Galangin attenuates cadmium-evoked nephrotoxicity: Targeting nucleotide-binding domain-like receptor pyrin domain containing 3 inflammasome, nuclear factor erythroid 2-related factor 2, and nuclear factor kappa B signaling.
The kidney is highly vulnerable to cadmium-evoked oxidative injury. Galangin is a natural flavone with reported antioxidant properties. This study investigated the potential modulating activity of galangin against cadmium-induced nephrotoxicity and explored the underlining mechanisms. Western blot analysis, spectrophotometric, ELISA, and histopathological techniques were employed. The results revealed that galangin suppressed tubular injury and improved glomerular function in the cadmium-intoxicated rats as evidenced by downregulation of kidney injury molecule-1, serum creatinine, and blood urea nitrogen. Galangin reduced cadmium-evoked inflammatory response and oxidative stress as indicated by reduced levels of interleukin-1 beta and TNF-α, decreased DNA damage, and improved antioxidant potential of the renal tissues. Mechanistically, galangin suppressed the nucleotide-binding domain-like receptor pyrin domain containing 3 inflammasome and efficiently decreased caspase-1 activity in the cadmium-intoxicated rats. Equally important, it inhibited the cadmium-induced nuclear translocation of nuclear factor kappa B and upregulated nuclear factor erythroid 2-related factor 2 signaling. The results highlight the ability of galangin to attenuate cadmium-evoked nephrotoxicity and support its therapeutic implementation although clinical investigations are warranted.


Urea movement across erythrocyte membrane during artificial kidney treatment.
Previous work by other investigators indicates that erythrocyte urea and creatinine in uremic whole blood leaving the hemodialyzer do not move down the concentration gradients established by loss of these solutes across the dialyzer membrane. This puzzling disequilibrium is at odds with work indicating ready movement of both solutes across the erythrocyte membrane of nonuremic erythrocytes studied in vitro. The present study shows that contact with the dialyzer does not noticeably alter the erythrocyte membrane of the uremic patient, so that urea distribution between plasma and erythrocyte water is the same as that in the blood of normal control subjects. Furthermore, urea does not show a disequilibrium in concentration across the erythrocyte membrane in response to 50% dilution with a modified Ringer's solution but rather equilibrates swiftly and completely.


Investigating Pathogenicity and Virulence of Staphylococcus pettenkoferi: An Emerging Pathogen.
Staphylococcus pettenkoferi is a coagulase-negative Staphylococcus identified in 2002 that has been implicated in human diseases as an opportunistic pathogenic bacterium. Its multiresistant character is becoming a major health problem, yet the pathogenicity of S. pettenkoferi is poorly characterized. In this study, the pathogenicity of a S. pettenkoferi clinical isolate from diabetic foot osteomyelitis was compared with a Staphylococcus aureus strain in various in vitro and in vivo experiments. Growth kinetics were compared against S. aureus, and bacteria survival was assessed in the RAW 264.7 murine macrophage cell line, the THP-1 human leukemia monocytic cell line, and the HaCaT human keratinocyte cell line. Ex vivo analysis was performed in whole blood survival assays and in vivo assays via the infection model of zebrafish embryos. Moreover, whole-genome analysis was performed. Our results show that S. pettenkoferi was able to survive in human blood, human keratinocytes, murine macrophages, and human macrophages. S. pettenkoferi demonstrated its virulence by causing substantial embryo mortality in the zebrafish model. Genomic analysis revealed virulence factors such as biofilm-encoding genes (e.g., icaABCD; rsbUVW) and regulator-encoding genes (e.g., agr, mgrA, sarA, saeS) well characterized in S. aureus. This study thus advances the knowledge of this under-investigated pathogen and validates the zebrafish infection model for this bacterium.


Diagnostic role of optic nerve sheath diameter and brain blood flow in neonates with hypoxic-ischemic encephalopathy.
The primary aim was to study the optic nerve sheath diameter (ONSD) measurements and cerebral blood flows in neonates with hypoxic-ischemic encephalopathy (HIE) who were at risk of cerebral edema and to compare the measurements with healthy neonates. Neonates diagnosed as Stage II and III HIE patients were enrolled in the study group. ONSD measurements and blood flow Doppler studies in the first 24-48 h of life during hypothermia and following hypothermia treatment. Magnetic resonance imaging (MRI) and transfontanelle ultrasonography were performed within the first 4-7 days of life in all HIE patients. Saved US and MRI images were assessed by a blind pediatric radiologist later on. Data from a total of 63 infants (42 in the HIE group and 21 in the control group) were analyzed. Both the right and left ONSD measurements were comparable between HIE and control groups. However, both resistive index (RI) and pulsatility index (PI) of the middle cerebral artery were found to be significantly lower in HIE (0.69 ± 0.09 and 1.14 (0.98-1.30)) group when compared with controls (0.75 ± 0.04 and 1.41 (1.25-1.52)) (p < 0.01). Ultrasonographic ONSD measurements were significant and strongly correlated with MRI ONSD measurements for both sides (r = 0.91 and r = 0.93, p < 0.01). Doppler studies during normothermia were comparable with the control group and significantly increased following therapeutic hypothermia. Ultrasonographic ONSD measurements can be reliably performed in term neonates with high compatibility to MRI. No significant effect on ONSD measurements was found related to asphyxia and therapeutic hypothermia despite the significant alteration observed in Doppler studies.


Subcutaneous perfusion before and during surgery in obese and nonobese patients.
Hypoxia at the surgical site impairs wound healing and oxidative killing of microbes. Surgical site infections are more common in obese patients. We hypothesized that subcutaneous oxygen tension (Psq O2) would decrease substantially in both obese and non-obese patients following induction of anesthesia and after surgical incision. We performed a prospective observational study that enrolled obese and non-obese surgical patients and measured serial Psq O2 before and during surgery. Seven morbidly obese and seven non-obese patients were enrolled. At baseline breathing room air, Psq O2 values were not significantly different (p = 0.66) between obese (6.8 kPa) and non-obese (6.5 kPa) patients. The targeted arterial oxygen tension (40 kPa) was successfully achieved in both groups with an expected significant increase in Psq O2 (obese 16.1 kPa and non-obese 13.4 kPa; p = 0.001). After induction of anesthesia and endotracheal intubation, Psq O2 did not change significantly in either cohort in comparison to levels right before induction (obese 15.5, non-obese 13.5 kPa; p = 0.95), but decreased significantly during surgery (obese 10.1, non-obese 9.3 kPa; p = 0.01). In both morbidly obese and non-obese patients, Psq O2 does not decrease appreciably following induction of anesthesia, but decreases markedly (∼33%) after commencement of surgery. Given the theoretical risks associated with low Psq O2 , future research should investigate how Psq O2 can be maintained after surgical incision.


Primary emissions and secondary organic aerosol formation from in-use diesel vehicle exhaust: Comparison between idling and cruise mode.
Diesel vehicle exhaust is an important source of carbonaceous aerosols, especially in developing countries, like China. Driving condition impacts diesel vehicle emissions, yet its influence needs further understanding especially on secondary organic aerosol (SOA) formation. In this study tailpipe exhaust from an in-use light duty diesel vehicle at idling and driving speeds of 20 and 40 km h-1 was introduced respectively into a 30 m-3 indoor smog chamber to investigate primary emissions and SOA formation during photo-oxidation. The emission factors of SO2 at 20 and 40 km h-1 were higher than those at idling, whereas the emission factors of aromatic hydrocarbons (AHs), polycyclic aromatic hydrocarbons (PAHs) and oxygenated volatile organic compounds (OVOCs) decreased when driving speeds increased. The emission factors of black carbon (BC) and primary organic aerosol (POA) at idling were comparable to those at 20 and 40 km h-1. The SOA production factors were 0.41 ± 0.09 g kg-fuel-1 at idling, approximately 2.5 times as high as those at 20 km h-1 (0.16 ± 0.09 g kg-fuel-1) or 40 km h-1 (0.17 ± 0.09 g kg-fuel-1). Total carbonaceous aerosols, including BC, POA and SOA, from diesel vehicles at 20 and 40 km h-1 were 60-75% of those at idling, due largely to a reduction in SOA production. Measured AHs and PAHs altogether were estimated to explain <10% of SOA production, and eight major OVOCs could contribute 8.4-23% of SOA production. A preliminary comparison was further made for the same diesel vehicle at idling using diesel oils upgraded from China 3 to China 5 standard. The emission factors of total particle numbers decreased by 38% owing to less nuclei mode particles, which was probably caused by the reducing fuel sulfur content; the emission factors of BC were almost unchanged, the POA emission factors and SOA production factors however decreased by 72% and 37%.


Emergence of microbial infections in some hospitals of Cairo, Egypt: studying their corresponding antimicrobial resistance profiles.
Antimicrobial resistance is one of the ten major public health threats facing humanity, especially in developing countries. Identification of the pathogens responsible for different microbial infections and antimicrobial resistance patterns are important to help clinicians to choose the correct empirical drugs and provide optimal patient care. During the period from November 2020 to January 2021, one hundred microbial isolates were collected randomly from different specimens from some hospitals in Cairo, Egypt. Sputum and chest specimens were from COVID-19 patients. Antimicrobial susceptibility testing was performed according to CLSI guidelines. Most microbial infections were more common in males and in elderly people over 45 years of age. They were caused by Gram-negative, Gram-positive bacteria, and yeast isolates that represented 69%, 15%, and 16%, respectively. Uropathogenic Escherichia coli (35%) were the most prevalent microbial isolates and showed high resistance rates towards penicillin, ampicillin, and cefixime, followed by Klebsiella spp. (13%) and Candida spp. (16%). Of all microbial isolates, Acinetobacter spp., Serratia spp., Hafnia alvei, and Klebsiella ozaenae were extremely multidrug-resistant (MDR) and have resisted all antibiotic classes used, except for glycylcycline, in varying degrees. Acinetobacter spp., Serratia spp., and Candida spp. were secondary microbial infections in COVID-19 patients, while H. alvei was a bloodstream infection isolate and K. ozaenae was recorded in most infections. Moreover, about half of Staphylococcus aureus strains were MRSA isolates and reported low rates of resistance to glycylcycline and linezolid. In comparison, Candida spp. showed high resistance rates between 77 and 100% to azole drugs and terbinafine, while no resistance rate towards nystatin was reported. Indeed, glycylcycline, linezolid, and nystatin were considered the drugs of choice for the treatment of MDR infections. The prevalence of antimicrobial resistance in some Egyptian hospitals was high among Gram-negative, Gram-positive bacteria, and candida spp. The high resistance pattern -especially in secondary microbial infections in COVID-19 patients- to most antibiotics used is a matter of great concern, portends an inevitable catastrophe, and requires continuous monitoring to avoid the evolution of new generations.


