"Use of pedicled corticoperiosteal flap in resistant cases of distal femur non-union: Our learning experience".
Nonunion of distal femur is a complex problem with the added burden of poor bone stock, osteopenia, and joint contracture. Various procedures are described ranging from osteosynthesis using auto/allograft, to use of mega prosthesis. Use of vascularized corticoperiosteal flap based on descending genicular artery and superomedial genicular artery is a new technique to provide living vascular graft for the nonunion site. Although few free corticoperiosteal flap reconstructions have been reported in the past for these distal femur nonunions, this flap has seldom been used as a pedicled variety. Through this article, we aimed at highlighting the main obstacles faced while using pedicled corticoperiosteal flap for these patients given its dearth in literature. Five patients of at least two previously failed osteosynthesis for distal femur fracture non-union were selected for performing corticoperiosteal flaps. The intraoperative findings that were both favourable and unfavourable were documented along with the outcome of procedure in the form of callus formation or fracture healing. Dissection of the flap was more tedious in these cases than when performed for a different indication in a virgin territory. However, despite the previous trauma resulting in decreased pliability of their vessels, all flaps were viable at the end of procedure with favourable cosmetic and functional outcomes. Despite the complexities in flap harvest, use of the less morbid and technically easier "Pedicled corticoperiosteal flap" and osteosynthesis along with the auto technique is a worthwhile option for retaining the native joint with favourable outcome in non-unions of distal femur.


Use of tissue adhesive in the closure of small incisions and lacerations.
Over the last 10 years, in the operating rooms of Maternity and Children Hospital, Jeddah, more than 3,200 surgical incisions of skin made for minor surgical operations were closed without suturing by using tissue adhesive Histoacryl Blue. In addition to this, in the emergency rooms over 2,600 small lacerations of skin on various parts of the body were also repaired by the same technique. The method has certain distinct advantages over conventional suturing. The success rate was very high.


Liposome-anchored mesenchymal stem cells for radiation pneumonia/fibrosis treatment.
The effectiveness of mesenchymal stem cells (MSCs) on inflammation-related disease is limited and the pharmaceutical preparation that was used to enhance the efficacy of MSCs cannot reach the diseased tissue in large quantities. Herein, antioxidant liposome (Lipo-OPC) is designed to anchor onto the surface of MSCs membrane via click chemical reaction (MSC-Lipo-OPC) without affecting the viability and physiological characteristics of MSCs, thus allowing efficient accumulation of MSC-Lipo-OPC in X-ray irradiated lung sites. More importantly, MSC-Lipo-OPC promotes the change of the quantity and polarity of innate immunocytes, mainly including neutrophils, macrophages and Tregs, in favor of anti-inflammatory, finally preventing the formation of radioactive pulmonary fibrosis. Therefore, it could enhance the treatment outcome of both of MSCs and drugs to radiation-induced lung injury via modifying the drug-loaded nanoparticle on the surface of MSCs membrane, further promoting the application of MSCs in radiation damage and protection.


Hidradenitis suppurativa and vasculitis: A case series and literature review of a rare association.
Hidradenitis suppurativa is a chronic inflammatory skin disease with dysregulation of the immune system. Its pathophysiology is not clear, and it has been reported in association with various inflammatory disorders such as pyoderma gangrenosum, arthritis, familial Mediterranean fever and inflammatory bowel diseases. However, the co-existence of HS and vasculitis is exceptional and has not been investigated. We report on five patients with vasculitis that are followed in our centers: one with Takayasu's arteritis, three with granulomatosis with polyangiitis and one with Behcet's disease and compare them with those previously reported in the literature. A case series and literature review with key words of "vasculitis," "hidradenitis suppurativa," and "acne inversa" found only one previous report of hidradenitis suppurativa and cutaneous vasculitis and two with Behcet's disease. Whereas the association of pyoderma gangrenosum and vasculitis is well-known, that with hidradenitis suppurativa is rarer. There may be some pathogenic continuum between hidradenitis suppurativa, pyoderma gangrenosum and vasculitis.


Putative synaptic genes defined from a Drosophila whole body developmental transcriptome by a machine learning approach.
Assembly and function of neuronal synapses require the coordinated expression of a yet undetermined set of genes. Although roughly a thousand genes are expected to be important for this function in Drosophila melanogaster, just a few hundreds of them are known so far. In this work we trained three learning algorithms to predict a "synaptic function" for genes of Drosophila using data from a whole-body developmental transcriptome published by others. Using statistical and biological criteria to analyze and combine the predictions, we obtained a gene catalogue that is highly enriched in genes of relevance for Drosophila synapse assembly and function but still not recognized as such. The utility of our approach is that it reduces the number of genes to be tested through hypothesis-driven experimentation.


IL-17A-producing γδT cells promote muscle regeneration in a microbiota-dependent manner.
Subsequent to acute injury, skeletal muscle undergoes a stereotypic regenerative process that reestablishes homeostasis. Various types of innate and adaptive immunocytes exert positive or negative influences at specific stages along the course of muscle regeneration. We describe an unanticipated role for γδT cells in promoting healthy tissue recovery after injection of cardiotoxin into murine hindlimb muscle. Within a few days of injury, IL-17A-producing γδT cells displaying primarily Vγ6+ antigen receptors accumulated at the wound site. Punctual ablation experiments showed that these cells boosted early inflammatory events, notably recruitment of neutrophils; fostered the proliferation of muscle stem and progenitor cells; and thereby promoted tissue regeneration. Supplementation of mice harboring low numbers of IL-17A+ γδT cells with recombinant IL-17A largely reversed their inflammatory and reparative defects. Unexpectedly, the accumulation and influences of γδT cells in this experimental context were microbiota dependent, unveiling an orthogonal perspective on the treatment of skeletal muscle pathologies such as catastrophic wounds, wasting, muscular dystrophies, and myositides.


Litter decomposition, CO2-release and enzyme activities in a snowbed and on a windswept ridge in an alpine environment.
At two mountain sites in the Austrian Central Alps (Hohe Tauern), a windswept exposed ridge and a snowbed, at altitudes of 2,300 m and 2,550 m above sea level, respectively, microbial activities were investigated by measuring the decomposable organic matter, the CO2-release, the phosphatase, urease, xylanase and cellulase activities and the decomposition of litter.The microbial activities measured in the soil at the exposed ridge were generally lower than those at the flat site above and the slope below. These results may be explained by a deficiency of organic substrates, together with the effect of frequent drought stress during the vegetative growth period. The activities measured in the poorly drained soil of the snowbed were lower than those at the other sites. The highest activities were measured immediately after the thawing of the frozen topsoils at all sites. At this time the bacterial and fungal populations increase simultaneously with the disintegration, by physical action and enzymic activity, of the litter fall from the previous year.


A sequential comparison of etretinate (Tigason) and isotretinoin (Roaccutane) with special regard to their effects on serum lipoproteins.
Etretinate and isotretinoin were compared with respect to their clinical effects and changes in serum lipoprotein concentrations. Sixteen patients with hyperkeratotic and pustular disorders of hands and feet (mainly palmoplantar pustulosis) underwent a double-blind cross-over study. The daily doses of etretinate and isotretinoin were 50 and 40 mg, respectively. Each drug was given for 2 months with a 2-month intermission. The clinical score was reduced both by isotretinoin (P less than 0.05) and etretinate (P less than 0.001). Both drugs affected the lipoprotein concentrations. Isotretinoin increased the cholesterol concentration in low-density lipoprotein (LDL) by 20% and the triglyceride concentration in very low-density lipoprotein (VLDL) by 35%, but decreased the high-density lipoprotein cholesterol by 12%. Etretinate elevated LDL-cholesterol by 10%. These changes had reverted to normal 8 weeks after the end of treatment. The data suggest that in the diseases studied, etretinate is preferable to isotretinoin with regard to both clinical effect and serum lipid side-effects.


Calcineurin B-like domains in the large regulatory alpha/beta subunits of phosphorylase kinase.
Phosphorylase kinase (PhK) is a large hexadecameric complex that catalyzes the phosphorylation and activation of glycogen phosphorylase (GP). It consists in four copies each of a catalytic subunit (gamma) and three regulatory subunits (alpha beta delta). Delta corresponds to endogenous calmodulin, whereas little is known on the molecular architecture of the large alpha and beta subunits, which probably arose from gene duplication. Here, using sensitive methods of sequence analysis, we show that the C-terminal domain (named domain D) of these alpha and beta subunits can be significantly related to calcineurin B-like (CBL) proteins. CBL are members of the EF-hand family that are involved in the regulation of plant-specific kinases of the CIPK/PKS family, and relieve autoinhibition of their target kinases by binding to their regulatory region. The relationship highlighted here suggests that PhK alpha and/or beta domain D may be involved in a similar regulation mechanism, a hypothesis which is supported by the experimental observation of a direct interaction between domain D of PhKalpha and the regulatory region of the Gamma subunit. This finding, together the identification of significant similarities of domain D with the preceding domain C, may help to understand the molecular mechanism by which PhK alpha and/or beta domain D might regulate PhK activity.


Lyme neuroborreliosis: A case report.
Lyme neuroborreliosis is the manifestation of Lyme borreliosis that impacts the nervous system. It gives rise to various neurological and psychiatric conditions, and its diagnosis is challenging. The timely administration of antibiotics is effective. A male patient, aged 55, was admitted to the emergency department due to the sudden onset of tonic-clonic seizures. All standard laboratory examinations yielded unremarkable outcomes, except a favorable Wright and 2-mercaptoethanol test. The examination of cerebrospinal fluid revealed the presence of 380 white blood cells per milliliter. The protein level was also elevated, while the glucose level was within the normal range. The results of the serologic tests indicated the presence of both IgG and IgM antibodies to Borrelia burgdorferi. Following the administration of ceftriaxone, a significant improvement was observed in the patient's medical status, and he was subsequently discharged. Lyme neuroborreliosis is the manifestation of Lyme borreliosis that impacts the nervous system. It gives rise to various neurological and psychiatric conditions, and its diagnosis is challenging. The timely administration of antibiotics is effective in treating patients.


