020). Outcomes included: Psoriasis Area Severity Index (PASI) 75, disease activity measures [body surface area (BSA) ≤ 1, BSA ≤ 3, PASI90, PASI100, Investigator's Global Assessment (IGA) 0/1], and patient-reported outcomes [Dermatology Life Quality Index (DLQI) 0/1, itch, fatigue, skin pain, EuroQoL visual analog scale (EQ-VAS), patient global assessment, Work Productivity Activity and Impairment (WPAI) domains]. Unadjusted regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for achievement of binary outcomes and difference in mean change in continuous outcomes (β, 95% CI) at 6 months, followed by adjustment for age, sex, body mass index, alcohol, smoking, health insurance, education, comorbidities, scalp psoriasis morphology, psoriatic arthritis, biologic class, previous biologics, and baseline outcome value. Asians had lower proportions of women (32.8% versus 49.1%) and obesity (27.3% versus 54.5%), and higher proportions on Medicaid (19.9% versus 8.8%), graduated college (50.9% versus 40.1%) and never smoked (67.1% versus 44.1%). In unadjusted analyses, Asians had 52% higher odds of achieving PASI75 versus White patients (OR 1.52; 95% CI 1.15, 2.02). After adjustment, the association was attenuated (OR 1.11; 0.81, 1.52). Secondary outcomes experienced similar patterns except for DLQI: Asians had 33% lower odds of achieving DLQI 0/1 in both the unadjusted (OR 0.67; 0.50, 0.90) and adjusted (OR 0.67; 0.49, 0.92) models. Unadjusted differences in biologic therapy effectiveness between Asians compared with White patients were likely explained by differences in demographic, lifestyle, and psoriatic disease characteristics between groups. However, Asians still experienced lesser improvements in skin-related quality of life, even after adjustment.


Models for early chemoprevention trials in breast cancer.
Several models are being explored for use in the phase I and phase II evaluation of breast cancer chemoprevention agents. The short-term DCIS/small invasive cancer model is probably best used in late phase I trials in conjunction with agents likely to have activity in the progression phase of neoplastic development in addition to activity in earlier phases. The core biopsy or FNA hyperplasia models may be best used with drugs that are likely to have activity primarily in the promotion phase of neoplastic development and that are suitable for longer duration trials lasting several months to years. Morphology currently is the key surrogate endpoint biomarker for assessing efficacy in phase II trials. Other biomarkers that may undergo modulation will have to be validated, in that modulation will have to be shown to be directly related to decreased cancer risk in subsequent phase III trials. Only then can they be considered as validated surrogate endpoint biomarkers and used as stand-alone efficacy markers in phase II trials. Despite accrual challenges and technologic hurdles, interest in phase I and phase II chemoprevention trials is high.


Androgens and bone growth: it's location, location, location.
Androgens increase bone mass in specific skeletal compartments through effects on bone cells, enhancing osteoblast activity but inhibiting that of osteoclasts. The mechanism of action of androgens might involve both classic androgen receptor transcriptional activation and rapid non-genomic effects, and could also be dependent upon low levels of estrogen.


Kynurenine inhibits melanogenesis in human melanocyte-keratinocyte co-cultures and in a reconstructed 3D skin model.
Kynurenine (KYN), the most abundant metabolite of tryptophan, is classically associated with immune tolerance and tumor immune escape. In the last years, KYN is in the spotlight in other biological processes. Here, we showed that KYN inhibited tyrosinase expression and melanin content in primary human melanocyte and keratinocyte co-cultures. Furthermore, KYN decreased melanosome content in a 3D human skin reconstruction model. In these experiments, we used tyrosine + NH4 Cl to induce pigmentation. We compared the inhibitory effect of KYN on melanogenesis with the already known inhibitory effect promoted by IFN-γ. Since increased KYN production depends on the IFN-γ-inducible enzyme indoleamine-2,3-dioxygenase (IDO), we propose that part of the effect of IFN-γ on melanogenesis involves KYN production. From that, we tested if, during melanogenesis, changes in tryptophan metabolism would occur. For this purpose, we measured tryptophan, KYN and downstream products along with pigmentation. There were no significant changes in Trp metabolism, except for the high consumption of kynurenic acid. Our data identify the skin as a potential target for the action of KYN relevant for skin physiology and pigmentation. The results are discussed concerning the high production of KYN in skin inflammatory disorders and cancer.


