Dissociation of murine B-cell proliferation and differentiation by monoclonal antibody, NIM R2.
The rat monoclonal antibody NIM-R2 has been shown to be directed towards a cell surface differentiation antigen of murine B lymphocytes which is expressed to a greater or lesser extent at different phases of B-cell activation. In this report, NIM-R2 is shown to be capable of modulating the functional capacity of B cells. In the presence of the monoclonal antibody, the ability of fully mature antibody-forming cells to secrete their product is inhibited. This effect is, however, short-lived, with the cells quickly recovering secretory capacity, even in the continued presence of the monoclonal antibody. NIM-R2 also inhibits the generation of antibody-forming cells in culture, the addition of antibody as late as the third day of a 4-day culture period being effective in this respect. The evidence presented here suggests that these inhibitory effects of NIM-R2 are mediated through interference with separate mechanisms. Our data also indicate that, although NIM-R2 inhibits the generation of antibody-forming cells from their B-cell precursors, it does not affect the B-cell proliferative response. The findings are discussed in terms of their relevance to current models of B-cell activation and differentiation.


Anaerobic transformations of organic matter in collection systems.
Anaerobic transformations of wastewater organic matter in the bulk water phase of collection system networks were investigated in laboratory-scale experiments. The wastewater was collected from three locations, which provided samples with different characteristics, ranging from young to mature. Hydrolysis, fermentation, and sulfate reduction were identified as the most important anaerobic processes. Significant quantities of readily biodegradable substrate were produced by hydrolysis of complex organic substrates. The readily biodegradable substrate was further fermented into volatile fatty acids (VFA). The rate of fermentation was found to be limited by the hydrolysis process. The readily biodegradable substrate generated was almost entirely composed of VFA, primarily acetic and propionic acids. A production of sulfide was observed in all experiments, demonstrating that part of the readily biodegradable substrate was consumed by sulfate respiration. The sulfide production was most pronounced in mature wastewater that had previously undergone extended anaerobic transport.


Global challenges and globalization of bioethics.
This article analyzes problems and implications for man and nature connected with the formation of a new architecture of science, based on the convergence of nanotechnology, biotechnology, information technology, and cognitive science (NBIC). It also describes evolution and genesis of bioethics, a scientific discipline and social practice with a special role of ethical management of potential risks of scientific research. The aim was to demonstrate the necessity of bioethical social control in the development of a global bioeconomy driven by NBIC technologies.


The Impact of Second Coordination Sphere Methionine-Aromatic Interactions in Copper Proteins.
The interplay between the primary and secondary coordination spheres in biological metal sites plays an essential role in controlling their properties. Some of the clearest examples of this are from copper sites in blue and purple copper proteins. Many such proteins contain methionine (Met) in the primary coordination sphere as a weakly bound ligand to Cu. While the effects of replacing the coordinated Met are understood, less so is the importance of its second-sphere interactions. In this combined informatics and experimental study, we first present a bioinformatics investigation of the second-sphere environments in biological Met-Cu motifs. The most common interaction is between the Met-CH3 and the π-face of a phenylalanine (Phe) (81% of surveyed structures), tyrosine (Tyr) (11%), and tryptophan (Trp) (8%). In most cases, the Met-CH3 also forms a contact with a π-face of one of a Cu-ligating histidine-imidazole. Such interactions are widely distributed in different Cu proteins. Second, to explore the impact of the second-sphere interactions of Met, a series of artificial Pseudomonas aeruginosa azurin proteins were produced where the native Phe15 was replaced with Tyr or Trp. The proteins were characterized using optical and magnetic resonance spectroscopies, X-ray diffraction, electrochemistry, and an investigation of the time-resolved electron-transfer kinetics of photosensitizer-modified proteins. The influence of the Cu-Met-Aro interaction on azurin's physical properties is subtle, and the hallmarks of the azurin blue copper site are maintained. In the Phe15Trp variant, the mutation to Phe15 induces changes in Cu properties that are comparable to replacement of the weak Met ligand. The broader impacts of these widely distributed interactions are discussed.


Molecular and clinical characteristics of 26 cases with structural Y chromosome aberrations.
Structural abnormalities include various types of translocations, inversions, deletions, duplications and isochromosomes. Structural abnormalities of the Y chromosome are estimated to affect less than 1% of the newborn male population and are particularly hazardous for male reproductive function. The objective of this study was to characterize a group of patients with structural abnormalities of the Y chromosome. All patients who visited our laboratory between 2007 and 2010 underwent cytogenetic investigations. Among these, we detected 26 patients with structural abnormalities of the Y chromosome. To confirm the structural Y chromosome alterations, we used special bandings, FISH and multiplex PCR to detect Y chromosome microdeletions. Of the 26 patients presented here, 11 had an isodicentric Y chromosome, 7 had an inversion, 3 had a translocation, 2 had a derivative, 2 had a Yqs and 1 had a deletion. Sixteen were diagnosed with azoospermia, 8 as normal fertile males and 1 as a man who was unable to donate semen due to mental retardation. One of the patients having 45,X/46,X,idic(Y) was reported to be phenotypically female with primary amenorrhea and without uterus. Deletions of the AZFbc region were correlated with the sperm concentration (p < 0.05), but no correlation with the levels of FSH, LH, testosterone, prolactin and estradiol were found. The present report shows that the precise identification of structural Y chromosome aberrations may be clinically important for genetic counseling and assisted reproductive technology treatment.


Induction and repression of genes of the rat small intestine mucosa with excess and insufficiency of alimentary iron.
Three-month-old Wistar rats were fed with either an iron-deficient diet for 21 days or an iron-excessive diet for 10 days. Fifty thousand clones of a cDNA library of small intestine mucosa were hybridized with two radioactive samples synthesized on mRNA from the small intestine of rats fed with iron-excessive or iron-deficient diets. As a result, genes were found with mRNA level depending on the content of alimentary iron. Iron deficiency increased the mRNA level of genes of apolipoprotein AIV and class 1 antigen and decreased the mRNA level of the apolipoprotein AI gene and of an unknown gene, while no change was found in the mRNA level of the gene of fatty acid-binding protein. Excess of dietary iron resulted in the increase in mRNA of this gene and in a decrease in the apolipoprotein AI gene and in the unknown gene. The mRNA of apolipoprotein AIV did not change. The data indicate that changes in the level of alimentary iron influence the expression of genes involved in metabolism of lipids.


Ferroptosis Activation Scoring Model Assists in Chemotherapeutic Agents' Selection and Mediates Cross-Talk With Immunocytes in Malignant Glioblastoma.
Gliomas are aggressive tumors in the central nervous system and glioblastoma is the most malignant type. Ferroptosis is a programmed cell death that can modulate tumor resistance to therapy and the components of tumor microenvironment. However, the relationship between ferroptosis, tumor immune landscape, and glioblastoma progression is still elusive. In this work, data from bulk RNA-seq analysis, single cell RNA-seq analysis, and our own data (the Xiangya cohort) are integrated to reveal their relationships. A scoring system is constructed according to ferroptosis related gene expression, and high scoring samples resistant to ferroptosis and show worse survival outcome than low scoring samples. Notably, most of the high scoring samples are aggressive glioblastoma subtype, mesenchymal, and classical, by calculating RNA velocity. Cross-talk between high scoring glioblastoma cells and immunocytes are explored by R package 'celltalker'. Ligand-receptor pairs like the TRAIL or TWEAK signaling pathway are identified as novel bridges implying how ferroptosis modulate immunocytes' function and shape tumor microenvironment. Critically, potential drugs target to high scoring samples are predicted, namely, SNX2112, AZ628, and bortezomib and five compounds from the CellMiner database. Taken together, ferroptosis associates with glioblastoma aggressiveness, cross-talk with immunocytes and offer novel chemotherapy strategy.


Impact of Covid-19 on Pediatric Ophthalmology Care: Lessons Learned.
The COVID-19 pandemic came with many new challenges that forced personal and professional lifestyle modifications. Medical facilities were in scarcity against this new unknown enemy and were challenged with the overloaded patient flow, scarcity of healthcare staff, and evolving treatment modalities with a better understanding of the virus each day. Ophthalmology as a "branch of medicine" suffered challenges initially because of a lack of guidelines for patient management, close working distance during routine examinations, and halt of major surgeries, including cataracts. Pediatric ophthalmology had major implications, as reduced outpatient visits would mean deeper amblyopia, and changed lifestyles, including online classes and home refinement, predisposing children to myopia, digital eye strain, and worsening of strabismus. COVID-19 also unveiled underlying accommodation and convergence anomalies that predisposed pediatric and adolescent patients to an increased prevalence of headache and acute onset esotropia. Teleophthalmology and other innovative solutions, including the use of prism glasses, safe slit-lamp shields, alternative ways of school screening with the use of photoscreeners, performing retinoscopy only when needed, and using autorefractors were among the few guidelines or modifications adopted which helped in the efficient and safe management of pediatric patients. Many pediatric ophthalmologists also suffered in terms of financial constraints due to loss of salary or even closure of private practices. School screening and retinopathy of prematurity screening suffered a great setback and costed a lot of vision years, data of which remains under-reported. Important implications and learnings from the pandemic to mitigate future similar situations include using teleophthalmology and virtual platforms for the triage of patients, managing non-emergency conditions without physical consultations, and utilizing home-based vision assessment techniques customized for different age groups. Though this pandemic had a lot of negative implications, the innovations, modifications, and other important learnings helped pediatric ophthalmologists in navigating safely.


Identifying transport behavior of single-molecule trajectories.
Models of biological diffusion-reaction systems require accurate classification of the underlying diffusive dynamics (e.g., Fickian, subdiffusive, or superdiffusive). We use a renormalization group operator to identify the anomalous (non-Fickian) diffusion behavior from a short trajectory of a single molecule. The method provides quantitative information about the underlying stochastic process, including its anomalous scaling exponent. The classification algorithm is first validated on simulated trajectories of known scaling. Then it is applied to experimental trajectories of microspheres diffusing in cytoplasm, revealing heterogeneous diffusive dynamics. The simplicity and robustness of this classification algorithm makes it an effective tool for analysis of rare stochastic events that occur in complex biological systems.