Global proteome analysis in plants by means of peptide libraries and applications.
Like in animals plant proteins are differently expressed by organ with, for instance, few high abundance species such as RuBisCO in leaves colonizing the analytical space. Contrary to animals, a very large number of plant proteins are present at particularly low concentrations and in the presence of an excessive amount of polysaccharides and other natural polymers. This situation renders the functional investigations particularly challenging since the understanding of plant expression and interaction commences with the particularly laborious proteome deciphering. This fact impacts the investigations on protein differential biosynthesis in response to various stresses of physical, chemical and biological nature. This review updates the technical situation of global protein analysis while making a point on profiling changes resulting from external aggressions throughout recently published data. Within this context the importance of the combinatorial peptide ligand library methodology as an approach for facilitating the differential expression analysis is highlighted. The present review covers in extenso the latest progresses made in plant proteomics analyses with the use of the combinatorial peptide ligand library (CPLL) methodology. It well documents the ability of the CPLL technology in greatly extending the coverage of such proteomes, particularly in regard to the discovery and identification of low-abundance proteins, whose signal is obscured not only by the high-abundance species, as typically occurring in animal proteomics, but also by the overwhelming presence of plant polymers, such as polysaccharides, polyphenols, fibers and the like. The review covers the proteomics analysis aspect of modifications contingent upon plant stresses of physical, chemical and biological nature, as well as the discovery of hidden allergens on fruits and vegetable and their undiscovered proteomes. A sure conclusion can be made: no matter what mass spectrometry experts say, pre-fractionation in plant proteomics is a must and among such tools CPLLs appear to exert a major role in plant proteome discoveries.


Ventilatory control instability as a predictor of persistent periodic breathing in preterm infants.
Periodic breathing (PB) is common in preterm infants. We aimed to characterize the contribution of ventilatory control instability to the presence and persistence of PB longitudinally. Infants born between 28 and 32 weeks of gestation were studied using daytime polysomnography at: 32-36 weeks postmenstrual age (PMA) (N = 32), 36-40 weeks PMA (N = 20), 3 months corrected age (CA) (N = 18) and 6 months CA (N = 19). Loop gain, a measure of sensitivity of the ventilatory control system, was estimated by fitting a mathematical model to ventilatory patterns associated with spontaneous sighs. The time spent in PB decreased from 32-36 weeks PMA to 6 months CA (P = 0.005). Across all studies, studies with PB (N = 62) were associated with higher loop gain compared to those without PB (N = 23) (estimated marginal mean ± SEM: 0.445 ± 0.01 vs 0.388 ± 0.02; P = 0.020). A threshold of loop gain >0.415 (measured at 32-36 weeks PMA) provided a sensitivity of 86% and a specificity of 75% to detect the presence of PB at 6 months CA. The course of PB in preterm infants is related to changes in loop gain. Higher loop gain at 32-36 weeks PMA was associated with a greater risk of persistent PB at 6 months CA. The developmental trajectory of periodic breathing and its relationship to ventilatory control instability is currently unclear. Unstable ventilatory control is a determinant of periodic breathing in preterm infants up to 6 months corrected age. Infants who display greater ventilatory control instability at 32-36 weeks postmenstrual age may be at increased risk of persistent periodic breathing at 6 months corrected age. Assessment of ventilatory control stability may assist in the early identification of infants at risk of persistent periodic breathing and its potential adverse effects.


Extrafascial wound dehiscence: deep en bloc closure versus superficial skin closure.
To determine closure time, pain experienced during closure, and healing time in patients undergoing deep en bloc closure or superficial skin closure of extrafascial would dehiscence. Patients with extrafascial wound dehiscence on the obstetrics and gynecology service of the University of Mississippi Medical Center were randomized to deep en bloc closure or superficial skin closure. A 1:2 ratio was used to evaluate superficial skin closure, as deep en bloc closure is known to be effective. The wounds of patients in the deep en block group were closed with no. 1 polypropylene placed through the entire wound thickness as simple interrupted sutures. The wounds of patients in the superficial closure group were closed with 2-0 polypropylene placed through the skin as vertical mattress sutures. The wounds were closed on the patient care unit under local anesthesia. Closure was timed in minutes from initiation of local anesthesia to cutting of the last suture. Patients assessed pain by placing a mark on a 100-mm line (0 = none; 100 = maximum). Time for complete healing was measured from wound disruption to skin reepithelialization. During an 8-month period, seven patients were randomized to deep en bloc closure and 16 to superficial skin closure. The en bloc group required 27.1 +/- 5.5 minutes (mean +/- standard deviation) for closure, compared with 18.9 +/- 3.4 minutes in the superficial group (P < .001). The mean pain score in the en bloc group was 43.4 +/- 23.2 mm, compared with 16.6 +/- 11.4 mm in the superficial group (P < .001). The en bloc group required 22.7 +/- 7.7 days for complete healing, compared with 19.8 +/- 5.3 days in the superficial group, a nonsignificant difference. Superficial skin closure of extrafascial wound dehiscence appears to be superior to deep en bloc closure in terms of closure time and pain experienced during the procedure. These benefits are achieved with minimal risk while allowing timely wound healing.


Single-staged laparotomy versus multiple-staged laparotomy for traumatic massive hemoperitoneum with hemodynamic instability: a single-center, propensity score-matched analysis.
Currently, damage control surgery (DCS) employing multiple-staged laparotomy (MSL) is a standard hemostatic approach for treating trauma patients with unstable hemodynamics attributable to massive hemoperitoneum. Based on these findings, we had frequently employed MSL as a part of our hemostatic strategy for the patients, but with unsatisfactory outcomes. On the other hand, with the establishment of damage control resuscitation (DCR), it has become possible to avoid trauma-induced coagulopathy and to achieve adequate hemostasis with single-staged laparotomy (SSL). Consequently, our institutional strategy for surgical hemostasis of the patients has gradually shifted from MSL to SSL with implementation of DCR. The purpose of the study is to evaluate the impact of this shift in the strategy by comparing outcomes of the patients between those underwent MSL and those underwent SSL employing propensity score matching. This retrospective, single-center, observational study evaluated outcomes of hemodynamically unstable patients with traumatic massive hemoperitoneum requiring surgical intervention between 2005 and 2020. The patient population was divided into two groups: a SSL group and a MSL group. Propensity score matching was used to adjust for differences in baseline characteristics in the two groups, a one-to-one matched analysis using nearest-neighbor matching was performed based on the estimated propensity score of each group. The primary outcome was in-hospital mortality, and secondary outcomes were 48-h mortality and 28-day mortality. A total of 170 patients met the inclusion criteria; 141 patients underwent SSL, and 29 underwent MSL. In the propensity-matched analysis with 27 pairs, the SSL group had significantly lower in-hospital mortality (odds ratio [OR] 0.154; 95% confidence interval (CI) 0.035 to 0.682) and 28-day mortality (OR 0.200; 95% CI 0.044 to 0.913) than the MSL group, but the 48-h mortality did not differ significantly between the two groups (25.9% vs. 44.4%; OR 0.375; 95% CI 0.099-1.414). Single-staged laparotomy may be an effective surgical treatment for the traumatic massive hemoperitoneum cases with hemodynamic instability, if conducted following sufficient damage control resuscitation and performed by an experienced surgeon.


Hybrid treatment of inferior vena cava obstruction after orthotopic heart transplantation.
Caval stenosis with subsequent thrombosis may occur after orthotopic heart transplantation (HT). Management of this complication may include a percutaneous approach or an open surgical one. Here, we report the case of an obstruction and severe thrombosis of the inferior vena cava, following orthotopic HT, that was managed in a hybrid fashion with surgical venous thrombectomy, inferior vena cava stenting, and atrio-caval patch-plasty.


Epicardial coronary artery constriction with intravenous ethanol.
Although in vitro studies have demonstrated ethanol-induced coronary artery constriction, in vivo reports suggest an ethanol-related coronary dilator effect with increases in coronary blood flow. The principal difference in these studies is the demonstration of epicardial coronary constriction with ethanol, while dilation is described only in resistance vessels. Clinical studies have noted evidence of myocardial ischemia following ethanol ingestion in patients with coronary artery disease, suggesting ethanol-related constriction of diseased epicardial coronary arteries. This study hypothesized that intravenous ethanol would constrict canine epicardial coronary arteries while producing arteriolar resistance vessel dilatation. Ten closed-chest mongrel dogs weighing 24 +/- 1 kg (mean +/- SEM) were given 8 g of ethanol intravenously over 30 min. Left anterior descending and circumflex proximal artery diameters were measured by quantitative coronary angiography; myocardial flow was measured by Xenon washout, and myocardial flow distribution was measured with radioactive microspheres. Baseline proximal left anterior descending and circumflex artery areas were 6.3 +/- 0.5 and 5.8 +/- 0.4 mm2, respectively. Up to 30% left anterior descending and circumflex proximal artery narrowing was noted at 60 and 90 min following ethanol infusion. The constriction was reversed with nitroglycerin. There was a decrease in left anterior descending artery flow but no change in circumflex artery flow at 60 min. Blood ethanol level varied from 520 micrograms/ml initially to 205 micrograms/ml 90 min after the infusion terminated (intoxication = 1500 micrograms/ml). These data suggest that ethanol has significant vasoconstrictor action in vivo on epicardial coronary arteries.


Aneurysmal Patellar Bone Cyst: Case Reportt.
Patellar tumors are rare. Commonly benign, giant-cell tumors and chondroblastomas are the most frequent types of this tumor. Aneurysmal bone cysts are a less common type, corresponding to less than 1% of the cases. The authors present a case of a 23-year-old male patient who presented left patellar pain and swelling for two years. The radiographic images suggested tumoral causes, and the biopsy was negative for neoplasm. The treatment approach was a complete patellectomy, without complications. The imaging follow-up showed no recurrence.


A hair tourniquet resulting in strangulation and amputation of the clitoris.
Hair tourniquet syndrome involves fibers of hair or thread wrapped around an appendage producing tissue necrosis. Appendages commonly involved include the toe, finger, and penis. We report a hair tourniquet resulting in amputation of the clitoris. An adolescent presented with a 4-year history of intermittent genital pain that increased in severity over the preceding 5 days. Physical examination revealed a necrotic clitoris surrounded by a black hair. During the examination, the tissue fell off resulting in immediate improvement in the patient's pain. We report a case of a clitoral hair tourniquet syndrome leading to autoamputation of the clitoris. A high index of suspicion for this condition is important because of the potential consequences of delayed treatment.


