Use of remdesivir for COVID-19 pneumonia in patients with advanced kidney disease: A retrospective multicenter study.

Background and objectives: Remdesivir, an antiviral drug routinely used in the treatment of COVID-19 has not yet received FDA approval for use in patients with advanced kidney disease defined as GFR < 30 mL/min/1.73 m2. There is concern that an excipient in Veklury (Gilead's proprietary name for remdesivir) called sulfobutylether-beta-cyclodextrin (SBECD), which is renally cleared, may accumulate and reach toxic levels in patients with advanced kidney disease. The aim of this study was to summarize characteristics and incidence of adverse events of chronic kidney disease (CKD) patients who received remdesivir during hospitalization.Design, setting, participants, and measurements.We retrospectively studied patients admitted to one of several hospitals of the Mayo Clinic Foundation with the diagnosis of COVID-19 pneumonia and CKD. Laboratory values were also measured when remdesivir was first administered and stopped. All analyses were performed in the overall patient group and three separate subgroups of patients with a GFR ≥ 15, a GFR < 15 and dialysis, and a GFR < 15 and no dialysis. Results: A total of 444 CKD patients who were admitted to the hospital with COVID-19 pneumonia between May 2020 and September 2021 were included. Information was collected on patient characteristics, hospitalization, and adverse events. In the overall cohort, median age was 72 years (Range: 21-100 years), 55.2 % of patients were male, and most (86.5 %) were Caucasian. CKD stage was 3 for 114 patients (25.7 %), 4 for 229 patients (51.6 %), and 5 for 101 patients (22.7 %). A total of 146 patients (32.9 %) were admitted to the ICU, 103 (23.2 %) died in the hospital, and 120 (27.0 %) were on dialysis. The proportion of patients with an adverse event did not differ dramatically between the GFR ≥ 15 (20.9 %), GFR < 15 and dialysis (30.2 %), and GFR < 15 and no dialysis (32.3 %) groups (P = 0.12). Conclusion: Our results suggest that the use of remdesivir in patients with very severe CKD is safe, even in those who are not on renal replacement therapy.

Ontogenetic changes in frequency mapping of a mammalian ear.

Cochlear microphonic iso-response functions reported here suggest an explanation of frequency-dependent changes in hearing sensitivity during early development. The work is a direct demonstration of developmental changes in the spatial frequency map of the mammalian hearing organ. Intracochlear recordings from the midbasal turn in a series of age-graded gerbils reveal a progressive increase in best frequency, spanning approximately two octaves, from the time of onset of function until adultlike responses are seen. It is, therefore, suggested that ontogenetic changes in the cellular structure of the organ of Corti contribute to an age-dependent shift in micromechanical response.

Neuroprotective effects of novel phosphatidylglycerol-based phospholipids in the 6-hydroxydopamine model of Parkinson's disease.

Administration of VP025 (Vasogen Inc.), a novel drug formulation based on phospholipid nanoparticles incorporating phosphatidylglycerol, has previously been shown to have a neuroprotective effect in the brain. We examined the effect of VP025 in a rat model of Parkinson's disease, the 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. VP025 or phosphate-buffered saline (PBS) was administered to rats 14 days, 13 days and 1 day before the unilateral 6-OHDA lesion. Functional integrity of nigrostriatal dopaminergic neurons was assessed 7 and 21 days later by amphetamine-induced rotational testing and we observed that rotational counts were significantly less in rats that were pretreated with VP025 compared with PBS-pretreated 6-OHDA-lesioned rats. Neurochemical analysis at 10 and 28 days after lesion revealed that VP025 protected against a 6-OHDA-induced decrease in concentrations of striatal dopamine and its metabolites. Immunocytochemical studies of the ipsilateral substantia nigra showed that VP025 significantly inhibited 6-OHDA-induced loss of dopaminergic neurons. We also observed that increases in immunostaining for activated microglia and for activated p38 in dopaminergic neurons of 6-OHDA-lesioned rats were prevented by VP025. This study shows that VP025 has significant protective effects on the 6-OHDA-lesioned nigrostriatal pathway and may therefore have potential for the treatment of Parkinson's disease.

Phytoestrogens induce differential estrogen receptor alpha- or Beta-mediated responses in transfected breast cancer cells.

Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor alpha (ERalpha) and human estrogen receptor beta (ERbeta). Nine phytoestrogens were tested for their ability to transactivate ERalpha or ERbeta at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERalpha or ERbeta, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17beta-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERalpha- and ERbeta-induced transcription, with an up to 100-fold stronger activation of ERbeta. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17beta-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERalpha and ERbeta by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.

A rapid assay of endotoxin in whole blood using autologous neutrophil dependent chemiluminescence.