Detection of impaired glucose regulation and/or type 2 diabetes mellitus, using primary care electronic data, in a multiethnic UK community setting.
The aim of this study was to develop and validate a score for detecting the glycaemic categories of impaired glucose regulation (IGR) and type 2 diabetes using the WHO 2011 diagnostic criteria. We used data from 6,390 individuals aged 40-75 years from a multiethnic population based screening study. We developed a logistic regression model for predicting IGR and type 2 diabetes (diagnosed using OGTT or HbA(1c) ≥ 6.5% [48 mmol/mol]) from data which are routinely stored in primary care. We developed the score by summing the β coefficients. We externally validated the score using data from 3,225 participants aged 40-75 years screened as part of another study. The score includes age, ethnicity, sex, family history of diabetes, antihypertensive therapy and BMI. Fifty per cent of a population would need to be invited for testing to detect type 2 diabetes mellitus on OGTT with 80% sensitivity; this is slightly raised to 54% that need to be invited if using HbA(1c). Inviting the top 10% for testing, 9% of these would have type 2 diabetes mellitus using an OGTT (positive predictive value [PPV] 8.9% [95% CI 5.8%,12.8%]), 26% would have IGR (PPV 25.9% [95% CI 20.9%, 31.4%]). Using HbA(1c) increases the PPV to 19% for type 2 diabetes mellitus (PPV 18.6% [95% CI 14.2%, 23.7%]) and 28% for an HbA(1c) between 6.0% and 6.4% (PPV 28.3% [95% CI 23.1%, 34.0%]). The score can be used to reliably identify those with undiagnosed IGR and type 2 diabetes in multiethnic populations. This is the first score developed taking into account HbA(1c) in the diagnosis of type 2 diabetes.


Genetic mapping and identification of Rht8-B1 that regulates plant height in wheat.
Plant height (PH) and spike compactness (SC) are important agronomic traits that affect yield improvement in wheat crops. The identification of the loci or genes responsible for these traits is thus of great importance for marker-assisted selection in wheat breeding. In this study, we used a recombinant inbred line (RIL) population with 139 lines derived from a cross between the mutant Rht8-2 and the local wheat variety NongDa5181 (ND5181) to construct a high-density genetic linkage map by applying the Wheat 40 K Panel. We identified seven stable QTLs for PH (three) and SC (four) in two environments using the RIL population, and found that Rht8-B1 is the causal gene of qPH2B.1 by further genetic mapping, gene cloning and gene editing analyses. Our results also showed that two natural variants from GC to TT in the coding region of Rht8-B1 resulted in an amino acid change from G (ND5181) to V (Rht8-2) at the 175th position, reducing PH by 3.6%~6.2% in the RIL population. Moreover, gene editing analysis suggested that the height of T2 generation in Rht8-B1 edited plants was reduced by 5.6%, and that the impact of Rht8-B1 on PH was significantly lower than Rht8-D1. Additionally, analysis of the distribution of Rht8-B1 in various wheat resources suggested that the Rht8-B1b allele has not been widely utilized in modern wheat breeding. The combination of Rht8-B1b with other favorable Rht genes might be an alternative approach for developing lodging-resistant crops. Our study provides important information for marker-assisted selection in wheat breeding.


Hepatocyte growth factor gene transfer into the liver via the portal vein using electroporation attenuates rat liver cirrhosis.
Although a variety of gene transfer methods to the liver have been designed, there are some problems such as the transfection efficiency and safety. In the present study, we developed a modified method of gene transfer into the liver by infusion of plasmid DNA via the portal vein followed by electroporation. After green fluorescence protein gene transfer, transgene expressions were detected in 24 h, and then maximally at 3 days, and persisted for 3 weeks. Histological analysis revealed that very mild tissue damage was induced in the liver to which electroporation was applied. In the second study, human hepatocyte growth factor (HGF) was more detected in the liver injected with 500 microg of human HGF gene than 100 microg of human HGF gene. However, serum HGF did not increase with 100 or 500 microg of human HGF gene. Moreover, 500 microg of HGF gene transfer into the liver by using this method could achieve the long survival of all dimethylnitrosamine-treated rats and attenuate the fibrous regions in the liver. These results suggest that HGF gene transfer into the liver via the portal vein using electroporation might be one of the useful methods for the treatment of various liver diseases.


