Transient chemotherapy-induced alopecia after successful reversal of 5-fluorouracil myelosuppression and neurotoxicosis in a 9-month-old dog.

BACKGROUND: 5-Fluorouracil (5-FU) cream is a common human topical chemotherapy agent with potentially fatal neurotoxic effects on dogs if accidentally ingested. There are seldom reports in veterinary literature describing the successful outcome of intervention after accidental ingestion of 5-FU cream. CASE SUMMARY: A 9-month-old spayed female labradoodle presented 14 h after ingesting an unknown amount of 40 g tube of Efudex cream (5% 5-FU). The dog presented in status epilepticus, which was managed with benzodiazepines and levetiracetam in conjunction with induced coma and mechanical ventilation. No further seizure activity occurred throughout the ensuing 5 days of hospitalisation; however, myelosuppression was featured. The dog was discharged home after 5 days of hospitalisation. Three days post discharge, the dog was noted to develop focal alopecia around the eyes and temporal region. 14 days after discharge, the alopecia progressed to a majority of the head and body. CONCLUSION: To the authors' knowledge, this is the first report that documents the enduring adverse effects of 5-FU cream after survival of the initial episode, including an earlier onset of myelosuppression and diffuse alopecia. Successful treatment of accidental 5-FU ingestion is possible several hours after the initial event with minimal long-term consequences.

Cytokine release syndrome-associated encephalopathy in patients with COVID-19.

BACKGROUND AND PURPOSE: Neurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS. METHODS: In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit. RESULTS: Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF. CONCLUSIONS: Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

Clinical, electrophysiological and genetic characteristics of childhood hereditary polyneuropathies.

BACKGROUND: Hereditary polyneuropathies are heterogeneous group of diseases of the peripheral nervous system. In this study, we investigated the demographic, clinical, electrophysiological, and genetic characteristics of hereditary polyneuropathy patients diagnosed and followed up in our tertiary center clinic in Izmir, Turkey. METHODS: Patients who were diagnosed with hereditary polyneuropathies during nerve conduction studies in our center were evaluated retrospectively. RESULTS: In a total of 1484 nerve conduction studies, 207 patients were diagnosed with polyneuropathy. Ninety-nine of those patients were determined to have hereditary polyneuropathy, 52 of which were male and 47 were female. Sixty-nine patients with hereditary polyneuropathy were compatible with axonal and 30 were compatible with demyelinating polyneuropathy. Genetic analysis was performed in 69 patients, and 49 of those patients were genetically diagnosed, leading to a diagnosis rate of 71%. CONCLUSIONS: Advances in genetics have led to an increase in the heterogeneity of hereditary polyneuropathies, causing difficulties in the use of existing classifications. Although typical mutations expected in childhood-onset polyneuropathies are seen less frequently, polyneuropathies are frequently encountered as findings of complex, multisystemic diseases.

Diversity of Secondary Metabolism in Aspergillus nidulans Clinical Isolates.