Sport Participation in Patients with Implantable Cardioverter-Defibrillators.
Athletes diagnosed with cardiovascular disease may receive implantable cardioverter defibrillators (ICDs). Until recently, there were no data describing the safety of return to play for athletes receiving an ICD, and consensus recommendations restricted ICD patients to competitive sports no more vigorous than bowling or golf. The ICD Sports Registry prospectively followed 440 athletes who continued sports participation after receiving an ICD, for up to 4 years. While many received shocks, both appropriate and inappropriate, during competition or practice, as well as during other physical activity or rest, there were no failures to defibrillate and no injuries related to arrhythmia or shock during sports. Recent subanalyses as described below have focused on how best to program the ICD, and on the younger subgroup including interscholastic athletes. Based on these data, the most recent consensus statement from the AHA/ACC on athletic eligibility now describes sports participation with an ICD as a IIB recommendation, "may be considered".


Hormonal control of glucose production and pyruvate kinase activity in isolated rat liver cells: influence of hypothyroidism.
Hormonal control of glucose production and of L-pyruvate kinase activity has been measured in isolated liver cells from fed control and thyroidectomized rats. In hypothyroid rats, sensitivity to isoproterenol as measured by these parameters was increased: the apparent K0.5 for isoproterenol-induced stimulation of glucose production decreased from 8.0 +/- 3 X 10(-6) M in control rats to 2.0 +/- 0.2 X 10(-8) M in hypothyroid rats (P less than 0.001) and the apparent K0.5 for inhibition of L-pyruvate kinase was 5 +/- 2 X 10(-7) M vs. 7 +/- 2 X 10(-9) M (P less than 0.001) in control and thyroidectomized rats, respectively. Utilisation of specific adrenergic antagonists confirmed increased beta-adrenergic responsiveness in hypothyroid rats. This phenomenon was not reversed by 3 days of T3 treatment (10 micrograms/100 g body weight). Sensitivity to the alpha-agonist was unchanged by thyroid status. Stimulation of glucose production and inhibition of L-pyruvate kinase activity by glucagon and their reversal by insulin were not affected by hypothyroidism. The dose-response curve to vasopressin and its maximal effect measured on stimulation of glucose production were unchanged in thyroidectomized rats. Thus, hypothyroidism produces a specific enhancement of liver beta-adrenergic responsiveness without affecting sensitivity to glucagon, insulin and vasopressin.


Bank Cards Might as Well Be Tarot Cards.
This comic compares a lack of price transparency in health care billing to psychic card readings.


Effects of APOE e4-allele and mental work demands on cognitive decline in old age: Results from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe).
Previous studies have observed protective effects of high mental demands at work on cognitive functioning and dementia risk. However, it is unclear what types of demands drive this effect and whether this effect is subject to a person's genetic risk. We investigated to what extent eight different types of mental demands at work together with the APOE e4 allele, a major risk gene for late-onset Alzheimer's disease, affect cognitive functioning in late life. The population-based German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe, n = 2 154) followed cognitively healthy individuals aged 75 years and older in seven assessment waves. Cognitive functioning was assessed via the mini-mental status examination. Mixed-effects modeling (adjusted for education, gender, marital status, stroke, depression, and diabetes) indicated that participants who had an occupational history of working in jobs with high compared to low demands in "Language & Knowledge", "Pattern detection", "Information processing", and "Service" had a slower cognitive decline. APOE e4-allele carriers had an accelerated cognitive decline, but this decline was significantly smaller if they had a medium compared to a low level of demands in contrast to non-carriers. Our longitudinal observations suggest that cognitive decline could be slowed by an intellectually enriched lifestyle even in risk gene carriers. Fostering intellectual engagement throughout the life-course could be a key prevention initiative to promote better cognitive health in old age.


Association Between Low-Dose Aspirin Use and Colorectal Cancer Incidence in Taiwan.
Population-based East Asian data have corroborated reports from non-Asian settings on the association between low-dose aspirin and a lower risk of colorectal cancer (CRC). To evaluate the association between duration and recency of low-dose aspirin use and CRC risk. This nested case-control study included individuals who initiated aspirin use and matched individuals who did not use aspirin. Data were collected from Taiwan National Health Insurance and Taiwan Cancer Registry from 2000 through 2015. CRC cases were age- and sex-matched in a 1:4 ratio with individuals in a control group, identified from a cohort of individuals who used and did not use aspirin through risk-set sampling. Data analysis was conducted from June 2018 to July 2019. Low-dose aspirin use was defined as receiving less than 150 mg per day, whereas 100 mg/d was most commonly used. Based on duration and recency of low-dose aspirin use between cohort entry (initiation date of low-dose aspirin for aspirin use group or randomly assigned date for those who did not use aspirin) and index date (CRC diagnosis date for individuals in the case group and the diagnosis date for the 4 corresponding matched individuals in the control group), the 3 following mutually exclusive exposure groups served as the basis for analysis: (1) long-term current low-dose aspirin use, (2) episodic low-dose aspirin use, and (3) no low-dose aspirin use (the reference group). CRC risk among the 3 exposure groups. Among 4 710 504 individuals (2 747 830 [51.7%] men; median [interquartile range] age at cohort entry in initiator group, 61 [52-71] years; median [interquartile range] age at cohort entry in nonuse group, 59 [51-68] years), 79 095 CRC cases (1.7% of study cohort) were identified. Compared with no low-dose aspirin use, the adjusted odds ratio (OR) for long-term current low-dose aspirin use and CRC risk was 0.89 (95% CI, 0.85-0.93); for episodic use, 0.88 (95% CI, 0.86-0.89). Adjusted ORs of 0.69 (95% CI, 0.63-0.76) and 0.64 (95% CI, 0.61-0.67) were observed for long-term current use and episodic low-dose aspirin use within the subcohort of individuals who initiated low-dose aspirin between age 40 and 59 years. In this study, low-dose aspirin use was associated with 11% lower CRC risk in an East Asian population, and this association was larger when low-dose aspirin use started before age 60 years.


Uncovering allostery and regulation in SAMHD1 through molecular dynamics simulations.
The human sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a retroviral restriction factor in myeloid cells and non-cycling CD4+ T cells, a feature imputed to its phosphohydrolase activity-the enzyme depletes the cellular dNTP levels inhibiting reverse transcription. The functionally active form of SAMHD1 is an allosterically triggered tetramer which utilizes GTP-Mg+2 -dNTP cross bridges to link and stabilize adjacent monomers. However, very little is known about how it assembles into a tetramer and how long the tetramer stays intact. In this computational study, we provide a molecular dynamics based analysis of the structural stability and allosteric site dynamics in SAMHD1. We have investigated the allosteric links which assemble and hold the tetramer together. We have also extended this analysis to a regulatory mutant of SAMHD1. Experimental studies have indicated that phosphorylation of T592 downregulates HIV-1 restriction. A similar result is also achieved by a phosphomimetic mutation T592E. While a mechanistic understanding of the process is still elusive, the loss of structural integrity of the enzyme is conjectured to be the cause of the impaired dNTPase activity of the T592E mutant. MD simulations show that the T592E mutation causes slightly elevated local motions which remain confined to the short helix (residues 591-595), which contains the phosphorylation site and do not cause long-range destabilization of the SAMHD1 tetramer within the timeframe of the simulations. Thus, the regulatory mechanism of SAMHD1 is a more subtle mechanism than has been previously suspected. Proteins 2017; 85:1266-1275. © 2017 Wiley Periodicals, Inc.


Iron acquisition by Ornithobacterium rhinotracheale.
Ornithobacterium rhinotracheale (ORT) is an emerging respiratory pathogen of poultry in North America that is causing millions of dollars in economic losses to the poultry industry. Ornithobacterium rhinotracheale is associated with airsacculitis, pleuritis, pneumonia, and consolidation of lungs. Little is known about the molecular mechanisms of infection. In this study, the mechanism of iron acquisition by O. rhinotracheale was explored. O. rhinotracheale strains grown under iron deprivation in media containing 200 microM 2,2'-dipyridyl did not secrete siderophores as measured by the chrome azurol S (CAS) agar and CAS solution assays. Filter disks impregnated with various protein-bound iron compounds and inorganic iron salts of Fe(III) and Fe(II) placed on iron-restricted agar inoculated with a lawn of O. rhinotracheale supported growth from sheep and porcine hemoglobins, ovotransferrin, Fe(III), and Fe(II), but they did not support growth from bovine transferrin, bovine apo-transferrin, bovine lactoferrin, and hemin. However, both bovine hemoglobin and transferrin supported growth of O. rhinotracheale serotype C. Four immunoreactive proteins involved in iron acquisition were identified in an O. rhinotracheale membrane extract by using mass spectrometry. Furthermore, O. rhinotracheale field strains showed differential sensitivity to 2,2'-dipyridyl. Of the 72 field strains tested, 22 strains were resistant to the iron chelator at concentrations of 50 microM and 100 microM, suggesting this attribute may be related to disease-producing potential of these strains. This is the first report on the identification of the iron acquisition mechanism of O. rhinotracheale.


Prioritization Of Nonsynonymous Single Nucleotide Variants For Exome Sequencing Studies Via Integrative Learning On Multiple Genomic Data.
The rapid advancement of next generation sequencing technology has greatly accelerated the progress for understanding human inherited diseases via such innovations as exome sequencing. Nevertheless, the identification of causative variants from sequencing data remains a great challenge. Traditional statistical genetics approaches such as linkage analysis and association studies have limited power in analyzing exome sequencing data, while relying on simply filtration strategies and predicted functional implications of mutations to pinpoint pathogenic variants are prone to produce false positives. To overcome these limitations, we herein propose a supervised learning approach, termed snvForest, to prioritize candidate nonsynonymous single nucleotide variants for a specific type of disease by integrating 11 functional scores at the variant level and 8 association scores at the gene level. We conduct a series of large-scale in silico validation experiments, demonstrating the effectiveness of snvForest across 2,511 diseases of different inheritance styles and the superiority of our approach over two state-of-the-art methods. We further apply snvForest to three real exome sequencing data sets of epileptic encephalophathies and intellectual disability to show the ability of our approach to identify causative de novo mutations for these complex diseases. The online service and standalone software of snvForest are found at http://bioinfo.au.tsinghua.edu.cn/jianglab/snvforest.