[The objectivation of auditory and optical imaginations in the electroencephalogramm (author's transl)].
This study describes two new DC-potentials, which are related to auditory or optical imagination. The "auditory imagination potential" (AIP) is a negative DC-shift on the vertex lasting during the whole period of an auditory imagination. During an optical imagination there is a similar negative DC-shift in the ocipital region only. These "imagination potentials" can be already recognized in the "raw-EEG" by means of a special experimental technique. The magnitude of amplitudes correlates with the degree of concentration of the subject. In the case of intense imaginations potentials with amplitudes up to 20 muV and a duration of some seconds are recorded. The comparison between the vertex and the occipital lead permits the examination of the alternate occurence of auditory and optical conscious processes. The "imagination potentials" (AIP and OIP) are not related to any external stimulation or motor reaction and represent modality-specific EEG-correlates of cognitive, conscious processes (memory and imagination). Their significance for the "objective audiometry" is discussed.


Consistent normalization approach for Life Cycle Assessment based on inventory databases.
The process-based life cycle assessments (LCA) of goods and services are calculated using a bottom-up approach related to a functional unit. However, this does not provide any information regarding the scale of the environmental impacts. Therefore, the normalization allows to relate the impacts to a reference system (specific countries, regions or even the whole world). These references are usually obtained from top-down approach. The different data sources introduce inconsistencies on results and raise doubts on their adequacy and representativity. This paper proposes a novel approach for determining the data for the reference in order to ensure consistency about boundaries, data sources and modelling hypotheses describing the system. For this purpose, normalization is applied as an expression of the result relative to the average component of the reference system, instead of the sum of all the components. The reference values are determined from the geometric means of the datasets of the inventory database, used for assessing the studied systems. The exemplary application to the ecoinvent databases provides normalization references for 878 versions of the impacts categories listed by ecoinvent and for the 2077 involved substances. For eight impact assessment methods, the results are compared with 16 normalization sets from the literature and point out highly significant correlations.


Responses of protocerebral neurons in Manduca sexta to sex-pheromone mixtures.
Male Manduca sexta moths are attracted to a mixture of two components of the female's sex pheromone at the natural concentration ratio. Deviation from this ratio results in reduced attraction. Projection neurons innervating prominent male-specific glomeruli in the male's antennal lobe produce maximal synchronized spiking activity in response to synthetic mixtures of the two components centering around the natural ratio, suggesting that behaviorally effective mixture ratios are encoded by synchronous neuronal activity. We investigated the physiological activity and morphology of downstream protocerebral neurons that responded to antennal stimulation with single pheromone components and their mixtures at various concentration ratios. Among the tested neurons, only a few gave stronger responses to the mixture at the natural ratio whereas most did not distinguish among the mixtures that were tested. We also found that the population response distinguished among the two pheromone components and their mixtures, prior to the peak population response. This observation is consistent with our previous finding that synchronous firing of antennal-lobe projection neurons reaches its maximum before the firing rate reaches its peak. Moreover, the response patterns of protocerebral neurons are diverse, suggesting that the representation of olfactory stimuli at the level of protocerebrum is complex.


Potentially inappropriate medication related to weakness in older acute medical patients.
The use of potentially inappropriate medications (PIMs) is common in the older population. Inappropriate medications as well as polypharmacy expose older people to a greater risk of adverse drug reactions and may result in hospitalizations. To evaluate the prevalence of PIMs among acutely hospitalized patients aged ≥65 years in an acute medical unit, and to investigate the relationship between use of PIMs and weakness. This longitudinal observational study was undertaken in the Acute Medical Unit, Hvidovre Hospital, University of Copenhagen, Denmark. Patients aged ≥65 years admitted to the acute medical unit during the period October to December 2011 were included. Patients were interviewed at admission and at a follow-up visit 30 days after discharge. Data included information about medications, social status, functional status, cognitive status, handgrip strength, health-related quality of life, visual acuity, days of hospitalization, and comorbidities, and was prospectively collected. Polypharmacy was defined as regular use of 5 or more drugs. The Charlson Comorbidity Index was used to categorize comorbidities. The prevalence of PIMs and the association with PIMs and functional status handgrip strength, HRQOL, comorbidities, social demographic data and vision. Seventy-one patients (55 % men) with a median age of 78.7 years participated. The median number of medications was eight per person. Eighty percent were exposed to polypharmacy. PIMs were used by 85 % of patients, and PIMs were associated with low functional status (p = 0.032), low handgrip strength (p = 0.006), and reduced health-related quality of life (p = 0.005), but not comorbidities (p = 0.63), age (p = 0.60), sex (p = 0.53), education (p = 0.94), cognition (p = 0.10), pain (p = 0.46), or visual acuity (p = 0.55). Use of PIMs was very common among older people admitted to an acute medical unit. The use of PIMs is associated with low functional status, low handgrip strength, and reduced health-related quality of life.