The filamentous fungus Aspergillus nidulans has been a primary workhorse used to understand fungal genetics. Much of this work has focused on elucidating the genetics of biosynthetic gene clusters (BGCs) and the secondary metabolites (SMs) they produce. SMs are both niche defining in fungi and of great economic importance to humans. Despite the focus on A. nidulans, very little is known about the natural diversity in secondary metabolism within this species. We determined the BGC content and looked for evolutionary patterns in BGCs from whole-genome sequences of two clinical isolates and the A4 reference genome of A. nidulans Differences in BGC content were used to explain SM profiles determined using liquid chromatography-high-resolution mass spectrometry. We found that in addition to genetic variation of BGCs contained by all isolates, nine BGCs varied by presence/absence. We discovered the viridicatumtoxin BGC in A. nidulans and suggest that this BGC has undergone a horizontal gene transfer from the Aspergillus section Nigri lineage into Penicillium sometime after the sections Nigri and Nidulantes diverged. We identified the production of viridicatumtoxin and several other compounds previously not known to be produced by A. nidulans One isolate showed a lack of sterigmatocystin production even though it contained an apparently intact sterigmatocystin BGC, raising questions about other genes and processes known to regulate this BGC. Altogether, our work uncovers a large degree of intraspecies diversity in BGC and SM production in this genetic model species and offers new avenues to understand the evolution and regulation of secondary metabolism.IMPORTANCE Much of what we know about the genetics underlying secondary metabolite (SM) production and the function of SMs in the model fungus Aspergillus nidulans comes from a single reference genome. A growing body of research indicates the importance of biosynthetic gene cluster (BGC) and SM diversity within a species. However, there is no information about the natural diversity of secondary metabolism in A. nidulans We discovered six novel clusters that contribute to the considerable variation in both BGC content and SM production within A. nidulans We characterize a diverse set of mutations and emphasize how findings of single nucleotide polymorphisms (SNPs), deletions, and differences in evolutionary history encompass much of the variation observed in nonmodel systems. Our results emphasize that A. nidulans may also be a strong model to use within-species diversity to elucidate regulatory cross talk, fungal ecology, and drug discovery systems.

FORTE - a multipurpose high-vacuum diffractometer for tender X-ray diffraction and spectroscopy at the SIRIUS beamline of Synchrotron SOLEIL.

A new high-vacuum multipurpose diffractometer (called FORTE from the French acronyms of the project) has recently been installed at the tender/hard X-ray SIRIUS beamline of Synchrotron SOLEIL, France. The geometry chosen allows one to work either in the classical Eulerian four-circle geometry for bulk X-ray diffraction (XRD) or in the z-axis geometry for surface XRD. The diffractometer nicely fits the characteristics of the SIRIUS beamline, optimized to work in the 1.1-4.5 keV range, and allows one to perform unprecedented diffraction anomalous fine structure (DAFS) experiments in the tender X-ray region, also around non-specular reflections, covering a large reciprocal-space volume. Installation of an X-ray fluorescence detector on a dedicated flange allows simultaneous DAFS and X-ray absorption (XAS) measurements. The access to the tender X-ray region paves the way to resonant investigations around the L-edges of second-row transition elements which are constituents of functional oxide materials. It also enables access to several edges of interest for semiconductors. Finally, the control architecture based on synchronized Delta Tau units opens up exciting perspectives for improvement of the mechanical sphere of confusion.

Universal screening for Clostridioides difficile in a tertiary hospital: risk factors for carriage and clinical disease.

OBJECTIVES: The role of asymptomatic carriers in Clostridioides difficile infection (CDI) epidemiology is not fully understood. Our aim was to evaluate CD carriage prevalence on admission, associated risk factors, and the risk of developing CDI. METHODS: A 10-week surveillance program for CD carriage of all medical patients admitted to the Sheba Medical Centre was implemented, utilizing an admission rectal swab PCR. Healthcare facility-onset CDI (HO-CDI) was recorded and divided into HO-CDI diagnosed in CD carriers and non-carriers. RESULTS: A total of 4601 admissions were recorded in 3803 patients; 2368 patients had technically analysable rectal swabs, of whom 81 (3.4%) were CD carriers. A multivariate logistic regression model showed that previous hospitalization, old age (>85 years) and low Norton scores were significant independent predictors of CD carriage. Carriers were more likely to receive antimicrobial therapy during hospitalization than non-carriers were. The incidence of HO-CDI in non-carriers was 4.6 cases per 10 000 patient-days; the incidence of HO-CDI in carriers was 76.7 cases per 10 000 patient-days (RR 16.6, 95% CI 4.0-69.1, p .002). CONCLUSIONS: In a prospective study, the rate of CD carriage on admission in medical patients was 3.4%. CD carriers were older, frailer, and more likely to have been hospitalized recently. HO-CDI incidence was significantly higher among CD carriers than among non-carriers, with at least a third of CDI in screened patients developing in carriers. Targeted screening of high-risk groups for CD carriage should be further considered.