The maturation and aging trajectory of Marchantia polymorpha at single-cell resolution.
Bryophytes represent a sister to the rest of land plants. Despite their evolutionary importance and relatively simple body plan, a comprehensive understanding of the cell types and transcriptional states that underpin the temporal development of bryophytes has not been achieved. Using time-resolved single-cell RNA sequencing, we define the cellular taxonomy of Marchantia polymorpha across asexual reproduction phases. We identify two maturation and aging trajectories of the main plant body of M. polymorpha at single-cell resolution: the gradual maturation of tissues and organs along the tip-to-base axis of the midvein and the progressive decline of meristem activities in the tip along the chronological axis. Specifically, we observe that the latter aging axis is temporally correlated with the formation of clonal propagules, suggesting an ancient strategy to optimize allocation of resources to producing offspring. Our work thus provides insights into the cellular heterogeneity that underpins the temporal development and aging of bryophytes.


The distribution of primary afferent terminals from the eyelids of macaque monkeys.
Trigeminal sensory afferents from the eyelids convey two types of information that are important for the blink reflex. Movement of the lashes activates low-threshold mechanoreceptors which evoke protective blinks. Information about eyelid position is also transmitted centrally and is used to adapt the metrics of the blink reflex to changing conditions over time. This study employed transganglionic transport of horseradish peroxidase conjugated to choleratoxin-B subunit or wheat-germ agglutinin to investigate trigeminal afferents supplying the eyelids of macaque monkeys. Ganglion cells labeled from upper- and lower-lid injections were located in the ophthalmic and maxillary portions of the trigeminal ganglion, respectively. In both cases, labeled terminals were observed ipsilateral to the injected eyelid in the principal and spinal trigeminal nuclei. However, only a few labeled terminals were present in the principal nucleus, and very sparse terminal labeling was confined to a few locations along the ventral border of the pars oralis and interpolaris of the spinal trigeminal nucleus. The main concentration of label was found in the pars caudalis at and immediately below the spinomedullary junction. The terminal field from the upper eyelid was located ventrally in the pars caudalis, and that from the lower eyelid was located more dorsally. In both cases, the labeled terminal field was densest within lamina II of the spinal trigeminal nucleus. The heavy concentration of eyelid central terminals at the spinomedullary junction is surprising in light of physiological studies indicating representation of all parts of the face throughout the trigeminal nucleus. The distribution of eyelid afferent terminals in the macaque is caudal to the main concentration of corneal afferent terminals at the pars interpolaris/caudalis border. This may be a basis for differences seen in blinks produced by corneal as opposed to supraorbital stimulation. The presence of a single major site of eyelid primary afferent terminals suggests that sensory input for both eyelid proprioception and blink-reflex activation passes through this segment of the spinal trigeminal nucleus. These results provide a basis for investigation of the central connections of pars caudalis neurons in order to better establish the pathways producing trigeminally evoked blinks and blink adaptation.


The effect of post-mastectomy radiation therapy on breast implants: Unveiling biomaterial alterations with potential implications on capsular contracture.
Post-mastectomy breast reconstruction with expanders and implants is recognized as an integral part of breast cancer treatment. Its main complication is represented by capsular contracture, which leads to poor expansion, breast deformation, and pain, often requiring additional surgery. In such a scenario, the debate continues as to whether the second stage of breast reconstruction should be performed before or after post-mastectomy radiation therapy, in light of potential alterations induced by irradiation to silicone biomaterial. This work provides a novel, multi-technique approach to unveil the role of radiotherapy in biomaterial alterations, with potential involvement in capsular contracture. Following irradiation, implant shells underwent mechanical, chemical, and microstructural evaluation by means of tensile testing, Attenuated Total Reflectance Fourier Transform InfraRed spectroscopy (ATR/FTIR), Scanning Electron Microscopy (SEM), high resolution stylus profilometry, and Time of Flight Secondary Ion Mass Spectrometry (ToF-SIMS). Our findings are consistent with radiation-induced modifications of silicone that, although not detectable at the microscale, can be evidenced by more sophisticated nanoscale surface analyses. In light of these results, biomaterial irradiation cannot be ruled out as one of the possible co-factors underlying capsular contracture.


[Attitudes Toward Influenza Vaccination in Fall/Winter 2021: Results of the COSMO Study].
There is a lack of knowledge about attitudes to influenza vaccination in Germany in 2021/2022. Based on the COSMO survey ("COVID-19 Snapshot Monitoring"), the aim of this study was to shed some light on this topic. Wave 49 (August 10 and 11, 2021) of the COSMO survey (n=967; Germany-wide non-probabilistic quota sample; 18 to 74 years). This year, about one-third of respondents (and health care workers) plan to get a flu shot, and among the at-risk group of people aged 60 and older (up to 74 years in our sample), more than half. Correlates (such as gender: women with a lower likelihood of a planned flu shot) were identified. Physicians should inform women in particular about the advantages of influenza vaccination, especially during the pandemic, and communicate data on the proven protective effect of influenza vaccination as convincingly as possible (e. g., using existing brochures).


Contraceptive use at first sexual intercourse among adolescent and young adult women with disabilities: The role of formal sex education.
This study examines receipt of formal sex education as a potential mechanism that may explain the observed associations between disability status and contraceptive use among young women with disabilities. Using the 2011-2017 National Survey of Family Growth, we analyzed data from 2861 women aged 18 to 24 years, who experienced voluntary first sexual intercourse with a male partner. Women whose first intercourse was involuntary (7% of all women reporting sexual intercourse) were excluded from the analytic sample. Mediation analysis was used to estimate the indirect effect of receipt of formal sex education before first sexual intercourse on the association between disability status and contraceptive use at first intercourse. Compared to nondisabled women, women with cognitive disabilities were less likely to report receipt of instruction in each of 6 discrete formal sex education topics and received instruction on a fewer number of topics overall (B = -0.286, 95% CI = -0.426 to -0.147), prior to first voluntary intercourse. In turn, the greater number of topics received predicted an increased likelihood of contraceptive use at first voluntary intercourse among these women (B = 0.188, 95% CI = 0.055-0.321). No significant association between noncognitive disabilities and receipt of formal sex education or contraceptive use at first intercourse was observed. Given the positive association between formal sex education and contraceptive use among young adult women with and without disabilities, ongoing efforts to increase access to formal sex education are needed. Special attention is needed for those women with cognitive disabilities.


Method of Patient Classification System in obstetric staff scheduling. III. Demand for direct nursing in the delivery room among mothers who deliver by Caesarean section.
In own studies concerning the determination of the demand for the direct nursing time in the delivery room, the mothers examined were divided into two groups: those who delivered naturally and those who delivered by Caesarean section. The results of the study showed that no statistically significant differences were observed between the nursing time received from midwives by the women who delivered by Caesarean section and the model time. Therefore, the standards concerning the number of nursing staff for this group of women may be determined based on either provided or model times.


Surgical Technique: Minimally Invasive First-Rib Resection.
Minimally invasive surgical approaches to the treatment of thoracic outlet syndrome (TOS) will become increasingly common as more surgeons gain experience in thoracoscopic and robotic technique. Robotic surgery may be more technically advantageous because of improved visualization and maneuverability of wristed instruments. Longer-term outcome data are necessary to definitively establish the equivalency or superiority of minimally invasive TOS compared with open surgery in the treatment of TOS.


High-precision fluorescence assay for sphingomyelinase activity of isolated enzymes and cell lysates.
Sphingomyelinases are important enzymes of signal transduction. They catalyze the hydrolysis of sphingomyelin, giving rise to the intracellular formation of biologically active ceramide and phosphatidylcholine. Here we report on a fluorescence method for the fast and accurate determination of this enzyme in biological samples. The assay is based on a fluorescent sphingomyelin analog carrying fluorescent 7-nitro-2-1,3-benzooxadiazolyl amino-dodecanoic acid instead of an aliphatic acyl chain at the nitrogen atom. The fluorescent substrate is hydrolysed by sphingomyelinases to form fluorescent ceramide, which can be separated from the remaining substrate using TLC on silica gel. The fluorescence intensity pattern obtained on the TLC plate can accurately be determined using a CCD camera. Typically, a large number of samples can be analyzed simultaneously. Examples for the quantitative analysis of sphingomyelinases from freshly prepared cellular homogenates as well as from commercial sources are given.


Modeling of the pH- and the temperature-dependent deviations of the free to total PSA (prostate specific antigen) ratios for clinical predictability of prostate cancer and benign prostate hyperplasia.
Both the free and total PSA had been reported to be pH- and temperature-labile. We have introduced two submodels to describe the decay of PSAs. The overall pH-dependent decay model (OPDDM) describes the ratio of free to true scientific total PSA including both the immunoreactive and the nonimmunoreactive. We elucidated four pH-dependent formation constants for the free PSA with hydronium ion [H(+)], the PSA-ACT (alpha 1-antichymotrypsin), the PSA-API (alpha 1-protease inhibitor), and the nonimmunoreactive PSA-AMG (alpha 1-macroglobulin) complexes, respectively, to model the stability of the free to total PSA ratios. Model simulation indicated a highly pH-sensitive behavior of the free to total PSA ratios. While the temperature dependent decay model (TDDM) indicated that kinetically, free PSA revealed the most rapid decay rates due to its low activation energy, total PSA was shown to be relatively more thermally stable. The decay of all PSA species could be more accelerated at temperatures higher than -4 degrees C, while it is kept below -70 degrees C throughout. It is thus recommended to use the preparation fresh (better within 8 h) after venipuncture. And it is advisable that all the results are advised to perform corrections for each determination by calculating back to the data at the original physiological pH prior to clinical diagnostic interpretation.


Aminoterminal propeptide of type-III procollagen in serum--an indicator of clinical behavior of advanced ovarian carcinoma?
In ovarian carcinoma, elevated serum concentrations of the aminoterminal propeptide of type-III procollagen are related to the clinical stage of the disease and to the presence of ascites, which contains very high concentrations of the propeptide. In a follow-up of patients with advanced disease, favorable clinical course was associated with normalizing propeptide values, whereas in progressing disease the values increased several weeks before clinical progression. In stable disease the concentrations were constantly above the reference range. Laminin and type-IV-collagen-related serum antigens were mostly within the reference range.