Sickle cell and G-6-PD deficiency gene in cord blood samples: experience at King Khalid University Hospital, Riyadh.
Cord blood samples (1039) collected at King Khalid University Hospital were analysed for abnormal haemoglobins using electrophoresis at alkaline and acid pH, for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency using spectrophotometric method and for G-6-PD phenotypes using electrophoresis and specific staining. Only two samples showed the presence of Hb AS and no case of sickle cell anaemia was identified. The Hb S gene frequency was 0.00096. This was the lowest frequency identified so far in different regions of Saudi Arabia. The frequency of G-6-PD deficiency was calculated separately in the males and females, and was found to be 3.605 per cent in the males and 0.195 per cent in the females. Phenotyping showed the presence of G-6-PD-B+ as the normal enzyme at a frequency of 0.943 in both males and females and G-6-PD-A+ at a frequency of 0.0208 in males and 0.0059 in females. The deficient variant was mainly G-6-PD Mediterranean which occurred at a frequency of 0.0341 and 0.0019 in males and females, respectively. Only one case of G-6-PD-A- was identified in the males giving a frequency of 0.0019. This is the first report of Hb S and G-6-PD deficiency genes in cord blood samples in Riyadh. Comparison of the results in Riyadh with values reported elsewhere showed that Riyadh had the lowest frequency of both Hb S and G-6-PD deficiency gene.


Thymoquinone ameliorates obesity-induced metabolic dysfunction, improves reproductive efficiency exhibiting a dose-organ relationship.
Women with obesity are more likely to have a complicated reproductive life. Insulin resistance and metabolic dysfunction are associated with obesity. Thymoquinone (TQ) is a well-known antioxidant, considered to be an AMPK-activator. The goal of this work was to investigate the ability of TQ to improve fertility and lactation and clarify the possible mechanism. Female C57BL/6 mice were subjected to High Fat Diet (HFD) supplemented with TQ (10% pmm) and TQ (20% pmm). Histopathological examination was conducted on mammary and ovarian samples. Metabolic and oxidant status was evaluated, and qRT-PCR analysis was performed to verify AMPK/PGC1α/SIRT1 metabolic pathway activity. The present study reports positive effects of TQ on ovarian metabolic function in a dose-dependent manner. TQ showed its positive effects on mammary gland metabolic function at lower dose. This is the first study that indicates these dose related impacts of TQ. Abbreviations: AKT1: serine-threonine protein kinase 1; AMPK: 5' AMP-activated protein kinase; CAT: catalase; CON: control; FBS: fasting blood sugar; GLUT1: glucose transporter 1; GSH: reduced glutathione; GSSG: Glutathione disulfide; HE: hematoxylin and eosin stains; HDL: high-density lipoprotein; HFD: high fat diet; IL-6: interleukin-6; K18: keratin 18; LD: lactation day; LDL: low-density lipoprotein; LKB1: serine-threonine liver kinase B1; MDA: malondialdehyde; mTOR: the mammalian target of rapamycin; NAD: nicotinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide phosphate; NS: nigella sativa; PBS: phosphate-buffered saline; PGC1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SIRT1: sirtuin 1; SOD: superoxide dismutase; T-AOC: total antioxidants; TFAM: transcription factor A mitochondrial; TG: triglycerides; TNF-α: tumor necrosis factor-α; TQ: thymoquinone; TQ10: high fat diet + thymoquinone 10% ppm; TQ20: high fat diet + thymoquinone 20% ppm; UCP2: uncoupling Protein 2.


Intra-aneurysmal pressure difference in human saccular aneurysms.
Intra-aneurysmal pressure and piezometric head differences with respect to common carotid values have been recorded by unidirectional and differential transducers in two patients undergoing craniotomy for aneurysms of the anterior communicating and middle cerebral arteries. Recordings were taken under normal systemic arterial pressure during temporary occlusion of the common carotid artery, during intra operative carotid arteriography and under controlled arterial hypotension. Predominance of the common carotid pressure head and piezometric head over the aneurysmal value was found in the two cases.


Factors Influencing Staff's Attitude Toward Electroconvulsive Therapy: A Comparison of New Versus Experienced Electroconvulsive Therapy Clinics.
Despite being a highly effective treatment, electroconvulsive therapy (ECT) is still stigmatized even among professionals. The aim of this study was to identify factors associated with a positive attitude toward ECT among health care workers. We investigated staff's attitude and their self-assessment of knowledge while introducing ECT in 3 German psychiatric clinics. Furthermore, we compared this data to that of a clinic where ECT has been applied with a long tradition. An anonymous questionnaire was answered by n = 182 employees in the ECT-introducing clinics (novices) and n = 68 employees in the clinic with a long history of ECT (experts). Irrespective of the clinical history, the majority of participants approved the application of ECT in their clinic. Factors associated with a positive attitude were (a) profession (physicians presented a more positive mindset about ECT than nursing staff), (b) subjective feeling of being adequately informed, and (c) having had contact to patients undergoing ECT. Interestingly, the general attitude toward ECT did not differ between subjects who reported to have seen an ECT and those who had not. When introducing ECT as a new treatment into a clinic, formal information should be adapted to the needs of each profession with a special emphasis on nurses. To further increase acceptance, contact to ECT-experienced patients (professionals taught by patients) might result in a more positive attitude toward ECT than participation in an ECT treatment itself.


Possible mechanism of central nervous system targeting and neurological symptoms of the new-coronavirus (COVID-19): literature review.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the 2019 Coronavirus Disease (COVID-19) has been associated with several neurological symptoms. This review aimed to highlight the possible mechanism of central nervous system (CNS) targeting and the neurological symptoms that may occur with the COVID-19 infection. The case reports containing the keywords "neurological symptoms" and "COVID-19" were thoroughly reviewed to identify possible mechanisms of CNS targeting and neurological manifestations associated with COVID-19 infection. The angiotensin-converting enzyme-2 (ACE2) receptors have been identified as the functional receptor for SARS-CoV-2. SARS-CoV-2 can affect the CNS through the following mechanisms: 1) Direct infection. 2) Blood pathway. 3) Neuronal pathway. 4) Immune-mediated injury/pathway (Cytokine Storm Syndrome). COVID-19 virus, a neurotropic virus, was isolated from the cerebral fluid (CSF) and responsible for several neurological manifestations. The COVID-19 infection primarily affects CD4+ and CD8+ T-lymphocytes and it induces a surge of inflammatory cytokines, known as Cytokine Storm Syndrome (CSS). The Interlukine-6 (IL-6) is the primary CSS component. The IL-6, interferon-γ and endothelial growth factor were significantly higher in COVID-19 infected compared to non-infected individuals. The improvement of the COVID-19 patients after interleukin receptor blockers supports the CSS theory. The spectrum of SARS-CoV-2 neurological manifestations includes encephalitis, viral meningitis, post-COVID-19 infectious acute disseminated encephalitis, Guillain-Barré Syndrome (GBS), Miller-Fisher syndrome (MFS) and acute cerebrovascular disease (CVD). Several COVID-19-associated neurological manifestations have been reported. Thus, it is important to identify and treat neurological symptoms as soon as possible to avoid long-term effects. The care providers should take the appropriate preventive precautions because patients can present with neurological manifestations of COVID-19 without any respiratory symptoms. Future research is warranted to confirm the relationship between SARS-CoV-2 and the development of neurological manifestations.


Extrafascially harvested radial artery in CABG: technique of harvest, complications, and mid-term angiographic patency.
The initial use of radial artery (RA) for myocardial revascularization was abandoned due to high incidence of early occlusion. The revival of radial artery graft use was attributable to the improved harvesting techniques as well as the introduction of antispasm prophylaxis by calcium channel blockers. Various techniques of harvesting RA have been described and extrafascial harvest is one of the techniques to minimize trauma during harvest. The immediate arm complications and mid-term angiographic patency of the radial artery grafts harvested using extrafascial no-touch technique and used as a conduit for myocardial revascularization were not documented well in the literature. Between January 1997 and February 2003, 385 patients were operated for coronary artery bypass grafting using radial artery graft as one of the conduits. We used extrafascial no-touch technique and a coagulation current cautery at a strength of 10 to 15 W to control the bleeding during the blunt dissection of the radial artery. The complications related to the radial artery harvest were prospectively recorded and analyzed. This conduit was used as a free graft in 272 patients, left internal mammary artery and radial artery Y graft in 61 patients, Right internal mammary artery, and radial artery composite in situ graft in 52 patients. The radial artery donor arm in these patients was evaluated for complications. Angiographic evaluation of the radial artery graft was carried out randomly in 51 patients and angiography was done after an interval of 6 to 72 months (mean 29.55 +/- 21.77 months). In two patients, although the preoperative Allen test was negative, the radial artery was not harvested after completion of the dissection and was left in situ because the pulse could not be felt in the radial artery distal to the clamp after trial occlusion of the mid part of RA. The arm complications noticed were cutaneous parasthesias in 9 patients (2.33%), which subsided in 4 weeks, stitch abscess and superficial wound infection in 4 patients (1.03%), hematoma/seroma treated with drainage in outpatient department in 3 patients (0.78%), and wound infection requiring open drainage in an operating room in one patient (0.76%). Angiographically radial artery was patent in 48 of 51 patients (94.11%). The extrafascial technique of radial artery harvest is safe and an easily reproducible method with minimal arm complications and good mid-term clinical and angiographic results. The mid-term angiographic patency rates of RA harvested using this technique are comparable to that of the published results of intrafascially harvested radial artery grafts and left internal mammary artery grafts.


Preceding stimulus sequence effects on the oddball-P300 in young and healthy older adults.
The present study examined the mechanisms underlying stimulus sequence effects on the parietal P300 and frontal P3a elicited by infrequent targets in an oddball paradigm and compared these effects between young and older adults. Fifty young and 50 healthy older adults completed a simple visual oddball task including an infrequent (20%) target stimulus. A temporo-spatial principal component (PCA) analysis was used to disentangle the parietal P300 and frontal P3a from overlapping ERP components. The typical age-related anterior-shift of the P300 was, according to the PCA, due to a disproportionately large contribution of a frontal P3a in older adults. Up to about five successive standards preceding a target, the results replicated the typical increase in parietal P300 amplitude to targets with increases in preceding standards. A novel finding was that with further increases in preceding standards, P300 amplitude to targets gradually decreased. This pattern is consistent with a combination of relatively automatic, temporary expectations and higher level, conscious expectations driving P300 sequential effects, with different dynamics over the course of successively presented standards. However, an expectancy-based account of these sequential effects was challenged by an analogous analysis of RTs. Sequential effects on the frontal P3a differed from the parietal P300: The P3a was largest when a target followed another target and continually decreased with the number of intervening standards. Notably, sequential effects were strikingly similar for young and older adults, and implications for the functional significance of morphological changes in P300 due to aging are discussed.