Predicting extinction phenotype to optimize fear reduction.

Fear conditioning is widely employed to study dysregulations of the fear system. The repeated presentation of a conditioned stimulus in the absence of a reinforcer leads to a decrease in fear responding-a phenomenon known as extinction. From a translational perspective, identifying whether an individual might respond well to extinction prior to intervention could prove important to treatment outcomes. Here, we test the hypothesis that CO2 reactivity predicts extinction phenotype in rats, and that variability in CO2 reactivity as well as extinction long-term memory (LTM) significantly predicts orexin activity in the lateral hypothalamus (LH). Our results validate a rat model of CO2 reactivity and show that subcomponents of behavioral reactivity following acute CO2 exposure explain a significant portion of the variance in extinction LTM. Furthermore, we show evidence that variability in CO2 reactivity is also significantly predictive of orexin activity in the LH, and that orexin activity, in turn, significantly accounts for LTM variance. Our findings open the possibility that we may be able to use CO2 reactivity as a screening tool to determine if individuals are good candidates for an extinction/exposure-based approach.

Human polyspecific immunoglobulin attenuates group A streptococcal virulence factor activity and reduces disease severity in a murine necrotizing fasciitis model.

OBJECTIVES: Streptococcus pyogenes causes life-threatening invasive infections including necrotizing fasciitis (NF). Current treatment guidelines recommend the use of a cell-wall-active antibiotic combined with a protein synthesis inhibitor and surgical debridement in NF patients. Adjunctive therapy with intravenous immunoglobulin (IVIG) has been proposed for superantigen-associated streptococcal toxic shock syndrome. So far, benefits of IVIG treatment remain unclear and prospective clinical studies are scarce. Thus, we aimed to assess the effects of IVIG on virulence factor activity in vitro, ex vivo in patients and in vivo in a NF mouse model. METHODS: We investigated the effect of IVIG on the activity of the virulence factors streptolysin O (SLO), streptodornase 1 (Sda1), S. pyogenes cell envelope protease and streptococcal pyrogenic exotoxin B in vitro and ex vivo in patient sera. Additionally, we assessed the influence of IVIG on the clinical outcome in a murine NF model. RESULTS: In vitro, IVIG inhibited various streptococcal virulence factors. Further, IVIG treatment of group A Streptococcus-infected mice led to a reduced skin lesion size (median (interquartile range) day 3 intraperitoneal administration: 12 mm2 (9-14.5) vs. 4 mm2 (0.8-10.5), subcutaneous: 10.3 mm2 (6.9-18.6) vs. 0.5 mm2 (0.1-6.8)) and lower SLO activity. After treatment with IVIG, patient sera showed an elevated titre of specific SLO (7/9) and Sda1 (5/9) antibodies, reducing SLO and Sda1 activity. CONCLUSIONS: The clear reduction in disease severity in IVIG-treated mice and inhibition of virulence factor activity in mouse and human sera suggest that IVIG may be beneficial in invasive group A Streptococcus infections such as NF in addition to streptococcal toxic shock syndrome.

Suspended Liquid Subtractive Lithography: One-step generation of 3D channel geometries in viscous curable polymer matrices.

The miniaturization of synthesis, analysis and screening experiments is an important step towards more environmentally friendly chemistry, statistically significant biology and fast and cost-effective medicinal assays. The facile generation of arbitrary 3D channel structures in polymers is pivotal to these techniques. Here we present a method for printing microchannels directly into viscous curable polymer matrices by injecting a surfactant into the uncured material via a steel capillary attached to a 3D printer. We demonstrate this technique using polydimethylsiloxane (PDMS) one of the most widely used polymers for the fabrication of, e. g. microfluidic chips. We show that this technique which we term Suspended Liquid Subtractive Lithography (SLSL) is well suited for printing actuators, T-junctions and complex three dimensional structures. The formation of truly arbitrary channels in 3D could revolutionize the fabrication of miniaturized chips and will find broad application in biology, chemistry and medicine.