The radiation responsive promoter of the Deinococcus radiodurans pprA gene.
In a previous study, we identified a novel radiation-inducible protein PprA that plays a critical role in the radiation resistance of Deinococcus radiodurans [Narumi, I., Satoh, K., Cui, S., Funayama, T., Kitayama, S., Watanabe, H., 2004. PprA: a novel protein from Deinococcus radiodurans that stimulates DNA ligation. Mol. Microbiol. 54, 278-285.]. Despite the interest in mechanisms underlying radiation responses in D. radiodurans, little is known about the radiation responsive promoter for radiation-inducible proteins. In this study, three transcriptional start points for pprA mRNA were identified by primer extension analysis, located at positions -156, -154 and -22 upstream from the pprA translation initiation site. The amount of the three extended products increased in cells exposed to 2 kGy followed by a 0.5-h post-incubation. This suggested the existence of at least two radiation responsive promoters for pprA expression. Functional characterization of the upstream region of the pprA gene using a luciferase reporter assay revealed that the distal promoter is located between positions -208 and -156 from the translation initiation site, while the proximal promoter is located between positions -57 and -22. The region located between positions -57 and -38 was indispensable for proximal promoter activity. Site-directed mutagenesis of a thymine positioned at -33 resulted in severe impairment of promoter activity, and suggested that the thymine functions as a master base for the proximal radiation responsive promoter. The product of the D. radiodurans pprI gene is thought to be a general switch in the radiation response [Hua, Y., Narumi, I., Gao, G., Tian, B., Satoh, K., Kitayama, S., Shen, B., 2003. PprI: a general switch responsible for extreme radioresistance of Deinococcus radiodurans. Biochem. Biophys. Res. Commun. 306, 354-360.]. We examined the effect of pprI disruption on pprA promoter activity. The results suggested that up-regulation of pprA expression by the pprI gene product is triggered at the promoter level.


Biological and psychological processes in recovery from depression during cognitive therapy.
This study investigated the relationship between biological and psychological processes in the recovery phase of depression during treatment with cognitive therapy. In particular, we tested the hypothesis that biological and psychological processes are independent; the hypothesis that they are related in a linear or sequential process; and the hypothesis that there is a circular relationship between them. 35 depressed patients completed a 12 week program of cognitive therapy. Changes in measures of negative thinking and amine dysfunction over the course of therapy were compared for those who improved and those who did not. There was a significant relationship between improvement in symptoms and change for ATQ scores, DAS scores, and epinephrine levels. There was significant change in metanephrine levels during therapy which was not related to improvement. The changes were not consistent across indices. Although the results did not provide definite support for any of the four models of the relationship between biological and psychological variables during recovery from depression, the finding that there was some change in some of the indices of amine dysfunction during cognitive therapy indicates that the interface between biological and psychological processes in depression should continue to be studied.


STAT Transcription Factors in T Cell Control of Health and Disease.
The Jak-STAT pathway is one of many pleiotropic signaling pathways that plays an important role in organismal development and in response to changing environmental cues. As a key signaling cascade for cytokines and growth factors, Jak-STAT plays central role in the innate and adaptive immune system. Cytokines control the stability, commitment, and maturation of cytotoxic and helper T cells, parts of the adaptive immune system that mediate immunity to pathogens and are linked to inflammatory diseases. Dysregulation of Jak-STAT protein expression or function leads to autoimmunity, allergic diseases, and cancer. Because of their central role in these responses, Jak and STAT molecules have been targeted to develop therapeutics. This review extensively discusses the mechanism of how Jak-STAT signaling in T cells defines our immune responses in the battle against foreign pathogens.


Practical asymmetric synthesis of the herbicide (S)-indanofan via lipase-catalyzed kinetic resolution of a diol and stereoselective acid-catalyzed hydrolysis of a chiral epoxide.
Racemic indanofan [(+/-)-1] was efficiently converted to enantiopure (S)-indanofan [(S)-1] by a combination of enzymatic resolution and chemical inversion techniques. An additional important technique is the use of an o-xylene complex of a hemiketal (S)-3c as a precursor, which can be quantitatively converted to (S)-indanofan and easily purified by recrystallization from o-xylene.


Effect of deep inspiration on airway conductance in subjects with allergic rhinitis and allergic asthma.
We measured specific airway conductance (Gaw/Vtg) in a body plethysmograph before and after a deep inspiratory maneuver in 8 subjects with allergic rhinitis and 8 subjects with allergic asthma. In hay fever subjects deep inspiration had no effect on Gaw/Vtg if it was performed in the control state; however, when methacholine-induced bronchoconstriction was present, deep inspiration transiently increased Gaw/Vtg. In asthmatic subjects deep inspiration was followed by a transeint fall in baseline Gaw/Vtg in the control state; however, when bronchoconstriction was present, deep inspiration was followed by small and variable changes in Gaw/Vtg in 7 subjects and marked improvement in Gaw/Vtg in 1 subject. In asthmatic subjects the bronchoconstrictor response to deep inspiration performed in the control state is thought to be due to reflex changes in bronchomotor tone mediated by cholinergic (vagal) nerve pathways. Like asthmatic subjects, hay fever subjects, hay fever subjects also possess cholinergic-mediated airway hyperreactivity compared with normals. Our results indicate that, in spite of their increased airway reactivity, hay fever subjects respond more like normal subjects than like asthmatic subjects after a deep inspiratory maneuver.


DNA methylation and transcriptional noise.
DNA methylation is one of the most phylogenetically widespread epigenetic modifications of genomic DNA. In particular, DNA methylation of transcription units ('gene bodies') is highly conserved across diverse taxa. However, the functional role of gene body methylation is not yet fully understood. A long-standing hypothesis posits that gene body methylation reduces transcriptional noise associated with spurious transcription of genes. Despite the plausibility of this hypothesis, an explicit test of this hypothesis has not been performed until now. Using nucleotide-resolution data on genomic DNA methylation and abundant microarray data, here we investigate the relationship between DNA methylation and transcriptional noise. Transcriptional noise measured from microarrays scales down with expression abundance, confirming findings from single-cell studies. We show that gene body methylation is significantly negatively associated with transcriptional noise when examined in the context of other biological factors. This finding supports the hypothesis that gene body methylation suppresses transcriptional noise. Heavy methylation of vertebrate genomes may have evolved as a global regulatory mechanism to control for transcriptional noise. In contrast, promoter methylation exhibits positive correlations with the level of transcriptional noise. We hypothesize that methylated promoters tend to undergo more frequent transcriptional bursts than those that avoid DNA methylation.


[Increased reliability of the legal protection of Soviet inventions in the field of microbiology].
The reliability of juridical protection of microbiological inventions which may result in the production of a commercial product is discussed in the paper. If the structure of an invention is strain-method-product, then juridical protection of each of the objects is possible. Protection of a product would be most reliable, but this is not always possible. Protection of a microbial strain is less typical of an invention, and is not reliable. Protection of a microbiological method of production has advantages over protection of a microbial strain since, in this case, the theory of equivalents can be applied.


Surgical techniques according to anatomic variations in living donor liver transplantation using the right lobe.
In living donor liver transplantation, the right lobe has many anatomic variations in the vascular tree, which could lead to surgical complications. We need to define surgical technique according to anatomy. From January 2000 to September 2007, 310 living donor liver transplantations using the right lobe were performed in patients with end-stage liver disease. The vascular trees were evaluated preoperatively with computed tomography and magnetic resonance angiography. We classified anatomic points for safe harvest in the hepatic artery, portal vein, and hepatic vein and described technical points based on anatomic variations. There were many anatomic variations in the hepatic vasculature. Hepatic artery variations were observed in 16.8% of cases. Double hepatic artery was observed in 14 cases (4.5%). Of these 14 cases, reconstruction as a single artery was performed in 6 and dual reconstruction was performed in 8 cases. Portal vein variation was observed in 45 cases (14.5%): Dual anastomosis to right and left portal vein was performed in type III (n = 20; 6.4%) and type IV (n = 3; 1.0%) variations. There were 70 cases of portal vein thrombosis. In 8 of the 70, a jump or interposition graft with iliac vein was utilized. Of the middle hepatic vein variant, segment V vein only was reconstructed in 188 (60.6%) cases. In 21 (6.8%) cases, segment VIII vein only was reconstructed, and in 43 (13.9%) cases, both segment V and segment VIII veins were reconstructed using the recipient's portal vein, a cryopreserved iliac vein, or a prosthetic graft. The most common variation of right inferior hepatic vein was type II (n = 141; 45.5%), which has 1 right inferior hepatic vein. Living donor liver transplantation using the right lobe can be performed safely, but there is a potential operative risk because of various anatomic variations. To minimize operative complications, anatomic variations should be kept in mind to ensure a safe and successful operation.


Synthesis and pharmacological evaluation of triazolo derivatives of 8-amino-10,11-dihydro-dibenzo[b,e]1,4-thiazepine-11-one.
In the present communication, the syntheses, characterization and pharmacological evaluation of 8-amino-(1,2,4)-triazolo[4,3-d][b,e]1,4-dibenzothiazepine (4) and its various substituted analogs (6-9) are reported.


Probing calmodulin protein-protein interactions using high-content protein arrays.
The calcium ion (Ca(2+)) is a ubiquitous second messenger that is crucial for the regulation of a wide variety of cellular processes. The diverse transient signals transduced by Ca(2+) are mediated by intracellular -Ca(2+)-binding proteins. Calcium ions shuttle into and out of the cytosol, transported across membranes by channels, exchangers, and pumps that regulate flux across the ER, mitochondrial and plasma membranes. Calcium regulates both rapid events, such as cytoskeleton remodelling or release of vesicle contents, and slower ones, such as transcriptional changes. Moreover, sustained cytosolic calcium elevations can lead to unwanted cellular activation or apoptosis. Calmodulin represents the most significant of the Ca(2+)-binding proteins and is an essential regulator of intracellular processes in response to extracellular stimuli mediated by a rise in Ca(2+) ion concentration. To profile novel protein-protein interactions that calmodulin participates in, we probed a high-content recombinant human protein array with fluorophore-labelled calmodulin in the presence of Ca(2+). This protein array contains 37,200 redundant proteins, incorporating over 10,000 unique human proteins expressed from a human brain cDNA library. We describe the identification of a high affinity interaction between calmodulin and the single-pass transmembrane proteins STIM1 and STIM2 that localise to the ER. Translocation of STIM1 and STIM2 from the endoplasmic reticulum to the plasma membrane is a key step in store operated calcium entry in the cell.


Identification of the optically active vibrational modes in the photoluminescence of MEH-PPV films.
The temperature dependence of the photoluminescence properties of a thin film of poly[2-methoxy-5-(2(')-ethylhexyloxy)-p-phenylene-vinylene], MEH-PPV, fabricated by spin coating, is analyzed. The evolution with temperature of the peak energy of the purely electronic transition, of the first vibronic band, of the effective conjugation length, and of the Huang-Rhys factors are discussed. The asymmetric character of the pure electronic transition peak and the contribution of the individual vibrational modes to the first vibronic band line shape are considered by a model developed by Cury et al. [J. Chem. Phys. 121, 3836 (2004)]. The temperature dependence of the Huang-Rhys factors of the main vibrational modes pertaining to the first vibronic band allows us to identify two competing vibrational modes. These results show that the electron coupling to different vibrational modes depends on temperature via reduction of thermal disorder.