Family harmony as a protective factor against adolescent tobacco and alcohol use in Wuhan, China.
To investigate the association between family harmony (FH) and tobacco and alcohol use (TAU) in Chinese adolescents. Participants completed a survey in 1998 as part of a larger study of adolescent health in Wuhan, China. Analyses were performed on subjects for whom complete data were available (n = 183; 50.8% male; mean age = 13.17 yrs, std dev = 0.59). Structural equation modeling was utilized to quantify the relationships between the FH, TAU, depression, and academic aptitude factors. The conceptualized structural equation model was found to have a good fit to the data (CFI = 0.995; chi2 = 39.57 df = 38; p = 40). FH was a significant predictor of TAU (beta = -0.42, p < 0.05) and was protective. FH' was also negatively related to depression (r = -0.24, p < 0.05) and positively related to academic achievement/aptitude (r = 0.35, p < 0.05). These central findings highlight the value and importance placed on FH within the Chinese culture. Future prevention programs may benefit by taking into account FH as a potential mediator of TAU in adolescents in China.


Biochemical compartmentation of fish tissues. II. Nonspecific phosphomonoesterases in brain.
The specific activities of acid and alkaline phosphatases in different regions of the brain of 9 nutritionally important fishes were worked out. The region consisting of pituitary, hypothalamus and thalamus showed the highest acid and alkaline phosphatase activities. Least activities of both the enzymes were found in the cerebellum and medulla oblongata. The piscivorous fishes contain the highest acid and alkaline phosphatase activity followed by cat fishes and major carps. The distributional pattern of these 2 enzymes in 4 regions of the brain of 9 fishes is the same.


Design and synthesis of environmentally sensitive fluorescent 2-naphthylethynylated 2'-deoxyadenosines: Detection of target DNA via changes in fluorescence intensity and wavelength.
Various C2-naphthylethynylated 2'-deoxyadenosines were synthesized as environmentally sensitive fluorescent (ESF) nucleosides and their photophysical properties were examined. Among the ESF nucleosides synthesized, four exhibited strong solvatochromicity, two of which were incorporated into oligodeoxynucleotides (ODNs). These ODN probes were able to detect target DNA through distinct changes in fluorescence intensity and wavelength and acted as effective reporter probes.


The importance of the thickness of femoral lateral wall for treating intertrochanteric fractures: a finite elements analysis.
To explore how the thickness of the femoral lateral wall influences the effectiveness of internal fixation systems used to treat intertrochanteric fractures. CT images of the pelvis and femur of a male adult were used to construct an intertrochanteric fracture model (AO/OTA 31-A2) with various thicknesses of the femoral lateral wall (FLW). Four finite element (FE) models were created with the lateral femoral walls being 10 mm, 20 mm, 30 mm, and 40 mm thick. The fracture models were fixed with a dynamic hip screw (DHS), a proximal femoral nail anti-rotation (PFNA), and a proximal femoral locking compression plate (P-FLCP). A simulated vertical load was applied to the femoral head. The stress and displacement of the implant and femur in each model were recorded for comparison. The FE analysis of the intertrochanteric fracture models showed that the PFNA system could provide better stability than the DHS and P-FLCP with the same thickness of FLW. The FLW provided buttress support to the femoral head and neck when using a DHS and PFNA, and the buttress strength was proportional to the thickness of FLW. The maximum stress in the DHS model was recorded on the DHS plate which accommodated the lag screw. For the PFNA model, the maximum stress appeared at the connection between the nail and blade. In the P-FLCP model, the maximum stresses were highly concentrated at the connection between the cephalic nails and the proximal plate. The thickness of the femoral lateral wall should be considered an important factor when selecting a suitable internal fixation system for intertrochanteric fractures. Based on the FE analysis, intramedullary fixation, such as PFNA, experiences lower stress levels and a moderate displacement in comparison to DHS and P-FCLP when used to treat intertrochanteric fractures.


Internal mammary vessels as recipient vessels to the free TRAM flap.
For the reconstruction of the breast after mastectomy, it is possible to use the internal mammary artery and vein as recipient vessels. The authors consider their experience and some new knowledge gained on the basis of 53 cases. They try to promote the indisputable advantages of the use of the mentioned recipient vessels.


