Invited Review Article: "Hands-on" laser-driven ion acceleration: A primer for laser-driven source development and potential applications.
An overview of progress and typical yields from intense laser-plasma acceleration of ions is presented. The evolution of laser-driven ion acceleration at relativistic intensities ushers prospects for improved functionality and diverse applications which can represent a varied assortment of ion beam requirements. This mandates the development of the integrated laser-driven ion accelerator system, the multiple components of which are described. Relevant high field laser-plasma science and design of controlled optimum pulsed laser irradiation on target are dominant single shot (pulse) considerations with aspects that are appropriate to the emerging petawatt era. The pulse energy scaling of maximum ion energies and typical differential spectra obtained over the past two decades provide guidance for continued advancement of laser-driven energetic ion sources and their meaningful applications.


Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity.
Aggregated and highly phosphorylated tau protein is a pathological hallmark of Alzheimer's disease (AD) and other tauopathies. We identified motifs of alternating polar and apolar amino acids within the microtubule-binding repeats of tau which were interrupted by small breaking stretches. Minimal mutation of these breaking sequences yielded a unique instantly aggregating tau mutant containing longer stretches of polar/apolar amino acids without losing its microtubule-binding capacity. These modifications produced rapid aggregation and cytotoxicity with accompanying occurrence of pathologic tau phosphoepitopes (AT8, AT180, AT270, AT100, Ser(422), and PHF-1) and conformational epitopes (MC-1 and Alz50) in cells. Similar to pathological tau in the pretangle state, toxicity appeared to occur early without the requirement for extensive fibril formation. Thus, our mutant protein provides a novel platform for the investigation of the molecular mechanisms for toxicity and cellular behavior of pathologically aggregated tau proteins and the identification of its interaction partners.


Steroid hormones induce in vitro human first trimester trophoblast tubulogenesis by the lysophosphatidic acid pathway.
Successful implantation and placentation requires that extravillous cytotrophoblast acquires an endovascular phenotype and remodels uterine spiral arteries. Progesterone (P4) and estradiol (E2) control many of the placental functions, but their role in vascular remodeling remains controversial. Here, we investigated whether P4 and E2 regulate the acquisition of the human first trimester trophoblast endovascular phenotype, and the participation of the lysophosphatidic acid pathway. For this purpose, human first trimester HTR-8/SVneo cells were seeded on Geltrex and assayed for capillary-like tube formation. P4 and E2 increased HTR-8/SVneo tube formation in a concentration-dependent manner and this effect is mediated by the LPA3 receptor. Moreover, sex steroids increased the mRNA levels of the main enzyme that produce lysophosphatidic acid (lysophospholipase-D) but did not regulate LPA3 mRNA levels. Overall, we demonstrate that steroid hormones regulate HTR-8/SVneo trophoblast capillary-like structures formation and we propose that this process could be modulated directly or indirectly by mechanisms associated to the LPA/LPA3 pathway.


Complete Genomic Sequence of Dengue virus 1, Isolated from Plasma Collected from a Haitian Child in 2014.
An outbreak of dengue fever followed a chikungunya fever outbreak in Haiti in 2014. We detected Dengue virus 1 (DENV-1) in plasma samples collected between May 2014 and February 2015. A representative isolate was fully sequenced, and phylogenetic analyses indicate that it groups within the genotype V South American and Caribbean DENV-1 clades.


Advantages and limitations of clear-native PAGE.
Clear-native PAGE (CN-PAGE) separates acidic water-soluble and membrane proteins (pI < 7) in an acrylamide gradient gel, and usually has lower resolution than blue-native PAGE (BN-PAGE). The migration distance depends on the protein intrinsic charge, and on the pore size of the gradient gel. This complicates estimation of native masses and oligomerization states when compared to BN-PAGE, which uses negatively charged protein-bound Coomassie-dye to impose a charge shift on the proteins. Therefore, BN-PAGE rather than CN-PAGE is commonly used for standard analyses. However, CN-PAGE offers advantages whenever Coomassie-dye interferes with techniques required to further analyze the native complexes, e.g., determination of catalytic activities, as shown here for mitochondrial ATP synthase, or efficient microscale separation of membrane protein complexes for fluorescence resonance energy transfer (FRET) analyses. CN-PAGE is milder than BN-PAGE. Especially the combination of digitonin and CN-PAGE can retain labile supramolecular assemblies of membrane protein complexes that are dissociated under the conditions of BN-PAGE. Enzymatically active oligomeric states of mitochondrial ATP synthase previously not detected using BN-PAGE were identified by CN-PAGE.


Late Presentation for Kidney Biopsy: Clinical Presentations and Laboratory Findings.
Although the number of patients reaching end-stage kidney disease without a biopsy- proven diagnosis is increasing, kidney biopsies play a key role in diagnosing kidney disease. We analyzed prospective data from patients with kidney disease who underwent percutaneous native kidney biopsies from January 2006 to December 2017. Demographic data, clinical presentations, and the laboratory and radiological findings at the time of biopsy were analyzed. Of 530 patients, 42.8% were male. The mean age was 33.9 (32.8-34.9.2) years; 66.3% were aged 25-64 years. Edema was the main clinical presentation (61.9%), with clinical urine changes seen in 66.7%. Most (89.6%) were nondiabetic; 46.8% had high blood pressure or were on antihypertensive therapy. Most patients (77.5%) were in Stages I, II, and III, and 12.3% underwent hemodialysis at the time of admission. Most (54.4%) were obese. Low hemoglobin (31.8%), high triglycerides (30%), high total cholesterol (58.2%), low serum albumin (73.9%), nephrotic proteinuria (61.8.6%), and microscopic hematuria (79.8%) were the main laboratory findings. The immunological investigations showed that antinuclear antibodies, positive anti-double-stranded DNA (anti-dsDNA), and extractable nuclear antigens were positive in 29.6%, 20.7%, and 19.7%, respectively. Perinuclear antineutrophil cytoplasmic antibodies (ANCA) were positive in 9.6% and cytoplasmic ANCA were positive in 5.4%, whereas immunoglobulin A was detected in 4.6%. More than one- third of the patients had reached advanced chronic kidney disease (CKD) Stages IIIB, IV, and V. This indicates the need to increase awareness about CKD, greater utilization of kidney biopsies, and earlier investigations to enable accurate diagnoses, and proper and timely management.


Concentration-dependent diffusion of unlabeled protein within an in vitro hyaluronic acid matrix.
Diffusion and movement of subcutaneously injected biologics and high-concentration immunoglobulin G (IgG) therapeutics away from the injection site and through the subcutaneous (SC) tissue may be concentration dependent. This possibility was confirmed by in situ measurement of diffusion coefficients of unlabeled bovine IgG in phosphate-buffered saline within an in vitro hyaluronic acid matrix that represents the SC electrostatic environment. Diffusion decreased from 2.67 to 0.05 × 10-7 cm2 /s when IgG concentration increased from 25 to 73 mg/mL. The results demonstrated that in situ detection of unlabeled proteins within an in vitro SC environment provides another useful tool for the preclinical characterization of injectable biologics.


Autoimmune thyroid disease is associated with a diagnosis of secondary Sjögren's syndrome in familial systemic lupus.
Autoimmune thyroid disease is common in systemic lupus erythematosus (SLE). About 20% of patients with SLE have secondary Sjögren's syndrome. Families with more than one patient with SLE were identified. All patients met the revised classification criteria, although SLE-unaffected relatives were confirmed not to satisfy these criteria. Diagnosis of autoimmune thyroid disease and Sjögren's syndrome was made on the basis of a review of medical records, interview and questionnaire administered to patients with SLE, and by a questionnaire administered to SLE-unaffected subjects. Of a total of 1138 patients with SLE, 169 had a diagnosis of Sjögren's syndrome. Of these 50 (29.6%) patients also had autoimmune thyroid disease. Of the 939 patients with SLE with no diagnosis of Sjögren's syndrome, 119 (12.7%) had autoimmune thyroid disease (chi2 = 20.1, p = 0.000009). There was no association of a diagnosis of hypertension with secondary Sjögren's syndrome (42% vss 47%). Among 2291 SLE-unaffected relatives, 44 had diagnosed primary Sjögren's syndrome and 16 (36.3%) of these also had autoimmune thyroid disease. 265 of 2247 (11.8%) subjects had autoimmune thyroid disease but no Sjögren's syndrome (chi2 = 24.2, p<0.001). Autoimmune thyroid disease is found in excess among patients with SLE with a diagnosis of secondary Sjögren's syndrome, as well as among their SLE-unaffected relatives with a diagnosis of primary Sjögren's syndrome.


Adeno-associated Virus Virus-like Particle Characterization via Orthogonal Methods: Nanoelectrospray Differential Mobility Analysis, Asymmetric Flow Field-Flow Fractionation, and Atomic Force Microscopy.
Adeno-associated virus (AAV)-based virus-like particles (VLPs) are thriving vectors of choice in the biopharmaceutical field of gene therapy. Here, a method to investigate purified AAV serotype 8 (AAV8) batches via a nanoelectrospray gas-phase mobility molecular analyzer (nES GEMMA), also known as an nES differential mobility analyzer, is presented. Indeed, due to AAV's double-digit nanometer scale, nES GEMMA is an excellently suited technique to determine the surface-dry particle size termed electrophoretic mobility diameter of such VLPs in their native state at atmospheric pressure and with particle-number-based detection. Moreover, asymmetric flow field-flow fractionation (AF4, also known as AFFFF) and atomic force microscopy (AFM) techniques were employed as orthogonal techniques for VLP characterization. In addition, AF4 was implemented to size-separate as well as to enrich and collect fractions of AAV8 VLPs after inducing analyte aggregation in the liquid phase. Bionanoparticle aggregation was achieved by a combination of heat and shear stress. These fractions were later analyzed with nES GEMMA (in the gas phase) and AFM (on a solid surface). Both techniques confirm the presence of dimers, trimers, and putative VLP oligomers. Last, AFM reveals even larger AAV8 VLP aggregates, which were not detectable by nES GEMMA because their heterogeneity combined with low abundance was below the limit of detection of the instrument. Hence, the combination of the employed orthogonal sizing methods with the separation technique AF4 allow a comprehensive characterization of AAV8 VLPs applied as vectors.