The pathobiology of proto-oncogenes.
The search for genetic damage in neoplastic cells now occupies a central place in cancer research. Diverse examples of such damage are in hand, and they in turn hint at biochemical explanations of why cancer cells go astray. The way may be open to solve the riddles of how normal cells govern their replication and why cancer cells do not.


FGF coordinates air sac development by activation of the EGF ligand Vein through the transcription factor PntP2.
How several signaling pathways are coordinated to generate complex organs through regulation of tissue growth and patterning is a fundamental question in developmental biology. The larval trachea of Drosophila is composed of differentiated functional cells and groups of imaginal tracheoblasts that build the adult trachea during metamorphosis. Air sac primordium cells (ASP) are tracheal imaginal cells that form the dorsal air sacs that supply oxygen to the flight muscles of the Drosophila adult. The ASP emerges from the tracheal branch that connects to the wing disc by the activation of both Bnl-FGF/Btl and EGFR signaling pathways. Together, these pathways promote cell migration and proliferation. In this study we demonstrate that Vein (vn) is the EGF ligand responsible for the activation of the EGFR pathway in the ASP. We also find that the Bnl-FGF/Btl pathway regulates the expression of vn through the transcription factor PointedP2 (PntP2). Furthermore, we show that the FGF target gene escargot (esg) attenuates EGFR signaling at the tip cells of the developing ASP, reducing their mitotic rate to allow proper migration. Altogether, our results reveal a link between Bnl-FGF/Btl and EGFR signaling and provide novel insight into how the crosstalk of these pathways regulates migration and growth.


Northern hybridization analysis of VH gene expression in murine monoclonal antibodies directed to cancer-associated ganglioside antigens having various sialic acid linkages.
The expression of the VH genes in 46 murine hybridoma cells that secrete mAb directed to the cancer-associated carbohydrate Ag, especially acidic glycolipids such as gangliosides and sulfated glycoplipids, was analyzed by Northern hybridization of poly(A)+ RNA of hybridoma with cDNA probes for nine VH gene families. Different hybridomas tended to express VH genes of the same family when the cognate Ag had the same or similar carbohydrate structures; i.e., the VH genes of the J558 family (group 1) were preferentially expressed in the mAb directed to various gangliosides that have NeuAc alpha (or NeuGc alpha) 2-3 and/or 2-8 linkage (71%), the most common linkage of sialic acid residues in the gangliosides of higher animals, and the hybridomas directed to sulfated glycolipids also expressed mainly the VH genes of the J558 family (80%). In contrast, the five mAb directed to various gangliosides with NeuAc alpha 2-6 linkage were exclusively encoded by the VH genes of Q52 family (group 2, 100%), and three antibodies directed to gangliosides with a NeuAc alpha 2-9 linkage all expressed genes of J606 family (group 6, 100%). The VH family usage was largely correlated with the linkage of sialic acid residues in the cognate carbohydrate Ag, but was not correlated at all with the difference in the fine specificities toward the core neutral carbohydrate chain, to which the sialic acid residues were attached. These findings suggest that the VH gene family in these anticarbohydrate antibodies is selected, depending primarily on the linkage of the sialic acid residues in carbohydrate Ag; these residues form the immunodominant sugar residue in the respective antigenic determinant.


Correction: Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients.
Following the publication of this article, the authors noted that Patrick M. Vanderboom was inadvertently omitted from the author list. The correct author list is as follows: Sanjay Kumar, David Murray, Surendra Dasari, Paolo Milani, David Barnidge, Benjamin Madden, Patrick M. Vanderboom, Taxiarchis Kourelis, Bonnie Arendt, Giampaolo Merlini, Marina Ramirez-Alvarado, Angela Dispenzieri. Patrick M. Vanderboom is affiliated with the Mayo Clinic in Rochester, MN.


The interaction of urinary tract infection and renal insufficiency.
Urinary tract infections (UTIs) are among the most common infections caused by microorganisms, and pyelonephritis is the most severe infection of the urogenital tract. The risk of developing chronic renal insufficiency due to a UTI without other risk factors is low. The pathogenicity and virulence of the infective microorganisms as well as the efficiency of local or systemic defence mechanisms determine the course and severity of the disease. Virulence properties (adhesins, toxins, capsule, iron uptake) are encoded by genomic structures and the determination of virulence is influenced by the host situation. In renal insufficiency, a variety of quite different substances (uraemic toxins, betaine, amino acids, creatinine, urea, glucose) influence the microbial environment. Defence factors (Tamm-Horsfall protein, defensin, phagocytic activity of granulocytes) and underlying anatomical lesions as well as pre-existing renal disease determine the severity of UTI and the prognosis of renal insufficiency.


Nutrient and productivity relations of the dune grasses Ammophila arenaria and Elymus mollis : I. Blade photosynthesis and nitrogen use efficiency in the laboratory and field.
A comparative study of blade photosynthesis and nitrogen use efficiency was made on the dune grasses Ammophila arenaria and Elymus mollis. In the laboratory, an open system gas analysis apparatus was used to examine the gas exchange characteristics of blades as influenced by nitrogen supply. Plants were grown under near-ambient coastal conditions in a greenhouse near Bodega Bay, California, and given either high or low supplies of nitrogen in an otherwise complete nutrient solution. In the field, 14CO2 uptake techniques were employed to measure the seasonal patterns of blade photosynthesis of plants growing in situ at Point Reyes National Seashore. Blades used in the lab and field studies were analyzed for total nitrogen content, thus allowing for calculations of photosynthetic nitrogen use efficiency (CO2 fixed/unit of blade N.).Under laboratory conditions, the introduced Ammophila developed higher rates of light-saturated photosynthesis than the native Elymus, especially under the nitrogenlimited growth regime. Higher rates of photosynthesis and lower concentrations of blade N resulted in a significantly greater nitrogen use efficiency for Ammophila regardless of nutrient treatment. Low N availability induced qualitatively similar physiological responses in both species, including reductions in maximum net photosynthesis, mesophyll conductance, leaf conductance, dark respiration, and blade nitrogen content, and an increase in the CO2 compensation point.Although the photosynthetic rates of Ammophila blades were higher in the lab, those of Elymus blades were consistently higher in the field. This could have resulted from differential effects of drought on the two species (i.e. Ammophila may have been more sensitive) or a higher photosynthetic capacity in Elymus that reflected the greater (1.2-1.5 X) nitrogen content of its blades. However, the nitrogen use efficiency of Ammophila blades was greater than that of Elymus throughout most of the sampling year, despite lower average rates of field photosynthesis.The results indicated that rates of photosynthesis perunit of blade area do not account for the greater aboveground productivity of Ammophila stands along the Pacific coast of North America. Instead, efficient nitrogen use in photosynthesis maycomplement other structural and physiological traits and thereby enhance long-term carbon gain in Ammophila relative to Elymus.


Treatment of overt isolated testicular relapse in children on therapy for acute lymphoblastic leukemia. A report from the Childrens Cancer Group.
Fifty-seven children with acute lymphoblastic leukemia (ALL) receiving therapy who experienced overt isolated testicular relapse while in bone marrow remission were entered into a study that featured an intensive retreatment regimen. The objective was to determine whether a change in chemotherapy and local irradiation would prevent subsequent marrow relapse and increase the survival rate. The regimens used (modified Berlin-Frankfurt-Munster or modified New York) delivered acceptable therapy based on analyses of toxicity data. Overall survival at 5 years from the time of testicular relapse was 47%, with an event-free survival of 43%. Events have been documented in 28 of 55 evaluable children. Analysis of these patients revealed that 23 children had bone marrow relapse, 4 children had central nervous system relapse, and 1 child had testicular relapse. In addition, two patients were removed from the study for toxicity, one child for infection (mucormycosis), and five children had a bone marrow transplantation while in remission and became ineligible to continue in the study. Two children were removed at the request of their parents, and nine children were lost to follow-up. Because of their high risk of developing systemic relapse, boys with ALL who experience isolated overt testicular relapse during active therapy should be retreated with intensive treatment.


Progressivity and redistributive effects of income taxes: evidence from India.
We analyse the progressivity and redistributive effects of India's income tax system utilizing Income Tax Department data for 2011-18. By fitting Lorenz and tax concentration curves to these data, we find that despite exhibiting high levels of progressivity, the redistributive effects of income taxes remain modest amongst tax assessees and miniscule within the adult population. We also find that plugging the gap between statutory and actual average tax rates will do little to improve redistributive effects, and lowering income thresholds for top marginal tax rates offers greater redistributive and revenue potential than reducing exemption limits or increasing top marginal tax rates.


Electrochemical Umpolung C-H Functionalization of Oxindoles.
Herein, we present a general electrochemical method to access unsymmetrical 3,3-disubstituted oxindoles by direct C-H functionalization where the oxindole fragment behaves as an electrophile. This Umpolung approach does not rely on stoichiometric oxidants and proceeds under mild, environmentally benign conditions. Importantly, it enables the functionalization of these scaffolds through C-O, and by extension to C-C or even C-N bond formation.


Long-term dementia risk prediction by the LIBRA score: A 30-year follow-up of the CAIDE study.
As no causal treatment for dementia is available yet, the focus of dementia research is slowly shifting towards prevention strategies. Therefore, this study aimed to examine the predictive accuracy of the "LIfestyle for BRAin Health" (LIBRA) score, a weighted compound score of 12 modifiable risk and protective factors, for dementia and mild cognitive impairment (MCI) in midlife and late-life, and in individuals with high or low genetic risk based on presence of the apolipoprotein (APOE) ε4 allele. The LIBRA score was calculated for participants from the Finnish Cardiovascular Risk Factors, Aging and Dementia (CAIDE) population-based study examined in midlife (n = 1024) and twice in late-life (n = 604) up to 30 years later. Diagnoses of MCI and dementia were made according to established criteria. Cox proportional hazards models were used to assess the association between LIBRA and risk of dementia and MCI in models adjusted for sex and education (age as timescale). Higher midlife LIBRA scores were related to higher risk of dementia (hazard ratio [HR] = 1.27; 95% confidence interval [CI], 1.13-1.43) and MCI (unadjusted model: HR = 1.12; 95% CI, 1.03-1.22) up to 30 years later. Higher late-life LIBRA scores were related to higher risk of MCI (HR = 1.11; 95% CI, 1.00-1.25), but not dementia (HR = 1.02; 95% CI, 0.84-1.24). Higher late-life LIBRA scores were related to higher dementia risk among apolipoprotein E (APOE) ε4 non-carriers. Findings emphasize the importance of modifiable risk and protective factors for dementia prevention.


