Limitations of antifungal prophylaxis in preventing invasive Candida surgical site infections after liver transplant surgery.

Invasive primary Candida surgical site infections (IP-SSIs) are a common complication of liver transplantation, and targeted antifungal prophylaxis is an efficient strategy to limit their occurrence. We performed a retrospective single-center cohort study among adult single liver transplant recipients at Duke University Hospital in the period between 1 January 2015 and 31 December 2020. The study aimed to determine the rate of Candida IP-SSI according to the peri-transplant antifungal prophylaxis received. Of 470 adult single liver transplant recipients, 53 (11.3%) received micafungin prophylaxis, 100 (21.3%) received fluconazole prophylaxis, and 317 (67.4%) did not receive systemic antifungal prophylaxis in the peri-transplant period. Ten Candida IP-SSIs occurred among 5 of 53 (9.4%) micafungin recipients, 1 of 100 (1.0%) fluconazole recipients, and 4 of 317 (1.3%) recipients who did not receive antifungal prophylaxis. Our study highlights the limitations of antifungal prophylaxis in preventing invasive Candida IP-SSI after liver transplant surgery. We hypothesize that pathogen, host, and pharmacokinetic-related factors contributed to the occurrence of Candida IP-SSI despite antifungal prophylaxis. Our study reinforces the need for a risk-based, multi-pronged approach to fungal prevention, including targeted antifungal administration in patients with risks for invasive candidiasis and close monitoring, especially among patients with surgically complex procedures, with timely control of surgical leaks.

Strength of relationship between body mass index and gross motor capacity in youth with intellectual disabilities.

BACKGROUND: Adequate skill levels of gross motor capacity affect activities of daily living, participation in recreational activities and general physical activity levels of youths (7-21 years). Most studies of typically developing youths have reported significant negative relationships between gross motor capacity and body mass index. The latter findings are especially of concern for youths with intellectual disabilities in that it has been estimated that 61% of children and 66% of adolescents were classified as overweight/obese. Therefore, the purpose of this study was to determine the strength of the relationship between body mass index and gross motor capacity among youths with mild to moderate intellectual disability (ID). METHODS: Components of the Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) were used for designated aspects of gross motor capacity: six items for upper limb coordination (ULC); seven items for balance (BAL); six items for bilateral coordination (BLC); and one item for agility (A-2). Participants consisted of 654 youths (438 men), ages 8-21 years with ID. Participants were divided into pre-puberty and post-puberty men (post ≥12 years) and women (post ≥10 years of age). Body mass index (BMI, kg/m2) was determined by height and weight measurements on the day of testing. A Kendall's tau correlation coefficient (τ) was used to determine the strength of the relationship between body mass index and gross motor capacity (BOT-2 test scores). RESULTS: The τ values for both pre-puberty and post-puberty for all BAL, BLC, A-2 tests and for three of the six ULC tests were negligible to very weak (τ = 0 to ±0.19). Higher τ values were seen for pre-puberty youths in three of the ULC tests, but they fell within the weak range (τ < 0.24). When combining all pre-puberty and post-puberty participants, τ values were in the negligible to very weak range for all tests. CONCLUSION: The strength of relationship between body mass index and gross motor capacity as measured by the BOT-2 subtest item scores used in this study is very weak and suggests that they are not clinically relevant.

Different management practices are associated with mesophilic and thermophilic spore levels in bulk tank raw milk.