Chemokines and chemokine receptors coordinate the inflammatory immune response in human cutaneous leishmaniasis.
Cutaneous leishmaniasis (CL) includes different clinical manifestations displaying diverse intensities of dermal inflammatory infiltrate. Diffuse CL (DCL) cases are hyporesponsive, and lesions show very few lymphocytes and a predominance of macrophages. In contrast, localized CL (LCL) cases are responsive to leishmanial antigen, and lesions exhibit granulocytes and mononuclear cell infiltration in the early phases, changing to a pattern with numerous lymphocytes and macrophages later in the lesion. Therefore, different chemokines may affect the predominance of cell infiltration in distinct clinical manifestations. In lesions from LCL patients, we examined by flow cytometry the presence of different chemokines and their receptors in T cells, and we verified a higher expression of CXCR3 in the early stages of LCL (less than 30 days of infection) and a higher expression of CCR4 in the late stages of disease (more than 60 days of infection). We also observed a higher frequency of T cells producing IL-10 in the late stage of LCL. Using immunohistochemistry, we observed a higher expression of CCL7, CCL17 in lesions from late LCL, as well as CCR4 suggesting a preferential recruitment of regulatory T cells in the late LCL. Comparing lesions from LCL and DCL patients, we observed a higher frequency of CCL7 in DCL lesions. These results point out the importance of the chemokines, defining the different types of cells recruited to the site of the infection, which could be related to the outcome of infection as well as the clinical form observed.


Community based estimation of extent and determinants of cost of injuries in a north Indian city.
Very few community based studies on the economic impact of injuries are available from India. Being based on secondary data sources these underestimate the true burden. Current study aimed to ascertain the incidence and economic impact of injuries in an Indian city. Details of injury events during the reference period were elicited in the study population through a community based survey in 2008. The severity of injury was categorized on the basis of need and duration of hospitalization. Direct and productivity costs were assessed for each event of injury. Out of 230 households contacted 212 participated in the study. Overall, 985 people were interviewed. The overall incidence of injury was 48.73/1000 population, Road traffic injuries (RTIs) were the leading cause (35%) of injury, followed by the falls (17%), contact with hot substances (13%), inanimate mechanical force (13%), animate mechanical force (8%), assault (8%) and others (6%). The ratio of fatal: severe non-fatal: mild injuries were 1:14:33. The total direct cost (DC) incurred was Rs. 310,951.67, contributed by medical (44%), surgical (21%), legal (15%), cost of informal care (10%). The total productivity cost of injuries was Rs. 416,700, contributed by mortality cost of Rs. 336,000 (81%) and morbidity cost of Rs. 807,00 (19%). For every case of fatal injury, there were 14 cases of severe hospitalized injuries and 33 cases of mild injuries. RTIs were the commonest. Injuries had sizeable direct and indirect cost on the society.


Left main coronary artery aneurysm.
Left main coronary artery aneurysm is rare finding at coronary angiography. We report a case of a large left main coronary artery aneurysm in a 59-year-old male who had cardiac catheterization for effort angina and inducible myocardial ischemia.


Functional properties of Grass pea protein concentrates prepared using various precipitation methods.
Pulses are an affordable source of proteins, starch, lipids, minerals and high value nutritional sources. This study was conducted to evaluate relationship between protein functional properties and their preparation methods. Therefore, the functional properties of Grass pea protein concentrates (GPPC) prepared using isoelectric precipitation (IE), salt extraction (SE) and ultrafiltration-diafiltration methods (UF/D) were determined. The GPP processed by those three precipitation methods contained all of the amino acids which aspartic acid and glutamic acid were dominate amino acids followed by arginine and leucine. However, methionine and tryptophan were limited amino acids. Water binding capacity was in following order: UF/D-GPPC > SE-GPPC > IE-GPPC. Meanwhile, highest value of oil binding capacity belonged to UF/D-GPPC. GPPC prepared using UF/D method had highest solubility. In term of interfacial tension, it was revealed that the interfacial tension of all isolates did not significantly reduced (P > 0/05). Net negative zeta potential with values was observed which IE-GPPC had highest surface charge followed by UF/D-GPPC and SE-GPPC, respectively. In terms of surface hydrophobicity, it was altered in the following order: IE-GPPC > SE-GPPC > UF/D-GPPC. It was observed that foaming capacity ranged between 85.06 and 89.78% and foaming stability ranged between 77.34 and 84.35%. Emulsifying capacity, emulsifying activity index and emulsifying stability index ranged between 105.06-109.78%, 31.09-36.29 m2/g and 12.90-18.86 min respectively. Evaluation of least gelling concentration showed that UF/D-GPPC were capable to form firm gel at low concentration (10% W/V). The functional properties of proteins are influenced by their extraction technique and can be achieve maximum functional characteristics by selecting appropriate extraction method. The results indicated the technological potential of GPP for health-promoting food formulations.