[Retrograde intravenous perfusion as ultima ratio in potential amputation patients with peripheral arterial occlusive disease].
In 21 patients with critical ischemia and/or inflammation of the leg facing possible amputation, retrograde intravenous perfusion (RVP) was used to administer fibrinolytics, vasodilators and antibiotics. Amputation was avoided in 15 patients. In 4 patients, RVP was interrupted due to unsuitable veins for putting in cannulas. After introducing a 3-in-1-Block (Winnie) for analgesia, 7 courses of treatment at least were reached before unbearable pain became a reason for stopping therapy. RVP should, therefore, be considered as the last resort in the treatment of critical ischemia and/or inflammation of the leg of patients facing possible amputation.


Difference in Postoperative Periprosthetic Bone Mineral Density Changes Between 3 Major Designs of Uncemented Stems: A 3-Year Follow-Up Study.
Although few studies have examined the direct effect of stress shielding on clinical outcomes, periprosthetic bone loss due to stress shielding is still an issue of concern, especially when physicians perform uncemented total hip arthroplasty (THA) in younger patients. Differences in femoral stem design may affect the degree of postoperative stress shielding. Therefore, the characteristics of the behavior for stress shielding of each type of femoral stem should be determined. This study compares differences in bone mineral density (BMD) change in the femur after primary THA between 3 major types of uncemented stems. Among a total of 89 hips, 26 hips received THA with a fit-and-fill type stem (VerSys Fiber Metal MidCoat; Zimmer, Inc, Warsaw, IN), 32 hips received a tapered rectangular Zweymüller-type stem (SL-Plus; Smith & Nephew Inc, Memphis, TN), and 31 received a tapered wedge-type stem (Accolade TMZF; Stryker Orthopaedics, Mahwah, NJ). BMD measurements were performed with a HOLOGIC Discovery device (Hologic Inc, Waltham, MA). BMD in the medial-proximal femur was maintained for 3 years after THA in the group with the tapered wedge-type stem. BMD in the lateral-proximal femur was maintained for 3 years after THA in the group with the Zweymüller-type stem. There were no significant differences in the Harris Hip Score among the 3 stem groups preoperatively and 1, 2, and 3 years after surgery. There are clear differences in postoperative BMD loss of the proximal femur among these 3 commonly used uncemented stems.


Comparison of homocitrulline and carbamylated albumin as biomarkers of carbamylation reactions in hemodialyzed patients.
To describe the association between levels of homocitrulline (HCit) and the degree of albumin carbamylation in a cohort of hemodialyzed patients. Plasma total and protein-bound HCit concentrations in samples from hemodialyzed patients included in NICOREN trial were determined by LC-MS/MS at baseline and after 24 weeks of treatment with either sevelamer or nicotinamide. HCit concentrations at all timepoints and in both groups were positively and significantly correlated with the degree of albumin carbamylation. Plasma concentrations of total HCit, protein-bound HCit and carbamylated albumin did not decrease after 24 weeks of treatment with either sevelamer or nicotinamide. The present results demonstrate that plasma total and protein-bound HCit concentrations were closely associated with albumin carbamylation in hemodialyzed patients. Therefore, total and protein-bound HCit concentrations might be valuable biomarkers of the overall intensity of protein carbamylation in this context. Given the less complex and time-consuming analytical methods required, these markers should be favored in future clinical studies of carbamylation reaction.


Advances in brain imaging of neuropathic pain.
To review the literature on the use of brain imaging, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetic resonance spectroscopy (MRS) and voxel-based morphometry (VBM) in investigation of the activity in diverse brain regions that creates and modulates chronic neuropathic pain. English literatures from January 1, 2000 to July 31, 2007 that examined human brain activity in chronic neuropathic pain were accessed through MEDLINE/CD ROM, using PET, fMRI, VBM, MRS and receptor binding. Published articles about the application of fMRI, PET, VBM, MRS and chronic neuropathic pain were selected. Data were mainly extracted from 40 representative articles as the research basis. The PET studies suggested that spontaneous neuropathic pain is associated with changes in thalamic activity. Both PET and fMRI have been used to investigate the substrate of allodynia. The VBM demonstrated that brain structural changes are involved in chronic neuropathic pain, which is not seen in a matched control group. However, the results obtained had a large variety, which may be due to different pain etiology, pain distribution, lesion tomography, symptoms and stimulation procedures. Application of the techniques of brain imaging plays a very important role in the study of structural and functional reorganization in patients with neuropathic pain. However, a unique "pain matrix" has not been defined. Future studies should be conducted using a prospective longitudinal research design, which would guarantee the control for many confounding factors.


The effect of glucagon on myoinositol levels in the blood serum and its excretion with urine.
The investigations were carried out with a group of ten healthy men aged 20--26 years who were injected intravenously with glucagon in a single dose of 50 microgram per kg of body weight. Glucagon had no effect on myoinositol levels in the blood serum. It caused however, a significant decrease in the myoinositol discharge into urine and lowered the index of renal myoinositol clearance. The creatinine clearance index remained unchanged.


Achieving a "all in one" Fe/Tm-MOFs with controllable photothermal and catalytic performance for imaging-guided multi-modal synergetic therapy.
Targeting excess H2O2 in the tumor microenvironment, nanotheranostic agents for catalytic therapy are designed based on Fenton reaction, catalyzing H2O2 into oxygen and hydroxyl radical (OH). But the catalytic efficiency in tumor microenvironment is not satisfactory. In order to solve the problem, a series of bimetallic-dual ligands metal-organic frameworks Fe/Tm-MOFs were designed, that Fe3+ and Tm3+ as metalions, 2-methylimidazole and trimesic acid as ligands. Due to the doped Tm3+ in Fe/Tm-MOFs and the conjugated structures formed by two ligands, the rate of electron transfer was improved, thus promoting the generation of OH at some extent. In addition, the photothermal effect of Fe/Tm-MOFs further promotes the generation of OH, which was evidenced by the 3,3',5,5'-tetramethylbenzidine(TMB). Combining the drug loading and release capabilities of Fe/Tm-MOFs, synergetic therapy of photothermal/chemo-/catalytic therapy can be achieved. In vitro results reveal that DOX release behaviors are both pH- and thermal-responsive. In vivo anti-cancer results show that the tumors of mice almost disappeared within 10 days, which were injected with Fe/Tm-MOFs/DOX and irradiated with 808 nm for 10 min. Thus, an excellent therapeutic performance has been achieved. Besides, Fe/Tm-MOFs can serve as a multimodality bioimaging contrast agent, covering fluorescence imaging, photothermal imaging and magnetic resonance imaging. Thus, an all-in-one nanotheranostic agent is constructed, improving the catalytic efficiency and providing a novel method to design an efficient nanotheranostic agent.


Biogeochemistry of mercury and methylmercury in sediment cores from Sundarban mangrove wetland, India--a UNESCO World Heritage Site.
This study was performed to elucidate the distribution, concentration trend and possible sources of total mercury (Hg(T)) and methylmercury (MeHg) in sediment cores (<63 μm particle size; n = 75) of Sundarban mangrove wetland, northeastern part of the Bay of Bengal, India. Total mercury was determined by atomic absorption spectrometry (AAS) in a Leco AMA 254 instrument and MeHg by gas chromatography-atomic fluorescence spectrometry (GC-AFS). A wide range of variation in Hg(T) (0.032-0.196 μg g(-1) dry wt.) as well as MeHg (0.04-0.13 ng g(-1) dry wt.) concentrations revealed a slight local contamination. The prevalent low Hg(T) levels in sediments could be explained by sediment transport by the tidal Hugli (Ganges) River that would dilute the Hg(T) values via sediment mixing processes. A broader variation of MeHg proportions (%) were also observed in samples suggesting that other environmental variables such as organic carbon and microbial activity may play a major role in the methylation process. An overall elevated concentration of Hg(T) in surface layers (0-4 cm) of the core is due to remobilization of mercury from deeper sediments. Based on the index of geoaccumulation (I (geo)) and low effects-range (ER-L) values, it is considered that the sediment is less polluted by Hg(T) and there is less ecotoxicological risk. The paper provides the first information of MeHg in sediments from this wetland environment and the authors strongly recommend further examination of Hg(T) fluxes for the development of a detailed coastal MeHg model. This could provide more refine estimates of a total flux into the water column.


Toxicokinetic and bioavailability studies on retrorsine in mice, and ketoconazole-induced alteration in toxicokinetic properties.
Retrorsine (RTS) is a toxic retronecine-type pyrrolizidine alkaloid, which is widely distributed. The purpose of this study was to develop a high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for serum RTS determination in mice. Serum samples were deproteinated by acetonitrile, separated on a C18 -PFP column and delivered at 0.8 ml/min with an eluting system composed of water containing 0.1% (v/v) formic acid and acetonitrile containing 0.1% (v/v) formic acid as mobile phases. RTS and the internal standard S-hexylglutathione (H-GSH) were quantitatively monitored with precursor-to-product transitions of m/z 352.1 → 120.1 and m/z 392.2 → 246.3, respectively. The method showed excellent linearity over the concentration range 0.05-50 μg/ml, with correlation coefficient r2 = 0.9992. The extraction recovery was >86.34%, and the matrix effect was not significant. Inter- and intra-day precisions (RSD) were <4.99%. The validated LC-MS/MS method was successfully applied to study the toxicokinetic profiles of serum RTS in mice after intravenous, oral administration and co-treated with ketoconazole, which showed that RTS displayed a long half-life (~11.05 h) and good bioavailability (81.80%). Co-administration of ketoconazole (KTZ) increased the peak serum concentration and area under the concentration-time curve and decreased the clearance and mean residence time. Summing up, a new standardized method was established for quantitative determination of RTS in sera.