Bacterial endospores (also referred to as spores) present in raw milk are capable of surviving pasteurization and other adverse conditions encountered during dairy powder production. Therefore, requiring low spore levels in raw ingredients (e.g., raw milk) may be necessary for producing dairy powders with low spore counts. To identify potential associations between management practices and spore levels in raw milk, we sampled bulk tank raw milk from 33 farms throughout New York State every other month for 1yr. Following spore pasteurization (80°C for 12min), samples were incubated at 3 different temperatures to enumerate psychrotolerant (6°C for 10 d), mesophilic (32°C for 48h), and thermophilic (55°C for 48h) spores. An additional enrichment procedure was used to detect spores present at low levels (<10 spores/mL). Overall, psychrotolerant, mesophilic, and thermophilic spores were detected (at levels ≥10 spores/mL) in 1, 74, and 58% of bulk tank raw milk samples, respectively. Although thermophilic spore levels could not be quantified (due to bacterial swarming), mesophilic spore levels ranged from below detection (<10 spores/mL) to 680 spores/mL. Data collected through surveys were used to identify management practices associated with either mesophilic or thermophilic spore levels. We found that different management practices are associated with mesophilic and thermophilic spore levels. Low mesophilic spore levels in bulk tank raw milk samples were associated with (1) large herd size, (2) use of sawdust or sand bedding, and (3) not fore stripping during the premilking routine. Management practices that were associated with lower odds of having a thermophilic spore level ≥10 spores/mL are (1) large herd size, (2) spray-based application of the postmilking disinfectant, (3) dry massaging the udder during the premilking routine, and (4) the use of straw bedding. Collectively, these results suggest that different management practices may influence mesophilic and thermophilic spore levels in raw milk.

Communication gaps for solid organ transplant-transmitted infections among infectious disease physicians: an Emerging Infections Network survey.

Infectious disease (ID) physicians were surveyed concerning knowledge and management of potential transplant-transmitted infections (TTIs). On the basis of cumulative responses to 4 questions that assessed solid organ transplant-related clinical exposures and experience, respondents were divided into 3 groups: most, some, or little transplant experience. Rapid access to donor data was identified as the most important factor when evaluating a potential TTI. Despite varying experience in transplant infections, ID physicians are frequently asked for opinions regarding donor suitability and TTI management. Improved ID physician access to donor information and educational resources will allow more optimal management of potential TTIs.

Induction of idiotope suppression in the anti-azophenylarsonate response of T-depleted A/J mice.

The homologous, monoclonal antiidiotope, MB, induced idiotope suppression that was remarkably stable and could be transferred by B lymphocytes. Marked depletion of T cell function, confirmed by limiting diluting analysis, did not affect the ability of MB to suppress the corresponding idiotope. Suppression induced by MB appears to result from direct interaction with idiotope-positive B cells, without the intervention of idiotope-specific T suppressor cells.

The aging immune system: primer and prospectus.

Changes in T lymphocyte populations underlie much of the age-related decline in the protective immune response. Aging leads to the replacement of virgin T cells by memory T cells and to the accumulation of cells with signal transduction defects. Studies of antibody gene assembly, accessory cell function, post-thymic T cell development, skewed selection of T cell receptor repertoire, and the clinical concomitants of immune senescence will shed new light on the causes and consequences of age-dependent immune failure.

Phytostat for continuous culture and automatic sampling of plant-cell suspensions.

An apparatus for growing plant cells in suspension culture is described; it may be used for continuous or batch culture, and is equipped with a valve for automatic collection of samples. Aeration is by continuous bubbling of air into the culture through fritted glass. Normal culture-duplication times are from 30 to 35 hours.

Multiple organ carcinogenicity of 1,3-butadiene in B6C3F1 mice after 60 weeks of inhalation exposure.

Groups of 50 male and 50 female B6C3F1 mice were exposed 6 hours per day, 5 days per week, for 60 to 61 weeks to air containing 0, 625, or 1250 parts per million 1,3-butadiene. These concentrations are somewhat below and slightly above the Occupational Safety and Health Administration standard of 1000 parts per million for butadiene. The study was designed for 104-week exposures but had to be ended early due to cancer-related mortality in both sexes at both exposure concentrations. There were early induction and significantly increased incidences of hemangiosarcomas of the heart, malignant lymphomas, alveolar-bronchiolar neoplasms, squamous cell neoplasms of the forestomach in males and females and acinar cell carcinomas of the mammary gland, granulosa cell neoplasms of the ovary, and hepatocellular neoplasms in females. Current workplace standards for exposure to butadiene should be reexamined in view of these findings.

Rapamycin but not acarbose decreases age-related loss of outer hair cells in the mouse Cochlea.