[Evaluation of in vivo labeled cytotoxic T lymphocytes and cytokine-induced killer cells migration and distribution of subcutaneous gastric tumor model in nude mice].
To investigate the migration and distribution of CTL (cytotoxic T lymphocyte) and CIK (cytokine-induced killer) cells in gastric tumor model. Subcutaneous gastric tumor model was established by BGC-823 cancer cells in nude mice. Both CTL and CIK cells were labeled with 99Tc(m) directly and then inoculated into nude mice with subcutaneous tumor by intravenous injection separately. Three mice of each group were evaluated by single-photon emission computerized tomography (SPECT) at 1 h, 6 h and 24 h post-inoculation. After SPECT imaging, 3 mice in each group were sacrificed and got samples of the tumor, liver, spleen, kidney, lung, intestine, etc. The tissue samples were weighed and radioactivity was determined with a well-type scintillation counter. The accumulation of labeled CTL and CIK cells in tissues were expressed as %ID/g (percentage activity of injection dose per gram of tissue) and T/NT (tumor/non-tumor) values were analyzed. The tracing of both cells in SPECT showed a clear migration path away from the injection point to solid tumor, and can be detected in all organs and tissues such as liver, spleen, kidney, lung and intestine, etc not long after injection. The %ID/g peak values of CTL in organs from the highest to the lowest were as follows: tumor (7.79 +/- 0.46), liver (4.12 +/- 0.51), intestine (2.71 +/- 0.16), kidney (1.44 +/- 0.25), spleen (1.24 +/- 0.12), kidney (1.12 +/- 0.11), and all the T/NTs were above 1. The %ID/g peak values of CIK cells in organs from the highest to the lowest were as follows: liver (6.64 +/- 0.67), tumor (5.47 +/- 0.87), intestine (3.55 +/- 0.23), kidney (2.34 +/- 0.41), spleen (1.45 +/- 0.17), lung (1.27 +/- 0.21), and T/NTs > 1 except for liver. After injection, the %ID/g values of tumor in CTL group were 2.35 +/- 0.28 (1 h), 4.58 +/- 0.52 (6 h) and 7.79 +/- 0.46 (24 h) respectively while the %ID/g values of tumor in CIK group 2.23 +/- 0.46 (1 h), 3.25 +/- 0.70 (6 h) and 5.47 +/- 0.87 (24 h) respectively. At 24 h point, the %ID/g of CTL in tumor was much higher than CIK cells (P < 0.05). The definite directional tumor-targeting capacity of CTL and CIK cells in tumor-bearing nude mice is promising.


Gamma Knife Radiosurgery in Sphenopetroclival Meningiomas: Preliminary Experience at the Iran Gamma Knife Center.
The aims of this study were to characterize the epidemiologic, histologic, and radiologic aspects of sphenopetroclival meningiomas (SpPCMs) and to evaluate the outcome of Gamma Knife radiosurgery (GKRS) either as an adjunct to microsurgery or as a primary SpPCM treatment modality. In this retrospective study, medical records of patients with SpPCM who underwent GKRS at the Iran Gamma Knife Center between April 2003 and March 2012 were analyzed. We assessed 122 patients with SpPCMs, including 101 women and 21 men, aged 24-94 years. The mean tumor volume was 12.24 ± 9.30 mL. Patients received 22.32 ± 3.29 Gy and 13.18 ± 1.02 Gy maximal and average marginal dose of GKRS, respectively. The most common complaint was visual impairment, followed by facial sensory impairment and headache. The most frequently involved cranial nerves were III, IV, and VI in 72.1% of patients, followed by II in 52.9%, and V in 35.5%. After radiosurgery, headaches improved in 90.0%, diplopia in 75.0%, and ptosis in 63.0% of patients. On magnetic resonance imaging, tumor size was reduced, unchanged, or increased in 77, 44, and 1 patient, respectively. Progression-free survival at the 5-year follow-up was 56.6%. Younger age (hazard ratio = 0.972, P = 0.011) and lower tumor volume (hazard ratio = 0.959, P = 0.009) were the main prognostic factors for progression-free survival. GKRS can be an effective alternative treatment for controlling the progression of SpPCM tumors, producing appropriate clinical outcomes and few complications.


Glucan, Water-Dikinase 1 (GWD1), an ideal biotechnological target for potential improving yield and quality in rice.
The source-sink relationship determines the overall agronomic performance of rice. Cloning and characterizing key genes involved in the regulation of source and sink dynamics is imperative for improving rice yield. However, few source genes with potential application in rice have been identified. Glucan, Water-Dikinase 1 (GWD1) is an essential enzyme that plays a pivotal role in the first step of transitory starch degradation in source tissues. In the present study, we successfully generated gwd1 weak mutants by promoter editing using CRISPR/Cas9 system, and also leaf-dominant overexpression lines of GWD1 driven by Osl2 promoter. Analysis of the gwd1 plants indicated that promoter editing mediated down-regulation of GWD1 caused no observable effects on rice growth and development, but only mildly modified its grain transparency and seed germination. However, the transgenic pOsl2::GWD1 overexpression lines showed improvements in multiple key traits, including rice yield, grain shape, rice quality, seed germination and stress tolerance. Therefore, our study shows that GWD1 is not only involved in transitory starch degradation in source tissues, but also plays key roles in the seeds, which is a sink tissue. In conclusion, we find that GWD1 is an ideal biotechnological target with promising potential for the breeding of elite rice cultivars via genetic engineering.


SARS-CoV-2 infections in migrants and the role of household overcrowding: a causal mediation analysis of Virus Watch data.
Migrants are over-represented in SARS-CoV-2 infections globally; however, evidence is limited for migrants in England and Wales. Household overcrowding is a risk factor for SARS-CoV-2 infection, with migrants more likely to live in overcrowded households than UK-born individuals. We aimed to estimate the total effect of migration status on SARS-CoV-2 infection and to what extent household overcrowding mediated this effect. We included a subcohort of individuals from the Virus Watch prospective cohort study during the second SARS-CoV-2 wave (1 September 2020-30 April 2021) who were aged ≥18 years, self-reported the number of rooms in their household and had no evidence of SARS-CoV-2 infection pre-September 2020. We estimated total, indirect and direct effects using Buis' logistic decomposition regression controlling for age, sex, ethnicity, clinical vulnerability, occupation, income and whether they lived with children. In total, 23 478 individuals were included. 9.07% (187/2062) of migrants had evidence of infection during the study period vs 6.27% (1342/21 416) of UK-born individuals. Migrants had 22% higher odds of infection during the second wave (total effect; OR 1.22, 95% CI 1.01 to 1.47). Household overcrowding accounted for approximately 36% (95% CI -4% to 77%) of these increased odds (indirect effect, OR 1.07, 95% CI 1.03 to 1.12; proportion accounted for: indirect effect on log odds scale/total effect on log odds scale=0.36). Migrants had higher odds of SARS-CoV-2 infection during the second wave compared with UK-born individuals and household overcrowding explained 36% of these increased odds. Policy interventions to reduce household overcrowding for migrants are needed as part of efforts to tackle health inequalities during the pandemic and beyond.


Penetration of peripheral glucose and insulin into cerebrospinal fluid in rats.
In this study the penetration of plasma insulin and glucose into the cerebrospinal fluid (CSF) was investigated. Rats were implanted with cannulas in the cisterna magna and into the left and right jugular veins. Freely moving rats were intravenously infused during 4 h with either glucose solution (10 mg/min) or saline. Before, during, and after the infusions, simultaneous blood and CSF samples were taken. Infusion of glucose led to an immediate rise of both plasma glucose and insulin. Although CSF glucose followed plasma glucose within 10 min, CSF insulin was unchanged until 40 min. After termination of the glucose infusion, levels of all substances returned to base line within 10 min. Twenty-four-hour food deprivation resulted in a significant decrease of plasma glucose, plasma insulin, CSF glucose, and CSF insulin. At the onset of eating after deprivation, an increase of plasma glucose and insulin occurred within 10 min, whereas CSF glucose was delayed between 10 and 40 min, after which ad libitum values were attained or surpassed. CSF insulin always remained below ad libitum levels. It is concluded that 1) glucose and insulin penetrate into the CSF and 2) CSF insulin and glucose can fulfill a putative feedback in homeostatic control of food intake and body weight.


Analysis and Validation of Contactless Time-Gated Interrogation Technique for Quartz Resonator Sensors.
A technique for contactless electromagnetic interrogation of AT-cut quartz piezoelectric resonator sensors is proposed based on a primary coil electromagnetically air-coupled to a secondary coil connected to the electrodes of the resonator. The interrogation technique periodically switches between interleaved excitation and detection phases. During the excitation phase, the resonator is set into vibration by a driving voltage applied to the primary coil, whereas in the detection phase, the excitation signal is turned off and the transient decaying response of the resonator is sensed without contact by measuring the voltage induced back across the primary coil. This approach ensures that the readout frequency of the sensor signal is to a first order approximation independent of the interrogation distance between the primary and secondary coils. A detailed theoretical analysis of the interrogation principle based on a lumped-element equivalent circuit is presented. The analysis has been experimentally validated on a 4.432 MHz AT-cut quartz crystal resonator, demonstrating the accurate readout of the series resonant frequency and quality factor over an interrogation distance of up to 2 cm. As an application, the technique has been applied to the measurement of liquid microdroplets deposited on a 4.8 MHz AT-cut quartz crystal. More generally, the proposed technique can be exploited for the measurement of any physical or chemical quantities affecting the resonant response of quartz resonator sensors.


One-Pot Protolignin Extraction by Targeted Unlocking Lignin-Carbohydrate Esters via Nucleophilic Addition-Elimination Strategy.
Protolignin extraction can facilitate structure elucidation and valorization of lignin in biorefinery, but is rather challenging due to the complex chemical bonds present. Here, we developed the in situ generated NH3-reline (IGNR) system to realize one-pot protolignin extraction from lignocellulose. In the IGNR system, reline consisting of choline chloride and urea acted as both a solvent and a nucleophile generator, and the nucleophilic addition-elimination mechanism was verified by model compound studies. The in situ generated NH3 could precisely cleave the lignin-carbohydrate esters in lignocellulose with a near-quantitative retention of carbohydrates. The extracted IGNR-Protolignin exhibited native lignin substructure with high molecular weight and high β-O-4' content (41.5 per 100 aromatic units). In addition, the up-scaled kilogram reaction demonstrated the feasibility of the IGNR system for potential industrial application in a green and sustainable pathway. This work represents a breakthrough toward protolignin extraction in practice with the future goal of achieving total biorefinery.