A cluster of invasive meningococcal disease revealed by the characterization of a novel serogroup B meningococcal clone.

The incidence of invasive infections due to Neisseria meningitidis in Israel is about 1/100 000 population annually. Three cases of meningococcal meningitis were reported in employees at a single plant; the first case appeared in March 2013 and the second and third cases appeared in December, almost 9 months later. N. meningitidis serogroup B was isolated from cerebrospinal fluid samples. Multilocus sequence typing assigned the three meningococcal isolates to ST10418, a new sequence type and a member of the ST32 clonal complex. The clonality was confirmed by performance of pulsed-field gel electrophoresis. Post-exposure antibiotic prophylaxis was administered to close contacts of the first case. Upon the diagnosis of the additional two cases, post-exposure prophylaxis was administered to all the plant employees. This report demonstrates the importance of combining public health measures and advanced laboratory studies to confirm clonality and to prevent further disease spread in a closed setting.

Titania-Supported Catalysts for Levulinic Acid Hydrogenation: Influence of Support and its Impact on γ-Valerolactone Yield.

A series of titania-supported ruthenium and platinum catalysts was investigated in the levulinic acid hydrogenation towards γ-valerolactone, a key reaction for the catalytic transformation of biomass. It was shown that various morphologies and phases of titania strongly influence the physicochemical and catalytic properties of supported Ru and Pt catalysts in different ways. In the case of the catalyst supported on mixed TiO2 phases, Ru particles are exclusively located on the minority rutile crystallites, whereas such an effect was not observed for platinum. The platinum catalyst activity could be increased when the metal was dispersed on the large surface-area anatase, which was not the case for ruthenium as a result of its agglomeration on this support. The activity of ruthenium on anatase could be increased in two ways: a) when RuO2 formation during catalyst preparation was avoided; b) when pure anatase support material was modified so that it exhibited no microporosity. The obtained results allow a better understanding of the role of the support for Ru and Pt catalysts.

Tying up loose ends: a method for constructing and evaluating decision aids that meet blunt and sharp-end goals.

We present a methodological framework for constructing and evaluating decision aids--fast and frugal trees (FFTs)--ideally suited to the front line of an organisation. Their performance can be analysed in signal detection theory, allowing for transparent selection of FFTs given managerial-level trade-offs among type I and II errors. We extend FFTs from binary classification to selection from multiple actions (FFT multiple) as well as performance analysis to organisational goal states beyond type I and II error reduction. Concepts and framework are introduced and a tutorial-style example application (threat assessment at military checkpoints) is provided. Throughout, we discuss ways to deal with missing or incomplete data and show that the performance of decision aids may be overestimated if the effectiveness of actions is not heeded. The methodology can be used to construct and evaluate decision aids in any area characterised by dichotomised cues and a one-to-many mapping between categorisation outcomes and actions.

Caspase-8 as a regulator of tumor cell motility.

The caspases are a family of ubiquitously expressed cysteine proteases best known for their roles in programmed cell death. However, caspases play a number of other roles in vertebrates. In the case of caspase-8, loss of expression is an embryonic lethal phenotype, and caspase-8 plays roles in suppressing cellular necrosis, promoting differentiation and immune signaling, regulating autophagy, and promoting cellular migration. Apoptosis and migration require localization of caspase-8 in the periphery of the cells, where caspase-8 acts as part of distinct biosensory complexes that either promote migration in appropriate cellular microenvironments, or cell death in inappropriate settings. In the cellular periphery, caspase-8 interacts with components of the focal adhesion complex in a tyrosine-kinase dependent manner, promoting both cell migration in vitro and metastasis in vivo. Mechanistically, caspase-8 interacts with components of both focal adhesions and early endosomes, enhancing focal adhesion turnover and promoting rapid integrin recycling to the cell surface. Clinically, this suggests that the expression of caspase-8 may not always be a positive prognostic sign, and that the role of caspase-8 in cancer progression is likely context-dependent.

hVISA and MRSA endocarditis: an 8-year experience in a tertiary care centre.