Diabetes mellitus and its associated factors among patients with tuberculosis attending directly observed treatment centres in Oyo State, Nigeria: a cross-sectional evaluation.
Diabetes mellitus (DM) and tuberculosis (TB) comorbidity is evolving into an emerging epidemic globally. In Nigeria, a high burden of both diseases, respectively, exists with limited information on tuberculosis-diabetes mellitus (TB-DM) comorbidity. We determined the fasting blood glucose (FBG) level among patients with TB and factors associated with TB-DM comorbidity in Oyo State, South-west Nigeria. A cross-sectional study was conducted among patients with TB aged 15 years and above, who were selected using multistage sampling. Data were collected on patients' biodata, anthropometric measurements and FBG levels using a pretested semistructured questionnaire. The FBG test was conducted on patients with confirmed pulmonary TB (old and newly diagnosed patients with TB) at any stage of anti-TB treatment. Background characteristics and FBG level were summarised using descriptive statistics and factors associated with TB-DM comorbidity were examined at bivariate and multivariable analyses. Of the 404 patients with TB, 30 (7.4%) had impaired fasting glucose and 32 (7.9%) were diagnosed with diabetes. The mean age of the male and female respondents was 41 (±14.2) and 36.8 (±15.0), respectively. Females were more likely than males to have diabetes (10.6% vs 6.3%). Median FBG level for the patients was 88 (IQR: Q1: 99, Q3: 79) mg/dL. Age, marital status and educational level were not associated with TB-DM comorbidity. In the multivariable model, only normal body mass index was independently and significantly associated with diabetes. TB-DM was prevalent among the studied population in South-west Nigeria. We recommend the integration of DM screening within the continuum of care for TB management.


Survival of primary arteriovenous fistula in 463 patients on chronic hemodialysis.
To assess the survival of the primary arteriovenous fistula created for dialysis in 463 chronic hemodialysis patients, because the main causes of morbidity among such patients are associated with vascular access-related complications. We analyzed 269 (58%) men and 194 (42%) women with median age of 58 years (range 12-83), who underwent 0-14,784 (median 1,584) hours of hemodialysis. Data analyzed were age, gender, body weight loss during hemodialysis session, smoking habits, cause of renal failure, diabetes, myocardial infarction, stroke, malignant neoplasm, arterial hypertension or hypotension, drugs (salicylates, dipyridamole, coumarin anticoagulants, heparin, oral antidiabetics, insulin), number of hemodialysis sessions and hours of hemodialysis per week, fistula location, platelet count, hematocrit, institution in which the fistula had been created, and dialysis center where the fistula had been used. Kaplan-Meier and univariate analysis (Mantel-Cox and generalized Wilcoxon test) with 0.05 statistical significance were used for data analysis, and the outcome of the fistula survival was determined with logistic regression. Out of 597 patients with primary arteriovenous fistula, 134 patients were lost to follow-up. In the remaining 463 patients the fistula survival was 73%, 63%, 52%, 44%, 36%, 10%, 3%, and <1% after 1, 2, 3, 4, 5, 10, 15, and 20 years, respectively. Factors affecting the survival of arteriovenous fistula were administration of heparin (p=0.004) and dipyridamole (p=0.012), hemodialysis-dependent hypotension (p=0.045), diabetes (p=0.009), presence of malignant neoplasm (p=0.003), institution in which the fistula had been created (p<0.001) or used (p=0.037), hours of hemodialysis per week (p=0.023), and number of hemodialysis sessions per week (p=0.007). Primary arteriovenous fistula survival was shorter in end-stage renal disease patients with diabetes, hypotension, who underwent less than 3 hemodialysis sessions (<12 h) per week without heparin administration. Insufficient surgical experience, dipyridamole administration, and concomitant neoplasm contributed to arteriovenous fistula failure.


[Experimental study of augmentation phalloplasty using tunica vaginalis grafts in bilateral albuginea of penile corpus].
To study the effect and complications of augmentation phalloplasty by implanting autogenous tunica vaginalis grafts into the bilateral albuginea of the penile corpus. Five mongrel dogs underwent augmentation phalloplasty with bilateral autogenous tunica vaginalis grafts. The increase in the volume of the corpora cavernosa was achieved by applying autogenous tunica vaginalis grafts to longitudinal openings made bilaterally in the albuginea along the whole length of the penile cavernous corpora. The perimeter of the penile cavernous corpora was measured in the flaccid state and during erection and dynamic infusion cavernosometry (DIC) was conducted for each dog before and after the operation. Histology of the penis was examined using hematoxylin and eosin stains. The average increase in the perimeter of the penile cavernous corpora was 21. 1% in the erectile state but unobvious in the flaccid state 3 months after surgery. There were no statistically significant differences in cavernosometric parameters before and after the operation, and neither were there any other severe postoperative complications. The grafts had mild inflammatory reaction and fibrosis with apparent reformation of the tunica albuginea over the patch site. The augmentation phalloplasty technique with bilateral autogenous tunica vaginalis grafts was proved to be effective and reliable with few complications, particularly conspicuous in increasing the volume of the erectile tissues during erection.


Gastrointestinal Motility Disorders and Their Clinical Implications in Cirrhosis.
Gastrointestinal motility is impaired in a substantial proportion of patients with cirrhosis. Cirrhosis-related autonomic neuropathy, increased nitric oxide production, and gut hormonal changes have been implicated. Oesophageal dysmotility has been associated with increased frequency of abnormal gastro-oesophageal reflux. Impaired gastric emptying and accommodation may result in early satiety and may have an impact on the nutritional status of these patients. Small intestinal dysmotility might be implicated in small intestinal bacterial overgrowth and increased bacterial translocation. The latter has been implicated in the pathophysiology of hepatic encephalopathy and spontaneous bacterial peritonitis. Enhanced colonic motility is usually associated with the use of lactulose. Pharmacological interventions aiming to alter gastrointestinal motility in cirrhosis could potentially have a beneficial effect reducing the risk of hepatic decompensation and improving prognosis.


Recent advances in central congenital hypothyroidism.
Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic-pituitary-thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed.


Unusual complications of heroin abuse: transverse myelitis, rhabdomyolysis, compartment syndrome, and ARF.
Heroin overdose can cause various rare neurological complications like spongiform leukoencephalopathy, seizures, stroke, toxic amblyopia, transverse myelopathy, mononeuropathy, plexopathy, acute inflammatory demyelinating polyradiculoneuropathy, rhabdomyolysis, compartment syndrome, fibrosing myopathy, and acute bacterial myopathy. We report here the simultaneous presentation of multiple complications of heroin toxicity. A young heroin addict was found unarousable lying in the lotus posture. Examination showed quadriplegia and left leg gangrene. He subsequently developed heroin-induced transverse myelitis, rhabdomyolysis, left leg compartment syndrome, and myoglobin-induced acute renal failure. This case leads us to consider a common linked or systemic mechanism of injury rather than a local mechanism when multiple simultaneous organ failure occurs complicating heroin abuse.


Relevant Infections in Inflammatory Bowel Disease, and Their Relationship With Immunosuppressive Therapy and Their Effects on Disease Mortality.
There is controversy as to whether the risk of relevant infection in IBD is related to immunosuppressants or the disease itself. The aims of this study were to evaluate: [1] the life-long prevalence and types of relevant infections in patients with IBD related to immunosuppressive treatment, and [2] the relationship of both infection and patient comorbidity to mortality. Observational multicentre retrospective study of IBD patients that presented a relevant infection. For each case, four periods of infection exposure were analysed: P1: pre-IBD diagnosis, P2: from IBD diagnosis to immunosuppressant initiation, P3: during immunosuppressant therapy, and P4: after treatment withdrawal. The life-long prevalence of relevant infection in the total cohort of patients [6914] was 3%, and 5% in immunosuppressed patients [4202]. 366 relevant infections were found in 212 patients [P1: 9, P2: 17, P3: 334, and P4: 6]. Differences between periods were significant [p < 0.0001]. The most frequent types of infection were respiratory, intestinal and urinary. The most frequent opportunistic infections were tuberculosis [prevalence: 2.6/1000] and herpes zoster [prevalence: 3.9/1000]. Herpes zoster infection was associated with thiopurines alone or in combination with anti-TNF in 75% of the cases, whereas tuberculosis was associated with anti-TNF in 94% of patients. The overall mortality was 4.2%. Infection-related mortality was 2.8% and it was not influenced by comorbidity. Relevant infections in IBD patients are rare and appear to be related to immunosuppression. Relevant infection is a major cause of death in IBD.


Evidence of human hantavirus infection and zoonotic investigation of hantavirus prevalence in rodents in western Java, Indonesia.
During febrile surveillance in the western Java City of Bandung, Indonesia, a patient with clinical symptoms consistent with hantavirus infection was found to have elevated titers of hantavirus-specific immunoglobulin M (IgM) and IgG antibodies. A subsequent epizoological investigation demonstrated a higher prevalence of hantavirus IgG antibodies in rodents trapped in the vicinity of the patient's home compared with rodents from a control area (13.2% vs. 4.7%, p = 0.036). The Old World Seoul hantavirus was detected by reverse transcriptase-polymerase chain reaction in the organs of 71% of the seropositive rodents tested. This is the first report of a Seoul virus infection in Indonesia supported by clinical, serological, and epizoological evidences. These findings suggest that hantavirus infection should be on the clinical differential diagnosis when acutely ill febrile patients report for care in western Java.


ATF-1 is a hypoxia-responsive transcriptional activator of skeletal muscle mitochondrial-uncoupling protein 3.
Hypoxia induces oxidative damage in skeletal muscle. Uncoupling protein 3 (UCP3) is the skeletal muscle enriched uncoupling protein and has previously been shown to confer resistance against oxidative stress. We show that hypoxia robustly up-regulates skeletal muscle UCP3 and that the absence of UCP3 in primary skeletal myocytes exacerbates hypoxia-induced reactive oxygen species generation. In this context, we reasoned that the investigation of the regulation of UCP3 may identify novel hypoxia-responsive regulatory pathways that modulate intrinsic anti-oxidant defenses. By screening a transcription factor array of 704 full-length cDNAs in murine C2C12 myoblasts following cotransfection of a murine UCP3 promoter-luciferase construct and myoD we identified numerous candidate regulatory factors that up-regulate UCP3. Active transcription factor-1 (ATF-1) was identified, and as this transcription factor is a known component of a multiprotein hypoxia-induced regulatory complex, we explored its role in hypoxia-mediated UCP3 up-regulation. Site-directed mutagenesis and chromatin immunoprecipitation assays identify a 10-bp region required for ATF-1 induction of UCP3 promoter activity. Hypoxia promotes the phosphorylation of ATF-1, and the knockdown of ATF-1 by shRNA prevents hypoxia-mediated up-regulation of UCP3. Pharmacologic inhibition of p38 MAP kinase prevents both hypoxia-mediated ATF-1 phosphorylation and UCP3 up-regulation. PKA signaling does not modulate hypoxia-induced UCP3 up-regulation and neither does HIF-1alpha activation by cobalt chloride. In conclusion, ATF-1, via p38 MAP kinase activation, functions as a novel regulatory pathway driving UCP3 expression. These data reinforce the role of ATF-1 as a hypoxia-responsive trans-activator and identifies a novel regulatory program that may modulate cellular responses to oxygen-deficit.