Ocular Trauma Score in Siderosis Bulbi With Retained Intraocular Foreign Body.
The purpose of this study was to investigate the clinical characteristic and visual outcome of siderosis bulbi with retained intraocular foreign body (IOFB) and to validate the predictive value of the Ocular Trauma Score (OTS) in siderosis bulbi. Certain numerical values rendered to the OTS variables at present were summated (Table 1) and converted into 5 OTS categories as performed in the OTS study. The prognostic value of OTS was first assessed in cases of siderosis bulbi resulting from a chemical reaction of retained IOFBs. Twenty-four eyes of 24 patients diagnosed with siderosis bulbi who underwent surgery between 2007 and 2013 at our medical centre were reviewed. Due to patients' ignorance in ocular injuries, delayed presentation by the patient (54.17%) and no history of trauma (16.67%) were the most common cause of siderosis bulbi with IOFB retention. The main symptom of all these patients was impaired vision. The most common complications were cataract (23/24, 95.83%), followed by retinal pigmentary degeneration (15/22, 68.18%), iris heterochromia (14/24, 58.33%), pupillary mydriasis (10/21, 47.62%), secondary glaucoma (6/24, 25.00%), relative afferent pupillary defect (6/24, 25.00%), and retinal detachment (3/24, 12.50%). IOFBs were removed in 22 eyes (91.67%), except 2 enucleated eyes with absolute glaucoma (8.33%). Among all the patients (24 eyes), the best-corrected visual acuity improved in 63.64%, unchanged in 18.18% and deteriorated in 18.18% after surgical intervention. No statistically significant difference was found between the categorical distributions of our patients and those in the OTS study group. Further promotion and education on eye protection are needed to minimize visual loss from siderosis bulbi. The OTS, which was designed to predict visual outcomes of general ocular trauma, may also provide reliable information about the prognosis of siderosis bulbi resulting from a chemical reaction of retained IOFBs.


dsRNA Binding Domain of PKR Is Proteolytically Released by Enterovirus A71 to Facilitate Viral Replication.
Enterovirus 71 (EV-A71) causes hand, foot and mouth disease in young children and infants, but can also cause severe neurological complications or even death. The double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), an interferon-induced antiviral protein, phosphorylates the regulatory α-subunit of the eukaryotic translation initiation factor 2 in response to viral infection, thereby blocking the translation of cellular and viral mRNA and promoting apoptosis. The cleavage of PKR after infection with poliovirus, a prototype enterovirus, has been reported by others, but the underlying mechanism of this cleavage and its role in viral replication remain unclear. In the present study, we show that viral 3C protease cleaves PKR at a site, Q188, which differs from the site cleaved during apoptosis, D251. In contrast to the conventional phosphorylation of PKR by dsRNA, EV-A71 3C physically interacts with PKR to mediate the phosphorylation of PKR; this effect is dependent on 3C protease activity. Overexpression of a catalytically inactive PKR mutant (K296H) accelerates viral protein accumulation and increases virus titer, whereas a K64E substitution in the dsRNA binding site abolishes this advantage. We also demonstrate that PKR cleavage mediated by EV-A71 3C protease produces a short N-terminal PKR fragment that can enhance EV-A71 replication, in terms of viral RNA, viral protein, and viral titers. We conclude that PKR is co-opted by EV-A71 via viral protease 3C-mediated proteolytic activation to facilitate viral replication.


Genotype specific starch characteristics in relation to resistant starch formation in table potatoes.
Table potatoes are important staple foods with a higher satiety index than rice or pasta, but also reach a higher glycemic index (GI), leading to contradictory dietary recommendations. Previous studies identified resistant starch (RS) content as primary criterium for the GI. Hence, the relevance of starch molecular properties for genotype specific RS formation was investigated. Six common table potato varieties were used to investigate the starch pasting and digestibility in whole tubers and their isolated starches. A Micro-Visco Amylograph was used to simulate the cooking process for isolated starches and determine their pasting curves. In vitro starch digestibility was determined for raw freeze-dried cooked tubers kept at 4 °C for up to 72 h and for isolated starches. Moreover, important molecular starch properties, including granule size distribution, molar mass distribution, amylose content and inter- and intra-molecular structures were determined. The results show substantial differences in starch digestibility and pasting characteristics among genotypes. Soraya starch showed small and low-branched amylopectin and small granule size as characteristics for rapid RS formation in isolated starch, which was not evident in the whole tuber. In contrast, Huckleberry Gold formed RS in the tuber already shortly after cooking, whereas slow RS formation was evident in the isolated starch. The results suggest, that starch structural characteristics play a role in RS formation, but non-starch constituents of the tuber have to be considered as well. The results help to identify breeding goals for varieties with low GI and high nutritional value.


Immunofluorescent analysis of plasma fibronectin incorporation into the lung during acute inflammatory vascular injury.
Incorporation of plasma fibronectin into tissues is believed to influence endothelial cell-cell interaction, as well as endothelial cell adhesion to matrix. We used immunofluorescent microscopy coupled with tissue extraction of noncovalently incorporated fibronectin to delineate the time course for matrix incorporation of soluble plasma-derived fibronectin into the lung of sheep during postoperative bacteremia. Adult sheep were surgically prepared with both lung and peripheral lymph fistulas. Sheep were anesthetized 2 days following surgery and injected intravenously with a sublethal dose of live Pseudomonas aeruginosa, which consisted of 5 x 10(8) live organisms suspended in 0.9% saline. Bacterial infusion elicited a 300% increase in lung transvascular protein clearance but no increase in peripheral transvascular protein clearance. Purified dimeric human plasma fibronectin (hFn), used as an "immunologic marker," was then infused intravenously (100 mg/sheep) into two additional groups of sheep (nonbacteremic control group and bacteremic experimental group) and allowed to mix with the plasma pool of endogenous soluble sheep fibronectin (sFn). Incorporation of the plasma-derived hFn into the lung matrix and its distribution in relation to endogenous sheep fibronectin in the matrix was assessed by dual-label immunofluorescence using antibodies specific to either sFn or hFn. Human fibronectin from the vascular compartment codistributed with endogenous sheep fibronectin in the lung matrix. Moreover, its deposition into the lung was markedly increased in postoperative bacteremic sheep compared with nonbacteremic control sheep. Increased hFn deposition in the lung with bacteremia was clearly apparent within 2 h. The hFn deposited in the lung was nonextractable using a heparin-urea tissue extraction buffer, suggesting its rapid covalent cross-linking and incorporation into the lung matrix. Microscopic analysis of serial lung biopsies revealed focal areas of inflammation with an intense mononuclear infiltrate into the lungs by 2 h in the bacteremic sheep. Interstitial edema and vascular endothelial injury were observed by 4 h, with alveolar edema apparent over 6 to 8 h. Thus, postoperative bacteremia results in a rapid incorporation of plasma fibronectin into the lung matrix. This may be a physiologic mechanisms to stabilize the integrity of the lung vascular barrier.


Advanced Glycation End Products Modulate Amyloidogenic APP Processing and Tau Phosphorylation: A Mechanistic Link between Glycation and the Development of Alzheimer's Disease.
Advanced glycation end products (AGEs) are implicated in the pathology of Alzheimer's disease (AD), as they induce neurodegeneration following interaction with the receptor for AGE (RAGE). This study aimed to establish a mechanistic link between AGE-RAGE signaling and AD pathology. AGE-induced changes in the neuro2a proteome were monitored by SWATH-MS. Western blotting and cell-based reporter assays were used to investigate AGE-RAGE regulated APP processing and tau phosphorylation in primary cortical neurons. Selected protein expression was validated in brain samples affected by AD. The AGE-RAGE axis altered proteome included increased expression of cathepsin B and asparagine endopeptidase (AEP), which mediated an increase in Aβ1-42 formation and tau phosphorylation, respectively. Elevated cathepsin B, AEP, RAGE, and pTau levels were found in human AD brain, coincident with enhanced AGEs. This study demonstrates that the AGE-RAGE axis regulates Aβ1-42 formation and tau phosphorylation via increased cathepsin B and AEP, providing a new molecular link between AGEs and AD pathology.


Lectin-like, oxidized low-density lipoprotein receptor-1-deficient mice show resistance to age-related knee osteoarthritis.
The lectin-like, oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1)/ox-LDL system contributes to atherosclerosis and may be involved in cartilage degeneration. The purpose of this study was to determine whether the LOX-1/ox-LDL system contributes to age-related osteoarthritis (OA) in vivo, using LOX-1 knockout (LOX-1 KO) mice. Knee cartilage from 6, 12, and 18-month old (n = 10/group) C57Bl/6 wild-type (WT) and LOX-1 KO mice was evaluated by determining the Osteoarthritis Research Society International (OARSI) score of Safranin-O stained samples. The prevalence of knee OA in both mouse strains was also investigated. Expression levels of LOX-1, ox-LDL, runt-related transcription factor-2 (Runx2), type-X collagen (COL X), and matrix metalloproteinase-13 (MMP-13) in the articular chondrocytes were analyzed immunohistologically. No significant difference was observed in the mean scores of WT (2.00±0.61) and LOX-1 KO mice (2.00±0.49) at 6 months of age (P=1.00, n=10). At 12 and 18 months of age, the mean scores of LOX-1 KO mice (3.75±0.93 and 5.50±0.78) were significantly lower than those of WT mice (5.25±1.14 and 9.00±1.01; P<0.001 in both cases; n=10). The prevalence of OA in LOX-1 KO mice was lower than that in WT mice at 12 and 18 months of age (40 vs 70%, 70 vs 90%, respectively; n=10). The expression levels of Runx2, COL X, and MMP-13 in articular chondrocytes significantly decreased in LOX-1 KO, mice compared with those in WT mice. The study indicated that the LOX-1/ox-LDL system in chondrocytes plays a role in the pathogenesis of age-related knee OA, which is potentially a target for preventing OA progression.


Disseminated brown macules in an infant.
Urticaria pigmentosa is the most common form of mastocytosis. Mastocytosis usually presents at birth or early childhood, and may involve only the skin or, less commonly, other internal organs. Diagnosis is clinical, but a skin biopsy may be useful. Prognosis is usually good, and treatment focuses on the avoidance of certain triggers and administration of topical and systemic medications. Appropriate counselling of parents regarding the benign nature of this disease is important as most cases resolve by adolescence.