Interactive effects of maternal and environmental exposure to coal combustion wastes decrease survival of larval southern toads (Bufo terrestris).
We conducted a mesocosm study to assess the individual and interactive effects of previous maternal exposure and larval exposure to trace element-laden sediments on southern toads (Bufo terrestris). Previous maternal exposure to coal combustion wastes (CCW) reduced larval survival to metamorphosis up to 57% compared to larvae of unexposed females. Larvae reared on CCW accumulated significant concentrations of trace elements resulting in extended larval periods, reduced growth rates, and reduced mass at metamorphosis. However, the effects were dependent on age of sediments, suggesting the effects of contaminants from CCW may be partially ameliorated over time through the reduced bioavailability of trace elements in aged CCW. Most importantly, maternal exposure to contaminants coupled with larval exposure to fresh CCW interacted to reduce survival to metamorphosis by 85% compared to reference conditions. Our study yields further evidence that disposal of CCW in aquatic basins potentially creates ecological traps for some amphibian populations.


Parenteral nutrition in bone marrow transplantation.
Twenty-nine patients undergoing bone marrow transplantation (BMT) were randomised prospectively to evaluate the effect of parenteral nutrition (TPN) on morbidity and mortality. Fourteen patients received a standard regimen of TPN for 10 +/- 4 days (mean +/- SD). All patients had free access to oral diet, which was significantly reduced compared to pre-transplant intake. In the TPN group, serum bilirubin by day 14 and serum bilirubin and gamma glutamyl transferase by day 21 were significantly higher than in the controls (p < 0.05). These differences probably reflect the higher incidence of serious pyrexia (T > 38.5' C) and blood culture positive rates in the TPN group. Weight loss in the control group was significantly greater than that of the TPN group (p < 0.05). TPN did not affect time to grafting or incidence of graft-versus-host disease. The use of TPN in the nutritional support of patients in small BMT units requires careful consideration.


Community-associated CMRSA-10 (USA-300) is the predominant strain among methicillin-resistant Staphylococcus aureus strains causing skin and soft tissue infections in patients presenting to the emergency department of a Canadian tertiary care hospital.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging pathogen first described among individuals with no contact with health care facilities. The purpose of this study was to determine the proportion of CA-MRSA, defined by pulsed field gel electrophoresis (PFGE), in MRSA skin and soft tissue infections presenting to the Emergency Department (ED). We also aimed to describe the laboratory and clinical characteristics of CA-MRSA infections. From June 1, 2001 to May 30, 2005, MRSA isolates from skin and soft tissue infections presenting to the ED were reviewed. They were characterized by antibiotic susceptibilities and PFGE, and the presence of staphylococcal cassette chromosome (SCC) mec type IVa and Panton-Valentine leukocidin (PVL) genes was assessed on representative isolates. The medical records were reviewed to define risk factors. There were 95 isolates available for analysis, of which 58 (61%) were CMRSA-10 (USA-300), the predominant clone from 2003 onward. All representative isolates (24%) tested in this group had PVL genes and SCCmec type IVa. Their antibiogram showed 100% susceptibility to trimethoprim-sulfamethoxazole, rifampin, and fusidic acid, and 79% to clindamycin. Clinical comparison of CMRSA-10 vs. hospital PFGE type strains showed 22% vs. 60%, respectively, for recent antibiotic use (p < 0.0001), 26% vs. 6%, respectively, for intravenous drug use (p < 0.05), and 57% vs. 6%, respectively, for soft tissue abscess (p < 0.001). CMRSA-10 is a major pathogen in skin and soft tissue abscesses in our ED. It has a characteristic susceptibility, and was associated with intravenous drug use, but not with recent antibiotic usage.


Investigation of TL and OSL detectors in ultra-high dose rate electron beams.
Objective.This work aims at investigating the response of various thermally stimulated luminescence detectors (TLDs) and optically stimulated luminescence detectors (OSLDs) for dosimetry of ultra-high dose rate electron beams. The study was driven by the challenges of dosimetry at ultra-high dose rates and the importance of dosimetry for FLASH radiotherapy and radiobiology experiments.Approach.Three types of TLDs (LiF:Mg,Ti; LiF:Mg,Cu,P; CaF2:Tm) and one type of OSLD (Al2O3:C) were irradiated in a 15 MeV electron beam with instantaneous dose rates in the (1-324) kGy s-1range. Reference dosimetry was carried out with an integrating current transformer, which was calibrated in absorbed dose to water against a reference ionization chamber. Additionally, dose rate independent BeO OSLDs were employed as a reference. Beam non-uniformity was addressed using a matrix of TLDs/OSLDs.Main results.The investigated TLDs were shown to be dose rate independent within the experimental uncertainties, which take into account the uncertainty of the dosimetry protocol and the irradiation uncertainty. The relative deviation between the TLDs and the reference dose was lower than 4 % for all dose rates. A decreasing response with the dose rate was observed for Al2O3:C OSLDs, but still within 10 % from the reference dose.Significance.The precision of the investigated luminescence detectors make them suitable for dosimetry of ultra-high dose rate electron beams. Specifically, the dose rate independence of the TLDs can support the investigation of the beam uniformity as a function of the dose rate, which is one of the challenges of the employed beam. Al2O3:C OSLDs provided high precision measurements, but the decreasing response with the dose rate needs to be confirmed by additional experiments.


Star quality.
Around 150 wards are participating in the voluntary Star Wards scheme to provide mental health inpatients with more activities with therapeutic value. Suggested activities range from a library, to horse riding Internet access and comedy. Service users are particularly keen to have more exercise, which can be a challenge in inpatient settings.


Long noncoding RNA SOX2-OT facilitates laryngeal squamous cell carcinoma development by epigenetically inhibiting PTEN via methyltransferase EZH2.
Long noncoding RNAs (lncRNAs) play important roles in the initiation and progression of various cancers, including laryngeal squamous cell carcinoma (LSCC). Recently, lncRNA Sox2 overlapping transcript (SOX2-OT) has been identified as an oncogene in various cancers. However, the functional role and the regulatory mechanism of SOX2-OT in LSCC remains unclear. In this study, we found that SOX2-OT expression was increased and negatively correlated with PTEN expression in LSCC tissues. Furthermore, SOX2-OT overexpression promoted LSCC cell proliferation, migration, invasion, and suppressed cell apoptosis in vitro, as well as facilitated the in vivo tumorigenicity. By contrast, SOX2-OT silencing exerted the opposite effect. Mechanically, SOX2-OT interacted with EZH2 and recruited EZH2 to induce H3K27me3 and epigenetically inhibited PTEN expression in LSCC cells. Additionally, EZH2 silencing and PTEN overexpression significantly abrogated the SOX2-OT overexpression-mediated promotion of LSCC cell malignant behavior. Collectively, our findings demonstrate that SOX2-OT inhibits PTEN expression to facilitate LSCC development through EZH2-mediated H3K27me3. © 2019 IUBMB Life, 71(9):1230-1239, 2019.


Mulinane-type diterpenoids from Mulinum spinosum.
In addition to the known mulinolic and mulinenic acids, two diterpenoids, mulin-11-ene-13-alpha,14-alpha-dihydroxy-20-oic and mulin-12-ene-14-one-20-oic acids, were isolated from the aerial parts of Mulinum spinosum (Cav.) Pers. (Apiaceae). Their structures were determined based on spectroscopic studies.


Laser Doppler velocimetry and platelet-derived growth factor as prognostic indicators for the healing of ulcers and ischaemic lesions of the lower limb.
The prognostic potential of skin blood flow measured by laser Doppler and serum platelet-derived growth factor (PDGF) levels was evaluated in patients with ischaemic lesions or ulceration of the lower limb. The laser Doppler-derived skin blood flow and perfusion pressure were measured in 93 patients with ischaemic lesions or ulceration in 98 lower limbs. Of these lesions, 61% healed spontaneously or with conservative local therapy, while 39% required major surgery. The likelihood for healing was reduced by older age. Comparison of receiver operating curves demonstrated that the optimal sensitivity and specificity were obtained for a combination of skin blood flow and perfusion pressure measured at 44 degrees C rather than at room temperature. If the skin perfusion pressure and blood flow were greater than 15 mmHg and 100 U respectively at 44 degrees C, 91% lesions healed, while if they were less than these values none healed. This provided a sensitivity and specificity of 100% and 83% respectively. The serum PDGF concentration was measured by radioimmunoassay in 48 patients with ischaemic lesions or ulceration of the lower limb, and compared with that in 34 healthy controls and 15 patients who had undergone abdominal surgery 3-5 days previously. The median PDGF level in the control group (83 pmol/l) was significantly less than that in the post-laparotomy group (217 pmol/l). The median PDGF level in the 31 patients whose ulcers healed with conservative therapy (210 pmol/l) was significantly higher compared with that in the 17 patients with unhealed ulcers (70 pmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)


A case of bilateral lower cranial nerve palsies after base of skull trauma with complex management issues: case report and review of the literature.
Fractures of the skull base can cause lower cranial nerve palsies because of involvement of the nerves as they traverse the skull. A variety of syndromes have been described, often involving multiple nerves. These are most commonly unilateral, and only a handful of cases of bilateral cranial nerve involvement have been reported. We describe a 64-year-old man with occipital condylar fracture complicated by bilateral palsies of IX and X nerves associated with dramatic physiological derangement causing severe management challenges. Apart from debilitating postural hypotension, he developed dysphagia, severe gastrointestinal dysmotility, issues with airway protection as well as airway obstruction, increased oropharyngeal secretions and variable respiratory control. This is the first report of a patient with traumatic bilateral cranial nerve IX and X nerve palsies. This detailed report and the summary of all 6 previous case reports of traumatic bilateral lower cranial nerve palsies illustrate clinical features, treatment strategies, and outcomes of these rare events.