Diffuse-charge effects on the transient response of electrochemical cells.
We present theoretical models for the time-dependent voltage of an electrochemical cell in response to a current step, including effects of diffuse charge (or "space charge") near the electrodes on Faradaic reaction kinetics. The full model is based on the classical Poisson-Nernst-Planck equations with generalized Frumkin-Butler-Volmer boundary conditions to describe electron-transfer reactions across the Stern layer at the electrode surface. In practical situations, diffuse charge is confined to thin diffuse layers (DLs), which poses numerical difficulties for the full model but allows simplification by asymptotic analysis. For a thin quasi-equilibrium DL, we derive effective boundary conditions on the quasi-neutral bulk electrolyte at the diffusion time scale, valid up to the transition time, where the bulk concentration vanishes due to diffusion limitation. We integrate the thin-DL problem analytically to obtain a set of algebraic equations, whose (numerical) solution compares favorably to the full model. In the Gouy-Chapman and Helmholtz limits, where the Stern layer is thin or thick compared to the DL, respectively, we derive simple analytical formulas for the cell voltage versus time. The full model also describes the fast initial capacitive charging of the DLs and superlimiting currents beyond the transition time, where the DL expands to a transient non-equilibrium structure. We extend the well-known Sand equation for the transition time to include all values of the superlimiting current beyond the diffusion-limiting current.


Expression and Function of Granzymes A and B in Escherichia coli Peritonitis and Sepsis.
Escherichia (E.) coli is the most common causative pathogen in peritonitis, the second most common cause of sepsis. Granzymes (gzms) are serine proteases traditionally implicated in cytotoxicity and, more recently, in the inflammatory response. We here sought to investigate the role of gzms in the host response to E. coli-induced peritonitis and sepsis in vivo. For this purpose, we used a murine model of E. coli intraperitoneal infection, resembling the clinical condition commonly associated with septic peritonitis by this bacterium, in wild-type and gzmA-deficient (gzmA-/- ), gzmB-/- , and gzmAxB-/- mice. GzmA and gzmB were predominantly expressed by natural killer cells, and during abdominal sepsis, the percentage of these cells expressing gzms in peritoneal lavage fluid decreased, while the amount of expression in the gzm+ cells increased. Deficiency of gzmA and/or gzmB was associated with increased bacterial loads, especially in the case of gzmB at the primary site of infection at late stage sepsis. While gzm deficiency did not impact neutrophil recruitment into the abdominal cavity, it was accompanied by enhanced nucleosome release at the primary site of infection, earlier hepatic necrosis, and more renal dysfunction. These results suggest that gzms influence bacterial growth and the host inflammatory response during abdominal sepsis caused by E. coli.


Alternation of two doses of intravenous gammaglobulin in the maintenance treatment of patients with immune thrombocytopenic purpura: more is not always better.
Intravenous infusion of gammaglobulin (IVGG) has been shown to be effective in the maintenance treatment of children and adults with immune thrombocytopenic purpura (ITP). The objective of this treatment is not to increase the platelet count into the normal range but rather to keep the platelet count above a safe level, usually 20,000-30,000/microliters. This use requires periodic infusion whenever the platelet count falls. The dose of gammaglobulin in previous studies was 1 gm/kg/infusion in the majority of patients. This study compared doses of 0.5 and 1.0 gm/kg/infusion by alternating the two doses in the maintenance treatment of 11 patients with ITP. There was no significant difference in the duration of response following single IVGG infusion between these two doses. This finding suggests that there is no advantage to the greater dose of IVGG and will substantially lower the cost of as well as facilitating IVGG maintenance treatment. It was not possible to determine whether a lower dose would impact adversely on the curative potential of IVGG. This effect of IVGG has never been proved and, if it exists, may be mediated by a different mechanism from the acute platelet response.


[Superwarfarine Poisoning].
The superwarfarin-type anticoagulant rodenticides are used throughout the world and distinguish themselves from warfarin for its high potency and long acting anticoagulant activity. Easy access to these products enables the accidental or deliberate human poisoning. A case of voluntary rodenticide poisoning (RATIBRONÂ) by a woman who ingested an estimated 27.5 mg of bromadiolone total quantity for two weeks, with minor bleeding episodes, whose reversal of the anticoagulant effect with the correction of the abnormal values of the clotting tests took about one month to reverse is reported here. The correction of the haemostasis defects takes usually a long time and there are no treatment guidelines, but a gradually vitamin K dosage reduction, as out patients, along with the monitoring of the International Normalized Ratio levels, allows a safe evaluation of the therapeutic response.


Transient Ischemic Attack and Carotid Web.
Carotid web was recognized as a cause of ischemic stroke. We sought to determine the clinical and imaging profiles of patients with a carotid web as well as its association with TIA. A retrospective review of carotid CT angiography studies and brain MR imaging in patients with TIA during the past 3 years (n = 135) was performed to determine the presence of carotid webs by 2 experienced neuroradiologists according to previously published criteria. Demographics and clinical and imaging characteristics are shown by descriptive statistics for patients with an identified carotid web. The agreement in the detection of carotid webs between 2 neuroradiologists was examined using κ statistics. There were 12 (8.9%) carotid webs at the symptomatic bifurcation and 1 carotid web (0.7%) at the asymptomatic bifurcation, and no hyperintensity was seen on DWI of these 12 patients. Eight of these 12 (75%) patients with a carotid web were women. None of the 12 patients with a carotid web had major risk factors or other causes of TIA. Fair-to-good interobserver agreement (κ = 0.87) was seen for diagnosing a carotid web with CT angiography. The rate (10/12, 83.3%) of short-term recurrent episodes of TIA in patients with TIA with a carotid web was significantly higher than that of patients without a carotid web (15/123, 12.2%) (P < .001). The incidence of carotid web in patients with TIA was 8.9%. There is an association between carotid web and patients with TIA without other identified risks. Carotid web may be an underestimated risk factor for TIA.


[Neurohumoral mechanism of the action of levomycetin on intestinal motor function].
It was found that chloramphenicol (levomycetin) in concentrations of 0.07 to 0.14 mg/ml induced suppression of contractions of the isolated small intestine of rabbits. The mechanism of that action was studied with the use of pharmacological analysis of the changes in activity of the smooth muscle organs under the effect of chloramphenicol, as well as with the use of direct determination of catecholamines in the perfusion liquid washing the intestine. The studies with the isolated intestine, uterus and ear vessels of the rabbit ear, the isolated uterus of cats and rats before and after exposure to acetylcholine and adrenaline, atropine, prozerine, ergotamine, cocaine, urea and barium chloride showed that the adrenenergic properties of chloramphenicol played the main role in the mode of its action on the smooth muscle organs. It was demonstrated that treatment of the rabbit isolated intestine with chloramphenicol resulted in an increase in the catecholamine concentration in Tirode liquid washing the organ. The data provided a supposition that the mechanism of the suppressing action of chloramphenicol on the intestine lies in irritation of the adrenenergetic nervous fibres and liberation of catecholamines, which excite the adrenoreceptors of the intestine myoneural system resulting in inhibition of the organ contractions.


Open surgical retrieval of a migrated patent foramen ovale closure device from the descending aorta following failed percutaneous retrieval from the aortic arch: a case report with a word of caution.
Percutaneous patent foramen ovale (PFO) closure is considered safe and has been used widely for over 25 years. A rare but potentially life-threatening complication is device migration, especially to the aorta. We present a 30-year-old male with a PFO occlusion device implanted for cryptogenic stroke, which asymptomatically migrated to the aortic arch. A percutaneous retrieval attempt failed at complete removal but relocated the device to the proximal descending aorta. It was then successfully removed by open surgery. Severe intimal damage necessitated resection and interposition grafting. Manipulation of migrated intravascular devices can cause intimal damage and subsequent complications, such as local dissections. We advocate caution with percutaneous removal of such large, migrated closure devices to avoid additional intimal damage, especially after endothelialization has occurred. The interventional cardiologist should be aware of the risk of intimal damage as a result, and surgical removal, though invasive, should always be considered.


A Semantic-Based Cognitive Training Programme on Everyday Activities: A Feasibility and Acceptability Study among Cognitively Healthy Older Adults.
During the normal ageing process, a person's cognitive functions and memory gradually decline, which can affect their ability to perform everyday activities including cooking, cleaning, managing finances, and shopping. Semantic memory encoding strategies benefit older adults' cognitive and functional performance. Such strategies can be taught by an accessible, cost-effective, and flexible app-based programme. Currently, no studies examine such an app-based programme focussed on everyday activities. To determine if an app-based programme constructed on the principles of semantic memory encoding strategies, targeted towards older adults, called Enhancing Memory in Daily Life (E-MinD Life) is (1) feasible by examining acceptance, engagement, and attendance and (2) acceptable by examining the perceived effectiveness, relevancy, clarity, and convenience. Eleven participants were recruited to a nine-week (18 sessions) programme using E-MinD Life. Feasibility was measured by collecting data on recruitment and retention rates, attendance, and duration of sessions. Acceptability was measured via a Likert scale questionnaire and free comments. Likert scale responses were analysed using descriptive statistics; open-ended responses were categorised qualitatively via constant comparative approach. Nine participants completed the programme. Overall, most participants found the programme relevant, convenient, logical, and easy to understand and perceived it to be effective to address functional cognitive problems impacting performance of everyday activities. The results from the qualitative analysis showed that participants found the programme enjoyable and the interaction with the research team throughout the intervention beneficial. E-MinD Life shows promise as the focus of further research to determine the effectiveness of the programme and sematic-based cognitive strategies in maintaining cognition and performance in everyday activities among older adults with and without cognitive impairment.