Diet and Gut Microbiota in Health and Disease.
Gut microbiota plays an important role in host health maintenance and disease pathogenesis. The development of a stable and diverse gut microbiota is essential to various host physiologic functions such as immunoregulation, pathogen prevention, energy harvest, and metabolism. At the same time, a dysbiotic gut microbiota associated with disease is altered in structure and function, and often characterized by a decrease in species richness and proliferation of pathogenic bacterial taxa. As a shared substrate between the host and the gut microbiota, diet significantly impacts the health and disease states of the host both directly and through gut microbial metabolite production. This is demonstrated in the examples of short-chain fatty acid and trimethylamine production via bacterial metabolism of dietary complex carbohydrates and choline, respectively. In disorders related to mucosal immune dysregulation such as inflammatory bowel disease, the dysbiotic gut microbiota and diet contribute to its pathogenesis. Reversal of dysbiosis through fecal microbiota transplantation and dietary interventions may thus represent important strategies to modify the gut microbiota and its metabolite production for health maintenance as well as disease prevention and management.


Herpes simplex virus type 2 trivalent protein vaccine containing glycoproteins C, D and E protects guinea pigs against HSV-1 genital infection.
A vaccine to prevent genital herpes is an unmet public health need. We previously reported that a trivalent vaccine containing herpes simplex virus type 2 (HSV-2) glycoproteins C, D, and E (gC2, gD2, gE2) produced in baculovirus and administered with CpG/alum as adjuvants blocks immune evasion mediated by gC2 and gE2 and virus entry by gD2. The vaccine protected guinea pigs against HSV-2 vaginal infection. We evaluated whether the HSV-2 vaccine cross-protects against HSV-1 because many first-time genital herpes infections are now caused by HSV-1. Guinea pigs were mock immunized or immunized with the trivalent vaccine and challenged intravaginally with a different HSV-1 isolate in two experiments. Guinea pigs immunized with the trivalent vaccine developed genital lesions on fewer days than the mock group: 2/477 (0.4%) days compared to 15/424 (3.5%) in experiment one, and 0/135 days compared to 17/135 (12.6%) in experiment two (both P < .001). No animal in the trivalent group had HSV-2 DNA detected in vaginal secretions: 0/180 days for trivalent compared to 4/160 (2.5%) for mock (P < .05) in experiment one, and 0/65 days for trivalent compared to 4/65 (6%) for mock in experiment two. Therefore, a vaccine designed to prevent HSV-2 also protects against HSV-1 genital infection.


Recent advances in the treatment of heart failure.
Treatment strategies for patients with heart failure and left ventricular systolic dysfunction continue to evolve as the complex pathophysiology of this disease is better understood. A number of advances have been made in recent years, most notably the addition of beta-receptor antagonists. In addition, recent studies have provided important information regarding the utility of angiotensin receptor antagonists, aldosterone receptor antagonists, and natriuretic peptides in the management of heart failure. Nonpharmacologic advances include resynchronization therapy, which appears to confer symptomatic improvement in some patients, and improvements in ventricular assist device technology. As the importance of neurohormonal activation in the progression of heart failure becomes increasingly apparent, new therapeutic strategies targeting these neurohormonal systems are being investigated.


Elevated risk of stillbirth in males: systematic review and meta-analysis of more than 30 million births.
Stillbirth rates have changed little over the last decade, and a high proportion of cases are unexplained. This meta-analysis examined whether there are inequalities in stillbirth risks according to sex. A systematic review of the literature was conducted, and data were obtained on more than 30 million birth outcomes reported in observational studies. The pooled relative risk of stillbirth was estimated using random-effects models. The crude mean rate (stillbirths/1,000 total births) was 6.23 for males and 5.74 for females. The pooled relative risk was 1.10 (95% confidence interval (CI): 1.07-1.13). The attributable fraction in the whole population was 4.2% (95% CI: 3.70-4.63), and the attributable fraction among male fetuses was 7.8% (95% CI: 7.0-8.66). Study populations from countries with known sex-biased sex selection issues had anomalous stillbirth sex ratios and higher overall stillbirth risks than other countries, reflecting increased mortality among females. Risk of stillbirth in males is elevated by about 10%. The population-attributable risk is comparable to smoking and equates to approximately 100,000 stillbirths per year globally. The pattern is consistent across countries of varying incomes. Given current difficulties in reducing stillbirth rates, work to understand the causes of excess male risk is warranted. We recommend that stillbirths are routinely recorded by sex. This will also assist in exposing prenatal sex selection as elevated or equal risks of stillbirth in females would be readily apparent and could therefore be used to trigger investigation.


Developmental changes in effects of histamine on segmental pulmonary vascular resistances.
In mature animals histamine infusion typically causes an H1-mediated increase and H2-mediated decrease in pulmonary vascular resistance (PVR). Moreover, low histamine concentrations can cause H1-mediated relaxation of vascular strips in mature animals, and in newborn animals histamine infusion causes only H1-mediated decreases in PVR. The mechanisms responsible for the different H1-mediated responses are unknown. We used an inflow-outflow occlusion technique to identify the sites of H1- and H2-mediated responses in lungs of developing lambs. Histamine was infused at 1.0 and 10.0 micrograms.kg-1.min-1 in control and H1- and H2-blocked lungs of newborn and juvenile lambs under "normoxic" and hypoxic conditions and in hypoxic H2-blocked lungs of mature sheep. In newborns histamine caused significant H1-mediated decreases in resistance across the arterial (delta Pa) and middle (delta Pm) segments of the circuit during both normoxia and hypoxia. In normoxic juveniles low-dose histamine caused H1-mediated decreases in the resistance across delta Pa and delta Pm, but the resistances across delta Pm rose above baseline at the higher dose. The venous segment exhibited only a high-dose increase in resistance. During hypoxia, the high-dose H1-mediated pressor response of delta Pm was attenuated compared with that during normoxia; however, the increase in venous resistance was unaffected. In hypoxic mature sheep, no low dose H1-mediated decrease in segmental resistances was seen, but at the higher dose an increase in all resistances occurred.(ABSTRACT TRUNCATED AT 250 WORDS)


Frequency-specific auditory brainstem responses to clicks masked by notched noise.
Frequency-specific auditory brainstem responses were recorded as a function of the intensity of a click masked by notch-filtered white noise (i.e. band-stop-filtered). The bandwidth of the notch was fixed at five-thirds octave and the center frequency was 0.5, 1.0, 2.0 or 4.0 kHz. For normally hearing subjects the latency of the main peak in the responses is increasing with decreasing center frequency of the notch and with decreasing click intensity. At a click sensation level of 60 dB, the mean of 7 subjects' peak latency was 6.7 ms for the center frequency 4.0 kHz and 10.2 ms for the center frequency 0.5 kHz. The thresholds derived from the frequency-specific responses were within 20 dB above the subjective thresholds of audibility of the clicks as heard when masked by notched noise.


Multi-stability and pattern-selection in oscillatory networks with fast inhibition and electrical synapses.
A model or hybrid network consisting of oscillatory cells interconnected by inhibitory and electrical synapses may express different stable activity patterns without any change of network topology or parameters, and switching between the patterns can be induced by specific transient signals. However, little is known of properties of such signals. In the present study, we employ numerical simulations of neural networks of different size composed of relaxation oscillators, to investigate switching between in-phase (IP) and anti-phase (AP) activity patterns. We show that the time windows of susceptibility to switching between the patterns are similar in 2-, 4- and 6-cell fully-connected networks. Moreover, in a network (N = 4, 6) expressing a given AP pattern, a stimulus with a given profile consisting of depolarizing and hyperpolarizing signals sent to different subpopulations of cells can evoke switching to another AP pattern. Interestingly, the resulting pattern encodes the profile of the switching stimulus. These results can be extended to different network architectures. Indeed, relaxation oscillators are not only models of cellular pacemakers, bursting or spiking, but are also analogous to firing-rate models of neural activity. We show that rules of switching similar to those found for relaxation oscillators apply to oscillating circuits of excitatory cells interconnected by electrical synapses and cross-inhibition. Our results suggest that incoming information, arriving in a proper time window, may be stored in an oscillatory network in the form of a specific spatio-temporal activity pattern which is expressed until new pertinent information arrives.


Large-scale analysis of gene expression: methods and application to the kidney.
Characterization of tissue-specific gene expression profiles, or transcriptomes, may serve two purposes: a) establishing relationships between cell transcriptomes and functions (i.e. molecular and physiological phenotypes) under physiological and pathophysiological conditions serves to elucidate gene functions, and b) determination of the totality of genes expressed in a cell seems a prerequisite for understanding cell functions, because the properties of proteins vary with their environment. Sophisticated methods are now available for transcriptome analysis. They are based on serial, partial sequencing of cDNAs (sequencing of expressed sequenced tags (ESTs) and serial analysis of gene expression (SAGE)), or on parallel hybridization of labeled cDNAs to specific probes immobilized on a grid (macro- and microarrays and DNA chips). Some methods were designed specifically to compare gene expression under different conditions (substractive hybridization, glass microarrays). However, all these methods require several microg of mRNA as starting material, making impossible, in most tissues, to analyse gene expression in homogeneous cell populations. To get around this limitation, we developed a scaled-down SAGE method (SAGE adaptation to downsized extracts: SADE) in our laboratory. SAGE is based on the following: a) each cDNA is characterized by a 10-bp informative sequence called tag, b) the information from several transcripts is condensed into a single DNA molecule by concatenation of several tags, c) sequencing of individual clones from the library of concatemers, computer analysis of sequences and interrogation of sequence databases allow quantitative gene expression profiling. Applied to microdissected mouse nephron segments, SADE made it possible to determine segment-specific transcriptomes.


Extrinsic allergic alveolitis (hypersensitivity pneumonitis) caused by Sphingobacterium spiritivorum from the water reservoir of a steam iron.
A case of extrinsic allergic alveolitis (EAA) caused by Sphingobacterium spiritivorum is described. The symptoms were associated with the use of a steam iron. The water reservoir was heavily contaminated with S. spiritivorum (10(6) CFU ml(-1)). This is the first report of S. spiritivorum as a causative agent of EAA.


Invasive aspergillosis.
Invasive fungal disease of humans caused by species of the genus Aspergillus Micheli ex Linnaeus has become a significant and prevalent problem in contemporary medicine, particularly with regard to the compromised host. This review addresses the current status of invasive aspergillosis, including microbiological, clinical, and pathologic aspects. Diagnostic and therapeutic considerations are discussed with a view toward early and aggressive intervention in order to prevent the high mortality rate associated with aspergillosis.