Adding rapamycin or acarbose to diet at 9-10 months of age has been shown to significantly increase life span in both male and female UM-HET3 mice. The current study examined cochleae of male and female UM-HET3 mice at 22 months of age to determine if either treatment also influenced age-related loss of cochlear hair cells. A large loss of cochlear outer hair cells was observed at 22 months of age in untreated mice in both apical and basal halves of the cochlear spiral. Addition of acarbose to diet had no significant effect on the amount of outer hair cell loss at 22 months of age or in its pattern, with large loss in both apical and basal halves. The addition of rapamycin to diet, however, significantly reduced outer hair cell loss in the basal half of the cochlea at 22 months of age when compared to untreated mice. There was no significant difference between male and female mice in any of the conditions. Age-related outer hair cell loss in the apical cochlea precedes outer hair cell loss in the base in many mouse strains. The results of the present study suggest that rapamycin but not acarbose treatment can delay age-related loss of outer hair cells at doses at which each drug increases life span.

Protease-cleaved iron-transferrin augments oxidant-mediated endothelial cell injury via hydroxyl radical formation.

Previous work has shown that the Pseudomonas-derived protease, pseudomonas elastase (PAE), can modify transferrin to form iron complexes capable of catalyzing the formation of hydroxyl radical (.OH) from neutrophil (PMN)-derived superoxide (.O2-) and hydrogen peroxide (H2O2). As the lung is a major site of Pseudomonas infection, the ability of these iron chelates to augment oxidant-mediated pulmonary artery endothelial cell injury via release of 51Cr from prelabeled cells was examined. Diferrictransferrin previously cleaved with PAE significantly enhanced porcine pulmonary artery endothelial cell monolayer injury from 2.3-6.3 to 15.8-17.0% of maximum, resulting from exposure to H2O2, products of the xanthine/xanthine oxidase reaction, or PMA-stimulated PMNs. Iron associated with transferrin appeared to be responsible for cell injury. Spin trapping and the formation of thiobarbituric acid-reactive 2-deoxyribose oxidation products demonstrated the production of .OH in this system. The addition of catalase, dimethyl thiourea, and the hydrophobic spin trap, alpha-phenyl-n-terbutyl-nitrone, offered significant protection from injury (27.8-58.2%). Since sites of Pseudomonas infection contain other proteases, the ability of porcine pancreatic elastase and trypsin to substitute for PAE was examined. Results were similar to those observed with PAE. We conclude .OH formation resulting from protease alteration of transferrin may serve as a mechanism of tissue injury at sites of bacterial infection and other processes characterized by increased proteolytic activity.

Human T cell leukemia virus-I-associated T-suppressor cell inhibition of erythropoiesis in a patient with pure red cell aplasia and chronic T gamma-lymphoproliferative disease.

Human retroviruses have recently been linked with T cell lymphoproliferative disorders and with the acquired immune deficiency syndrome. We investigated the mechanisms for acquired pure red cell aplasia and cutaneous anergy in a patient with the chronic T gamma-lymphoproliferative disease (T gamma-LPD) syndrome. Patient marrow erythroid progenitors (BFU-E) were 17 +/- 9% of control and were selectively increased to 88-102% of control after marrow T cell depletion. Patient Leu 2+ suppressor T cells spontaneously produced high titers of human gamma-interferon and resulted in a concentration-dependent selective inhibition (74-91%) of BFU-E when co-cultured with autologous or allogeneic marrow. Conditioned media (CM) derived from patient Leu 2+ T cells similarly inhibited growth of autologous or allogeneic marrow BFU-E. The inhibitory factor derived from patient CM was acid-labile (pH 2) and sensitive to trypsin; prior treatment of patient T cells with anti-HLA-DR monoclonal antibody plus complement abrogated the suppressive effect of T cell-derived CM. Patient peripheral blood mononuclear cells (PBMC) were unable to support growth of cultured interleukin 2 (IL 2)-dependent T cells, but responded to exogenous IL 2 in vitro with a 16-21-fold augmentation, relative to control, in mitogen-induced proliferation. Antibodies to HTLV-I core proteins p19 and p24 but not to HTLV-III proteins were detected in patient serum by Western blotting; patient cultured PBMC stained (7-11%) with antibodies to p19 and p24. Patient cultured PBMC demonstrated integrated HTLV-I genomic sequences by the Southern technique and expressed both specific HTLV-I genomic sequences by RNA dot blot plus reverse transcriptase activity. Utilizing a cloned DNA probe for the beta chain of the T cell receptor gene, patient PMBC demonstrated gene rearrangements providing presumptive evidence for clonality. The presence in serum of HTLV-I p19 and p24 antibodies, the expression of p19 and p24 core antigens on patient mononuclear cells, the evidence of HTLV-I proviral integration sequences and the expression of HTLV-I genomic sequences in patient cells, indicates infection with HTLV-I and raises the possibility of an etiologic link between human retrovirus infection and some instances of large granular lymphocytic leukemia (T gamma-LPD).