Venous thromboembolism risk and erythropoiesis-stimulating agents for the treatment of cancer-associated anemia: a meta-analysis.
Erythropoiesis-stimulating agents (ESAs) reduce anemia in patients with cancer and could improve their quality of life, but ESA-related safety concerns exist. To evaluate the overall risk of venous thromboembolism (VTE) associated with the use of ESAs, a systematic review and meta-analysis of published randomized controlled trials (RCTs) was performed. The databases of PubMed and Web of Science and the abstracts presented at the American Society of Clinical Oncology conferences were searched to identify relevant clinical trials. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated. A total of 12,115 patients with a variety of cancer types from 51 RCTs were identified and included in the meta-analysis. Among patients receiving ESAs, the summary incidence of all-grade VTE was 7.78%. Patients with cancer who received ESAs had increased VTE risks (484 events among 6,301 patients treated with ESA vs. 276 events among 5,814 control patients; RR = 1.75 [95% CI, 1.50–2.05]). The highest risk of VTE was found in patients with ovarian and cervical cancers (RR = 2.45 [CI = 1.12–5.33]). The VTE risk among hematologic malignancies was higher than that among solid tumors. The administration of ESAs was significantly associated with an increased risk of developing VTE in cancer patients receiving these drugs. The risks of VTE may vary with various tumor types, including hematologic malignancies.


A case of uterine inclusion cysts in a sow.
Serosal inclusion cysts are thin walled-structures located on the peritoneal surface of the uterus, frequently observed as multiple cystic structures in aggregates or grape-like clusters containing a clear, non-viscous fluid. In human and veterinary medicine, they are thought to be developed under hormonal effects, or after manipulation or inflammation of the reproductive tract. However, they have not yet been described in swine. A uterus of a 3-year-old crossbreed sow was condemned at slaughter due to the presence of multiples cystic cavities attached to the serosal surface. Microscopically, multiple cystic dilations emerging from the serosa were lined by a simple and flattened epithelium (cytokeratine positive and vimentin negative on immunohistochemistry) supported by a subepithelial layer of collagen. Grossly and histologically, they were diagnosed as serosal inclusion cysts. To the authors' knowledge, this report represents the first description of serosal inclusion cysts in sows. These lesions should be taken into consideration within the differential diagnostic list of cystic peritoneal lesions such as cystic neoplasms, congenital cysts, and parasitic diseases.


"Satellite pedicle screws" - A novel technique of pedicle screw insertion in obese patients undergoing lumbar fusion.
The presence of thick sub-cutaneous fat and bulky paraspinal musculature mandates extensive surgical dissection in obese patients undergoing open Transforaminal lumbar interbody fusion surgery. Securing a 'converging' pedicle screw trajectory becomes difficult by the counterforces of the erector spinae muscles and thick sub-cutaneous fat in obese patients, especially at the L5-S1 level. We describe the use of a limited standard posterior midline exposure and a separate, far lateral 'satellite' incision to insert pedicle screws in an optimal trajectory in obese patients. Through proper pre-operative planning of the axial and sagittal MRI, the appropriate entry site is determined which is executed intra-operatively to insert pedicle screws freehand. Through a single 1.5 cm incision, both L5-S1 screws were inserted. Fourteen obese patients (mean BMI was 30.5 ± 1.1) received 56 satellite pedicle screws for TLIF at L5-S1 level. The mean age was 48.3 ± 9.7 years. The mean blood loss was 244.8 ± 114 ml and the mean operative time was 126.7 ± 82.8 min. In all patients, the screws were inserted as per pre-operative planning without any difficulties. All wounds healed well without wound complications. There were no screw related complications, and in the antero-posterior and lateral radiographs, there were no screw breaches. Satellite free-hand pedicle screws are safe and easily reproducible. They enable limited dissection of the main surgical wound and well-medialised converging pedicle screws in obese patients.


Control of angiotensinogen production by H4 rat hepatoma cells in serum-free culture.
A serum-free, hormone and attachment factor supplemented culture for rat H4 hepatoma cells was established. In the defined medium (Dulbecco's Modified Eagle's + Ham's F12 + insulin, transferrin, fibronectin liver cell growth factor, and sodium selenite), H4 cells grew equally well as in 10% fetal bovine serum supplemented medium. H4 cells in either defined or serum-containing culture conditions produce transferrin but not albumin or alpha-fetoprotein. In this paper we have studied the effect of various hormones and pressor peptides on the production of angiotensinogen by H4 cells cultured in defined conditions. Only glucocorticoid hormone had a significant effect on the production of angiotensinogen, whereas other hormones previously reported to exert their effect on angiotensinogen production had little or no effect.


Green tea catechin leads to global improvement among Alzheimer's disease-related phenotypes in NSE/hAPP-C105 Tg mice.
Amyloid β (Αβ) has been reported to be responsible for the functional and structural abnormalities of Alzheimer's disease (AD) through the induction of oxidative stress. The aim of this study was to determine whether or not treatment of transgenic (Tg) mice with green tea catechin (GTC), a radical scavenger, improves AD phenotypes. To test this, 7-month-old Tg mice were treated with a low (1 mg) or high (10 mg) dose of GTC for 6 months. Surprisingly, GTC-treated Tg mice exhibited significant decreases in behavioral impairment, Aβ-42 production, APP-C99/89 expression, γ-secretase component and Wnt protein levels, γ-secretase activity and MAPK activation. In contrast, the levels of APP-C83 protein and enzyme activities (α-secretase, neprilysin and Pin1) were elevated in the GTC-treated groups. Moreover, GTC-treated groups showed lower levels of total cholesterol and low-density lipoprotein cholesterol, whereas the level of high-density lipoprotein cholesterol increased. These results provide the first experimental evidence that GTC improves AD phenotypes, thereby suggesting that GTC can be used in the prevention of AD or treatment of AD patients.


Effect of metoprolol versus carvedilol on outcomes in MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy).
This study sought to compare the effects of metoprolol and carvedilol in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study. The impact of beta-blockers in heart failure (HF) patients with devices is uninvestigated. All patients receiving either metoprolol or carvedilol in the MADIT-CRT study were identified and compared. Time-dependent Cox proportional hazard regression analyses were performed to assess differences in hospitalization for HF or death and ventricular arrhythmias. Hospitalization for HF or death occurred in 30% of the patients on metoprolol and in 23% on carvedilol. Treatment with carvedilol was associated with a significantly decreased risk of hospitalization for HF or death when compared with metoprolol (hazard ratio [HR]: 0.70, [95% confidence interval (CI): 0.57 to 0.87], p = 0.001). This reduction in risk was further attenuated in the subgroup of cardiac resynchronization therapy with implantable cardioverter-defibrillator (CRT-D) patients (HR: 0.61 [95% CI: 0.46 to 0.82], p = 0.001) and CRT-D patients with left bundle branch block (LBBB) (HR: 0.51 [95% CI: 0.35 to 0.76], p < 0.001). Ventricular arrhythmias occurred in 26% and in 22%, respectively, of the patients receiving metoprolol or carvedilol (HR: 0.80 [95% CI: 0.63 to 1.00], p = 0.050). General use of beta-blockers and adherence in this study was high, and a clear dose-dependent relationship was found in carvedilol, but not in metoprolol. In HF patients in New York Heart Association functional class I and II and with wide QRS complexes, carvedilol was associated with a 30% reduction in hospitalizations for HF or death when compared with metoprolol. A novel beneficial and synergistic effect of carvedilol was seen in patients with CRT-D and LBBB. Furthermore, we found a pronounced dose-dependent relationship in carvedilol, but not in metoprolol.


Multicentre observational study of the Gatekeeper for faecal incontinence.
A variety of therapeutic approaches are available for faecal incontinence. Implantation of Gatekeeper prostheses is a new promising option. The primary endpoint of this prospective observational multicentre study was to assess the clinical efficacy of Gatekeeper implantation in patients with faecal incontinence. Secondary endpoints included the assessment of patients' quality of life, and the feasibility and safety of implantation. Patients with faecal incontinence, with either intact sphincters or internal anal sphincter lesions extending for less than 60° of the anal circumference, were selected. Intersphincteric implantation of six prostheses was performed. At baseline, and 1, 3 and 12 months after implantation, the number of faecal incontinence episodes, Cleveland Clinic Faecal Incontinence, Vaizey and American Medical Systems, Faecal Incontinence Quality of Life Scale and Short Form 36 Health Survey scores were recorded. Endoanal ultrasonography was performed at baseline and follow-up. Fifty-four patients were implanted. After Gatekeeper implantation, incontinence to gas, liquid and solid stool improved significantly, soiling was reduced, and ability to defer defaecation enhanced. All faecal incontinence severity scores were significantly reduced, and patients' quality of life improved. At 12 months, 30 patients (56 per cent) showed at least 75 per cent improvement in all faecal incontinence parameters, and seven (13 per cent) became fully continent. In three patients a single prosthesis was extruded during surgery, but was replaced immediately. After implantation, prosthesis dislodgement occurred in three patients; no replacement was required. Anal implantation of the Gatekeeper in patients with faecal incontinence was effective and safe. Clinical benefits were sustained at 1-year follow-up.


Multiple Correspondence Analysis and HLA-Associations of Organ Involvement in a Large Cohort of African-American and European-American Patients with Sarcoidosis.
Sarcoidosis is a systemic granulomatous disease with predominant pulmonary involvement and vast heterogeneity of clinical manifestations and disease outcomes. African American (AA) patients suffer greater morbidity and mortality. Using Multiple Correspondence Analysis, we identified seven clusters of organ involvement in European American (EA; n = 385) patients which were similar to those previously described in a Pan-European (GenPhenReSa) and a Spanish cohort (SARCOGEAS). In contrast, AA (n = 987) had six, less well-defined and overlapping clusters with little similarity to the cluster identified in the EA cohort evaluated at the same U.S. institutions. Association of cluster membership with two-digit HLA-DRB1 alleles demonstrated ancestry-specific patterns of association and replicated known HLA effects.These results further support the notion that genetically influenced immune risk profiles, which differ based on ancestry, play a role in phenotypic heterogeneity. Dissecting such risk profiles will move us closer to personalized medicine for this complex disease.