Bleeding disorders and heavy menses in adolescents.
The aim of this article is to review the current evidence for optimal management of the adolescent who presents with heavy periods. A recent survey of clinicians involved in adolescent gynaecology revealed a lack of consistency in the management of acute adolescent heavy menses. Very few randomized trials have been undertaken for acute heavy menses in women of any age, although one recent trial compared the oral contraceptive pill with oral medroxy progesterone acetate in adult women and showed them to be equally effective. The applicability of this trial to adolescents is unclear. Furthermore, although guidelines have been produced for menorrhagia management in adults, there is again only limited clinical research specific to adolescents and thus room for concern that the approaches for adult women may not always be appropriate for teenagers. One small study on the successful use of the levonorgestrel intrauterine system in teenagers does mean that this management option can now be considered. There is a need for careful assessment of the menstrual problem for, although anovulatory bleeds are the most common cause, bleeding disorders also need to be considered. Pelvic pathology is uncommon. Adolescents can also present with acute ongoing heavy bleeding. Whilst a range of approaches is reported, there are no studies to guide optimal management.


Spinal osteotomy in the presence of massive lumbar epidural scarring.
The combination of Massive epidural scarring and spinal deformity represents the ultimate challenge for the spinal deformity surgeon. This is observed more and more as the population is aging and the number of spine surgery is increasing. In assessing the patient with spinal deformity and epidural scarring, one should carry out a thorough medical work up including Dexa scan, comorbidities, and in most cases a Myelo-CT scan that will identify the extent of the previous fusion, the fixed or semi-rigid nature of the deformity with complete anterior fusion or only bone bridges, the evaluation of the previous instrumentation (if present) with possible screw misplacement, or halo around the screws, the extent of the previous laminectomy, the spinal stenosis and possible arachnoiditis and or meningocele. Once the requirement of deformity correction has been established with specific attention to the pelvic incidence and amount of lordosis required two basic choices can be made. The first one is to perform the spine realignment outside the massive epidural scarring whether this will be performed through simple posterior osteotomies, TLIF combined with Smith-Petersen osteotomies or Pedicle subtraction osteotomies. One should not forget about all the possibilities of an anterior or lateral approach to the spine that can also judiciously realign the spine at the level or at distance of the massive epidural scarring. These anterior realignments have to be supplemented with posterior fixation and or osteotomies. The other alternative is to perform the spine osteotomy at the level of the massive epidural scarring preferably at the junction of normal dura and epidural scar. Working around the dura that will require to be thinned down before the osteotomy is performed represents another challenge where incidental durotomies are not infrequent. During the closing of the osteotomy the dura may not be as giving as a normal dura and too aggressive closure of the osteotomy may not be possible. Instead a closing/opening osteotomy may be preferable, but will require an additional anterior column support. Attention to anterior column reconstruction and solid posterior instrumentation (iliac screws, four rods) should be given to all these revisions to have a long-lasting result.


Biomanagement of paper mill sludge using an indegenous (Lampito mauritii) and two exotic (Eudrilus eugineae and Eisenia foetida) earthworms.
Paper mills have severe problem in disposing effluent or semisolid sludge despite repeated recycling. It requires treatment prior to disposal of sludge. In recent years biological treatment methods received much attention and considered as efficient low-cost treatment. One such method is vermiculture treatment. The present study was carried out to dispose the paper mill sludge biologically using 2 exotic species (Eudrilus eugineae and Eiseniafoetida) and an indigenous species (Lampito mauritii) of earthworm. The paper mill sludge in various concentration 25%,50% and 75% were subjected to vermitub treatment for a period of 60 days. During the period of study data were collected on reproductive strategies of earthworm and chemical analysis of wastes before and after treatment. Results obtained indicate that 25% concentration of sludge was ideal and of the three worms used Eiseniafoetida proved to be the best worm for biomanagement.


[Demonstration of a 100-110 kd immunosuppressive fraction in the seminal fluid of swine].
The boar seminal fluid was fractionated in order to purify semen immunosuppressive factors. This species was chosen for its extremely abundant semen which allows large scale purifications and analyses. The fractions were tested on Balb/c mice spleen cells stimulated with LPS or PHA. The most active fraction was found in the 100-110 kd molecular weight range. The immunosuppressive activity occurred on both B and T cells, but was higher on the former. The active molecule is likely to be a protein. Another fraction of greater than 500 kd MW was also immunosuppressive but its activity disappeared by concentration. It possibly contained aggregates of the 100 kd molecules. The biological role of these immunosuppressive agents could be to protect sperm against female local immune reactions. Similar molecules in human semen might exist and favor the occurrence of acquired immunodeficiency syndrome in male homosexuals.


Recent Advances in Coronary Artery Bypass Grafting Techniques and Outcomes: A Narrative Review.
Coronary artery bypass grafting (CABG) has witnessed remarkable progress in recent years, driven by innovative techniques and refined approaches that have transformed patient outcomes and treatment paradigms. This review article comprehensively explores the latest advances in CABG techniques and their consequential impacts on patient outcomes. The advent of minimally invasive CABG techniques has revolutionized traditional surgical approaches. Robotic-assisted surgery and small thoracotomy methods offer reduced invasiveness, yielding shorter recovery times and improved patient satisfaction. Integrating CABG with percutaneous coronary intervention (PCI), hybrid procedures have emerged as a versatile strategy, providing tailored treatment solutions for complex coronary anatomies. The paradigm shift to off-pump CABG, which preserves the beating heart during surgery, has shown promise in reducing perioperative complications and neurocognitive deficits. Advances in graft selection, particularly the utilization of arterial grafts such as the internal thoracic artery and radial artery, have significantly enhanced graft patency rates and long-term survival. Adjunctive technologies, such as intraoperative imaging and graft flow assessment, have bolstered the precision of CABG procedures. Pharmacological agents have demonstrated their potential to improve graft outcomes. Surgical decision-making is now optimized based on patient characteristics and disease severity owing to the development of patient selection and risk stratification tools. Long-term results have also significantly improved. Patients undergoing CABG have higher survival rates, less angina, and better quality of life. Developing more resilient grafts through tissue engineering, using bioresorbable materials in graft fabrication, and using gene therapy to improve graft patency and overall cardiac recovery are all exciting future research directions. This review's summary of current developments in CABG procedures highlights their profoundly positive effects on patient outcomes. These developments can change the face of cardiovascular care by giving clinicians more tools to treat coronary artery disease (CAD) and enhance patients' quality of life.


TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets.
Phosphatidylserine (PtdSer) exposure on the surface of activated platelets requires the action of a phospholipid scramblase(s), and serves as a scaffold for the assembly of the tenase and prothrombinase complexes involved in blood coagulation. Here, we found that the activation of mouse platelets with thrombin/collagen or Ca(2+) ionophore at 20 °C induces PtdSer exposure without compromising plasma membrane integrity. Among five transmembrane protein 16 (TMEM16) members that support Ca(2+)-dependent phospholipid scrambling, TMEM16F was the only one that showed high expression in mouse platelets. Platelets from platelet-specific TMEM16F-deficient mice exhibited defects in activation-induced PtdSer exposure and microparticle shedding, although α-granule and dense granule release remained intact. The rate of tissue factor-induced thrombin generation by TMEM16F-deficient platelets was severely reduced, whereas thrombin-induced clot retraction was unaffected. The imaging of laser-induced thrombus formation in whole animals showed that PtdSer exposure on aggregated platelets was TMEM16F-dependent in vivo. The phenotypes of the platelet-specific TMEM16F-null mice resemble those of patients with Scott syndrome, a mild bleeding disorder, indicating that these mice may provide a useful model for human Scott syndrome.


Diverse stereocontrol effects induced by weakly coordinating anions. Stereospecific olefin polymerization pathways at archetypal C(s)- and C(1)-symmetric metallocenium catalysts using mono- and polynuclear halo-perfluoroarylmetalates as cocatalysts.
Counteranion effects on propylene polymerization rates and stereoselectivities are compared using Cs-symmetric Me2C(Cp)(Flu)ZrMe2 (1; Cp = C5H4,eta5-cyclopentadienyl; Flu = C13H8, eta5-fluorenyl) and C1-symmetric Me2Si(OHF)(CpR*)ZrMe2 (2; OHF = C13H16, eta5-octahydrofluorenyl; CpR* = eta5-3-(-)-menthylcyclopentadienyl) precatalysts activated with the mononuclear and polynuclear perfluoroarylborate, -aluminate, and -gallate cocatalysts/activators B(C6F5)3 (3), B(o-C6F5C6F4)3 (4), Al(C6F5)3 (5), Ph3C+B(C6F5)4- (6) Ph3C+FAl(o-C6F5C6F4)3- (7), Ga(C6F5)3 (8), and recently reported mono- and polymetallic trityl perfluoroarylhalometalates Ph3C+FB(C6F5)3- (9), Ph3C+FB(o-C6F5C6F4)3- (10), (Ph3C+)xFx[Al(C6F5)3]yx- (x = 1, y = 1, 11; x = 1, y = 2, 12; x = 2, y = 3, 13), Ph3C+(C6F5)3AlFAl(o-C6F5C6F4)3- (14), Ph3C+XAl(C6F5)3- (X = Cl, 15; X = Br, 16), and Ph3C+F[Ga(C6F5)3]2- (17). Temperature, propylene concentration, and solvent polarity dependence are surveyed in polymerizations catalyzed by 1 activated with cocatalysts 3-16 and with a 1:2 ratio of Ph3CCl and 5, and with a 1:2 ratio of Ph3CBr and 5, and by 2 activated with 3, 6, 7, 12, and 14. Remarkable stereocontrol with high activities is observed for 1 + 12 and 1 + 14. Polypropylene samples produced using C1-symmetric precatalyst 2 are subjected to microstructural analyses using stochastic models describing the relative contributions of enantiofacial misinsertion and backskip processes. A powerful technique is introduced for calculating interparametric correlation matrices for these nonlinear stochastic models. The collected results significantly extend what is known about ion-pairing effects in the case of Cs-symmetric precatalyst 1 and allow these findings to be applied to the case of C1-symmetric precatalyst 2 as an agent of isospecific propylene polymerization.


Respiratory rate as a predictor of weaning failure from mechanical ventilation.
There is not an ideal predictor of weaning from mechanical ventilation (MV). In a large meta-analysis, despite methodological limitations, respiratory rate (RR) was considered a promising predictor. The aim of this study was to evaluate RR as a predictor of weaning failure from MV. We prospectively evaluated 166 patients scheduled for weaning from MV. RR and other essential criteria for weaning were evaluated at an early stage of screening. Patients who met the essential screening criteria for weaning underwent spontaneous breathing trial. RR was compared with the following outcomes: weaning success/failure or extubation failure. Weaning success was present in 76.5% and weaning failure in 17.5% of patients. There were 6% of reintubations. The predictive power for RR weaning failure, RR best cut-off point > 24 breaths per minute (rpm), was: sensitivity 100%, specificity 85%, and accuracy 88% (ROC curve, p<0.0001). Of the patients with weaning failure, 100% were identified by RR during screening (RR cut-off > 24 rpm). There were 15% false positives, weaning successes with RR > 24 rpm. RR was an effective predictor of weaning failure. The best cut-off point was RR > 24 rpm, which differed from those reported in the literature (35 and 38 rpm). Only 6% of patients were reintubated, but RR or other weaning criteria did not identify them.