The Gurnham equation in characterizing the compressibility of pharmaceutical materials.

Limitations of the Heckel equation in characterizing material compression behavior have been well reported. In this work, the Gurnham equation, which was first introduced in chemical engineering, is proposed as an alternate method of evaluating the compressibility of pharmaceutical powders. The Gurnham equation was adapted for tablet compression and the estimated slope parameter c was proposed to represent material compressibility. Data from the compression of four commonly used excipients (microcrystalline cellulose, corn starch, lactose monohydrate, and dibasic calcium phosphate dihydrate) and one drug (acetaminophen) were evaluated using the Gurnham equation. Using compression data at different peak pressures, linear relationships between porosity and lnPressure of the five materials were obtained. The determined parameter c expresses the compressibility of materials. The analysis of previous experimental data, including granulations, mixtures and co-processed materials also indicates that c might be a representative parameter for material compressibility.

On exemplary scientific conduct regarding submission of manuscripts to biomedical informatics journals.

As the Editors of leading international biomedical informatics journals, the authors report on a recent pattern of improper manuscript submissions to journals in our field. As a guide for future authors, we describe ethical and pragmatic issues related to submitting work for peer-reviewed journal publication. We propose a coordinated approach to the problem that our respective journals will follow. This Editorial is being jointly published in the following journals represented by the authors: Computer Methods and Programs in Biomedicine, International Journal of Medical Informatics, Journal of Biomedical Informatics, Journal of the American Medical Informatics Association, and Methods of Information in Medicine.

Histologic analyses of experimental tumors from mouse blastocyst-derived cell lines.

Previous work has shown that established cell lines can be derived from cultured mouse blastocysts. Although these cell lines differed from one another morphologically, immunologically, and biochemically, it has not been easy to determine what embryonic cell type (if any) each cell line represents. We showed in this report that these blastocyst-derived lines could produce tumors in syngeneic mice at low yields and presented the results of histologic analyses of the tumors which we carried out to learn more about the kinds of cells present in each of the lines. Tumors derived from cell line MB2 contained two kinds of cells. Most of the cells were similar to those found in so-called "parietal yolk sac carcinomas," secreted Reichert's membrane-like material, and could be found in subsequent transplant generations. The other cell type resembled trophoblast giant cells morphologically and did not survive transplantation. These results showed that MB2 contained cells which were either parietal endoderm cells or a closely related precursor. The tumor derived from MB4 consisted of small, closely packed cells intermixed with larger cells with foamy cytoplasm and occasional giant cells. Cells in subsequent passages of the tumor were often organized into acinar clusters. Biochemical evidence has suggested that MB4 cells resembled one or both components of visceral yolk sac. Visceral yolk sac sarcomas have not previously been reported; the MB4-derived tumor may prove to be the first. Tumors derived from line MB31 contained both fibroblastic and epithelioid cell types which could not be more definitively identified. Cultures derived from each kind of tumor in each case contained cells morphologically characteristic of those in the originally inoculated population. Our results showed that tumors produced from blastocyst-derived cell lines did not resemble the teratocarcinomas which formed when blastocysts were implanted into an ectopic site in vivo: They did not contain a wide variety of cell types, nor did they possess pluripotent embryonal carcinoma "stem" cells characteristic of the teratocarcinoma. That each blastocyst-derived line gave rise to a different kind of tumor suggested that each line may have been made up of cells "trapped" at some stage characteristic of the development of a particular embryonic or extraembryonic tissue. However, each tumor did contain at least two distinct cell types; this suggested that cells in the blastocyst-derived lines, though restricted to their developmental potential, may not yet have been completely determined.

Expression of liver phenotypes in cultured mouse hepatoma cells.