"Component separation" technique and panniculectomy for repair of incisional hernia.
Primary incisional hernia repair is rarely successful, with recurrence rates ranging from 18% to 62%. We describe the integration of "components separation" herniorrhaphy with panniculectomy. Twenty-two patients were treated. Standard panniculectomies and component separation were performed. Intravesical pressure was measured preoperatively, intraoperatively, and postoperatively. Measurement variations were compared using the Wilcoxon test. Complications or hernia recurrence were evaluated. The clinical appearance of the abdomen was subjectively evaluated by patients. Secure abdominal defect closure with midline approximation of the fascia was achieved in all patients. No major early complications occurred. Hernia recurred in 1 patient (4.5%). Intra-abdominal pressure increased in all the patients in our series but remained well below the danger level. Fifteen patients were fully satisfied with the appearance of their abdomen, whereas 7 were satisfied. Abdominal component separation provides a reliable autologous reconstructive option. Hernia repair combined with abdominoplasty provides functional and esthetic benefits.


The influence of preoperative MRI findings on lumbar fusion clinical outcomes.
Spinal fusion as a treatment for degenerative disc disease is controversial. Prior authors have identified various MRI findings as being pain generators, which might help guide patient selection for lumbar fusion procedures. These findings have included disc desiccation, disc contour, high-intensity zone annular disruption, the presence of Modic endplate changes, and disc space collapse. The purpose of this study is to investigate which MRI findings in patients with degenerative disc disease predict clinical improvement with lumbar fusion. A single-center surgical database of patients undergoing lumbar fusion was reviewed for patients whose indication for fusion surgery was primary disc pathology. We identified 51 patients (71 disc levels) who had completed 2-year prospectively collected outcomes questionnaires and had preoperative MRIs available for review. NRS (0-10) back and leg pain, Oswestry Disability Index (ODI) and SF-36 Physical Composite Summary scores were obtained preoperatively and at 1- and 2-year follow-up. MRIs were reviewed by three fellowship-trained spine surgeons who were asked to grade them for the following five characteristics: (a) disc desiccation, (b) disc contour, (c) presence of a high-intensity zone (HIZ) annular tear, (d) presence of Modic endplate changes and (e) disc height. Two-year outcome measures were compared to MRI findings to identify which findings correlated with improvement in outcome scores. Statistically significant improvements were noted in back pain, leg pain, SF-36 PCS and ODI in the group overall. Disc desiccation, disc contour, presence of an HIZ lesion, and the presence of Modic endplate changes did not correlate with 2-year outcomes. Disc height was correlated with 2-year change in outcome measures. Discs with preoperative height less than 5 mm demonstrated a 23.4 point ODI improvement compared to 9.2 points for discs >7 mm. Similarly, SF-36 PCS improved 9.5 points in discs <5 mm compared to 0.7 in discs greater than 7 mm. Discs between 5 and 7 mm demonstrated intermediate levels of improvement. Several commonly utilized MRI criteria proposed as indications for lumbar fusion do not seem to correlate with 2-year improvement in clinical outcomes. Discs which are narrowed and collapsed, preoperatively, demonstrate better improvement at 2 years postoperatively as compared to discs which have maintained disc height. Significant disc space collapse may represent a subset of "degenerative disc disease" which responds more favorably to treatment with fusion.


Effect of rioprostil, a methylprostaglandin E1 analog, on basal and stimulated plasma pancreatic hormone levels in man.
The effect of rioprostil, a methylprostaglandin E1 analog on circulating pancreatic hormones was evaluated in 13 healthy male subjects. Rioprostil administration, 300 micrograms twice daily resulted in a significant decrease of fasting insulin, C-peptide, glucagon, and pancreatic polypeptide. No change in fasting plasma glucose or somatostatin levels was observed. An oral glucose tolerance test induced similar increments in plasma glucose concentration before and during treatment, but a delayed rise of insulin and C-peptide levels occurred during the administration of the drug. On rioprostil, the glucose load no longer inhibited peripheral glucagon or somatostatin. Treatment with rioprostil remained without effect on mixed meal-induced changes in plasma glucose levels and concomitant increases in insulin, pancreatic polypeptide, and somatostatin levels. It is concluded that in healthy individuals rioprostil influences the basal and glucose-induced levels of glucagon, insulin, and somatostatin. In healthy men this effect did not, however, result in glucose intolerance.