It is not clear if patients with heterogeneous intermediate resistance to vancomycin (hVISA) infectious endocarditis (IE) differ from methicillin-resistant S. aureus (MRSA) IE patients. All cases of hVISA and MRSA IE diagnosed at the Sheba Medical Centre from 2003 to 2010 were included. Isolates were screened prospectively for hVISA. Medical records were reviewed. The t-test, chi-square test, Fisher exact test and Kaplan Meier analysis were used. Fourteen hVISA IE and 32 MRSA IE were identified. The mean age was 76 years, mean Charlson score was 4.5 and 24% of patients had prosthetic valves. Pacemakers and implantable cardioverter-defibrillators (P/ICDs) were more common in the hVISA group (50% vs. 22%, p 0.05). P/ICDs IE occurred in 29% of hVISA patients vs. 6.3% of MRSA patients (p 0.06). hVISA patients had more positive blood cultures (eight vs. five, p 0.007) and a trend toward longer bacteraemia (15 vs. 7.5 days, p 0.08). Vancomycin minimal inhibitory concentrations (MICs) were similar in the two groups (1.5 µg/mL vs. 1.1 µg/mL, p 0.11). The MIC to daptomycin was higher in hVISA (0.75 µg/mL vs. 0.32 µg/mL, p 0.049). MRSA patients received vancomycin. hVISA patients were switched to other antibiotics. Cardiac surgery and/or P/ICD extraction was performed more commonly in hVISA patients (50% vs. 16%, p 0.027). Mortality was high in both groups (57-66%). The median time to death was 39 days in the hVISA group and 19 days in the MRSA group (p 0.3). hVISA IE is associated with P/ICDs. Both hVISA and MRSA are associated with high mortality. Low rates of surgical intervention and P/ICD extraction reflect the high co-morbidity of patients. Caution should be employed in the empirical use of daptomycin in hVISA patients.

Direct evidence of Fe(2+)-Fe3+ charge ordering in the ferrimagnetic hematite-ilmenite Fe(1.35)Ti(0.65)O(3-δ) thin films.

In this Letter we highlight direct experimental evidence of Fe(2+)-Fe3+ charge ordering at room temperature in hematite-ilmenite Fe(1.35)Ti(0.65)O(3-δ) epitaxial thin films grown by pulsed laser deposition, using aberration-corrected scanning transmission electron microscopy coupled to high-resolution energy electron-loss spectroscopy. These advanced spectromicroscopy techniques demonstrate a strong modulation of the Fe2+ valence state along the c axis. Density functional theory calculations provide crucial information on the key role of oxygen vacancies in the observed charge distributions. Their presence at significant levels leads to the localization of extra electrons onto reduced Fe2+ sites, while Ti remains solely +4. The magnetic and transport properties of these films are reviewed in the light of the present results regarding their ferrimagnetic character correlated with the Fe2+ modulation and their semiconducting behavior interpreted by an Efros-Shklovskii variable-range hopping conduction regime via Fe2+ and Fe3+ centers. The experimental evidence of only one type of mixed valence state, i.e., Fe2+ and Fe3+, in the Fe(2-x)Ti(x)O(3-δ) system will thus help to interpret further the origin of its geomagnetic properties and to illuminate fundamental issues regarding its spintronic potential.

The impact of pseudomembrane formation on the outcome of Clostridium difficile-associated disease.