Habitat and indigenous gut microbes contribute to the plasticity of gut microbiome in oriental river prawn during rapid environmental change.
Growing evidence points out that the capacity of organisms to acclimate or adapt to new habitat conditions basically depends on their phenomic plasticity attributes, of which their gut commensal microbiota might be an essential impact factor. Especially in aquatic organisms, which are in direct and continual contact with the aquatic environment, the complex and dynamic microbiota have significant effects on health and development. However, an understanding of the relative contribution of internal sorting (host genetic) and colonization (environmental) processes is still unclear. To understand how microbial communities differ in response to rapid environmental change, we surveyed and studied the environmental and gut microbiota of native and habitat-exchanged shrimp (Macrobrachium nipponense) using 16S rRNA amplicon sequencing on the Illumina MiSeq platform. Corresponding with microbial diversity of their living water areas, the divergence in gut microbes of lake-to-river shrimp (CK) increased, while that of river-to-lake shrimp (KC) decreased. Importantly, among the candidate environment specific gut microbes in habitat-exchanged shrimp, over half of reads were associated with the indigenous bacteria in native shrimp gut, yet more candidates presented in CK may reflect the complexity of new environment. Our results suggest that shrimp gut microbiota has high plasticity when its host faces environmental changes, even over short timescales. Further, the changes in external environment might influence the gut microbiome not just by providing environment-associated microbes directly, but also by interfering with the composition of indigenous gut bacteria indirectly.


Should we take a history of prior treatment, and check sputum status at 2-3 months when treating patients for tuberculosis?
Pinetown, South Africa (1975-1983). To determine the value of previous treatment history and sputum smear examination at 2-3 months in predicting treatment failure and relapse in tuberculosis patients treated with four drugs given twice weekly for six months under direct observation. Four cohort studies among 562 ambulant adults with culture positive pulmonary tuberculosis, designed to test the effectiveness of isoniazid 600-900 mg, rifampicin 600 mg, pyrazinamide 2-3 g, and streptomycin 1-2 g, given twice weekly. The same drug regimen was given to all patients irrespective of previous treatment history. Therapy was not changed if smears remained positive at 2-3 months. Positive predictive values of a history of previous treatment for a positive smear at 2-3 months (18.3%), treatment failure (5.2%), and relapse (9.4%) were poor. Although patients with positive smears at 2-3 months were more likely to fail therapy than patients with negative smears (relative risk=4.5, 95% Confidence Interval [CI]: 1.6-12.8), positive predictive value for treatment failure was only 12.5%. Although relapse was more frequent in patients with positive smears than those with negative smears (9.7% vs 6.2%; P=0.4), most patients who relapsed had been smear negative at 2-3 months (18/21). A four-drug rifampicin-containing regimen can safely be given twice weekly under direct observation to both new and retreatment cases, and the 2-3 month smear examination can safely be omitted.


Monitoring the impact of bioaugmentation with a PAH-degrading strain on different soil microbiomes using pyrosequencing.
The effect of bioaugmentation with Sphingobium sp. AM strain on different soils microbiomes, pristine soil (PS), chronically contaminated soil (IPK) and recently contaminated soil (Phe) and their implications in bioremediation efficiency was studied by focusing on the ecology that drives bacterial communities in response to inoculation. AM strain draft genome codifies genes for metabolism of aromatic and aliphatic hydrocarbons. In Phe, the inoculation improved the elimination of phenanthrene during the whole treatment, whereas in IPK no improvement of degradation of any PAH was observed. Through the pyrosequencing analysis, we observed that inoculation managed to increase the richness and diversity in both contaminated microbiomes, therefore, independently of PAH degradation improvement, we observed clues of inoculant establishment, suggesting it may use other resources to survive. On the other hand, the inoculation did not influence the bacterial community of PS. On both contaminated microbiomes, incubation conditions produced a sharp increase on Actinomycetales and Sphingomonadales orders, while inoculation caused a relative decline of Actinomycetales. Inoculation of most diverse microbiomes, PS and Phe, produced a coupled increase of Sphingomonadales, Burkholderiales and Rhizobiales orders, although it may exist a synergy between those genera; our results suggest that this would not be directly related to PAH degradation.


X-linked adrenoleukodystrophy: the Australasian experience.
Our objective was to review the Australasian experience of X-linked adrenoleukodystrophy (ALD), to compare the spectrum of disease seen in Australasia with previously published data from elsewhere, and to assess the reliability of carrier testing. Study design was a retrospective review of records collected over a 15-year period, the setting was an international referral laboratory for the study of metabolic disease, and the subjects were all known cases of ALD diagnosed in Australia and New Zealand between 1981 and 1996 and their families. We estimate that the combined incidence of ALD and its variants in Australasia is at least 1.6 per 100,000. Of 95 affected males, 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison's disease only, and 5 remained asymptomatic when last examined. However, the distribution of phenotypes among newly diagnosed patients has changed substantially over the last 15 years, with cerebral forms of the disease forming a decreasing proportion of new diagnoses. The measurement of plasma very long chain fatty acids (VLCFAs) alone detects 93% of women who can be proven to be carriers. The addition of genetic linkage studies or assay of VLCFAs in cultured fibroblasts improved this detection rate to the point that there were no obligate carriers who could not be detected using a combination of two or more techniques.


Effects of esterified lactoferrin and lactoferrin on control of postharvest blue mold of apple fruit and their possible mechanisms of action.
The effects of esterified lactoferrin (ELF) and lactoferrin (LF) on blue mold caused by Penicillium expansum in apple fruit stored at 25 °C were investigated. Both ELF and LF provided an effective control and strongly inhibited spore germination and germ tube elongation of P. expansum in vitro. Assessment by propidium iodide staining combined with fluorescent microscopy revealed that the plasma membrane of P. expansum spores was damaged more seriously by ELF than by LF treatment, and the leakage of protein and sugar was higher from ELF-treated mycelia. Interestingly, ELF treatment induced a significant increase in the activities of chitinase, β-1,3-glucanase, and peroxidase in apple fruit, whereas both LF treatment and the control showed no obvious difference. These findings indicated that the effects of ELF on blue mold in apple fruit might be associated with the direct fungitoxic property against the pathogens and the elicitation of defense-related enzymes in fruit.


Growth-associated production and characterization of poly (3-hydroxybutyric acid) of Azotobacter beijerinckii DAR-102.
Production of poly (3-hydroxybutyric acid) [P(3HB)] by Azotobacter beijerinckii DAR-102 isolated in this laboratory has been optimized under batch-culture. The accumulatad polymer attained 58% of cell dry mass during mid-stationary phase with an yield of 0.58 g/l when grown in nitrogen-free medium. The optimum concentration of glucose and fructose for P(3HB) production was 3% (w/v) and 2% (w/v) respectively while that of casamino acid and tryptose was 0.1% (w/v). Phosphate at a concentration suboptimal for growth and limitation of oxygen in the medium favoured P(3HB) accumulation. The production of P(3HB) was maximum with an inoculum dose of 4% (v/v). The accumulated polymer was isolated by direct chloroform extraction of the dry cell mass and purified by precipitation with diethyl ether. The purified polymer has been characterized in terms of its solubility properties, melting temperature, and UV-, IR- and NMR-spectroscopic analyses.


Quantification of the FLI1 and CXCR4 gene expressions in acute lymphoblastic leukemia (ALL) patients with t(12,21).
The presence of the t(12,21) is associated with good response to therapy in acute lymphoblastic leukemia (ALL) but molecular background of this pathology is not clear. FLI1 gene plays important roles in normal regulation of myeloid hematopoiesis and leukemogenesis. The chemokine receptor CXCR4 gene may play a role in the homing of hematopoietic stem cells. Our aim was to investigate possible relationships between t(12,21) existence and expression changes of these two genes (FLI1, CXCR4) in ALL. Thirty-one ALL patients were investigated. Twenty-one of these patients were t(12,21) carriers. We used the Quantitative Real-Time RT-PCR. Obtained results were compared to normal bone marrow samples of five healthy subjects. Expression differences were not found significant in both groups. Our study was the first attempt to quantify these genes in t(12,21) patients. We conclude that Quantitative RT-PCR is a reliable method for the monitoring of these gene expressions and similar studies should expand to other translocations in haematology.


Light-Driven Self-Recruitment of Biomimetic Semiconducting Polymer Nanoparticles for Precise Tumor Vascular Disruption.
Tumor vascular disrupting therapy has offered promising opportunities to treat cancer in clinical practice, whereas the overall therapeutic efficacy is notably limited due to the off-target effects and repeated dose toxicity of vascular disrupting agents (VDAs). To tackle this problem, a VDA-free biomimetic semiconducting polymer nanoparticle (SPNP ) is herein reported for precise tumor vascular disruption through two-stage light manipulation. SPNP consists of a semiconducting polymer nanoparticle as the photothermal agent camouflaged with platelet membranes that specifically target disrupted vasculature. Upon the first photoirradiation, SPNP administered in vivo generates mild hyperthermia to trigger tumor vascular hemorrhage, which activates the coagulation cascade and recruits more SPNP to injured blood vessels. Such enhanced tumor vascular targeting of photothermal agents enables intense hyperthermia to destroy the tumor vasculature during the second photoirradiation, leading to complete tumor eradication and efficient metastasis inhibition. Intriguingly, the mechanism study reveals that this vascular disruption strategy alleviates splenomegaly and reverses the immunosuppressive tumor microenvironment by reducing myeloid-derived suppressor cells. Therefore, this study not only illustrates a light-driven self-recruitment strategy to enhance tumor vascular disruption via a single dose of biomimetic therapeutics but also deciphers the immunotherapeutic role of vascular disruption therapy that is conducive to clinical studies.