Patient factors and glycaemic control--associations and explanatory power.
To investigate the association between glycaemic control and patient socio-demographics, activation level, diabetes-related distress, assessment of care, knowledge of target HbA(1c), and self-management behaviours, and to determine to what extent these factors explain the variance in HbA(1c) in a large Danish population of patients with Type 2 diabetes. Cross-sectional survey and record review of 2045 patients from a specialist diabetes clinic. Validated scales measured patient activation, self-management behaviours, diabetes-related emotional distress, and perceived care. The electronic patient record provided information about HbA(1c), medication, body mass index, and duration of diabetes. Data were analysed using multiple linear regression models with stepwise addition of covariates. The response rate was 54% (n = 1081). Good glycaemic control was significantly associated with older age, higher education, higher patient activation, lower diabetes-related emotional distress, better diet and exercise behaviours, lower body mass index, shorter duration of disease and knowledge of HbA(1c) targets (P < 0.05 for all). Patient socio-demographics, behaviour; perceptions of care and diabetes distress accounted for 14% of the total variance in HbA(1c) levels (P = 0.0134), but the variance explained was higher for respondents treated with medications other than insulin. Our study emphasizes the complex relationships between patient activation, distress and behaviour, specific treatment modalities and glycaemic control. Knowledge of treatment goals, achieving patient activation in coping with diabetes, and lowering disease-related emotional stress are important patient education goals. However, the large unexplained component of HbA(1c) variance highlights the need for more research to understand the mechanisms of glycaemic control.


Extrapulmonary tuberculosis in a university hospital in Spain.
Pulmonary tuberculosis in Europe has been decreasing over the last decades. This study evaluates the current importance of extrapulmonary tuberculosis and its trend over the last 10 years. In a University Hospital in Spain, 20% of all bacteriologically confirmed tuberculosis cases were extrapulmonary. The most frequent site was the urinary tract (73.5%). Ziehl-Neelsen staining was positive in 50.6% of the cases. Löwenstein-Jensen cultures became positive, on average, after 4.6 +/- 1.4 weeks. The proportion of extrapulmonary tuberculosis among the total number of tuberculosis cases has steadily increased trend over the period of observation.


Effects of grapefruit juice on the pharmacokinetics of sildenafil.
Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N -desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N -desmethylsildenafil. In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N -desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography-tandem mass spectrometry (limit of quantification, 1 ng/ml). Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethyl sildenafil AUC(0-infinity) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (C(max)) of sildenafil and N -desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach C(max) during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0-0.63 hour). Interindividual variability was pronounced in both periods. Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.


Deciphering the pathogenesis of retinopathy associated with carnitine palmitoyltransferase I deficiency in zebrafish model.
Fatty acid oxidation disorders (FAODs) are a group of rare genetic metabolic disorders caused by mutations in genes responsible for transporting and metabolizing fatty acids in the mitochondria. One crucial enzyme involved in this process is carnitine palmitoyltransferase I (CPT1), which transports long-chain fatty acids to the mitochondrial matrix for beta-oxidation. Defects in beta-oxidation enzymes often lead to pigmentary retinopathy; however, the underlying mechanisms are not entirely understood. To investigate FAOD and its impact on the retina, we employed zebrafish as a model organism. Specifically, we used antisense-mediated knockdown strategies to target the cpt1a gene and examined the resulting retinal phenotypes. We demonstrated that the cpt1a MO-injected fish significantly reduced the length of connecting cilia and severely affected photoreceptor cell development. Moreover, our findings highlight that the loss of functional cpt1a disrupted energy homeostasis in the retina, leading to lipid droplet deposition and promoting ferroptosis, which is likely attributed to the photoreceptor degeneration and visual impairments observed in the cpt1a morphants.


Simultaneous qualitative and quantitative analysis of eight alkaloids in Corydalis Decumbentis Rhizoma (Xiatianwu) and Corydalis Rhizoma (Yanhusuo) by high-performance liquid chromatography and high-resolution mass spectrometry combined with chemometric methods.
In this study, we established a comprehensive high-performance liquid chromatography coupled with diode array detection and high-resolution mass spectrometry method to identify 10 and quantified eight constituents in Corydalis Decumbentis Rhizoma ("Xiatianwu" in Chinese) and Corydalis Rhizoma ("Yanhusuo" in Chinese). Chemometric methods were applied to distinguish the botanical origins of the Xiatianwu and Yanhusuo samples. Chromatographic separation was achieved using an Agilent Poroshell EC-C18 column with mobile phases A (1000 ml of 0.2% acetic acid solution containing 2.8 ml of triethylamine) and B (acetonitrile) and stepwise gradient elution. The analytical method was fully validated in terms of linearity, sensitivity, intra- and interday precision and repeatability, the limit of detection, the limit of quantitation, and recovery. Twenty-six Xiatianwu samples and 10 Yanhusuo samples were analyzed for quality evaluation. In addition, hierarchical clustering analysis and principal component analysis were used to discriminate among samples of different botanical origins. The results showed that the contents of eight alkaloids in Xiatianwu and Yanhusuo were significantly different. Moreover, it was found that chemometric methods could be applied to accurately distinguish these two often conflated Chinese medicinal materials. In conclusion, this study provides a relatively comprehensive method for botanical origin identification and Xiatianwu and Yanhusuo quality control.