PURPOSE: Although pseudomembranes are the hallmark manifestation of Clostridium difficile-associated diarrhea (CDAD), there are scant data specifically addressing their impact on the clinical outcome. We investigated whether the formation of pseudomembranes predicts a worse CDAD outcome. METHODS: CDAD patients hospitalized during 2010 underwent sigmoidoscopy and were followed prospectively. In addition, all hospitalized CDAD patients in the period 01/2000-12/2009 who underwent lower endoscopy were retrospectively identified and their charts reviewed. Patients with detectable pseudomembranes on endoscopy were compared to those in whom pseudomembranes were absent. Thirty-day mortality and a composite outcome comprised of mortality within 30 days of diagnosis, admission to the intensive care unit (ICU), colectomy, peritonitis, hemodynamic instability, or respiratory insufficiency were addressed. Additional clinical outcomes used for comparison between the two groups were 60-day mortality, duration of hospitalization, and the failure of metronidazole and vancomycin. RESULTS: A total of 117 CDAD patients (mean age 62.9 ± 19 years) who underwent lower endoscopy were included; 46 with pseudomembranes and 71 without. Seven out of the 46 patients with pseudomembranes died within 30 days compared to 9/71 in the non-pseudomembrane group [odds ratio (OR) 1.2, 95% confidence interval (CI) 0.4-3.6, P = 0.8]. Similarly, there was no correlation between the occurrence of pseudomembranes and the rate of the composite adverse outcome (P = 0.6). In contrast, acute renal insufficiency (OR 15, 95% CI 3.2-72, P < 0.001) and hypoalbuminemia (OR 5.7, 95% CI 1.8-18, P = 0.002) were both independently predictive of a severe clinical outcome. CONCLUSIONS: Our findings suggest that the presence of pseudomembranes is not associated with an adverse outcome in CDAD patients.

Dynamics of childhood invasive meningococcal disease in Israel during a 22-year period (1989-2010).

AIM: To describe the dynamics in the incidence of childhood invasive meningococcal disease (IMD) in Israel during a 22-year period (1989-2010). METHODS: A longitudinal prospective surveillance in all 27 medical centers with pediatric services in Israel. All cases of children <15 years old with positive blood/cerebrospinal fluid (CSF) culture for Neisseria meningitidis were reported. Demographic, clinical, and bacteriological data were recorded. Meningococcal vaccine was not routinely given to Israeli children during the study period. RESULTS: The mean age ± standard deviation (SD) among the 743 cases was 40.7 ± 40.2 months. The mean yearly incidence/100,000 was 2.0 ± 0.8. Age-specific incidences were 8.7 ± 2.8, 2.9 ± 1.5, and 0.8 ± 0.5 for children <1, 1-4, and >4 years old, respectively. The overall incidence decreased significantly from 3.7 in 1989 to 1.5 in 2010. Meningitis constituted 69.2 % of all cases. The most common serogroups were: B (76.9 %), C (10.9 %), Y (8.0 %), and W(135) (2.9 %). 78.6 % of all serogroup B isolates were from children <5 years old (p < 0.01). Serogroup C was found mainly in children ≥5 years old (63.4 %). The case fatality rates (CFRs) for children <1, 1-4, >4 years old, and the total study population were 9.2, 12.3, 7.7, and 9.9 %, respectively. CFRs were higher for children without meningitis (14.9 %) compared to children with meningitis (7.9 %) (p < 0.01). CONCLUSIONS: Overall, and for serogroups B and W135, childhood IMD rates decreased significantly in Israel during the study period, without routine vaccine usage. The most common serogroup in all age groups was B, which was most prevalent in children <5 years old. No change in the trend of the overall CFR was noted during the study period.

Distribution of fluconazole-resistant Candida bloodstream isolates among hospitals and inpatient services in Israel.

The emergence of fluconazole-resistant Candida (FRC) is worrisome, but little is known about susceptibility patterns in different nosocomial settings. We prospectively analysed Candida bloodstream isolates in 18 medical centres in Israel (six tertiary-care and 12 community hospitals). The study included 444 episodes of candidaemia (450 patient-specific isolates, 8.5% fluconazole-resistant). Institutional FRC bloodstream infection rates correlated with annual inpatient days, and were strongly associated with the presence and activity of haematology/oncology services. Infection with Candida krusei and fluconazole-resistant Candida glabrata occurred exclusively in hospitals with >600 beds. These findings suggest that empirical antifungal strategies should be tailored to the nosocomial setting.