A rapid (30 min) whole blood assay for the detection of lipopolysaccharide (LPS) is described. This chemiluminescent (CL) assay utilizes the CR1 and CR3 receptor-induced oxidant production of polymorphonuclear leucocytes as a detection platform. The differential priming of neutrophils in whole blood by LPS-antibody complexes allows the specificity of the assay to be achieved. Oxidant released in response to complement opsonized zymosan results in luminol oxidation and subsequent light emission. This is dependent on heat labile putative complement proteins in the plasma. The assay consists of a control which measures baseline whole blood neutrophil oxidant production. The test assay contains murine monoclonal IgM antibody against the Lipid A epitope of LPS and measures the enhanced chemiluminescent response of the neutrophils in the presence of LPS-antibody complexes. Maximal sensitivity of the CL assay is dependent upon optimal antigen-antibody equivalence and duration of pre-incubation with the whole blood sample. The quantification of LPS is possible by inclusion of a positive control containing a maximally reactive LPS dose (800 pg/ml Escherichia coli 055:B5 LPS at an antibody concentration of 0.8 microg/assay). The CL assay is insensitive to variations in patient neutrophil concentration over a minimum range of 0.5 to 20 x 10(9) cells/l. The CL assay is widely reactive with the LPS of many strains of gram negative bacteria but not with the cell wall products of gram positive bacteria or Candida and Aspergillus. In comparison to acid extraction chromogenic LAL, the CL assay demonstrates superior recovery precision and accuracy in in vitro studies. This was reproducible over a wide range of LPS concentrations (0.017-1.6 EU/ml or 20-2000 pg/ml). This assay may be a clinically useful tool for the diagnosis of infection or endotoxin in patients.

Staining of urinary leucocytes as an aid to the diagnosis of inflammation in the urinary tract.

Five hundred specimens of urine have been examined for pyuria and bacteriuria, the leucocytes being stained by the Sternheimer-Malbin method. Most urines contained either less than 1 or more than 10 leucocytes per cmm; a few specimens contained 1 to 10 cells per cmm, whatever their viable bacterial count. The presence of leucocytes in urine was usually related to the bacterial count, pyuria being commonest in urines showing ;significant bacteriuria'. However, urinary tract instrumentation caused pyuria in the absence of infection. Leucocytes with nuclei staining blue by the Sternheimer-Malbin technique were considered to be indicative of active inflammation, but the incidence of such cells appeared to be a reflection of the total leucocyte count of the specimen rather than of its viable bacterial count. In the majority of cases the diagnosis of infection can be made on the basis of the bacterial count and the degree of pyuria. The staining technique appears to have a limited use, restricted to the interpretation of cases in which the results of culture and conventional leucocyte counts are ambiguous.

Evaluation of commercially available antisera for serotyping of Pseudomonas aeruginosa.

Commercially available O antisera have been compared with a standard pyocine typing method in the investigation of 156 strains of Pseudomonas aeruginosa. A third of the strains belonged to serotypes 3 or 6 and 42.3% to pyocine type 1. Good differentiation of strains belonging to the predominant serotypes was achieved by pyocine typing. Although routine use of both methods provides a more complete discrimination between strains, the simplicity of serotyping renders it more suitable for use in the smaller laboratory, where only one method may be feasible. If desired, pyocine typing can be reserved for the strains which cannot be distinguished serologically.

Meningitis caused by Pseudomonas maltophilia.

A case of meningitis caused by Pseudomonas maltophilia is described, which was unusual in that it appeared to lack the predisposing factors commonly associated with this organism. Attention is drawn to the difficulties which may be encountered in the identification of Ps. maltophilia.

Evaluation of Malthus 128H microbiological growth analyser for detecting significant bacteriuria.

In a pilot study a prototype Malthus 128H microbiological growth analyser was used to study the growth of six commonly encountered urinary pathogens in a range of five different laboratory media. No single medium had been able to show acceptable conductance changes for all bacteria within five hours. Subsequently, the Malthus system, with fastidious anaerobe broth as the culture medium, was used to screen 500 consecutive clinical specimens of urine for significant bacteriuria. After two and a half hours the Malthus system detected 32 out of the 40 true positives and eight of the 44 contaminated urines. Increasing the detection time to five hours permitted the recognition of 39 true positives and 37 contaminated urines.

Synergistic antidiabetic activities of zinc, cyclo (his-pro), and arachidonic acid.