Patient and Provider Perceptions of Weight Gain, Physical Activity, and Nutrition Counseling during Pregnancy: A Qualitative Study.
This study investigated patient and provider perceptions of weight gain, physical activity, and nutrition counseling during prenatal care visits. Individual qualitative interviews were conducted with 30 pregnant women between 20 and 30 weeks gestation (15 African American, 15 White) and 11 prenatal care providers (5 attending physicians, 5 residents, 1 nurse practitioner) in 2014. The majority of patients and providers reported receiving or giving advice on weight gain (87% and 100%, respectively), physical activity (87% and 91%), and nutrition (100% and 91%) during a prenatal visit. Discussion of counseling content was largely consistent between patients and providers. However, counseling was limited and not fully consistent with current weight gain, physical activity, or dietary guidelines during pregnancy. Most patients viewed provider advice positively, but some wanted more detailed information. Providers discussed many barriers to lifestyle counseling, including lack of time, inadequate training, concern about the sensitivity of the topic, lower education or income level of the patient, cultural differences, and lack of patient interest. Providers discussed weight gain, physical activity, and nutrition during prenatal care visits and patients accurately recalled this advice. However, counseling was limited and not fully consistent with guidelines. Future studies are needed to develop and evaluate the efficacy of interventions to help providers overcome perceived barriers and more effectively counsel women on weight and healthy lifestyles during pregnancy.


Chromatin structure of Drosophila melanogaster ribosomal genes.
The chromatin structure of ribosomal genes of D. melanogaster has been studied by crosslinking proteins to DNA. We found that a number of histone contacts with DNA through histidine in the approximately 1 kb-long region surrounding the transcription initiation site, coding regions and the region of 240 bp-long repeats from the intergenic spacers (Alu-repeats) were weakened as compared to the inactive chromatin of the type II insertion. A protein with the molecular mass of 50 kDa (p50), associated with all DNA sequences analysed, has been discovered. Another protein with molecular mass of about 70 kDa (p70) has been found to be specific only for the Alu-repeats.


Chlorinated biphenyls induce cytochrome P450IA2 and uroporphyrin accumulation in cultures of mouse hepatocytes.
Previous enzymatic and immunological studies from this laboratory have indicated a critical role for cytochrome P450IA2-catalyzed uroporphyrinogen oxidation in the development of uroporphyria caused by halogenated aromatic hydrocarbons. To extend these studies, we investigated whether primary cultures of mammalian hepatocytes which are inducible for cytochrome P450IA2 are also inducible for chemically mediated uroporphyria. Hepatocytes were isolated from C57BL/6 mice and maintained on Matrigel, an extracellular matrix isolated from a mouse tumor. When these cultures were treated with 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) and 5-aminolevulinic acid (ALA), they accumulated cytochrome P450IA2 as well as uroporphyrin (URO) and heptacarboxyporphyrin for up to 12 days. Cultures treated with ALA alone accumulated no P450IA2 and very little URO. Neither URO accumulation nor the level of P450IA2 was affected by addition of iron as the nitrilotriacetate complex. Other inducers of P450IA2 in vivo (3,4,5,3',4'-pentachlorobiphenyl, 3,4,3',4'-tetrachlorobiphenyl, and 3-methylcholanthrene) also increased P450IA2 in the cultures and caused URO accumulation in the presence of added ALA. The tetrachlorobiphenyl and methylcholanthrene caused these effects only when given repeatedly. Inducers of other forms of P450 failed to cause URO accumulation in the presence of ALA and iron. Cultures of hepatocytes from DBA mice (which are resistant to the uroporphyria in vivo) accumulated much less P450IA2 or URO when treated with HCB and ALA. These primary cultures of mammalian hepatocytes represent a new experimental model to investigate the role of cytochrome P450IA2 in the mechanism of chemically induced uroporphyria.


Normal Ethanol Sensitivity and Rapid Tolerance Require the G Protein Receptor Kinase 2 in Ellipsoid Body Neurons in Drosophila.
G protein signaling pathways are key neuromodulatory mechanisms for behaviors and neurological functions that affect the impact of ethanol (EtOH) on locomotion, arousal, and synaptic plasticity. Here, we report a novel role for the Drosophila G protein-coupled receptor kinase 2 (GPRK2) as a member of the GRK4/5/6 subfamily in modulating EtOH-induced behaviors. We studied the requirement of Drosophila Gprk2 for naïve sensitivity to EtOH sedation and ability of the fly to develop rapid tolerance after a single exposure to EtOH, using the loss of righting reflex (LORR) and fly group activity monitor (FlyGrAM) assays. Loss-of-function Gprk2 mutants demonstrate an increase in alcohol-induced hyperactivity, reduced sensitivity to the sedative effects of EtOH, and diminished rapid tolerance after a single intoxicating exposure. The requirement for Gprk2 in EtOH sedation and rapid tolerance maps to ellipsoid body neurons within the Drosophila brain, suggesting that wild-type Gprk2 is required for modulation of locomotion and alertness. However, even though Gprk2 loss of function leads to decreased and fragmented sleep, this change in the sleep state does not depend on Gprk2 expression in the ellipsoid body. Our work on GPRK2 has established a role for this GRK4/5/6 subfamily member in EtOH sensitivity and rapid tolerance.


Repercussions of the COVID-19 pandemic on preventive health services in Brazil.
The increasing burden of non-communicable diseases and limited public financing are major challenges facing health care systems in Latin America. Although COVID-19 severely impacted the Brazilian health care system, it is crucial to further characterize the degree of disruption caused to public health efforts, in order to address and manage long term effects of this pandemic. We therefore quantified the demand for preventive and treatment services from the Brazilian Unified Health System (Sistema Único de Saúde/SUS) in 2020 to evaluate potential repercussions of COVID-19 in this setting. Using the SUS database, we compared preventative and treatment services rendered in 2020 to the same services rendered from 2017 to 19. We also evaluated the frequency of respiratory infection (RI) diagnoses during the pandemic, relative to the preceding years. Compared to 2017-19, in 2020 non-urgent medical appointments decreased 1.4-fold (p = 0.0017), dental consultations 2.8-fold (p = 0.05), and immunization coverage 1.5 fold (p = 0.0005). The number of RI visits to SUS ambulatory care units in 2020 was 4.2 times higher than in preceding years (p = 0.0014), with a peak of 280,898 diagnoses in July 2020. The COVID-19 pandemic appears to have led to a dramatic decline in preventative and treatment services provided by SUS to the Brazilian population. Our findings may aid decision-makers in formulating policies to increase the availability of outpatient services in the aftermath of the pandemic. Counter measures will be critical to avoid a resurgence in vaccine-preventable diseases and complications stemming from non-communicable, chronic health conditions.


Comparison of Phase I-II designs with parametric or semi-parametric models using two different risk-benefit trade-off criteria.
A semi-parametric stochastic ordering model (SPSO) is introduced to characterize functional relationships between dose level and the probabilities of binary Efficacy and Toxicity events. This model is used to implement a Bayesian adaptive phase I-II clinical trial using one of two different optimality criteria, either dose desirability defined as a function of the marginal Efficacy and Toxicity probabilities, or mean utility based on numerical scores of the four possible (Efficacy, Toxicity) events. A simulation study is conducted to compare designs using the SPSO model to the parametric EffTox model described in Thall and Cook, with each (model, optimality criterion) combination. Each of these four designs adaptively assigns patient cohorts to estimated optimal dose levels after restricting assignments to dose levels that are acceptably efficacious and safe. The simulation study shows that different design configurations may have superior performance depending on the assumed true dose-outcome scenario.


Long-term follow-up study of radiocarpal arthrodesis for the rheumatoid wrist.
Pain-free stability of the wrist is a prerequisite for the rheumatoid hand to maintain power and perform various tasks. The purpose of this study was to investigate whether a radiocarpal (radiolunate, radioscapholunate, or radiolunotriquetral) arthrodesis produces a stable wrist and whether the results remain satisfactory for more than 10 years. A retrospective review was performed on 25 wrists of 25 patients with rheumatoid arthritis who had radiocarpal arthrodesis. All patients had a synovectomy of the extensor tendons and the wrist joint combined with a Darrach procedure. The indications for radiocarpal arthrodesis included radiographic changes in Larsen-Dale-Eek grades II to IV, midcarpal joint space of greater than 1 mm, and ulnar shift or palmar subluxation of the carpus. The presence of scapholunate dissociation was an optional indication. The mean follow-up period was 13 years (range, 10-18 y) and radiographs taken just before the surgery and 0 to 2 years, 2 to 5 years, 5 to 10 years, and more than 10 years after the surgery were evaluated as were pain relief, swelling, grip power, range of motion, and complications. Pain was resolved for 22 of the patients and 3 experienced occasional mild pain. Swelling generally decreased, grip power increased significantly, flexion decreased, and forearm rotation increased significantly. The complication rate was low. Radiographically ulnar shift and palmar subluxation improved initially and were maintained at the time of the 10-year follow-up evaluation; carpal collapse improved initially but returned to the preoperative level by the time of the 5-year follow-up evaluation. The midcarpal joint space was preserved in 16 wrists, and all but 1 wrist (in a patient with mutilating type of the disease) remained stable. Radiocarpal arthrodesis for treatment of the rheumatoid wrist results in good stability with preservation of motion despite radiographic progression of the disease. We therefore recommend this treatment for the unstable wrist with moderate deterioration.


A brush-polymer conjugate of exendin-4 reduces blood glucose for up to five days and eliminates poly(ethylene glycol) antigenicity.
The delivery of therapeutic peptides and proteins is often challenged by a short half-life, and thus the need for frequent injections that limit efficacy, reduce patient compliance and increase treatment cost. Here, we demonstrate that a single subcutaneous injection of site-specific (C-terminal) conjugates of exendin-4 (exendin) - a therapeutic peptide that is clinically used to treat type 2 diabetes - and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) with precisely controlled molecular weights lowered blood glucose for up to 120 h in fed mice. Most notably, we show that an exendin-C-POEGMA conjugate with an average of 9 side-chain ethylene glycol (EG) repeats exhibits significantly lower reactivity towards patient-derived anti-poly(ethylene glycol) (PEG) antibodies than two FDA-approved PEGylated drugs, and that reducing the side-chain length to 3 EG repeats completely eliminates PEG antigenicity without compromising in vivo efficacy. Our findings establish the site-specific conjugation of POEGMA as a next-generation PEGylation technology for improving the pharmacological performance of traditional PEGylated drugs, whose safety and efficacy are hindered by pre-existing anti-PEG antibodies in patients.