Estriol blunts postprandial blood glucose rise in male rats through regulating intestinal glucose transporters.
Despite increased total food intake in healthy, late-stage pregnant women, their peak postprandial blood sugar levels are normally much lower than the levels seen in healthy nonpregnant women. In this study, we sought to determine whether estriol (E3), an endogenous estrogen predominantly produced during human pregnancy, contributes to the regulation of the postprandial blood glucose level in healthy normal rats. In vivo studies using rats showed that E3 blunted the speed and magnitude of the blood glucose rise following oral glucose administration, but it did not appear to affect the total amount of glucose absorbed. E3 also did not affect insulin secretion, but it significantly reduced the rate of intestinal glucose transport compared with vehicle-treated animals. Consistent with this finding, expression of the sodium-dependent glucose transporter 1 and 2 was significantly downregulated by E3 treatment in the brush-border membrane and basolateral membrane, respectively, of enterocytes. Most of the observed in vivo effects were noticeably stronger with E3 than with 17β-estradiol. Using differentiated human Caco-2 enterocyte monolayer culture as an in vitro model, we confirmed that E3 at physiologically relevant concentrations could directly inhibit glucose uptake via suppression of glucose transporter 2 expression, whereas 17β-estradiol did not have a similar effect. Collectively, these data showed that E3 can blunt the postprandial glycemic surge in rats through modulating the level of intestinal glucose transporters.


Transcranial Magnetic Stimulation over Left Inferior Frontal and Posterior Temporal Cortex Disrupts Gesture-Speech Integration.
Language and action naturally occur together in the form of cospeech gestures, and there is now convincing evidence that listeners display a strong tendency to integrate semantic information from both domains during comprehension. A contentious question, however, has been which brain areas are causally involved in this integration process. In previous neuroimaging studies, left inferior frontal gyrus (IFG) and posterior middle temporal gyrus (pMTG) have emerged as candidate areas; however, it is currently not clear whether these areas are causally or merely epiphenomenally involved in gesture-speech integration. In the present series of experiments, we directly tested for a potential critical role of IFG and pMTG by observing the effect of disrupting activity in these areas using transcranial magnetic stimulation in a mixed gender sample of healthy human volunteers. The outcome measure was performance on a Stroop-like gesture task (Kelly et al., 2010a), which provides a behavioral index of gesture-speech integration. Our results provide clear evidence that disrupting activity in IFG and pMTG selectively impairs gesture-speech integration, suggesting that both areas are causally involved in the process. These findings are consistent with the idea that these areas play a joint role in gesture-speech integration, with IFG regulating strategic semantic access via top-down signals acting upon temporal storage areas.SIGNIFICANCE STATEMENT Previous neuroimaging studies suggest an involvement of inferior frontal gyrus and posterior middle temporal gyrus in gesture-speech integration, but findings have been mixed and due to methodological constraints did not allow inferences of causality. By adopting a virtual lesion approach involving transcranial magnetic stimulation, the present study provides clear evidence that both areas are causally involved in combining semantic information arising from gesture and speech. These findings support the view that, rather than being separate entities, gesture and speech are part of an integrated multimodal language system, with inferior frontal gyrus and posterior middle temporal gyrus serving as critical nodes of the cortical network underpinning this system.


Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates.
HIV patients on combination oral drug therapy experience insufficient drug levels in lymph nodes, which is linked to viral persistence. Following success in enhancing lymph node drug levels and extending plasma residence time of indinavir formulated in lipid nanoparticles, we developed multidrug anti-HIV lipid nanoparticles (anti-HIV LNPs) containing lopinavir (LPV), ritonavir (RTV), and tenofovir (PMPA). These anti-HIV LNPs were prepared, characterized, scaled up, and evaluated in primates with a focus on plasma time course and intracellular drug exposure in blood and lymph nodes. Four macaques were subcutaneously administered anti-HIV LNPs and free drug suspension in a crossover study. The time course of the plasma drug concentration as well as intracellular drug concentrations in blood and inguinal lymph nodes were analyzed to compare the effects of LNP formulation. Anti-HIV LNPs incorporated LPV and RTV with high efficiency and entrapped a reproducible fraction of hydrophilic PMPA. In primates, anti-HIV LNPs produced over 50-fold higher intracellular concentrations of LPV and RTV in lymph nodes compared to free drug. Plasma and intracellular drug levels in blood were enhanced and sustained up to 7 days, beyond that achievable by their free drug counterpart. Thus, multiple antiretroviral agents can be simultaneously incorporated into anti-HIV lipid nanoparticles to enhance intracellular drug concentrations in blood and lymph nodes, where viral replication persists. As these anti-HIV lipid nanoparticles also prolonged plasma drug exposure, they hold promise as a long-acting dosage form for HIV patients in addressing residual virus in cells and tissue.


Identification of 20(S)-protopanaxadiol metabolites in human liver microsomes and human hepatocytes.
20(S)-Protopanaxadiol (PPD, 1) is one of the aglycones of the ginsenosides and has a wide range of pharmacological activities. At present, PPD has progressed to early clinical trials as an antidepressant. In this study, its fate in mixed human liver microsomes (HLMs) and human hepatocytes was examined for the first time. By using liquid chromatography-electrospray ionization ion trap mass spectrometry, 24 metabolites were found. Four metabolites were isolated, and their structures were elucidated as (20S,24S)-epoxydammarane-3,12,25-triol (2), (20S,24R)-epoxydammarane-3,12,25-triol (3), (20S,24S)-epoxydammarane-12,25-diol-3-one (4), and (20S,24R)-epoxydammarane-12,25-diol-3-one (5) based on a detailed analysis of their spectroscopic data. The predominant metabolic pathway of PPD observed was the oxidation of the 24,25-double bond to yield 24,25-epoxides, followed by hydrolysis and rearrangement to form the corresponding 24,25-vicinal diol derivatives (M6) and the 20,24-oxide form (2 and 3). Further sequential metabolites (M2-M5) were also detected through the hydroxylation and dehydrogenation of 2 and 3. All of the phase I metabolites except for M1-1 possess a hydroxyl group at C-25 of the side chain, which was newly formed by biotransformation. Two glucuronide conjugates (M7) attributed to 2 and 3 were detected in human hepatocyte incubations, and their conjugation sites were tentatively assigned to the 25-hydroxyl group. The findings of this study strongly suggested that the formation of the 25-hydroxyl group is very important for the elimination of PPD.


Neuropeptides and disuse of the rat parotid gland.
Rats were fed a liquid diet with the aim of decreasing nervous reflex activity in the parotid glands. In rats killed after 21 days on this diet the glands were atrophied and the total amounts of the neuropeptides, substance P, vasoactive intestinal peptide and calcitonin gene-related peptide, were lower than in control glands.


Browsing herbivores improve the state and functioning of savannas: A model assessment of alternative land-use strategies.
Changing climatic conditions and unsustainable land use are major threats to savannas worldwide. Historically, many African savannas were used intensively for livestock grazing, which contributed to widespread patterns of bush encroachment across savanna systems. To reverse bush encroachment, it has been proposed to change the cattle-dominated land use to one dominated by comparatively specialized browsers and usually native herbivores. However, the consequences for ecosystem properties and processes remain largely unclear. We used the ecohydrological, spatially explicit model EcoHyD to assess the impacts of two contrasting, herbivore land-use strategies on a Namibian savanna: grazer- versus browser-dominated herbivore communities. We varied the densities of grazers and browsers and determined the resulting composition and diversity of the plant community, total vegetation cover, soil moisture, and water use by plants. Our results showed that plant types that are less palatable to herbivores were best adapted to grazing or browsing animals in all simulated densities. Also, plant types that had a competitive advantage under limited water availability were among the dominant ones irrespective of land-use scenario. Overall, the results were in line with our expectations: under high grazer densities, we found heavy bush encroachment and the loss of the perennial grass matrix. Importantly, regardless of the density of browsers, grass cover and plant functional diversity were significantly higher in browsing scenarios. Browsing herbivores increased grass cover, and the higher total cover in turn improved water uptake by plants overall. We concluded that, in contrast to grazing-dominated land-use strategies, land-use strategies dominated by browsing herbivores, even at high herbivore densities, sustain diverse vegetation communities with high cover of perennial grasses, resulting in lower erosion risk and bolstering ecosystem services.


Interaction of thiazide and loop diuretics with the basolateral para-aminohippurate transport system in isolated S2 segments of rabbit kidney proximal tubules.
The effect of thiazide and loop diuretics on the tubular uptake of [3H]para-aminohippurate ([3H]PAH), a marker of the organic anion transport system, was tested in vitro on single S2 segments of the proximal tubule of rabbit kidneys. Because the tubules were not perfused, and hence were collapsed, the tubular [3H] PAH uptake reflects [3H]PAH transport across the contraluminal membrane. The diuretics were added to the bath solution in at least six different concentrations. The concentration of [3H]PAH in the bath solution amounted to 1.3 mumol/l, and was 12 times lower than the PAH concentration (16 mumol/l) at half-maximum PAH uptake. The results show that all of the nine diuretics tested inhibited [3H]PAH uptake. The IC50 values of the individual drugs ranged from 3 to 400 mumol/l. In general, thiazide diuretics had a lower affinity to the PAH transporter than loop diuretics. This probably results from differences in the pKa values which range from 3.6 to 4.1 for the loop diuretics and from 9.2 to 10 for the thiazide diuretics. Furthermore, there was a highly significant dependence of affinity on the hydrophobic properties of the diuretics. At concentrations 10- to 100-fold lower than the IC50 values all diuretics stimulated [3H]PAH uptake which may indicate a positive cooperative interaction of these drugs with the PAH transporter. Within the group of loop diuretics the order of the affinity to the PAH transporter and to the Na, 2 Cl, K cotransporter in the thick ascending limb of Henle's loop was identical.(ABSTRACT TRUNCATED AT 250 WORDS)


Selective versus exclusive use of drug-eluting stents in treating multivessel coronary artery disease: a real-world cohort study.
There have been attempts to find new approaches to the treatment of multivessel coronary artery disease without increasing adverse events. Deployment of drug-eluting stents (DES) for complex lesions and bare-metal stents (BMS) for simpler lesions, although already in wide use, has not been well supported by clinical study. A cohort of 1,658 patients who underwent multivessel percutaneous coronary intervention from March 2003 through June 2011 was studied for 1 year. These patients were divided into 3 groups: BMS only (599 patients); DES only (481 patients); and hybrid stenting (578 patients). Baseline characteristics were similar except for hyperlipidemia and moderate-to-severe mitral regurgitation, which were more frequent in the DES and hybrid groups, respectively. Lesion characteristics were more complex in the DES group, compared with the other groups: more B2/C type lesions, longer stents, and smaller reference-vessel diameters (P <0.001). The rates of major adverse cardiac events (MACE) at 1 year were similar between the groups (BMS=5.2%, hybrid=3.9%, and DES=3.4%; P=0.248). Subgroup analysis yielded no differences in death, nonfatal myocardial infarction, target-vessel revascularization, or target-lesion revascularization. On multivariable analysis, the strongest predictors of 1-year MACE were percutaneous intervention complicated by dissection, renal failure, left ventricular ejection fraction below 0.40, mean lesion length, reference vessel diameter, and percutaneous intervention on the left circumflex coronary artery. The latter two had inverse relationships with MACE. In conclusion, implanting the DES for more complex lesions and the BMS for simpler lesions seems more sensible than the exclusive use of the DES or the BMS.