Previous studies have already shown that prostate extract (PE) has antidiabetic activity when given to animals and humans. In this study, we explore whether this antidiabetic activity is related to the high concentrations of zinc, cyclo (his-pro) (CHP), and the prostaglandin precursor, arachidonic acid (AA), in prostate tissue. When streptozotocin-induced diabetic rats were given drinking water containing 10 mg/L zinc and 100 mg/L PE for 3 weeks, fasting blood glucose levels and glucose clearance rates, but not plasma insulin levels, were significantly lower than at pretreatment. In subsequent experiments, blood glucose levels in rats given PE for 3 weeks were significantly lower than in rats given distilled water or 10 mg/L zinc alone. However, in rats given 100 mg/L CHP with zinc, blood glucose levels were also lower than in rats given PE alone. Time-course studies in diabetic rats given drinking water containing 20 mg/L Zn, 20 mg/L L-histidine, and 10 mg/L CHP showed that blood glucose levels dropped 209 +/- 53 mg/dL in 1 day and stayed low for 2 weeks. When CHP was replaced with 100 mg AA/L, blood glucose levels dropped 230 +/- 64 mg/dL in 5 days, but returned to the original values 11 days later. Growth rate improved and water consumption decreased significantly in CHP- and AA-treated diabetic rats. High intake of L-histidine and testosterone increased blood glucose concentrations in diabetic rats. To determine optimal dosages of CHP and AA, we gave rats drinking water containing 10 mg/L Zn and 0.5 mg/L L-histidine with various concentrations of CHP or AA. The most effective doses for reducing blood glucose levels were 0.32 mg CHP/kg/day and 11 mg AA/kg/day. These data suggest that the active antidiabetic ingredients in the PE are CHP, zinc, and AA or its precursors.

Regulation of cholecystokinin-mediated amylase secretion by leptin in rat pancreatic acinar tumor cell line AR42J.

Expression of the long form of the leptin receptor, the isoform that is considered to have full signaling capability, has been reported in the central nervous system and several peripheral cell types. However, only a few cell lines have been shown to express the long form of the receptor. AR42J, a cell line derived from azaserine-treated rat pancreas, is a common model for pancreatic acinar cell secretion. In this study, the presence of leptin-receptor variants and leptin action was evaluated in this cell line. Messenger RNAs for both the long and a short form of the leptin receptor were detected by reverse transcription-polymerase chain reaction (RT-PCR) in AR42J cells, and authenticity of the receptor was confirmed by DNA sequencing. Competitive binding studies demonstrated that binding of radiolabeled leptin was specific and did not cross-react with cholecystokinin (CCK). Biologic effects of leptin on amylase release and intracellular calcium mobilization were further assessed in the presence and the absence of CCK, a known pancreatic secretagogue. Although leptin alone (< or =200 ng/ml) did not affect basal amylase release, it inhibited amylase release stimulated by 1 nM CCK by 48%. Leptin alone had no significant effect on calcium mobilization. However, pretreatment of leptin (10 and 100 ng/ml) enhanced calcium responses stimulated by CCK. These data demonstrate that the rat pancreatic tumor cell line AR42J expresses a functional form of the leptin receptor that modulates the action of CCK in calcium mobilization and amylase release.

A hospital study of ice-making machines: their bacteriology, design, usage and upkeep.

Ice-making machines have occasionally been implicated in nosocomial infection. We have examined the ice-making machines in our hospital both bacteriologically and for their general state of cleanliness and repair. Results were variable but, in most cases few organisms of significance were found. Some design features are considered and recommendations for the purchase, maintenance, cleaning and use of these machines are included.

Selective impairment of the retrieval of people's names: a case of category specificity.

Recent cases of 'proper names anomia' have been interpreted as arising from a category-specific recall deficit that is mediated either by the effects of 'uniqueness', or 'meaningfulness'. However, an alternative account is suggested by the report of a patient whose difficulties in naming familiar people arise from a selective learning impairment. The current case study presents data that are inconsistent with a learning interpretation of difficulties in naming people. We conclude that a dissociation exists between selective deficits affecting the learning and recall of people's names.

Effect of population and health care environment on hospital utilization.

A path analytic test of a causal model linking a county population's demographic and socioeconomic characteristics, the way its hospital services are delivered, and the health care resources available to it with its rate of short-term general hospital utilization is performed using data from 56 New York State counties. The results generally support the model and point to the central importance of an area's hospital bed supply for an understanding of its hospitalization rates. The path analysis reveals the patterns of direct and indirect effects of population and health care environment variables on hospitalization rates and supports the contention that health care environment characteristics intervene between population and hospitalization. The practical implications of these results for those in the health care field are discussed.

Current source density analysis of frequency coding in the inferior colliculus.

Current source density (CSD) analysis is a technique that provides information about the time course and spatial location of transmembrane currents derived from a laminar collection of evoked potentials. Restrictive conditions for acquisition of evoked potentials are required in order to yield a one-dimensional CSD analysis that is an accurate estimate of synaptic activity. Satisfaction of these conditions was assumed in recordings of tone-burst-evoked potentials along the axis of symmetry (tonotopic) in the inferior colliculus of adult mongolian gerbils. Off-line these data were converted into distance/voltage functions. The second spatial derivatives of these functions gave a family of profiles of the spatial distribution of current source and sink densities at discrete latencies relative to the stimulus. Results indicate a frequency-dependent spatial shift in the evoked current sink of about 280 microns octave. This sink, indicative of local excitatory synaptic drive, is surrounded, both spatially and temporally, by current sources. The spatial extent of excitation as estimated from CSD analysis, compares well quantitatively with predictions from an across-neuron model that is based on single unit data.