Efficacy of Early Postoperative Intraperitoneal Chemotherapy After Complete Surgical Resection of Peritoneal Metastasis from Colorectal Cancer: A Case-Control Study from a Single Center.
Early postoperative intraperitoneal chemotherapy (EPIC) is a type of intraperitoneal chemotherapy for patients with colorectal cancer and peritoneal metastasis. However, there is a paucity of clinical studies evaluating the efficacy of EPIC after complete cytoreductive surgery. This study was designed to evaluate the efficacy of EPIC in patients who underwent complete surgical resection of peritoneal metastasis from colorectal cancer. A 1:2 matched case-control study was conducted in patients undergoing complete surgical resection of peritoneal metastases from colorectal cancer at our institution between January 2000 and November 2013. The operative and survival outcomes of patients receiving EPIC (EPIC group) and those who did not (no EPIC group) were compared. Thirty patients who were treated with EPIC were matched with 15 patients who did not receive EPIC. The 3-year overall survival (OS) and disease-free survival (DFS) were 74.3 and 53.0 % in the EPIC group and 34.7 and 7.5 % in the no EPIC group (EPIC group vs. no EPIC group: OS, P = 0.016; DFS, P = 0.002). Multivariate analysis identified EPIC and adjuvant systemic chemotherapy as independent prognostic factors for OS, whereas only EPIC was prognostic factor for DFS. For peritoneal-DFS, EPIC was the only significant variable in the univariate analysis (hazard ratio, 2.70; 95 % confidence interval 1.17-6.21; P = 0.020). EPIC is a safe and efficacious option for intraperitoneal chemotherapy to prevent peritoneal recurrence and prolong survival after complete resection of peritoneal metastasis from colorectal cancer.


Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor.
Saxagliptin is an orally active, highly potent, selective and competitive dipeptidyl peptidase (DPP)-4 inhibitor used in the treatment of type 2 diabetes mellitus at doses of 2.5 or 5 mg once daily. DPP-4 is responsible for degrading the intestinally derived hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). Inhibition of DPP-4 increases intact plasma GLP-1 and GIP concentrations, augmenting glucose-dependent insulin secretion. Both saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, demonstrate high degrees of selectivity for DPP-4 compared with other DPP enzymes. Saxagliptin is orally absorbed and can be administered with or without food. The half-life of plasma DPP-4 inhibition with saxagliptin 5 mg is ~27 h, which supports a once-daily dosing regimen. Saxagliptin is metabolized by cytochrome P450 (CYP) 3A4/5 and is eliminated by a combination of renal and hepatic clearance. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with hepatic impairment. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with mild renal impairment, whereas dose reduction is recommended in patients with moderate or severe renal impairment because of greater systemic exposure [the area under the plasma concentration-time curve (AUC)] to saxagliptin total active moieties. Clinically relevant drug-drug interactions have not been detected; however, limiting the dose to 2.5 mg once daily is recommended in the USA when saxagliptin is coadministered with strong CYP inhibitors, because of increased saxagliptin exposure. In summary, saxagliptin has a predictable pharmacokinetic and pharmacodynamic profile.


[Inhibition of platelet aggregation and cyclic nucleotide phosphodiesterase (specifically cyclAMP) by 3-hydroxypyridine derivatives].
The effects of 3-hydroxypyridine (3-HP) derivatives on platelet aggregation and platelet phosphodiesterase (PDE) of cyclic nucleotides (cAMP-dependent) were studied. It was shown that some derivatives of 3-HP inhibit platelet aggregation (the most pronounced effect was exerted by 2-benzyl-3- oxypyridine ). Several derivatives o 3-HP given in a concentration 10(-3) M were discovered to inhibit PDE by 40 to 75%. No correlation was found between the efficacy of 3-HP as antiaggregation agents and PDE inhibitors.


Allergy treatment with a peptide vaccine.
An antiserum, obtained by immunising rabbits with a human peptide-protein conjugate, was shown to inhibit histamine release from rat mast cells both in vitro and in vivo. Immunisation of sensitised rats with the same peptide reduced IgE antibody formation and serum histamine concentration, and abolished systemic anaphylactic reactions in response to allergen challenge. This peptide may form the basis of a vaccine in a new approach to the immunotherapy of atopic disease.


Effects of some calcium channel blockers on isolated human penile erectile tissues.
The effects of the calcium channel blockers (CCBs) verapamil, nifedipine and diltiazem on contractile activation of isolated human penile erectile tissues were investigated. Specimens of the corpus spongiosum (CS) and corpora cavernosa (CC) were obtained from men with a history of normal penile erection undergoing cystourethrectomy because of bladder malignancy. Preparations were mounted in organ baths and isometric tension was recorded. Deprivation of extracellular calcium abolished electrically induced contractions in both CS and CC preparations within 15 min.; norepinephrine (NE)-induced contractions were reduced by 90% (CS) and 83% (CC) after 30 min. All the CCBs reduced electrically induced contractions concentration-dependently, nifedipine being the most potent agent. Contractions induced by exogenous NE were depressed by about 50%, whereas high K+ (124 mM) induced responses were abolished. It is concluded that contraction in penile erectile tissues is mediated mainly by neuronally released NE stimulating postjunctional alpha-adrenoceptors. The contraction is highly dependent on extracellular calcium and can partly be inhibited by CCBs. It cannot be excluded that some CCBs injected intracavernosally may be useful for diagnosis and even treatment of erectile dysfunction. However, calcium channel blockade may not be as effective as a therapeutic principle as blockade of alpha-adrenoceptors.


The Consolidation and Transformation of Memory.
Memory consolidation refers to the transformation over time of experience-dependent internal representations and their neurobiological underpinnings. The process is assumed to be embodied in synaptic and cellular modifications at brain circuits in which the memory is initially encoded and to proceed by recurrent reactivations, both during wakefulness and during sleep, culminating in the distribution of information to additional locales and integration of new information into existing knowledge. We present snapshots of our current knowledge and gaps in knowledge concerning the progress of consolidation over time and the cognitive architecture that supports it and shapes our long-term memories.


Proportion of Retinopathy of Prematurity That Was Treated across Regions in the United States.
Retinopathy of prematurity (ROP) is the leading preventable cause of blindness in children worldwide. Major eye and visual problems are strongly linked to ROP requiring treatment. Objectives of the study are to: (1) evaluate the trends and regional differences in the proportion of treated ROP, (2) describe risk factors, and (3) examine if treated ROP predicts mortality. Retrospective data analysis was conducted using the Kids' Inpatient Database from 1997 to 2012. ROP was categorized into treated ROP (requiring laser photocoagulation or surgical intervention) and nontreated ROP. Bivariate and multivariate logistic regression analyses were performed. Out of 21,955,949 infants ≤ 12 months old, we identified 70,541 cases of ROP and 7,167 (10.2%) were treated. Over time, the proportion of treated ROP decreased (p = < 0.001). While extremely low birth weight infants cared for in the Midwest was associated with treated ROP (adjusted odds ratio [aOR] = 29.05; 95% confidence interval [CI]: 10.64-79.34), black race (aOR = 0.57; 95% CI: 0.51-0.64) care for in the birth hospital (aOR = 0.44; 95% CI: 0.41-0.48) was protective. Treated ROP was not associated with mortality. The proportion of ROP that is surgically treated has decreased in the United States; however, there is variability among the different regions. Demographics and clinical practice may have contributed for this variability.


Hypoxia-inducible factor in brain.
HIF-1 is composed of HIF-1alpha and HIF-1beta protein subunits. HIF-1 is induced by hypoxia and binds to promoter/enhancer elements and stimulates the transcription of hypoxia-inducible target genes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of stroke on the expression of HIF-1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal cerebral ischemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several glycolytic enzymes including lactate dehydrogenase were up-regulated in the areas around the infarction. HIF and its target genes were induced by 7.5 hours after the onset of ischemia and increased further at 19 and 24 hours. Since hypoxia induces HIF in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF-1alpha protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2/3 hrs), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1alpha and HIF-1beta expression. We also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1alpha and HIF-1beta protein levels were markedly increased after i.p. injection of CoCl2 and DFX. Preconditioning with CoCl2 or DFX 24 hours before the stroke decreased infarction by 75% and 56% respectively, compared with vehicle-injected, littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning.


Acute pulmonary toxicity following occupational exposure to a floor stain protector in the building industry in Switzerland.
Waterproofing agents are widely applied to leather and textile garments; they are also used as floor stain protectors by professionals. Acute respiratory injury is described in three cases of young healthy adults following occupational inhalation of a new waterproofing formulation containing an acrylate fluoropolymer. Within 1 or 2 h after exposure they developed a rapidly progressive dyspnoea; two of them had hypoxaemia and flu-like reactions. All patients improved with supportive treatment in a few days. The mechanism of toxicity is still under investigation, but experimental data suggest the role of this new acrylate fluoropolymer. Tilers should be warned against spraying floor stain repellents; there is also a need to make consumers aware that the spraying of waterproofing agents in a closed environment and concomitant smoking should be avoided.


Effect of different orientations of screw fixation for radial head fractures: a biomechanical comparison.
Screw fixation is a common method used for the treatment of Mason type II radial head fractures. The purpose of our study was to evaluate the mechanical properties of three different screw orientations used for fixation of Mason type II radial head fractures. We sawed 24 medium-frequency fourth-generation Synbone radial bones to simulate unstable radial head fractures, which we then fixed with three different screw orientations. Implants were tested under axial load by the tension-torsion composite test system. If the implant-radial constructs did not fail after the axial load test, an axial failure load was added to the remaining constructs. The stiffness of the divergent group was the highest of the three orientations, and this group had statistically significant difference from the other two groups (p < 0.05). However, there was no statistically significant difference between the convergence group and the parallel group (p > 0.05). When the displacement reached 2 mm, the load of the divergent screw was still larger than the other two groups (p < 0.05). The divergent screw orientation was the most stable and had the greatest control of Mason type II fractures of these three groups. Therefore, it can be better applied in clinical settings.


[Allogeneic bone marrow transplantation in adult patients with serious hematological diseases 1985-1992].
We present updated results from allogeneic bone marrow transplantation in adult patients who received transplants between 1985 and 1992. Of 47 patients, 36 where disease-free survivors 8-93, mean 32 months after transplantation. Of these, seven had received marrow from unrelated donors. The present treatment capacity is insufficient to cover the demand for allogeneic bone marrow transplants for Norwegian patients.


Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways.
Histamine H1 receptor (H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treat inflammatory conditions such as allergic rhinitis, atopic dermatitis and asthma. Consistent with the high morbidity levels of such inflammatory conditions, these receptors are the targets of a vast number of approved drugs, and in many situations their ligands are co-administered. However, this drug association has no clear rationale and has arisen from clinical practice. We hypothesized that H1R signaling could affect GR-mediated activity, impacting on its transcriptional outcome. Indeed, our results show a dual regulation of GR activity by the H1R: a potentiation mediated by G-protein βγ subunits and a parallel inhibitory effect mediated by Gαq-PLC pathway. Activation of the H1R by its full agonists resulted in a composite potentiating effect. Intriguingly, inactivation of the Gαq-PLC pathway by H1R inverse agonists resulted also in a potentiation of GR activity. Moreover, histamine and clinically relevant antihistamines synergized with the GR agonist dexamethasone to induce gene transactivation and transrepression in a gene-specific manner. Our work provides a delineation of molecular mechanisms underlying the widespread clinical association of antihistamines and GR agonists, which may contribute to future dosage optimization and reduction of well-described side effects associated with glucocorticoid administration.


A comparison, by sweep sampling, of the insect fauna from corn and sweet potato monocultures and dicultures in Costa Rica.
The insect fauna of 80 day-old plots of corn and sweet potato monocultures and dicultures in Costa Rica were compared using sweep sampling. Six hundred sweeps were taken in each of the three habitats. There were 15% more total species in the diculture than either monoculture but approximately the same total number of individuals. There were 75% more species and approximately 100% more individuals of parasitic Hymenoptera in the diculture than the monocultures. The ratio of numbers of phytophagous individuals to predaceous/parasitic individuals was lowest in the diculture (2.5) and highest in the sweet potato monoculture (14.3). It is suggested that these patterns may be explained if phytophagous insects are limited basically by abundance and diversity of food so that a diculture is at best the sum of two monocultures. However if abundance and diversity of parasitic insects depends more on structural complexity, the result of putting together two monocultures would be synergistic in terms of numbers and species of insects.Two chrysomelid beetles and two leaf-hopper species that were extremely common in the monocultures were significantly less common or absent in the polyculture, and only one leaf-hopper that was rare in the monocultures was relatively more common in the diculture. Comparison of species similarity showed that the corn monoculture and the diculture were much more similar than the sweet potato monoculture and the diculture, and the two monocultures showed the least similarity.Statistically smoothed out species-subsample curves were constructed for each of the three habitats, the curves were fitted to a mathematical model, and they were then extended in order to predict the theoretical total number of species in all three communities sampled. Extrapolation of the curves suggests that approximately 33% of the total sweepable insect community was sampled in the three habitats.One year after the initial sweep samples were taken, the populations of two sweet potato pests, Diabrotica balteata and Diabrotica adelpha, were sampled ten times over a 120 day period in plots of corn and sweet potato monocultures and dicultures. Approximately 50 days after planting, the numbers of both beetles on sweet potato in monocultures were much higher than in dicultures. This trend continued the rest of the season, the difference reaching a maximum approximately 90 days after planting.These data suggest that indigenous agriculturalists are correct: increasing resource diversity in a cropping system may act as a form of biological control, by increasing the relative abundance and diversity of the predaceous parasitic fauna and decreasing the abundance of the major herbivores.


Organic synthesis in the Smith Group: a personal selection of a dozen lessons learned at the University of Pennsylvania.
The passionate study of the complex and ever-evolving discipline of organic synthesis over more than a four-decade span is certain to elucidate meaningful and significant lessons. Over this period, Amos B. Smith III, the Rhodes-Thompson Professor of Chemistry and Member of the Monell Chemical Senses Center at the University of Pennsylvania, has mentored well over 100 doctoral and masters students, more than 200 postdoctoral associates and numerous undergraduates, in addition to collaborating with a wide spectrum of internationally recognized scholars. His research interests, broadly stated, comprise complex molecule synthesis, the development of new, versatile and highly effective synthetic methods, bioorganic and medicinal chemistry, peptide mimicry chemistry and material science. Each area demands a high level of synthetic design and execution. United by a passion to unlock the secrets of organic synthesis, and perhaps of Nature itself, innumerable lessons have been, and continue to be, learned by the members of the Smith Group. This lead article in a Special Issue of the Journal of Antibiotics affords an opportunity to share some of those lessons learned, albeit a small selection of personal favorites.


Treatment and mortality risk of older adults with non-small cell cancer in Taiwan: A population-based cohort study.
Older patients tend to have decreased physical functions and more comorbidities than younger patients. At present, the best management for very elderly patients with lung cancer is not known. In this study, we aimed to investigate treatment and mortality risk of older adults with non-small cell cancer (NSCLC) in Taiwan. This study analyzed data from the Taiwan Cancer Registry database. Patients aged ≥80 years with newly diagnosed NSCLC between 2010 and 2017 were included. Treatment options were categorized as curative, palliative, and no treatment. Patients were followed up until death or December 31, 2020. Univariable and multivariable Cox proportional hazards models were used to estimate mortality risk, and Kaplan-Meier survival curves were drawn. A total of 11 941 patients, aged ≥80 years, with newly diagnosed NSCLC between 2010 and 2017 were identified from the Taiwan Cancer Registry and followed up until 2020. The mean age was 84.4 ± 3.7 years old, and 7468 (62.54%) were men. The Kaplan-Meier survival curves showed significant differences across the three treatment options (log-rank p < 0.001). Results from multivariate Cox regression demonstrated that patients on palliative treatment (adjusted HR: 0.52, 95% CI: 0.48-0.56, p < 0.001) and curative treatment (adjusted HR: 0.45, 95% CI: 0.42-0.48, p < 0.001) had a significantly lower mortality risk than those with no treatment. The subgroup analyses stratified by cancer stages also showed consistent findings. Elderly patients with NSCLC had significantly decreased mortality risk when receiving curative or palliative treatment compared with those without treatment. In the future, further studies are warranted to investigate complications and quality of life of elderly patients with NSCLC during palliative or curative treatment.


Use of offline artificial intelligence in a smartphone-based fundus camera for community screening of diabetic retinopathy.
The aim of the study was to analyse the reliability of an offline artificial intelligence (AI) algorithm for community screening of diabetic retinopathy. A total of 1378 patients with diabetes visiting public dispensaries under the administration of the Municipal Corporation of Greater Mumbai between August 2018 and September 2019 were enrolled for the study. Fundus images were captured by non-specialist operators using a smartphone-based camera covering the posterior pole, including the disc and macula, and the nasal and temporal fields. The offline AI algorithm on the smartphone marked the images as referable diabetic retinopathy (RDR) or non-RDR, which were then compared against the grading by two vitreoretinal surgeons to derive upon the sensitivity and specificity of the algorithm. Out of 1378 patients, gradable fundus images were obtained and analysed for 1294 patients. The sensitivity and specificity of diagnosing RDR were 100% (95% CI: 94.72-100.00%) and 89.55% (95% CI: 87.76-91.16%), respectively; the same values for any diabetic retinopathy (DR) were 89.13% (95% CI: 82.71-93.79%) and 94.43% (95% CI: 91.89-94.74%), respectively, with no false-negative results. The robustness of the offline AI algorithm was established in this study making it a reliable tool for community-based DR screening.


Complications of pediatric femur fractures treated with titanium elastic nails: a comparison of fracture types.
The purpose of this study was to analyze complications seen in children with femur fractures stabilized with titanium elastic nails, comparing their use in stable and unstable fracture patterns. A retrospective review was performed on 39 consecutive children with femur fractures treated with titanium elastic nails. Patients with comminuted or long oblique fractures were classified as having "length-unstable" fractures. Patients were analyzed qualitatively for any predictive factors or treatment variables that increased the risk of complications. There were 24 patients with complications (62%). Eight patients (21%) underwent unplanned surgery prior to complete fracture union. Six of the eight requiring unplanned surgery were treated for "length-unstable" fractures. The complications that required unplanned surgery for either prominent nails or loss of reduction occurred more commonly in unstable non-transverse fracture patterns. The authors conclude that in patients with "length-unstable" femur fractures, consideration should be given to methods of treatment other than titanium flexible intramedullary nails.


Radiotherapy-activated NBTXR3 nanoparticles modulate cancer cell immunogenicity and TCR repertoire.
Radiotherapy is a powerful and widely used technique for the treatment of solid tumors. Beyond its ability to destroy tumor cells, it has been demonstrated that radiotherapy can stimulate the anti-tumor immune response. Unfortunately, this effect is mainly restricted to the irradiated lesion, as tumor control outside the treated field (called the 'abscopal effect') is rarely obtained. In addition, many pro-tumoral factors prevent this anti-tumor immune response from being sustained and efficient. We previously reported that radiotherapy-activated NBTXR3 produced a significant CD8-dependent abscopal effect in immunocompetent mice bearing CT26.WT tumors, while radiotherapy failed to generate such a response. To identify the mechanisms that may explain this response, we evaluated the capacity of radiotherapy-activated NBTXR3 to modulate the immunogenicity of tumor cells by analysis of immunogenic cell death biomarkers and immunopeptidome sequencing. In vivo, we analyzed treated tumors for CD4+, CD8 + and CD68 + cell infiltrates by immunohistochemistry and digital pathology and sequenced the T cell receptor (TCR) repertoire in both treated and untreated distant tumors. We showed that NBTXR3 activated by radiotherapy both increased immunogenic cell death biomarkers and modulated the immunopeptidome profile of CT26.WT cells. Immunohistochemistry analysis of treated tumors revealed a significant increase in CD4+, CD8 + and CD68 + cell infiltrates for NBTXR3 activated by radiotherapy group, compared to radiotherapy. We also measured significant modifications in TCR repertoire diversity in the radiotherapy-activated NBTXR3 group, both in treated and distant untreated tumors, compared to radiotherapy alone. These results indicate that radiotherapy-activated NBTXR3 can act as an effective immunomodulator, modifying tumor cell immunogenicity and impacting the lymphocyte population.