The National Ignition Facility neutron imaging system.
The National Ignition Facility (NIF) is scheduled to begin deuterium-tritium (DT) shots possibly in the next several years. One of the important diagnostics in understanding capsule behavior and to guide changes in Hohlraum illumination, capsule design, and geometry will be neutron imaging of both the primary 14 MeV neutrons and the lower-energy downscattered neutrons in the 6-13 MeV range. The neutron imaging system (NIS) described here, which we are currently building for use on NIF, uses a precisely aligned set of apertures near the target to form the neutron images on a segmented scintillator. The images are recorded on a gated, intensified charge coupled device. Although the aperture set may be as close as 20 cm to the target, the imaging camera system will be located at a distance of 28 m from the target. At 28 m the camera system is outside the NIF building. Because of the distance and shielding, the imager will be able to obtain images with little background noise. The imager will be capable of imaging downscattered neutrons from failed capsules with yields Y(n)>10(14) neutrons. The shielding will also permit the NIS to function at neutron yields >10(18), which is in contrast to most other diagnostics that may not work at high neutron yields. The following describes the current NIF NIS design and compares the predicted performance with the NIF specifications that must be satisfied to generate images that can be interpreted to understand results of a particular shot. The current design, including the aperture, scintillator, camera system, and reconstruction methods, is briefly described. System modeling of the existing Omega NIS and comparison with the Omega data that guided the NIF design based on our Omega results is described. We will show NIS model calculations of the expected NIF images based on component evaluations at Omega. We will also compare the calculated NIF input images with those unfolded from the NIS images generated from our NIS numerical modeling code.


Nursing clinics in elder housing: providing access and improving health care outcomes.
This article describes one approach to helping elder individuals residing in subsidized senior housing achieve better health outcomes by providing health promotion and disease prevention services at on-site student nursing clinics. Clinics operate 2 days a week in the community room at the elderly housing sites and are staffed by senior baccalaureate nursing students who are in their community health clinical rotation. The student nursing clinic outcomes demonstrate improvement in residents' health through increased access to care, better identification and management of hypertension, more involvement for residents with diabetes in monitoring and management of their conditions, and better preparation for emergency medical situations.


In Argentina there are no multicenter studies evaluating the management of patients with acute pancreatitis (AP) nationwide. The main objective of this study is to know how the patients with AP are treated in Argentina. The secondary objective is to assess whether the results comply with the recommendation of the American College of Gastroenterology Guide. Twenty three center participated in the study. They include in a database hosted online consecutive patients with acute pancreatitis from june 2010 to june 2013. 854 patients entered the study. The average age was 46.6 years and 495 (58%) belonged to the female sex. The most common cause (88.2%) of AP was biliary. Some prognostic system was used in 99 % of patients and the most used was Ranson (74.5%). Were classified as mild 714 (83.6%) patients and severe 140 (16.4%). Systemic complications occurred in 43 patients and local complications in 21. 86 patients underwent dynamic CT scans and 73 patients had pancreatic and / or peripancreatic necrosis. Mortality was 1.5%. There was no difference in mortality in relation to the size, complexity or affiliation of the center. The comply of key recommendations of the American College of Gastroenterology Guide was over 80%. The diagnosis and treatment of patients with AP in 23 health centers located throughout the country was optimal. The management complied with most of the recommendations of the American College of Gastroenterology Guide.


Construction and stability of a sixfold repeated artificial gene.
The concatenation of an artificial gene consisting of 69 base pairs is described. A simple and versatile procedure was employed which is applicable to any DNA segment bordered by different restriction sites. If applied in the 'continuous duplication mode', it does not necessitate the isolation of any DNA fragment. The addition of adaptor oligonucleotides to one terminus of the segment is required to create complementary ends. The ligation of single-stranded oligonucleotides to single-stranded DNA termini was analyzed and optimized. A simple procedure is described for the separation of excess adaptor molecules. The in vivo stability of constructs containing up to six directly repeated genes was investigated. Up to four copies of the gene appeared stable during transformation of strain HB101. With six copies exact excision of ony copy was occasionally observed after transformations of rec+, recA, and recBC host cells. During long-term growth the hexameric construct appeared stable in all three strains.


Lung microdialysis study of levofloxacin in rats following intravenous infusion at steady state.
Lung microdialysis has been used with rats to investigate antibiotic distribution after single-dose administration. However, conducting such experiments after intravenous infusion at steady state would constitute a more convenient alternative, which was evaluated here, using levofloxacin (LVX) as a test compound. Microdialysis probes were inserted in blood and muscle, used as a comparator, between 9:00 a.m. and 11:00 a.m. Intravenous LVX infusion was started 6 h later and maintained until the end of the experiment at a rate of 1.0 mg.h(-1). Lung microdialysis probes were inserted on the morning of the next day. Rats were kept anesthetized during dialysate collection. In vivo probe recoveries were estimated by retrodialysis using a calibrator method, with ciprofloxacin (CIP) as the calibrator. LVX and CIP were analyzed in dialysates by high-performance liquid chromatography. The steady-state tissue-to-blood unbound-drug concentration ratios were 1.00 +/- 0.15 in muscle tissues and 1.06 +/- 0.40 in lungs, suggesting passive distribution of LVX in tissue. Although providing no information on rate of distribution, microdialysis investigations following drug infusion at steady state appear to be an interesting approach for characterization of antibiotic distribution in rat lungs.


[Risk factors for the development of phlebitis in peripheral infusions].
To study the incidence and risk factors of development of phlebitis caused by peripheral infusions. Prospective, descriptive. Westindies Hospital, The Hague, the Netherlands. For all 348 patients given infusions in a 6-week period the development of phlebitis, if any, and the contributing factors were studied. Phlebitis developed in 136 patients (39%), after an average of 2.9 days (range: 1-14). Risk factors were female sex, earlier phlebitis, insertion on the ventral surface of the forearm and administration of antibiotics via the infusion. These factors were not interdependent. No correlation was found between development of phlebitis and the size of the needle. Development of phlebitis depends on a number of factors. Timely removal of the infusion can prevent the development of phlebitis. Infusions should preferably be administered via the hand.


Quantum and thermal phase slips in superconducting niobium nitride (NbN) ultrathin crystalline nanowire: application to single photon detection.
We present low-temperature electronic transport properties of superconducting nanowires obtained by nanolithography of 4-nm-thick niobium nitride (NbN) films epitaxially grown on sapphire substrate. Below 6 K, clear evidence of phase slippages is observed in the transport measurements. Upon lowering the temperature, we observe the signatures of a crossover between a thermal and a quantum behavior in the phase slip regimes. We find that phase slips are stable even at the lowest temperatures and that no hotspot is formed. The photoresponse of these nanowires is measured as a function of the light irradiation wavelength and temperature and exhibits a behavior comparable with previous results obtained on thicker films.


Hepatitis C Virus: Efficacy of New DAAs Regimens.
HCV treatment showed dramatical change due to the introduction of potent, strong, direct antiviral drugs. Before the appearance of Direct-acting antivirals, multiple therapeutic interventions were used for hepatitis C, but none of these interventions were effective on patient-centered outcomes. Direct-acting antivirals cause disruption of viral replication because they target specific nonstructural viral proteins. To review the advantages of efficient HCV therapy and its long term drawbacks. A search of the literature published in indexed databases (PubMed, Medline In-Process, and Embase) within the last 5 years was conducted. Any duplicated citations were excluded before first-pass screening. Citations (titles and abstracts) were screened for eligibility by a single reviewer. Full texts (including congress abstracts, posters and other congress communications) of citations deemed relevant during title and abstract screening were retrieved for second-pass review. Studies on the clinical effects of DAAs for hepatitis C show better tolerance, improved survival and fewer complications when compared to previous interferon therapy. HCV treatment has improved dramatically. Since that time, there are multiple approved oral therapies all with high efficacy. The most important factor which should be considered during choosing appropriate therapy is to ensure that it covers the viral genotype of the infected patients.


Implants in bone: part I. A current overview about tissue response, surface modifications and future perspectives.
The aim of study paper is to present an overview of osseointegration of dental implants, focusing on tissue response, surface modifications and future perspective. Great progress has been made over the decades in the understanding of osseous peri-implant healing of dental implants, leading to the development of new implant materials and surfaces. However, failures and losses of implants are an indicator that there is room for improvement. Of particular importance is the understanding of the biological interaction between the implant and its surrounding bone. The survival rates of dental implants in bone of over 90 % after 10 years show that they are an effective and well-established therapy option. However, new implant materials and surface modifications may be able to improve osseointegration of medical implants especially when the wound healing is compromised. Advanced techniques of evaluation are necessary to understand and validate osseointegration in these cases. An overview regarding the current state of the art in experimental evaluation of osseointegration of implants and implant material modifications will be given in Part II.


Specific inhibition by prostaglandins E2 and I2 of histamine-stimulated [14C]aminopyrine accumulation and cyclic adenosine monophosphate generation by isolated canine parietal cells.
The effects of prostaglandins E2 and I2 on accumulation of [14C]aminopyrine and the generation of cyclic AMP by fractions of dispersed canine gastric mucosal cells, enriched in their content of parietal cells, have been studied. The parietal cell content of the fractions was enriched to between 43 and 70% using an elutriator rotor. The accumulation of [14C]aminopyrine was used as the index of parietal cell response to stimulation. Prostaglandin E2 (PGE2, 0.1 nM-0.1 mM) inhibited histamine stimulated aminopyrine uptake but did not block the response to carbachol, gastrin, or dibuturyl cyclic AMP. PGE2 did, however, inhibit aminopyrine uptake stimulated by carbachol and gastrin when the response to these agents was potentiated by histamine. PGE2 (0.1 NM-0.1 mM) inhibited histamine-stimulated cyclic AMP production in a dose-dependent fashion with maximal inhibition at 1 microM PGE2. Prostacyclin also inhibited both histamine-stimulated aminopyrine accumulation and histamine-stimulated cyclic AMP production. In the absence of added histamine, PGE2 in concentrations above 1 microM and prostacyclin in concentrations above 10 microM stimulated cyclic AMP production, probably by acting on the nonparietal cells as shown in previous studies. These present data are consistent with the hypothesis that prostaglandins E2 and I2 inhibit the response of isolated parietal cells to histamine by specifically blocking histamine-stimulated cyclic AMP production.