Chromosomal instability and inflammation: a catch-22 for cancer cells.
Chromosomal instability (CIN), an increased rate of chromosomal segregation abnormalities, drives intratumor heterogeneity and affects most human cancers. In addition to chromosome copy number alterations, CIN results in chromosome(s) (fragments) being mislocalized into the cytoplasm in the form of micronuclei. Micronuclei can be detected by cGAS, a double-strand nucleic acid sensor, which will lead to the production of the second messenger 2'3'-cGAMP, activation of an inflammatory response, and downstream immune cell activation. However, the molecular network underlying the CIN-induced inflammatory response is still poorly understood. Furthermore, there is emerging evidence that cancers that display CIN circumvent this CIN-induced inflammatory response, and thus immune surveillance. The STAT1, STAT3, and NF-κB signaling cascades appear to play an important role in the CIN-induced inflammatory response. In this review, we discuss how these pathways are involved in signaling CIN in cells and how they are intertwined. A better understanding of how CIN is being signaled in cells and how cancer cells circumvent this is of the utmost importance for better and more selective cancer treatment.


DFT-based reactivity and combined QSAR, molecular docking of 1,2,4,5-Tetrazine derivatives as inhibitors of Pim-1 kinase.
In the present work we have calculated several DFT reactivity descriptors for 1,2,4,5-Tetrazine at the B3LYP/6-311++G(d,p) level of theory in order to analyze its reactivity in vacuum and solvent phases. Whereas, the influence of the solvent was taken into account employing the PCM model. DFT-based descriptors such as (electronic chemical potential, electrophilicity, condensed Fukui function….) have been determined to predict the reactivity of 1,2,4,5-Tetrazine. A series of eighteen 1,2,4,5-Tetrazine derivatives was studied by using two computational techniques, namely, quantitative structure activity relationship (QSAR) and molecular docking. QSAR models of the antitumor activity of some 1,2,4,5-Tetrazine derivatives were established in gas and solvent phases which exhibited good statistical values for both cases. Whereas, multiple linear regression (MLR) procedure was used to obtain the best QSAR models and the leave-one-out (LOO) method to estimate the predictivity of our models. The most and the least active compounds were docked with the protein (3C4E) to confirm those obtained results from QSAR models and elucidate the binding mode between this type of compounds and corresponding protein.


Sodium Thiosulfate Preconditioning Ameliorates Ischemia/Reperfusion Injury in Rat Hearts Via Reduction of Oxidative Stress and Apoptosis.
Sodium thiosulfate (STS) has of late been proven efficacious in models of urolithiasis and vascular calcification. However, its cardiovascular effects on ischemia reperfusion injury (IR) have not been revealed. Being an antioxidant and calcium chelator, it is assumed to play a vital role in IR as ROS production and calcium overload are major perpetrators of IR injury. The cardioprotective effect of STS was evaluated in vitro using H9C2 cardiomyocytes and in vivo using both isolated rat heart and intact left anterior descending artery (LAD) occlusion models of ischemia reperfusion injury. Finally, in silico tools were utilized to establish its possible mode of action. Myocardial injury markers and expression of apoptotic proteins were studied along with myocardial histopathology. STS of 1 mM recovered H9C2 cells from glucose oxidase/catalase-induced apoptosis. The isolated rat heart treated with STS prior to IR injury improved its hemodynamics and reduced the infarct size to 9%. This was supported by the absence of derangement of cardiac fibers from H&E stained section of LAD-occluded rats. Plasma troponin levels decreased by 15% compared to IR and the myocardium showed diminished apoptotic proteins. An in silico docking analysis revealed higher binding affinity of STS for caspase-3 with a binding energy of - 60.523 kcal/mol for the complex. The effectiveness of STS as a cardioprotective agent is attributed to the reduction of apoptosis by binding to the active site of caspase-3 in silico, which was substantiated by the reduced expression of caspase-3 and poly ADP ribose polymerase levels.