Long-Term Outcomes in Burn Patients.
Better understanding of long-term outcomes after burn injury is essential for the burn clinician. Contractures are present in almost half of patients at discharge. Although less common, neuropathy and heterotopic ossification may be missed or go unaddressed. Close attention to psychological distress and to challenges with community reentry is essential. Obviously long-term problems with skin issues occur but other issues must be attended to maximize health and quality of life after injury. Facilitating access to community resources and providing long-term medical follow-up should be the standard of care.


Porogen effects in synthesis of uniform micrometer-sized poly(divinylbenzene) microspheres with high surface areas.
A new method of synthesizing uniform poly(divinylbenzene) (polyDVB) microspheres with high specific surface areas was designed by combining Shirasu porous glass (SPG) membrane emulsification, suspension polymerization, and post-crosslinking techniques. It was shown that the physicochemical properties of porogens have a great influence on the size distribution and porous features of microspheres. The low aqueous solubility of porogen facilitated preparation of uniform emulsions and microspheres, and high aqueous solubility led to polydispersed emulsions and poor microsphere yields. Such aqueous solubility effects can be tailored by adding a low molecular weight polystyrene (LPST) as costabilizer in porogen, thus improving the uniformity of microspheres. Moreover, different affinities of porogens for copolymers demonstrate various contributions to specific surface areas of microspheres in suspension polymerization especially post-crosslinking. Solvating porogen requires a much higher addition than nonsolvating porogen to obtain equal specific surface areas in polymerization, but has more potential to enhance the specific surface area in post-crosslinking. Two kinds of uniform microspheres were obtained with high specific surface areas, up to 706.6 m2/g by heptane and 937.5 m2/g by toluene.


Mycobacterium tuberculosis maltosyltransferase GlgE, a genetically validated antituberculosis target, is negatively regulated by Ser/Thr phosphorylation.
GlgE is a maltosyltransferase involved in the biosynthesis of α-glucans that has been genetically validated as a potential therapeutic target against Mycobacterium tuberculosis. Despite also making α-glucan, the GlgC/GlgA glycogen pathway is distinct and allosterically regulated. We have used a combination of genetics and biochemistry to establish how the GlgE pathway is regulated. M. tuberculosis GlgE was phosphorylated specifically by the Ser/Thr protein kinase PknB in vitro on one serine and six threonine residues. Furthermore, GlgE was phosphorylated in vivo when expressed in Mycobacterium bovis bacillus Calmette-Guérin (BCG) but not when all seven phosphorylation sites were replaced by Ala residues. The GlgE orthologues from Mycobacterium smegmatis and Streptomyces coelicolor were phosphorylated by the corresponding PknB orthologues in vitro, implying that the phosphorylation of GlgE is widespread among actinomycetes. PknB-dependent phosphorylation of GlgE led to a 2 orders of magnitude reduction in catalytic efficiency in vitro. The activities of phosphoablative and phosphomimetic GlgE derivatives, where each phosphorylation site was substituted with either Ala or Asp residues, respectively, correlated with negative phosphoregulation. Complementation studies of a M. smegmatis glgE mutant strain with these GlgE derivatives, together with both classical and chemical forward genetics, were consistent with flux through the GlgE pathway being correlated with GlgE activity. We conclude that the GlgE pathway appears to be negatively regulated in actinomycetes through the phosphorylation of GlgE by PknB, a mechanism distinct from that known in the classical glycogen pathway. Thus, these findings open new opportunities to target the GlgE pathway therapeutically.


New Levels of Vertebral Compression Fractures after Percutaneous Kyphoplasty: Retrospective Analysis of Styles and Risk Factors.
The causes of subsequent vertebral fractures after kyphoplasty are debated. It is reported that most new vertebral fractures after kyphoplasty develop in adjacent vertebrae. We explored whether kyphoplasty increases the incidence of adjacent vertebral fractures and identified risk factors for new vertebral compression fractures (VCFs) after kyphoplasty. Retrospective study. Inpatient population of a single center. We studied 356 patients treated with kyphoplasty from January 2008 to March 2012. Among those patients, there were 35 new VCFs after kyphoplasty. Subsequently, these patients were divided into 2 groups: an "adjacent fracture" group and a "nonadjacent fracture" group. In addition, all patients treated with kyphoplasty were further assigned to either a "new fracture" group or a "no fracture" group. The occurrence of new VCFs in the "nonadjacent fracture" group was significantly higher than that in the "adjacent fracture" group. The average bone mineral density (BMD) of the spine was -3.95 in the "new fracture" group and -2.86 in the "no fracture" group. The risk of new vertebral fracture increased as the bone mineral density decreased (P < 0.05). The morbidity of women was significantly higher in the "new fracture" group (94.29%) than in the "no fracture" group (77.88%) (P = 0.025). Retrospective study at a single center. New VCFs after kyphoplasty occurred most often in nonadjacent vertebrae. VCFs after kyphoplasty were common in patients with low bone mineral density and in women, suggesting that osteoporosis is an underlying mechanism. INSTITUTIONAL REVIEW: This study was approved by the institutional review board.


Pre-Transplant Plasma Potassium as a Potential Risk Factor for the Need of Early Hyperkalaemia Treatment after Kidney Transplantation: A Cohort Study.
Plasma potassium (K+) abnormalities are common among patients with chronic kidney disease and are associated with higher rates of death, major adverse cardiac events, and hospitalization in this population. Currently, no guidelines exist on how to handle pre-transplant plasma K+ in renal transplant recipients (RTR). The aim of this study is to examine the relation between pre-transplant plasma K+ and interventions to resolve hyperkalaemia within 48 h after kidney transplantation. In a single-centre cohort study, we addressed the association between the last available plasma K+ level before transplantation and the post-transplant need for dialysis or use of K+-lowering medication to resolve hyperkalaemia within 48 h after renal transplantation using multivariate logistic regression analysis. 151 RTR were included, of whom 51 (33.8%) patients received one or more K+ interventions within 48 h after transplantation. Multivariate regression analysis revealed that a higher pre-transplant plasma K+ was associated with an increased risk of post-transplant intervention (odds ratio 2.2 [95% CI: 1.1-4.4]), independent of donor type (deceased or living) and use of K+-lowering medication within 24 h prior to transplantation). This study indicates that a higher pre-transplant plasma K+ is associated with a higher risk of interventions necessary to resolve hyperkalaemia within 48 h after renal transplantation. Further research is recommended to determine a cutoff level for pre-transplant plasma K+ that can be used in practice.


Hypersensitivity reactions to metals in spine surgery.
Hypersensitivity to orthopedic devices is a rare condition with an underestimated incidence due to the lack of diagnostic guideline and ambiguous clinical manifestations. Although hypersensitivity to metal is common, a few cases of hypersensitivity reactions have been reported after spinal instrumentation. Spinal fusion and stabilization require a wide range of devices such as screws, wires, bands, and artificial disk replacement devices. Spinal instrumented surgeries are different from total joint arthroplasty in several aspects such as degree and pattern of motion, loading environment, and adjacent tissues with distinct characteristics. The interval for hypersensitivity reactions to occur after spinal metallic implantation is usually weeks to months. The present review covers the topic of hypersensitivity reactions that have been reported after spinal surgeries with the focus on cutaneous presentations.


A human T-cell clone cytotoxic for hepatocytes from patients with chronic non-A, non-B hepatitis.
A human T-cell clone (TA-NB-2) which could lyse hepatocytes from patients with chronic non-A, non-B (NANB) hepatitis was established (Proc Natl Acad Sci USA 1989;86:2883-2887). TA-NB-2 cells belonged to CD3+ CD8+ cytotoxic T lymphocytes, and recognized the target hepatocytes by T-cell receptor without restriction by major histocompatibility complex (MHC) antigens. TA-NB-2 cells significantly lysed hepatocytes from 22 of 23 patients with chronic NANB hepatitis, whereas they lysed hepatocytes from only one of 17 control patients with chronic type B hepatitis, acute hepatitis B or acute hepatitis A. TA-NB-2 cells also significantly lysed hepatocytes from 4 of 5 patients with autoimmune liver disease. The results suggest that TA-NB-2 cells specifically recognize a NANB hepatitis-related antigen expressed on NANB hepatitis virus-infected hepatocytes by T-cell receptor in non-MHC-restricted manner. The results also suggest that most, if not all, cases of chronic NANB hepatitis are caused by one agent and that a portion of cases of autoimmune liver disease may be induced by infection with a NANB hepatitis virus.


Cesarean section-related maternal mortality in Massachusetts, 1954-1985.
We analyzed the data of the Maternal Mortality Committee of the Massachusetts Medical Society to investigate cesarean section-associated maternal deaths. Between 1954-1985, the number of cesarean section-related deaths per 100,000 live births did not significantly change despite a quadrupling of the cesarean section rate. Between 1976-1984, there were 649,375 births and 121,217 cesarean sections in the state. Seven deaths were directly related to cesarean section, a rate of 5.8 per 100,000 cesarean sections. In contrast, the rate for vaginal deliveries was 10.8 per 100,000 vaginal deliveries. We conclude that the risk of maternal death from cesarean section is low.


Esophageal intramural metastasis from an adenocarcinoma of the gastric cardia: report of a case.
We report herein the rare case of a 65-year-old man found to have esophageal intramural metastasis from cancer of the gastric cardia. Endoscopic examination initially revealed an infiltrating ulcerative tumor of the gastric cardia involving the esophagogastric junction, as well as a submucosal tumor of the lower esophagus. A total thoracic esophagogastrectomy with lower mediastinal lymphadenectomy was performed, and the resected specimen demonstrated that both the cardia and esophageal tumors were adenocarcinomas with the same cellular differentiation. As lymphatic invasion and metastases to the paracardial and mediastinal lymph nodes were observed, the esophageal submucosal tumor was considered to be an intramural metastasis from the carcinoma of the gastric cardia resulting from extensive lymphatic spread. The patient died of recurrent disease 9 months after the resection. This case report serves to demonstrate that intramural metastasis may be a local indicator of the systemic spread of disease in patients with gastric carcinoma, as it is in esophageal carcinoma.