Large-scale protein modelling and integration with the SWISS-PROT and SWISS-2DPAGE databases: the example of Escherichia coli.
Knowledge-based molecular modelling of proteins has proven useful in many instances, including the rational design of mutagenesis experiments, but it has generally been limited by the availability of expensive computer hardware and software. To overcome these limitations, we developed the SWISS-MODEL server for automated knowledge-based protein modelling. The SWISS-MODEL server uses the Brookhaven Protein Data Bank as a source of structural information and automatically generates protein models for sequences which share significant similarities with at least one protein of known three-dimensional structure. We have now used the software framework of the server to generate large collections of protein models, and established the SWISS-MODEL Repository, a new database for automatically generated and theoretical protein models. This repository is directly integrated with the SWISS-PROT and SWISS-2DPAGE databases through the ExPASy World Wide Web server (URL is http://expasy.hcuge.ch). Here we present an illustration of this process by an application to the Escherichia coli sequences.


Chemical and antibacterial evaluation of Hypericum triquetrifolium Turra.
Five extracts and pure compounds from the aerial parts of Hypericum triquetrifolium were tested for their antibacterial activity against 31 gram-positive and gram-negative strains using the agar dilution method (Lorian). The ethyl acetate extract exhibited a weak antibacterial activity against Staphylococcus strains, and pure constituents such as quercetin and I3,II8-biapigenin were the active components of this extract.


AgCl precipitates in isolated cuticular membranes reduce rates of cuticular transpiration.
Counter diffusion of chloride, applied as NaCl at the inner side of isolated cuticles, and silver, applied as AgNO(3) at the outer side, lead to the formation of insoluble AgCl precipitates in isolated cuticles. AgCl precipitates could be visualized by light and scanning electron microscopy. The presence of AgCl precipitates in isolated cuticles was verified by energy dispersive X-ray analysis. It is argued that insoluble AgCl precipitates formed in polar pores of cuticles and as a consequence, cuticular transpiration of 13 out of 15 investigated species was significantly reduced up to three-fold. Water as a small and uncharged but polar molecule penetrates cuticles via two parallel paths: a lipophilic path, formed by lipophilic cutin and wax domains, and a aqueous pathe, formed by polar pores. Thus, permeances P (m s(-1)) of water, which is composed of the two quantities P (Lipid) and P (Pore), decreased, since water transport across polar pores was affected by AgCl precipitates. Cuticles with initially high rates of cuticular transpiration were generally more sensitive towards AgCl precipitates compared to cuticles with initially low rates of transpiration. Results presented here, significantly improves the current model of the structure of the cuticular transpiration barrier, since the pronounced heterogeneity of the cuticular transport barrier, composed of lipophilic as well as polar paths of diffusion, has to be taken into account in future.


A survey of zoonotic pathogens carried by house mouse and black rat populations in Yucatan, Mexico.
The house mouse (Mus musculus) and the black rat (Rattus rattus) are reservoir hosts for zoonotic pathogens, several of which cause neglected tropical diseases (NTDs). Studies of the prevalence of these NTD-causing zoonotic pathogens, in house mice and black rats from tropical residential areas are scarce. Three hundred and two house mice and 161 black rats were trapped in 2013 from two urban neighbourhoods and a rural village in Yucatan, Mexico, and subsequently tested for Trypanosoma cruzi, Hymenolepis diminuta and Leptospira interrogans. Using the polymerase chain reaction we detected T. cruzi DNA in the hearts of 4·9% (8/165) and 6·2% (7/113) of house mice and black rats, respectively. We applied the sedimentation technique to detect eggs of H. diminuta in 0·5% (1/182) and 14·2% (15/106) of house mice and black rats, respectively. Through the immunofluorescent imprint method, L. interrogans was identified in 0·9% (1/106) of rat kidney impressions. Our results suggest that the black rat could be an important reservoir for T. cruzi and H. diminuta in the studied sites. Further studies examining seasonal and geographical patterns could increase our knowledge on the epidemiology of these pathogens in Mexico and the risk to public health posed by rodents.


Motor Imagery of Speech: The Involvement of Primary Motor Cortex in Manual and Articulatory Motor Imagery.
Motor imagery refers to the phenomenon of imagining performing an action without action execution. Motor imagery and motor execution are assumed to share a similar underlying neural system that involves primary motor cortex (M1). Previous studies have focused on motor imagery of manual actions, but articulatory motor imagery has not been investigated. In this study, transcranial magnetic stimulation (TMS) was used to elicit motor-evoked potentials (MEPs) from the articulatory muscles [orbicularis oris (OO)] as well as from hand muscles [first dorsal interosseous (FDI)]. Twenty participants were asked to execute or imagine performing a simple squeezing task involving a pair of tweezers, which was comparable across both effectors. MEPs were elicited at six time points (50, 150, 250, 350, 450, 550 ms post-stimulus) to track the time course of M1 involvement in both lip and hand tasks. The results showed increased MEP amplitudes for action execution compared to rest for both effectors at time points 350, 450 and 550 ms, but we found no evidence of increased cortical activation for motor imagery. The results indicate that motor imagery does not involve M1 for simple tasks for manual or articulatory muscles. The results have implications for models of mental imagery of simple articulatory gestures, in that no evidence is found for somatotopic activation of lip muscles in sub-phonemic contexts during motor imagery of such tasks, suggesting that motor simulation of relatively simple actions does not involve M1.


Upper extremity limb loss: functional restoration from prosthesis and targeted reinnervation to transplantation.
For several decades, prosthetic use was the only option to restore function after upper extremity amputation. Recent years have seen advances in the field of prosthetics. Such advances include prosthetic design and function, activity-specific devices, improved aesthetics, and adjunctive surgical procedures to improve both form and function. Targeted reinnervation is one exciting advance that allows for more facile and more intuitive function with prosthetics following proximal amputation. Another remarkable advance that holds great promise in nearly all fields of medicine is the transplantation of composite tissue, such as hand and face transplantation. Hand transplantation holds promise as the ultimate restorative procedure that can provide form, function, and sensation. However, this procedure still comes with a substantial cost in terms of the rehabilitation and toxic immunosuppression and should be limited to carefully selected patients who have failed prosthetic reconstruction. Hand transplantation and prosthetic reconstruction should not be viewed as competing options. Rather, they are two treatment options with different risk/benefit profiles and different indications and, hence vastly different implications.


Long-term results after surgical correction of anorectal malformations.
Our surgical experience with 101 cases of anorectal malformations during the past 21 years includes staged abdominoperineal rectoplasty in 49 patients, perineoplasty in 35 patients, and permanent colostomy in 2 patients. The observations of this clinical study are especially focused on long-term anal continence. The functional results were assessed clinically on the basis of Kelly's criteria (5), and by manometric and radiologic studies. Fifty-one patients, aged 5-25 years, were personally interviewed and 36 of these 51 had manometric and radiologic studies to evaluate postoperative continence. Patients with low-type lesions were more likely to be continent, while patients with high-type lesions had more problems with continence, because a functional internal sphincter is absent in high-type lesions. However, continent patients with high-type lesions as well as those with low-type lesions characteristically had a marked high-pressure zone in the anal canal and an acute anorectal angulation in the defecogram . On the other hand, in the patients with fair or poor results, neither a high-pressure zone in the anal canal nor marked anorectal angulation was found. These results indicate that achievement of continence in patients with a high-type anomaly treated by abdominoperineal rectoplasty depends upon bringing the terminal bowel down exactly within the sling of the puborectalis and careful dilatation of the new anal canal after the creation of a cosmetically satisfactory anal opening.


Direct assay of free thyroxine in the newborn.
Several reagent sets are available, which allow a direct assay without dialysis of the free, bioavailable part of total thyroxine in plasma. A methodological investigation showed that the solid phase (coated tubes) kit from Clinical Assay gives reproducible results in plasma volumes of 50 microliter. Plasma samples from 95 newborns have been assayed at the 4th to 5th day of life. The mean concentration for free thyroxine of 62 infants born at term was 17 pmol/l with a log 2 SD range of 10-28 pmol/l. This value is similar to the normal value in adults (15.1 pmol/l, log 2 SD range 8.3-27.4 pmol/l). This is in contrast to the total T4 concentration: mean value for newborns 182 nmol/l (normal range 2 SD log 130-250 nmol/l) compared to a mean of 90 nmol/l (normal range 2 SD log 51-157) for adults. Mean free T4 concentration was 11.5 pmol/l in 18 premature infants (gestational ages 34-35 weeks: mean 8.7 pmol/l; gestational ages 36-37 weeks: mean 15.3 pmol/l). The lowest concentrations were found in infants with a respiratory distress syndrome: mean 8.9 pmol/l. TSH did not exceed 10 mU/l. It is concluded that the method used allows a direct estimation of free T4 in small plasma samples and allows a rapid decision in suspected thyroid disorders in infants.


Retrospective evaluation of the efficacy of first-line treatment of advanced gastric cancer with docetaxel and oxaliplatin.
The incidence rate of gastric cancer is highest in China, where 5 in 10 new cases of stomach cancer across the world are diagnosed. Even though surgical management is the treatment of choice, it is not significantly effective due to advanced stage of the disease at diagnosis and the increased chances of primary tumor recurrence and metastasis to secondary organs. First-line chemotherapy of advanced gastric cancer patients recommend oxaliplatin and docetaxel; however, not much is known about their usage in Chinese patients. Therefore we retrospectively analyzed 199 cases of advanced gastric cancer (intestinal, diffuse, and mixed types) receiving either docetaxel or oxaliplatin-based first-line chemotherapy. The end-points determined were objective response rate (ORR, sum of complete and partial responses), disease control rate (DCR, sum of complete response, partial response, and stable disease), median progression-free survival (mPFS), and median overall survival (OS) time. Both docetaxel and oxaliplatin-based chemotherapy exhibited improved ORR and DCR; however, the comparison of short-term objective efficacy (ORR and DCR) was not statistically significant (p > .05) between the two groups. Our results indicated that PFS and OS of intestinal-type gastric cancer were extended compared with diffuse-type and mixed-type gastric cancer. Adverse reactions were within the control range and after symptomatic treatment were significantly ameliorated. Both docetaxel and oxaliplatin-based chemotherapy thus had a robust treatment outcome and can prospectively be used as one of the effective chemotherapy regimens for advanced gastric cancer patients in China.