Evaluation of the potential role of a new mutation in mabA in modifying the response of Mycobacterium tuberculosis to isoniazid.
A new mutation in mabA, Thr4Ile, was identified in a Mycobacterium tuberculosis isolate from a patient whose culture remained positive after treatment. The same mutation was found in another 5 patients infected by different strains. A putative role for this mutation in the process of diminishing susceptibility to isoniazid is evaluated.


Effects of cell wall degrading enzymes on carbohydrate fractions and metabolites in stomach and ileum of pigs fed wheat bran based diets.
Pigs were fed diets containing 40% wheat bran incubated with a water: acetic acid mixture (control, C) and a cellulase (Cel-i) or xylanase (Xyl-i) preparation or with addition of the cellulase (Cel-a) or xylanase (Xyl-a) preparation immediately before feeding. Stomach and ileal samples were analysed for pH, osmolality, soluble saccharides, volatile fatty acids (VFA) and lactic acid. Incubation of wheat bran resulted in a small reduction of NDF and an increase in the amount of soluble starch, B-glucans and saccharides (glucose, xylose and arabinose), especially after incubation with the cellulase preparation. Two hours after feeding, significantly higher arabinose and xylose concentrations were present in the stomach for diets Cel-i, Cel-a and Xyl-i. In the ileum xylose and arabinose concentrations were higher 2 to 4 and 6 to 8 hours after feeding the enzyme-treated diets. In stomach and ileum there were no differences between the diets in pH, osmolality, VFA and lactic acid concentrations, but ileal VFA concentration from 4 h after feeding tended to be higher for diets Cel-i and Xyl-i. It can be concluded that the amount of soluble saccharides in stomach and small intestine and the ileal VFA concentration may be increased by cell wall degrading enzyme preparations.


Trajectories of the heart rate characteristics index, a physiomarker of sepsis in premature infants, predict Neonatal ICU mortality.
Trajectories of physiomarkers over time can be useful to define phenotypes of disease progression and as predictors of clinical outcomes. The aim of this study was to identify phenotypes of the time course of late-onset sepsis in premature infants in Neonatal Intensive Care Units. We examined the trajectories of a validated continuous physiomarker, abnormal heart rate characteristics, using functional data analysis and clustering techniques. We analyzed continuous heart rate characteristics data from 2989 very low birth weight infants (<1500 grams) from nine NICUs from 2004-2010. Despite the relative homogeneity of the patients, we found extreme variability in the physiomarker trajectories. We identified phenotypes that were indicative of seven and 30 day mortality beyond that predicted by individual heart rate characteristics values or baseline demographic information. Time courses of a heart rate characteristics physiomarker reveal snapshots of illness patterns, some of which were more deadly than others.


Sexual size dimorphism, canine dimorphism, and male-male competition in primates: where do humans fit in?
Sexual size dimorphism is generally associated with sexual selection via agonistic male competition in nonhuman primates. These primate models play an important role in understanding the origins and evolution of human behavior. Human size dimorphism is often hypothesized to be associated with high rates of male violence and polygyny. This raises the question of whether human dimorphism and patterns of male violence are inherited from a common ancestor with chimpanzees or are uniquely derived. Here I review patterns of, and causal models for, dimorphism in humans and other primates. While dimorphism in primates is associated with agonistic male mate competition, a variety of factors can affect male and female size, and thereby dimorphism. The causes of human sexual size dimorphism are uncertain, and could involve several non-mutually-exclusive mechanisms, such as mate competition, resource competition, intergroup violence, and female choice. A phylogenetic reconstruction of the evolution of dimorphism, including fossil hominins, indicates that the modern human condition is derived. This suggests that at least some behavioral similarities with Pan associated with dimorphism may have arisen independently, and not directly from a common ancestor.


CISH is a negative regulator of IL-13-induced CCL26 production in lung fibroblasts.
Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts. Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss- and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively. Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/β signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss- and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26. These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma.


Diffused light conditions in canopy gaps in a beech (Fagus crenata Blume) forest.
A simple model for diffused light conditions in canopy gaps is presented. The vertical changes of illuminance in gaps calculated from the model agreed with the changes observed in a beech forest in Japan. The illuminance in a given sized gap in the forest could be estimated from the model. Size distribution of gaps in the forest suggested that most gaps were too small for the frequent occurrence of pioneer tree species.


Baicalein protects mice against radiation-induced DNA damages and genotoxicity.
Baicalein is the major flavonoid extracted from the root of Scutellaria baicaleins. This flavonoid is used extensively in Chinese herbal medicine. In the present study baicalein is evaluated for its radioprotective properties. Human blood cells when exposed to the γ-radiation ex vivo in presence of baicalein underwent the reduced DNA damage compared to the control. Baicalein administration prior to the whole-body γ-radiation (4 Gy) exposure of mice resulted in protecting the damage to the DNA as measured in their blood cells by alkaline comet assay. Mice when exposed to the radiation (whole body; 1.7 Gy) resulted in damage to the bone marrow as measured by micronucleated reticulocyte (MNRET) formation. Baicalein pre-treatment reduces the radiation induced damage to the bone marrow cells, as there was decrease in the percentage MNRET formation. These findings indicate radio-protecting ability of baicalein.


Combination of site of infarct, unrecognized glucose intolerance, and reinfarction after acute myocardial infarction in normotensive subjects is determinant of the development of subsequent systemic hypertension: a pilot study.
The natural history of hypertension in healthy normotensive subjects has been described in the Framingham population. We aim to study the rate of progression to hypertension in normotensive subjects after acute myocardial infarction (AMI). One hundred seventy-three consecutive normotensive subjects admitted to the Coronary Care Unit with AMI were studied retrospectively with prospective follow-up 4 years after AMI. All the patients who were not known to be diabetic on admission (n = 150) underwent glucose tolerance test (GTT) at 2 months after AMI. Among the 15 patients (8.7%) who developed hypertension, GTT was abnormal in 75% (diabetes = 3, impaired glucose tolerance = 9). There were significantly more Indo-Asians and fewer whites in the hypertensive than in the normotesive patients but they were similar in age and gender, creatinine kinase level, and rate of thrombolysis during admission for AMI. Multiple regression analysis showed that progression to hypertension was a function of the presence of anterior AMI on admission (P = .0297), abnormal GTT (P = .0156), and subsequent MI on follow-up (P = .0122), but was independent of age, gender, smoking habit, body weight, previous MI, thrombolysis, creatinine kinase level, subsequent development of heart failure, and intake of beta-adrenergic blockade or angiotensin-converting enzyme (ACE) inhibitor. Of the hypertensive patients, 47% (n = 7) died compared to 8% (n = 13) of the normotensive subjects (P < .0001). Progression to hypertension in normotensive subjects after AMI is determined by a combination of the site of the infarct, GTT 2 months after AMI, and subsequent development of a second MI. Systemic hypertension after AMI is associated with a high mortality.


The European Portuguese version of the Reproductive Concerns After Cancer Scale (RCACS): A psychometric validation for young adult female cancer survivors.
The purpose of this study was to evaluate the psychometric properties of the Portuguese version of the 18-item Reproductive Concerns After Cancer Scale (RCACS) among young adult female cancer survivors. The psychometric validation was conducted based on a convenience sample of 192 cancer survivors aged between 18 and 40 years. An exploratory factor analysis (EFA) was used to test the factor structure of the Portuguese version of RCACS and reliabilities were examined. Convergent and discriminant validity was also used to assess the construct validity. The Hospital Anxiety and Depression Scale (HADS), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORT QLQ-C30) and the need for parenthood and rejection of child-free lifestyle subscales of the Fertility Problem Inventory (FPI) were used as convergent measures. A five-factor model was obtained with acceptable fit indexes and internal consistencies (.72<α<.89): (1) fertility potential, (2) children's health risk and future life, (3) partner disclosure, (4) barriers to getting pregnant/having children and (5) acceptance. Overall, convergent and discriminant validities were confirmed. Levels of anxiety and depression symptoms as well as health-related quality of life (QoL) had weak-to-moderate associations with reproductive concerns. Women who had a child or did not want a biological child were less concerned. This scale proved to be a reliable and valid measure of reproductive concerns for the Portuguese population with potential relevance for application in clinical practice.


Theoretical study on the geometry and vibration of 1-[6-(4-Chlorophenyl)-1-[(6-chloropyridin-3-yl)methyl]-2-[(6-chloropyridin-3-yl)methylsulfanyl]-4-methyl-1,6-dihydropyrimidin-5-yl]ethanone.
The solid phase FT-IR and FT-Raman spectra of 1-[6-(4-chlorophenyl)-1-[(6-chloropyridin-3-yl)methyl]-2-[(6-chloropyridin-3-yl)methylsulfanyl]-4-methyl-1,6-dihydropyrimidin-5-yl]ethanone (C25H21Cl3N4OS) were recorded in the region 4000-400 and 3500-100cm(-1), respectively. The vibrational spectra have been computed using density functional theory (B3LYP) and ab initio molecular orbital calculation (HF) with 6-31G(d, p) basis sets. A close agreement was achieved between the observed and calculated frequency by employing normal coordinate calculations. The observed and simulated spectra were found to be well comparable.


Correction to: Outcomes of hypercalcemia of malignancy in patients with solid cancer: a national inpatient analysis.
In the original publication the last column of the table 2 is aligned incorrectly. The correct version of table 2 is given below.


Rapid absorption from the urinary bladder of a series of n-alkyl carbamates: a route for the recirculation of drugs.
1 The rate of loss of a series of n-alkyl carbamates from the lumen of the urinary bladders of female rats has been studied. 2 The rate of loss obeys first order kinetics and was not affected by water flux across the bladder wall nor by binding of the carbamates to it. 3 The rate of loss of octyl carbamate was reduced by about 76% by the presence of 5% Tween 80. Histological evidence indicates that this may be due to the formation of a thin luminal lining which may be adsorbed Tween 80 or mucopolysaccharide material. 4 The absorption rate of the carbamates was limited by their hydrophilicity but reached a plateau for the more lipophilic homologues with a half life for loss of approximately 10 min. 5 The implications of these results with regard to the recirculation of unmetabolized drugs and hydrolysed conjugates of drugs, the systemic absorption of intravesically applied cancer chemotherapeutic agents and bladder wall permeability to carcinogens are discussed.