Quality improvement for stroke management at the Cleveland Clinic Health System.
The Cleveland Clinic Health System established a stroke quality improvement (QI) initiative across its nine hospitals. IMPLEMENTING THE STROKE QI INITIATIVE: A stroke QI team took a three-pronged approach to QI: professional education, public education, and hospital process improvements. Its activities and subsequent data analysis needs were divided into four cycles (1999-2003). All data were provided to the stroke QI team and then to the Medical Operations Council to review results, consider data integrity issues, and plan dissemination. The dissemination of performance results permitted broad organizational responses to facilitate improvement. Improvement activities included professional education, public awareness, process improvement, focused data collection with routine feedback, protocol refinement, and coordination of clinical personnel within and between hospitals. The frequency of brain hemorrhagic complications decreased by more than half, from 13.4% to 6.4%; the rate of intravenous tissue plasminogen activator use increased from 1.5% to 3.9% of all stroke patients; and protocol deviations were reduced from 33% to 17%. The keys to this initiative's success were the health system's leadership's support, physicians' engagement via multidisciplinary project committees at the health system and hospital levels, and flexibility in implementing locally tailored process interventions.


Implications of a History of Syncope in Patients Hospitalized With Heart Failure.
We assessed the frequency and implications of a history of syncope of up to 1 year prior to hospitalization with acute heart failure (AHF) between February and November 2012. Data were collected for 5005 patients hospitalized with AHF and analyzed and compared according to the absence/presence of a history of syncope (group 1 vs group 2). Prior syncope among patients with heart failure was 5.3%. Age, gender, hypertension, atrial fibrillation, bundle branch block, left ventricular ejection fraction (LVEF), and obstructed coronary vessels were comparable in the 2 groups. Group 2 patients were more likely to smoke or have diabetes mellitus, stroke, and cardiac arrest. Group 2 patients frequently required aggressive treatment and had more worse in-hospital and 1-year outcomes compared to group 1. After adjustment for age, sex, ethnicity, and LVEF, multivariate regression analysis showed that history of syncope predicted in-hospital mortality (odds ratio: 2.61; 95% confidence interval: 1.707-4.002). History of syncope during the year prior to the index admission with AHF is a marker of worse outcomes regardless of patient age and LVEF. Further studies are required to confirm this observation and its clinical implications.


Bacteroides fragilis ventriculitis and meningitis. Report of two cases.
Two patients with Bacteroides fragilis meningitis and ventriculitis were treated. In one infant infection developed at 2 1/2 months of age as a result of an infected ventriculoatrial shunt inserted to treat hydrocephalus. In the second patient ventriculitis and meningitis developed at 20 days of age, while he was convalescing from surgery for gastric perforation that had occurred at 5 days of age. Both patients were treated with ampicillin, chloramphenicol, and clindamycin, which sterilized the blood and lumbar cerebrospinal fluid but not the ventricular cerebrospinal fluid. The first patient received no further antibiotic therapy and died at 5 months of age. Metronidazole therapy sterilized the ventricular fluid of the second patient, who survived the infection. Ventriculitis should be suspected in patients with B fragilis meningitis. A brain scan should be done to detect signs of ventriculitis or brain abscess. Metronidazole may be the drug of choice in patients with B fragilis ventriculitis or meningitis who do not respond to chloramphenicol.


[Structural and functional bases of the intermolecular interaction of calix[4]arene C-97 with myosin subfragment-1 of myometrium].
Calix[4]arene C-97 (code is shown) is the macrocyclic compound which has lipophilic intramolecular higly-structured cavity formed by four aromatic cycles, one of which on the upper rim is modified by methylene bisphosphonic group. It was shown that calix[4]arene C-97 (100 microM) efficiently inhibits ATPase activity of myosin subfragment-1 from pig myometrium, the inhibition coefficient I(0.5) being 83 +/- 7 microM. At the same time, this compound at 100 microM concentration significantly increases the effective hydrodynamic diameter of myosin subfragment-1, that may be indicative of intermolecular complexation between the calix[4]arene and myosin head. Computer simulation methods (docking, molecular dynamics, involving the Grid) have been used to clarify structural basis of the intermolecular interaction of calix[4]arene C-97 with myosin subfragment-1 of the myometrium; participation of hydrophobic, electrostatic and pi-pi (stacking) interactions between calix[4]arene C-97 and amino acid residues of myosin subfragment-1, some of them being located near the active site of the ATPase has been found out.


Formal genetics of Fanconi's anemia.
The formal genetics of Fanconi's anemia were investigated on the basis of 21 families from different European countries, and of 69 families from the literature. 1. The result of segregation analysis is compatible with the hypothesis of a simple autosomal recessive mode of inheritance. 2. The number of sporadic cases is not greater than expected. 3. Among the affected siblings in the sibships analyzed, males are somewhat more frequent than females. However, this sex difference is also found among the unaffected siblings, and it is not statistically significant. 4. Contrary to assertions made in the literature, there is no clustering of affected in the sequence of siblings, no maternal age effect, and no preference of higher birth orders. 5. A high intrafamilial correlation for age at onset, and (very probably) number and severity of malformations points to genetic heterogeneity. Apart from the standard type, an especially mild type with late onset, few malformations, and a relatively benign course seems to exist. Its counterpart is possibly an especially severe type with early onset, many malformations, and a malignant course. However, definite conclusions on the special character of this heterogeneity will require application of additional methods.


Bortezomib-based Triplet Regimens for Remission Induction in Multiple Myeloma.
To compare the efficacy and side effect profile of different bortezomib-based triplet regimens for remission induction in patients with multiple myeloma (MM). Observational study. Armed Forces Bone Marrow Transplant Centre, Rawalpindi from January 2014 to December 2018. A total of 81 patients of MM, were registered from January 2014 to December 2018. In final analysis, 44 out of 81 patients were included as per inclusion/exclusion criteria. Bortezomib-based regimens were used either as first line (in newly diagnosed) or as second line (in relapsed/refractory bortezomib naïve patients) therapy. Three different bortezomib-based triplet therapies were used (1) VCd, (2) VRd and (3) VTd. As there were only two patients in VTd regimen group so for study purposes VRd and VTd were grouped together, i.e. Vd with an IMiD. Response to treatment was assessed using the IMWG criteria. Comparison between different bortezomib-based regimens was performed in terms of their tolerability and response rate after four cycles of chemotherapy. Out of 44 patients, 79.5% (n=35) patients received bortezomib-based triplet regimen as first line therapy, and in 20.5% (n=9) patients as second line therapy. VCd was administered to 56.8% (n=25) and Vd with an IMiD was used in 43.1% (n=19, VRd in 17 and VTd in 2) of the patients. Response was assessed at the end of fourth cycle. Overall response rate was comparable in both groups, 88% in VCd versus 89.4% in Vd with an IMiD group (p=0.432). In VCd and Vd with an IMiD group, CR was observed in 52% (n=13) and 57.9% (n=11) patients, respectively. Disease remained stable in 6.8% (n=3) patients. Treatment was generally well tolerated. Comparative analyses of both treatment groups revealed that the frequency of peripheral neuropathy was significantly higher in Vd with an IMiD group (47.3% vs 8% p=0.03). Grade III/IV neuropathy observed in 15.7% (n=3) of the patients in Vd with an IMiD group vs none in VCd group. Grade III/IV cytopenias were more seen in VCd group then in Vd with an IMiD group (16% vs. 5.2% p=0.16). The overall response rates were comparable in VCd and Vd with IMiD, with a better side effect profile seen with VCd regimen. Key Words: Multiple myeloma, Bortezomib, Triplet therapy, Remission induction, Peripheral neuropathy.


Using tissue texture surrounding calcification clusters to predict benign vs malignant outcomes.
The positive predictive value of mammography is between 20% and 25% for clustered microcalcifications. For very early cancers there is often a lack of concordance between mammographic signs and pathology. This study examines the usefulness of computer texture analysis to improve the accuracy of malignant diagnosis. Texture analysis of the breast tissue surrounding microcalcifications on digitally acquired images during stereotactic biopsy is used in this study to predict malignant vs benign outcomes. 54 biopsy proven cases (36 benign, 18 malignant) are used. The texture analysis calculates statistical features from gray level co-occurrence matrices and fractal geometry for equal probability and linear quantizations of the image data. Discriminant models are generated using linear discriminant analysis and logistic discriminant analysis. Results do not differ significantly by method of quantization or discriminant analysis. Jackknife results misclassify 2 of 18 malignant cases (sensitivity 89%) and 6 of 36 benign cases (specificity 83%) for logistic discriminant analysis. From this preliminary study, texture analysis appears to show significant discriminatory power between benign and malignant tissue, which may be useful in resolving problems of discordance between pathological and mammographic findings, and may ultimately reduce the number of benign biopsies.


Measles infection. Involvement of the complement system.
The complement system was examined in fifty patients with acute, apparently uncomplicated measles; forty-six were children less than 10 years old. Twenty showed evidence of pathological complement activation. In thirteen of these the pattern was consistent with activation of the classical pathway while in the other seven data suggested utilization of an alternative pathway. An additional eleven patients had isolated reduction in Clq without alteration in concentration of other components; these were excluded from the classical pathway group. No patient had detectable immune complexes or C3 splitting activity in serum; however, it is suggested that the abnormal complement patterns observed are likely to indicate the presence of circulating immune complexes in a high percentage of patients with this infection.