Co-designing a methodology for workforce development during the personalisation of allied health service funding for people with disability in Australia.
Internationally, health and social services are undergoing creative and extensive redesign to meet population demands with rationed budgets. This has critical implications for the health workforces that serve such populations. Within the workforce literature, few approaches are described that enable workforce development for health professions in the service contexts that emerge from large scale service redesign in times of industry shift. We contribute an innovative and robust methodology for workforce development that was co-designed by stakeholders in allied health during the personalisation of disability funding in Australia (the introduction of the National Disability Insurance Scheme). In the context of a broad action research project, we used program logic modelling to identify and enact opportunities for sustainable allied health education and workforce integration amidst the changed service provision context. We engaged with 49 industry stakeholders across 92 research engagements that included interviews (n = 43), a workshop explicitly for model development (n = 8) and a Project Advisory Group (n = 15). Data from these activities were inductively coded, analysed, and triangulated against each other. During the program logic modelling workshop, we worked with involved stakeholders to develop a conceptual model which could be used to guide trial and evaluation of allied health education which was fit-for-purpose to emerging workforce requirements. Stakeholder interviews showed that drivers of workforce design during industry shift were that (1) service provision was happening in turbulent times; (2) new concerns around skills and professional engagement were unfolding for AHP in the NDIS; and (3) impacts to AHP education were being experienced. The conceptual model we co-designed directly accounted for these contextual features by highlighting five underpinning principles that should inform methodologies for workforce development and AHP education in the transforming landscape: being (1) pedagogically sound; (2) person- or family-centred; (3) NDIS compliant; (4) informed by evidence and (5) having quality for all. We use a case study to illustrate how the co-designed conceptual model stimulated agility and flexibility in workforce and service redesign. Proactive and situated education of the emerging workforce during policy shift is essential to realise future health workforces that can appropriately and effectively service populations under a variety of changing service and funding structures - as well as their transitions. We argue that collaborative program logic modelling in partnership with key stakeholders including existing workforce can be useful for broad purposes of workforce (re)design in diverse contexts.


Correlation of H. pylori density with grading of chronic gastritis.
Histopathological study of endoscopic gastric mucosa obtained from 251 patients with acid peptic diseases were studied in relation to the degrees of inflammation and the degree of H. Pylori density. Haematoxylin-Eosin and modified Giemsa stains were used. Gastritis grading was done according to Warren and Marshall with slight modification and H. Pylori grading according to our criteria. In this study no definite relationship could be observed between histological grading of chronic gastritis with that of H. Pylori density.


Effect of Neoadjuvant Chemoradiotherapy on Lymph Node Micrometastases in Thoracic Esophageal Cancer.
The purpose of this study was to clarify the effect of neoadjuvant chemoradiotherapy (nCRT) on lymph node micrometastasis (LNM) in esophageal squamous cell carcinoma (ESCC). The therapeutic efficacy of nCRT was analyzed in 41 ESCC patients randomized to the Surgery group (n=21) and the nCRT group (n=20). Lymph node specimens from patients were classified into two categories, micrometastasis (MM) and tumor cell microinvolvement (MI), after immunohistochemical evaluation. The incidence rates of patients presenting MM with or without MI or MI alone in the Surgery group were significantly higher than those in the nCRT group. The 10-year survival rate of 15 patients with simultaneous histological metastasis (HM) and LNM was significantly lower than that in the 26 patients without LNM. Within the nCRT group, the 10-year survival rates of patients with versus those without HM were not significantly different; however, the 10-year survival rate of the 5 patients with simultaneous HM and LNM was significantly lower than that of the 15 patients without LNM. ESCC patients with LNM may benefit from nCRT, and evaluation of the simultaneous presence of HM and LNM may facilitate accurate prediction of survival in ESCC patients.


[Tunisian experience in the treatment of aggressive non Hodgkin's lymphoma in adults: about 337 patients].
From January 1997 to December 2005, 337 patients with aggressive non Hodgkin's lymphoma were treated with one of the two successive multicentric non randomized protocols established in Tunisia. The mean age was 53 years. Most patients had diffuse large cell lymphoma with B phenotype in 86% and T in 14%. The performance status was 2 or 3 in 34% of cases. The LDH were elevated in 74% of cases. Advanced disease (III or IV stage) was noted in 59% of cases and 10% had a tumoral mass greater than 10 cm. According to the international prognostic index (IPI) adjusted to age, we distinguish four groups: group 1 (0 factor and age < 70 years), group 2 (1-3 factors and age < or = 60 years), group 3 (1-3 factors and age between 61 and 70 years) and group 4 (1-3 factors and age > 70 years). The patients of group 1 (N = 47) received 3 courses of CHOP regimen followed by irradiation. The patients of group 2 (N = 160) received 4 courses of ACVBP regimen (+ rituximab for 21 patients) followed by consolidation (N = 92) or peripheral blood progenitor cell transplantation (N = 20). The patients of group 3 (N = 61) received 8 courses of CHOP regimen (+ rituximab for 20 patients). The patients of group 4 (N = 69) received 6 courses of mini-CEOP regimen (N = 48) or 6 courses CVP regimen (N = 21). The 4-year overall survival was 56% and the 4-year event free survival was 49%.


[Serum digoxin concentration: dependence on body weight and age].
In patients of a cardiological practice, 121 digoxin serum concentrations were determined by radioimmunoassay (RIA). Some drugs were suspected of interfering with the RIA or with the pharmacokinetics of digoxin. Patients having such additional drugs or patients with elevated serum creatinine were not included. The daily maintenance dose of digoxin was roughly adjusted to body weight. Patients with 0.5 mg digoxin daily showed unexpectedly low serum digoxin levels not fully explained by the relatively high body weight. This dose group was not included in the following correlations. At a maintenance dose of 0.25 and 0.375 mg digoxin and in the age groups 40-69 years (n = 66) there was an approximately inverse proportionality between serum digoxin concentration (per 0.25 mg digoxin daily) and body weight. When all age classes from 20 to 89 years were included (n = 96), a week positive correlation between serum digoxin concentration (per 0.25 mg digoxin daily and per 69.28 kg body weight) and age was found. A similar positive correlation resulted between serum digoxin concentration (per 0.25 mg digoxin daily) and the reciprocal of the nomographically determined creatinine clearance, always within the normal serum creatinine range. Based on these correlations, two simplified formulas are presented to predict the serum concentration and therapeutic maintenance dose of digoxin. The formulas are valid for the normal serum creatinine range and for digoxin tablets of optimal bioavailability.


To build an enzyme....
The structural components that lead to enzyme function are discussed for one simple enzyme-catalysed reaction: that mediated by triosephosphate isomerase. First, the recognition and binding of the substrates' phospho group is seen to involve four main-chain-NH-hydrogen bonds, two of which are positioned at the positive end of a short alpha-helix aimed precisely at the phospho group and interact with the three peripheral phospho group oxygens. Second, the chemical steps (of substrate enolization) are shown to require both base and general acid catalysis. The identity and the positioning of the base, a carboxylate group, nicely fulfils the expectations both of mechanistic economy and of stereoelectronics. The identity of the general acid is shown by Fourier transform infrared and by 15N nuclear magnetic resonance (NMR) to be a neutral imidazole group, lying between the two substrate oxygens. The positioning of the ring is ideal, but its protonation state is unexpected. Thus the pKa of this histidine side-chain is less than 4.5, lowered from 6.5 (the value in the denatured protein) by its position at the positive end of another well-aimed alpha-helix. Third, the need for enzymes to provide kinetic barriers to the loss of reaction intermediates from the active site is emphasized. Triosephosphate isomerase achieves this sequestration of the reaction intermediate by using a flexible loop of the protein, and thus improves the efficiency of the catalysed transformation.


Pressure-dependent luminescence spectroscopy of molybdenum(IV) oxo complexes.
Luminescence spectra are reported for trans-[MoOCl(CN-t-Bu)(4)]BPh(4) and trans-[MoOF(pyridine)(4)]BPh(4). The maxima of the broad luminescence bands are at energies of 12000 and 13000 cm(-1), respectively. Resolved vibronic structure involves the metal-oxo stretching mode with a vibrational frequency of approximately 950 cm(-1) (Raman) in both compounds. The pressure behavior of the luminescence bands shows a distinct difference: a blue shift of +12 cm(-1) kbar(-1) is observed for [MoOCl(CN-t-Bu)(4)]BPh(4), and a red-shift of -8 cm(-1) kbar(-1) is obtained for [MoOF(pyridine)(4)]BPh(4). At pressures above 25 kbar, the luminescence maximum of [MoOCl(CN-t-Bu)(4)]BPh(4) shows a change from a blue-shift to a red-shift and the Raman peak corresponding to the metal-oxo stretching mode at 954 cm(-1) becomes broad and its maximum decreases with increasing pressure, leading to a strong deviation from the linear increase of +0.24 cm(-1) kbar(-1) observed at pressures below 25 kbar. These unusual pressure effects are rationalized in terms of the influence of pressure on the metal-ligand bonds and oxo-metal-ligand angles using DFT calculations.


Stimulation of primed carbon under climate change corresponds with phosphorus mineralization in the rhizosphere of soybean.
Elevated CO2 and temperature likely alter photosynthetic carbon inputs to soils, which may stimulate soil microbial activity to accelerate the decomposition of soil organic carbon (SOC), liberating more phosphorus (P) into the soil solution. However, this hypothesis on the association of SOC decomposition and P transformation in the plant rhizosphere requires robust soil biochemical evidence, which is critical to nutrient management for the mitigation of soil quality against climate change. This study investigated the microbial functional genes relevant to P mineralization together with priming processes of SOC in the rhizosphere of soybean grown under climate change. Soybean plants were grown under elevated CO2 (eCO2, 700 ppm) combined with warming (+ 2 °C above ambient temperature) in open-top chambers. Photosynthetic carbon flow in the plant-soil continuum was traced with 13CO2 labeling. The eCO2 plus warming treatment increased the primed carbon (C) by 43 % but decreased the NaHCO3-extratable organic P by 33 %. Furthermore, NaHCO3-Po was negatively correlated with phosphatase activity and microbial biomass C. Elevated CO2 increased the abundances of C degradation genes, such as abfA and ManB, and P mineralization genes, such as gcd, phoC and phnK. The results suggested that increased photosynthetic carbon inputs to the rhizosphere of plants under eCO2 plus warming stimulated the microbial population and metabolic functions of both SOC and organic P mineralization. There is a positive relationship between the rhizosphere priming effect and P mineralization. The response of microorganisms to plant-C flow is decisive for coupled C and P cycles, which are likely accelerated under climate change.