Action potential suppresion, tuning curves and thresholds: comparison with single fiber data.

The collection of compound action potential (AP) threshold curves and their use to define the sensitivity of individual animals are described. Forward masking AP tuning curves (APTC) have also been collected in the chinchilla. Characteristics of APTCs are compared with single fiber frequency-threshold curves (FTC) in the same group of animals. The two sets of data are quite similar when the probe frequency used to collect the APTC is equated with a fiber's characteristic frequency (CF). The major difference is that APTCs are usually broader than FTCs. A paradigm utilizing two maskers in a forward masking situation, developed to study psychophysical unmasking [19,37], has been modified for measuring AP suppression. AP suppression areas are described as similar to single fiber two-tone suppression areas when probe frequency and CF are above 3 kHz. Relationships among single fiber, AP and psychophysical thresholds, tuning curves and suppression areas are discussed.

Postnatal growth of cochlear spiral in Mongolian gerbil.

Measurements were made of cochlear dimensions in an age-graded series of Mongolian gerbils. The radii of the cochlear spiral at five locations and the length of the modiolus were determined from in situ photographs of mid-modiolar sections. The anterior to posterior dimensions of the auditory bulla and of the inferior colliculus were also measured to provide a general context for inner ear growth functions. At birth in this species, the cochlear capsule is still growing, and, although the basal turn is closer to the final adult proportion than more apical turns, all radii approach adult dimensions together at 9-10 days after birth (DAB). Comparison of the morphological development of gerbil otic capsule with the change in cochlear tonotopic mapping observed during physiological development shows that growth is complete before the onset of measurable electrical responses at 12-14 DAB.

Multi-unit mapping of acoustic stimuli in gerbil inferior colliculus.

Multi-unit peristimulus time (MU-PST) histograms were recorded in the gerbil inferior colliculus (IC) in response to tone burst stimuli. Histograms were collected every 100 microns as the recording electrode was advanced along the tonotopic axis of the central nucleus of the IC. Space/time maps of neural activity were constructed from these data. In most of our sample the pattern of response changed systematically as the stimulating frequency was increased in octave steps. At low frequencies (< 500 Hz) the pattern of response was broadly distributed spatially and phase-locked to the stimulus frequency. At higher frequencies (> 1 kHz) the pattern of response was more localized and showed no evidence of phase locking. The location of the maximum response to tones from 1 to 32 kHz moved ventrally along the tonotopic axis at an approximate rate of 230 microns/stimulus octave. The patterns of response were localized near stimulus threshold and spread over a larger region as level increased. This method of collecting and displaying multi-unit response maps provides an overview of ensemble activity that allows concurrent observation of spatial and temporal variations in activity patterns. The quantitative analysis of components of MU-PST Maps are consistent with trends illustrated with single-unit tuning and level functions. This perspective of IC activity suggests potential processing mechanisms that are congruent with single-unit reconstructions.

Photodynamic therapy for corneal neovascularization.

We have previously described corneal neovascularization (CNV) induced by the intrastromal injection of interleukin-2 (IL-2) in inbred mice. Photodynamic therapy (PDT), administered by a deeply penetrating 630 nm fiberoptic laser, can destroy neoplasms and their associated neovascularization with some selectivity, but can damage neighboring tissues when used for CNV. We performed PDT with a 514 nm ophthalmic argon laser in an attempt to induce regression of CNV and reduce the associated toxicity. Eight weeks following IL-2 injection, mice with CNV were injected i.v. with dihematoporphyrin ether (DHE). Seventy-two hours later, 11 eyes (group I) were irradiated with eight 800 mW, 1000 mu, 2 s spots. Controls included 11 vascularized corneas from mice that received DHE but no laser (group II), 11 that received laser but no DHE (group III), and 35 untreated vascularized corneas (group IV). Comparison of the mean areas of CNV in groups I through IV pretreatment (6.0, 6.5, 6.7, and 7.6 mm2) and 12 weeks posttreatment (4.3, 6.3, 5.6, and 7.5 mm2) revealed that a significant decrease was seen in group I only (p less than 0.04, ANOVA). Complications in group I included blepharitis (9%) and iris damage (18%). Histologic studies revealed no evidence of posterior segment damage. PDT with the 514 nm laser is safe and efficacious for the treatment of IL-2-induced CNV in this model.