Comparisons in childhood obesity and cardiometabolic risk factors among urban Saudi Arab adolescents in 2008 and 2013.
We aimed to compare the prevalence of childhood obesity and other cardiometabolic risk factors from two independent cohorts (2008 and 2013) in Riyadh, Saudi Arabia. A total of 4549 adolescents aged 12-18 years [2454 boys, 2095 girls], taken from two independent cohorts, 5 years apart (2008 and 2013), were included. Anthropometrics were measured, and fasting blood samples were taken to ascertain glucose and lipid profile. The overall prevalence of obesity was significantly higher in 2013 [15.3 (95% confidence interval 13.7-16.9)] than 2008 [12.6 (11.3-13.9)] (P = 0.012). Stratified by sex, the prevalence of obesity among boys was significantly higher in 2013 than 2008 [2008 = 12.0 (10.3-13.7) versus 2013 = 17.4 (15.1-19.7); P < 0.001]. The age groups 13 and 15 years had a significantly higher mean triglycerides in 2013 than 2008 (P-values 0.003 and <0.001, respectively) and lower mean HDL-cholesterol also in the 13 years old age group (P < 0.001). The prevalence of childhood obesity in Saudi Arabia has increased in particular age groups (13-15 years) during a 5-year span. Special attention is warranted in these vulnerable age groups, particularly in boys, as cardiometabolic risk factors appear to worsen.


[Malignant peripheral nerve sheath tumor in the posterior mediastinum].
We report the case of a 52-year-old male patient who developed a malignant peripheral nerve sheath tumor (MPNST) localized in the posterior mediastinum. The diagnosis of this rare tumor is difficult because the clinical presentation of the benign or malignant types is often similar, i.e. elective pain and bone erosions. Similarly, radiological procedures do not always allow distinction between the two types. MNR and CT-scan are the first line procedures: they localize and characterize the lesions, and CT-scan can also be a guide for biopsies. Histological diagnosis is required, but diagnosis can be compromised by the heterogeneous nature of the tumor. Surgical treatment should be undertaken whenever possible. Survival was unusually long in our patient, more than 5 years after discovery of the MPNST. This type of sarcoma is often very aggressive with frequent development of local recurrences and metastases.


Preparative enantiomeric separation of potent AMP-activated protein kinase activator by HPLC on amylose-based chiral stationary phase. Determination of enantiomeric purity and assignment of absolute configuration.
The development of high performance liquid chromatography method on amylose-based stationary phases (Chiralpak AD) has permitted to achieve the preparative enantioseparation of one benzimidazole derivative, potent-AMP-kinase (AMPK) activator with satisfactory yields. Analytical enantioseparation method was optimized and validated to determine the enantiomeric purity. Using the UV detection, repeatability, limits of detection (LD) and quantification (LQ) were determined. Single-crystal X-ray analysis was successful to determine the absolute configuration of the individual enantiomers. A relation between the retention order and the absolute configuration of the enantiomers was established.


Adrenal steroid hormones in short children born small for gestational age.
Programming of the endocrine axis has been postulated to occur during critical phases of fetal development and is affected by intrauterine growth retardation. The aim of this study was to investigate this hypothesis with regard to adrenal steroid hormones. Thus, serum cortisol and dehydroepiandrosterone sulphate (DHEAS) levels were compared in children born small for gestational age (SGA) who remained short and in children born at an appropriate size for gestational age (AGA), of both short and normal stature. Seven serum samples for cortisol measurements were taken during a 24-h period from a total of 184 prepubertal individuals. The study group comprised 53 children born SGA who remained short (41 boys, 12 girls; mean chronological age, 8.8 +/- 2.5 years). The reference groups of children born AGA were as follows: 75 healthy short children (56 boys, 19 girls; mean chronological age, 10.8 +/- 2.6 years) and 56 healthy children of normal height (37 boys, 19 girls; mean chronological age, 11.3 +/- 1.8 years). A single serum sample for measurement of DHEAS was taken between 1000 and 1400 h in 110 of the 184 children (33 short SGA, 42 short AGA and 35 AGA of normal height). Serum cortisol and DHEAS were measured by radioimmunoassay. No differences were found between children born SGA and children born AGA in either cortisol levels, calculated as area under the curve (AUC), or the circadian cortisol rhythm, estimated from the calculated nadir, the peak and the amplitude. No difference between the groups was found for serum DHEAS concentrations. Serum cortisol levels, expressed as AUC, and serum DHEAS levels did not correlate with size at birth. However, when adjusted for age at investigation, serum DHEAS, but not serum cortisol, correlated with weight at birth. Serum cortisol levels and rhythms do not correlate with size at birth and are similar in children born small for gestational age who remain short and children born appropriate size for gestational age of both short and normal stature. However, DHEAS levels in young children before adrenarche correlated inversely with weight at birth, indicating a relationship with fetal growth.


Higher rate of serious perinatal events in non-Western women in Denmark.
To elucidate possible mechanisms behind the increased risk of stillbirth and infant mortality among migrants in Denmark, this study aimed to analyse characteristics of perinatal deaths at Hvidovre Hospital 2006-2010 - -according to maternal country of origin. We identified children born at Hvidovre Hospital who died perinatally and included the patient files in a series of case studies. Our data were linked to data from population-covering registries in Statistics Denmark. Timing, causes of death as well as social, medical and obstetric characteristics of the parents were described according to maternal country of origin. This study included 125 perinatal deaths. The data indicated that intrapartum death, death caused by maternal disease, lethal malformation and preterm birth may be more frequent among non-Western than among Danish-born women. Obesity and disposition to diabetes may also be more prevalent among the non-Western women. The role of obesity, gestational diabetes, preeclampsia and severe congenital anomalies should be a main focus in improving our understanding the increased risk of perinatal death among non-Western migrant women in Denmark. Six of 28 perinatal deaths in the non-Western group were intrapartum deaths and warrants further concern. This project was funded by the Danish Council for Strategic Research as part of the SULIM project. The linkage of data from patient files to data from Statistics Denmark was approved by the Danish Data Protection Agency. Only anonymised data were used.


Effect of zoledronate on the responses of osteocytes to acute parathyroid hormone.
The bone anabolic effect of parathyroid hormone (PTH) therapy is blunted when used in patients who were previously on bisphosphonate treatment. Osteocytes may play a role in the bisphosphonate silencing effect on PTH therapy since bisphosphonates have been shown to reach the lacunocanalicular system. In vivo osteocyte studies pose a significant challenge. For the current study, we developed a simple method to isolate RNA from cortical bone enriched with osteocytes. Our purpose was to investigate how zoledronate (ZA) treatment modulates the responses of osteocytes and the bone marrow (BM) to acute PTH treatment. Mice received ZA treatment for 3 months and a single PTH injection prior to death. Bone was histomorphometrically evaluated. Gene expression was assessed at the RNA level in osteocytes and BM. Endothelial progenitor cells (EPCs) and γδT cells were analyzed in the BM and blood using flow cytometry. We found that ZA treatment altered bone responses to PTH. Expression of Sfrp4, a Wnt antagonist, was significantly increased in ZA-affected osteocytes. BM EPCs were increased in response to acute PTH but not when treatment was combined with ZA. ZA treatment augmented EPCs in the BM but not in blood, which suggests that ZA treatment may have differential effects between the BM and blood. These findings indicate that osteocytes and BM EPCs in mice on ZA treatment respond differently to acute PTH from those not receiving ZA. This may partially explain the mechanisms of previous reports that ZA therapy attenuates the anabolic effect of PTH in bone.


Simultaneous modeling prediction of three key quality attributes of tablets by powder physical properties.
Tensile strength (TS), solid fraction (SF), and tablet weight variability (TWV) are all key quality factors to be considered during the tablet manufacturing process. For predicting them, a novel powder texture measurement methodology was proposed to study the texture attributes of 32 types of powders, and 10 types of unknown powders were used to validate the model. Principal component analysis (PCA) was used to classify the powders. Standard least-squares models were constructed to predict the TS and SF of tablets using texture properties as independent variables, with model R2 values of 0.9188 and 0.8672, respectively. Moreover, due to the advantages of decision trees in classification performance and computation time, multi-node decision trees were constructed, and the approximate range of the TS and SF can be quickly predicted by using only 2-4 key texture attributes. Partial least squares-discriminant method (PLS-DA) algorithm was used to determine whether TWV was qualified by using texture and other physical attributes of powders. In conclusion, the constructed models predicted TS, SF, and TWV well and provide an effective reference for facilitating the development of tablet formulation for direct compression (DC).


Economic evaluations of non-communicable diseases conducted in Sub-Saharan Africa: a critical review of data sources.
Policymakers in sub-Saharan Africa (SSA) face challenging decisions regarding the allocation of health resources. Economic evaluations can help decision makers to determine which health interventions should be funded and or included in their benefits package. A major problem is whether the evaluations incorporated data from sources that are reliable and relevant to the country of interest. We aimed to review the quality of the data sources used in all published economic evaluations for cardiovascular disease and diabetes in SSA. We systematically searched selected databases for all published economic evaluations for CVD and diabetes in SSA. We modified a hierarchy of data sources and used a reference case to measure the adherence to reporting and methodological characteristics, and descriptively analysed author statements. From 7,297 articles retrieved from the search, we selected 35 for study inclusion. Most were modelled evaluations and almost all focused on pharmacological interventions. The studies adhered to the reporting standards but were less adherent to the methodological standards. The quality of data sources varied. The quality level of evidence in the data domains of resource use and costs were generally considered of high quality, with studies often sourcing information from reliable databases within the same jurisdiction. The authors of most studies referred to data sources in the discussion section of the publications highlighting the challenges of obtaining good quality and locally relevant data. The data sources in some domains are considered high quality but there remains a need to make substantial improvements in the methodological adherence and overall quality of data sources to provide evidence that is sufficiently robust to support decision making in SSA within the context of UHC and health benefits plans. Many SSA governments will need to strengthen and build their capacity to conduct economic evaluations of interventions and health technology assessment for improved priority setting. This capacity building includes enhancing local infrastructures for routine data production and management. If many of the policy makers are using economic evaluations to guide resource allocation, it is imperative that the evidence used is of the feasibly highest quality.