Melatonin treatment entrains the rest-activity circadian rhythm in rats with chronic inflammation.
We assessed the therapeutic effect of exogenous melatonin (MEL), dexamethasone (DEXA), and a combination of both on nociceptive response induced by chronic inflammation and on the rest-activity circadian rhythm in rats. A total of 64 animals were randomly divided into eight groups of eight rats each: one control group and seven groups with complete Freund's adjuvant-inflamed animals (CFA; injection into the footpad). One of the CFA-inflamed groups did not receive any treatment; the other six were treated with melatonin (MEL), dexamethasone (DEXA), melatonin plus dexamethasone (MELDEXA), and their respective vehicles. Fifteen days after CFA injection, animals were treated with intraperitoneal injection of MEL (50 mg/kg) or its vehicle (8% ethanol in saline), DEXA (0.25 mg/kg) or its vehicle (saline), and MEL plus DEXA or their vehicles, for 8 days. The von Frey test was performed 24 h after the last administration of each treatment regimen. Hind paw thickness was measured using a pachymeter during the treatment days. The degree of swelling and histological findings were analyzed. All treated groups significantly reduced the severity of inflammation when compared with their vehicles (repeated-measures analysis of variance [ANOVA], p < 0.05 for all analyses). Inflamed animals treated with dexamethasone alone or associated with melatonin showed marked inhibition of histological findings. On the other hand, the group treated with melatonin remained with moderate inflammation. The CFA group showed a decrease in the mean rest-activity circadian rhythm, determined by the number of touch-detections per hour during water intake in comparison with the control group; only the group treated with melatonin showed a synchronized rest-activity rhythm. At the end of treatment, a significant increase was observed in hind paw withdrawal threshold on the von Frey test in the treated groups (one-way ANOVA, p < 0.05 for all). Our findings showed that melatonin (50 mg/kg) has strong chronobiotic and antinociceptive effects, but only mild anti-inflammatory effects. This evidence supports the hypothesis that melatonin can induce phase advance and circadian rhythm synchronization in rats with chronic inflammation.


FIP200 Suppresses Immune Checkpoint Therapy Responses in Breast Cancers by Limiting AZI2/TBK1/IRF Signaling Independent of Its Canonical Autophagy Function.
Immune checkpoint inhibitors (ICI) have the potential to induce durable therapeutic responses, yet response rates in breast cancer are modest and limited to particular subtypes. To expand the applicability of ICI, we examined the role of an essential autophagy gene, FIP200, which has been shown to be important for tumor progression in mammary tumors. Specific disruption of the autophagy function of FIP200 or complete ablation of FIP200 in genetic mouse models revealed that FIP200 autophagy function was required for progression of PyMT-driven mammary tumors. However, a noncanonical autophagy function of FIP200 was responsible for limiting T-cell recruitment and activation of the TBK1-IFN signaling axis. FIP200 also interacted with the TBK1 adaptor protein, AZI2, which was crucial for activation of TBK1 following FIP200 ablation. Accordingly, disrupting the noncanonical autophagy function of FIP200 in combination with ICI therapy led to superior, durable responses in immune-competent models of breast cancer. Collectively, these insights could guide future development of therapeutic agents against FIP200 for combinatorial ICI therapies in nonresponsive breast cancers. SIGNIFICANCE: These findings show that deletion of FIP200 enhances immune checkpoint inhibitor efficacy in nonresponsive breast cancer.


Pro-oncogenic and anti-oncogenic pathways: opportunities and challenges of cancer therapy.
Carcinogenesis is the uncontrolled growth of cells gaining the potential to invade and disrupt vital tissue functions. This malignant process includes the occurrence of 'unwanted' gene mutations that induce the transformation of normal cells, for example, by overactivation of pro-oncogenic pathways and inactivation of tumor-suppressive or anti-oncogenic pathways. It is now recognized that the number of major signaling pathways that control oncogenesis is not unlimited; therefore, suppressing these pathways can conceivably lead to a cancer cure. However, the clinical application of cancer intervention has not matched up to scientific expectations. Increasing numbers of studies have revealed that many oncogenic-signaling elements show double faces, in which they can promote or suppress cancer pathogenesis depending on tissue type, cancer stage, gene dosage and their interaction with other players in carcinogenesis. This complexity of oncogenic signaling poses challenges to traditional cancer therapy and calls for considerable caution when designing an anticancer drug strategy. We propose future oncology interventions with the concept of integrative cancer therapy.


Modular cryogenic interconnects for multi-qubit devices.
We have developed a modular interconnect platform for the control and readout of multiple solid-state qubits at cryogenic temperatures. The setup provides 74 filtered dc-bias connections, 32 control and readout connections with -3 dB frequency above 5 GHz, and 4 microwave feed lines that allow low loss (less than 3 dB) transmission 10 GHz. The incorporation of a radio-frequency interposer enables the platform to be separated into two printed circuit boards, decoupling the simple board that is bonded to the qubit chip from the multilayer board that incorporates expensive connectors and components. This modular approach lifts the burden of duplicating complex interconnect circuits for every prototype device. We report the performance of this platform at milli-Kelvin temperatures, including signal transmission and crosstalk measurements.


Physician-assisted suicide reconsidered: dying as a Christian in a post-Christian age.
The traditional Christian focus concerning dying is on repentance, not dignity. The goal of a traditional Christian death is not a pleasing, final chapter to life, but union with God: holiness. The pursuit of holiness requires putting on Christ and accepting His cross. In contrast, post-traditional Christian and secular concerns with self-determination, control, dignity, and self-esteem make physician-assisted suicide and voluntary active euthanasia plausible moral choices. Such is not the case within the context of the traditional Christian experience of God, which throughout its 2000 years has sternly condemned suicide and assisted suicide. The wrongness of such actions cannot adequately be appreciated outside the experience of that Christian life. Traditional Christian appreciations of death involve an epistemology and metaphysics of values in discordance with those of secular morality. This difference in the appreciation of the meaning of dying and death, as well as in the appreciation of the moral significance of suicide, discloses a new battle in the culture wars separating traditional Christian morality from that of the surrounding society.


Incremental Prognostic Value of Global Longitudinal Strain and 18F-Fludeoxyglucose Positron Emission Tomography in Patients With Systemic Sarcoidosis.
In independent studies, abnormal global longitudinal strain (GLS) and myocardial inflammation or scar detected by 18F-fludeoxyglucose positron emission tomography (FDG-PET) are associated with poor prognosis among patients with high likelihood for cardiac sarcoidosis. However, commonly used imaging modalities have not been evaluated in the same population. Our goals were to examine the relation between GLS and FDG-PET, and to evaluate the incremental prognostic value of these imaging techniques for predicting major adverse cardiac events (MACE) in patients suspected to have cardiac sarcoidosis. We identified patients with systemic sarcoidosis who underwent an echocardiogram and FDG-PET within 60 days. Regional strain (average of base, mid, and apical segmental strains from each of 6 wall regions) was calculated and compared with regional FDG-PET findings. The associations among GLS, FDG-PET findings, and MACE (defined as death, ventricular tachycardia, heart failure hospitalization, or transplantation) were evaluated using a Cox model. Of 84 patients, 51 had abnormal FDG-PET. GLS was impaired in patients with abnormal versus normal FDG-PET (-14.2 ± 4.7% vs -17.9 ± 3.5%, p <0.01). After adjusting for clinical risk factors, both GLS and the number of segments with abnormal perfusion and metabolism on FDG-PET were associated with adverse cardiac events (p <0.01 for both). In conclusion, GLS and regional LS are impaired in patients with abnormal perfusion and metabolism detected using FDG-PET. Additionally, both GLS and abnormal FDG-PET have incremental prognostic value for predicting MACE in patients with systemic sarcoidosis.


Eva M. Reese, excerpts from an oral history.
Eva Miller Reese is a former director of the Visiting Nurse Services of New York (1964-1976) and a past secretary of the Public Health Nursing section of the American Public Health Association. She is also the 1974 recipient of the Haven Emerson Award, the highest honor awarded by the Public Health Association of New York City. A nationally renowned leader in public health nursing, Reese influenced the course of home care nursing during a turbulent time of social unrest and Great Society initiatives in health care. Throughout her career, Reese continually advocated for coordinated, cost-effective services. Self-effacing and soft-spoken during a 1998 interview, Reese conjured an image of her younger self, and remembered some of the realities of reaching adulthood during the Great Depression. Her reflections on home health care, nursing, and the role of public health agencies are rooted in core values of social justice and multidisciplinary action.


ChromTime: modeling spatio-temporal dynamics of chromatin marks.
To model spatial changes of chromatin mark peaks over time we develop and apply ChromTime, a computational method that predicts peaks to be either expanding, contracting, or holding steady between time points. Predicted expanding and contracting peaks can mark regulatory regions associated with transcription factor binding and gene expression changes. Spatial dynamics of peaks provide information about gene expression changes beyond localized signal density changes. ChromTime detects asymmetric expansions and contractions, which for some marks associate with the direction of transcription. ChromTime facilitates the analysis of time course chromatin data in a range of biological systems.


Radioimmunocytochemistry with [3H]biotin.
The methods presented in this paper grew out of the current need for a more quantitative approach to immunocytochemistry. The problem was approached by exploiting the high affinity of biotin for avidin in the design of radioimmunocytochemical methods using [3H]biotin. [3H]Biotin and avidin D form a radioactive complex which can be linked onto a primary antibody by means of a biotinylated anti-rabbit IgG or biotinylated protein A link. With both approaches it was possible to localize a number of antigens such as somatostatin, substance P, avian pancreatic polypeptide, tyrosine hydroxylase, and enkephalin-like immunoreactivity in various regions of the rat and human brain. By using tritium-sensitive film, large regions of the brain could be studied and analyzed semiquantitatively using computerized microdensitometry. The technique was also taken to the electron microscopic level, and in the case of substance P immunoreactivity within the rat substantia nigra silver grains were found to be highly localized over axons and axon terminals. It was also possible to demonstrate co-existence or lack of co-existence of a number of different antigens within neurones. The first primary antibody was localized with biotinylated protein A followed by avidin-peroxidase, while the second primary antibody was linked to the [3H]biotin again with biotinylated protein A. As an example of the potential of these methods for semiquantification, the distribution of substance P within postmortem human spinal cord was examined 24 months after amputation. A 49% loss of peptide was found in the corresponding dorsal horn. In summary these methods using [3H]biotin have proved successful in quantification, electron microscopy and double labelling studies.