Mouse hepatoma cells were established in vitro as a permanently growing line designated Hepa. The mass population and a subclone were characterized for their karyotype and their retention of liver-specific properties. An examination of 17 hepatic traits revealed that the cell lines secreted several serum proteins. The activities of a number of liver-specific enzymes, however, appeared to be absent in these cells. The identification of differentiated properties of cultured hepatoma cells permits the use of these lines in a variety of studies such as cell hybridization, biochemical analysis of tissue-specific gene products, and the modulation of expression of genes governing differentiated phenotypes. This report presents the analysis of a broad spectrum of characteristics and thereby describes one of the most fully defined hepatoma cell lines of murine origin in the literature.

Multiple lymphokine production by a phorbol ester-stimulated mouse thymoma: relationship to cell cycle events.

Interleukin 2 (IL-2) production was studied in a subclone of the murine thymoma EL 4. Phenotypic characterization revealed the EL 4-17-2 line to be Thy-1.2+, Lyt-1.2+, and Lyt-2.2-. Costimulation with 500 ng 12-O-tetradecanoylphorbol 13-acetate (TPA)/ml and 5 micrograms concanavalin A (Con A)/ml induced optimal levels of IL-2. Three related phorbol esters stimulated comparable levels of IL-2 when used in conjunction with Con A. Kinetic experiments indicated that IL-2 first became detectable at 2 hours in TPA-treated cultures, whereas in cultures stimulated with Con A alone IL-2 production was not evident until 8 hours. Flow cytometry indicated that TPA and its related phorbol esters cause a perturbation in the cycling of the cell which may be related to increased IL-2 production. Under the conditions examined, no interferon-gamma (IFN-gamma) was detectable. Conversely, both granulocyte-macrophage colony-stimulating factor (CSF-GM) and interleukin-3 (IL-3) were found under conditions that led to stimulation of IL-2 synthesis. CSF-GM was produced in cultures treated singly with 500 ng TPA/ml or with Con A. IL-3 production was similar to IL-2 production, because optimal levels were found in cultures after combined treatment with phorbol ester and mitogen.

Carcinogenicity of 1,3-butadiene in C57BL/6 x C3H F1 mice at low exposure concentrations.

The carcinogenicity of inhaled 1,3-butadiene was evaluated in C57BL/6 x C3H F1 mice exposed to concentrations of this gas ranging from 6.25 to 625 ppm. Butadiene is a high production volume chemical, used mainly in the manufacture of synthetic rubber. In these 2-yr inhalation studies, a potent multisite carcinogenic response was observed, including neoplasms of the lung at concentrations as low as 6.25 ppm. Early occurrence and extensive development of lethal lymphocytic lymphomas in mice exposed to 625 ppm of butadiene reduced the number of animals at risk for the expression of later developing neoplasms at other sites; at lower exposure concentrations, dose responses were demonstrated for hemangiosarcomas of the heart and neoplasms of the lung, forestomach, Harderian gland, preputial gland, liver, mammary gland, and ovary. So far, no long-term studies on butadiene have been conducted at exposure concentrations that have not shown a carcinogenic response. In separate experiments with reduced exposure durations, butadiene induced neoplastic responses at multiple organ sites even after only 13 wk of exposure. Because of the correspondence between these animal data and recent epidemiology findings, there is a worldwide public health need to reevaluate current workplace exposure standards for 1,3-butadiene.

Determinants of the antitumor effect of radiolabeled monoclonal antibodies.

The murine B-cell lymphoma 38C13 model was used to study the radiobiological effect of 131I-monoclonal antibody (MAB) therapy compared with dose equivalent external beam irradiation. Continuous exponentially decreasing low dose rate (LDR) gamma-irradiation, and multiply fractionated (MF) X-irradiation were compared with dose equivalent 131I-MAB. The relative therapeutic efficacy of radioimmunotherapy, and the relative contribution of (a) low dose rate; (b) whole body irradiation; and (c) microdosimetry to the overall effect were determined. Groups of mice with or without B-cell lymphoma were treated with either (a) 131I-anti-idiotype MAB; (b) 131I-isotype-matched irrelevant control MAB; (c) 5-15 Gy 250 kV X-irradiation given as a single fraction; (d) 2.5-30 Gy 250 kV X-irradiation given in 10 fractions/2 weeks; or by (e) continuous exponentially decreasing gamma-irradiation via a 137Cs source, which simulated the effective t1/2 of the 131I-MAB. In tumor-free mice the LD50/30 was approximately 10 Gy for MF and LDR external irradiation, and 11-12 Gy for 131I-MAB. However, the effect of these modes of irradiation on tumor size differed significantly. The cumulative percentage of tumor reduction averaged over 12 days was 0.635 +/- 0.055%/Gy for MF, and 1.36 +/- 0.061%/Gy for LDR external irradiation (a relative efficacy factor of 1.63 for LDR irradiation; P = 0.01). Assuming homogeneous body distribution, the tumor reduction effect over 12 days for 131I-MAB was 2.064 +/- 0.133%/Gy for specific, and 1.742 +/- 0.1%/Gy for nonspecific isotype-matched irrelevant 131I-MAB (P = 0.02). When 131I-MAB was compared to LDR external irradiation, the relative efficacy factor was 1.99 (P less than 0.001). In summary, there was a dose rate effect on tumor response, which may in part explain the efficacy of radioimmunotherapy. The additional effect of 131I-MAB on tumor response was only partially explained by the cumulative concentration ratio of 131I-MAB tumor/131I-MAB whole body, which was on average 1.7. This relatively low concentration ratio was partly due to tumor-mediated dehalogenation. Thus, the overall tumor response was a function of the total dose, dose rate, and both the specific and nonspecific distribution of 131I-MAB.

Isoprene, an endogenous hydrocarbon and industrial chemical, induces multiple organ neoplasia in rodents after 26 weeks of inhalation exposure.

Isoprene, the 2-methyl analogue of 1,3-butadiene, is a high production chemical used largely in the manufacture of synthetic rubber and is the major endogenous hydrocarbon exhaled in human breath. Thirteen-week inhalation toxicology studies of isoprene were conducted in male and female F344 rats and B6C3F1 mice at exposure concentrations of 0, 70, 220, 700, 2200, and 7000 ppm (6 h/day; 5 days/week). In addition, 26-week inhalation studies at the same exposure levels, followed by a 26-week recovery period, were conducted in male rats and mice. The 13-week exposures produced no discernible exposure-related toxic effects in rats. Interstitial cell hyperplasia of the testis was observed in all male rats in the 7000 ppm group after 26 weeks of exposure; following the 26-week recovery period the only effect in rats was a marginal increase in benign testicular interstitial cell tumors. In mice, isoprene induced toxic and carcinogenic effects at multiple organ sites. Following the 26-week exposure and 26-week recovery periods, incidences of neoplastic lesions in the liver, lung, forestomach, and harderian gland were significantly increased. Neoplastic effects were observed at 700 ppm and higher exposures. Non-neoplastic lesions in mice exposed to isoprene included spinal cord degeneration, testicular atrophy, degeneration of the olfactory epithelium, and epithelial hyperplasia of the forestomach. A partial hindlimb paralysis and a nonresponsive macrocytic anemia were also seen in mice. Most of the toxic and carcinogenic effects caused by isoprene, as well as the species' difference in response, had been observed after inhalation exposures to 1,3-butadiene.

Radioimmunotherapy of human B-cell lymphoma with 90Y-conjugated antiidiotype monoclonal antibody.

We report the first case of 90Y-conjugated monoclonal antibody (MoAb) administration for human radioimmunotherapy. Ten mCi 90Y-labeled antiidiotype (anti-Id) MoAb were administered to a patient with B-cell lymphoma whose tumor successfully imaged with 111In-labeled anti-Id MoAb. No significant toxicities were observed. More than 2 g of unlabeled anti-Id MoAb were administered while clearing the circulating IgM idiotype prior to administration of the 90Y-MoAb. Transient partial regression of disease was observed. Serial fine needle aspirations of a malignant lymph node documented in vivo anti-Id penetration into a site that did not image by radioimmunoscintigraphy. The radiosensitivity of B-cell lymphoma, the tumor specificity of anti-Id, the antitumor activity of anti-Id alone, and the safe administration of 10 mCi 90Y-labeled anti-Id MoAb in this report suggest further investigation of this radioimmunoconjugate for therapy of B-cell lymphoma is warranted.