Bacterial two-component signalling as a therapeutic target in drug design. Inhibition of NRII by the diphenolic methanes (bisphenols).
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Anti-Bacterial Agents↗
Biomedical subjects
M Shapiro
Publications and source records attributed to M Shapiro.
Experimental infection of chimpanzees with hepatitis G virus and genetic analysis of the virus.
Hepatitis G virus (HGV) was transmitted to 2 chimpanzees by inoculation with human plasma containing approximately 10(8) genome equivalents (GE) of HGV. The infection was characterized by the late appearance (weeks 10 and 11 after inoculation [pi]) of viremia that persisted throughout the 120-week follow-up. Serum HGV titer increased steadily until it plateaued at 10(6)-10(7) GE/mL. However, despite this relatively high titer, neither of the chimpanzees developed hepatitis. The sequence of the viral genome, recovered from each chimpanzee at week 77 pi, differed from that of the inoculum by 5 nt (2 aa) and 27 nt (2 aa). Two more chimpanzees were inoculated with a first-passage plasma pool. The chimpanzee inoculated with approximately 10(6.7) GE of HGV had viremia at week 1 pi. However, the viral titer increased with the same kinetics as observed in the first passage. The second chimpanzee inoculated with approximately 10(4.7) GE of HGV had late appearance (week 7 pi) of viremia.
Amino Acid Substitution↗
Rhinocerebral mucormycosis treated with amphotericin B colloidal dispersion in three patients.
Rhinocerebral mucormycosis (zygomycosis) primarily affects diabetic or immunosuppressed patients and typically progresses rapidly, necessitating surgical excision and antifungal therapy with amphotericin B. Large doses of amphotericin B are required for cure, causing significant renal toxicity. Amphotericin B colloidal dispersion (ABCD; Amphocil, Sequus Pharmaceuticals, Menlo Park, CA) is a 1:1 complex of cholesteryl sulfate and amphotericin B, which results in significant reduction of toxicity, especially nephrotoxicity. We describe three patients with life-threatening rhinocerebral mucormycosis treated with ABCD. All patients had high serum creatinine levels due to prior treatment with amphotericin B; these levels reverted to normal during treatment with ABCD. Two patients with diabetes mellitus were cured after receiving a combination of surgery and ABCD therapy. The third patient, who had myelodysplastic syndrome, had an initial good response, with cure of the fungal infection; however, he eventually died of his primary illness. To the best of our knowledge, this is the first detailed clinical description of the treatment of mucormycosis with ABCD.
Adult↗
Use of antibiotic exposure to detect postoperative infections.
OBJECTIVE: To assess the utility of postoperative antibiotic exposure as an indicator of postoperative infection after coronary artery bypass graft surgery. DESIGN: We determined an optimal antibiotic exposure threshold by creating receiver operating characteristic curves. SETTING: Tertiary healthcare institution (United States); national sample (Israel). PATIENTS: 5,887 patients undergoing coronary artery bypass graft surgery. RESULTS: Postoperative antibiotic exposure with at least 9 days between the first and last dates of antibiotic administration, excluding the first postoperative day, had a sensitivity of 95% (261/276) and specificity of 85% (3,944/4,628) for identifying surgical-site infection, using as a gold standard surgical-site infections identified by conventional prospective surveillance or extrapolated from review of a sample of medical records. In contrast, using the same gold standard for surgical-site infections, the sensitivity of routine prospective surveillance alone was only 60%. The predictive value positive of the defined antibiotic exposure was 28% (261/945) for surgical-site infection and 60% (563/945) for any nosocomial infection. In the Israeli cohort, the sensitivity was 87% (74/85) and the specificity was 82% (735/898). CONCLUSION: Antibiotic exposure of sufficient duration and timing was more sensitive than conventional methods in detecting nosocomial infection and required substantially less effort to collect. Although the predictive value positive for surgical-site infection was only moderate, the majority of individuals identified this way had a nosocomial infection.
Antibiotic Prophylaxis↗
The Direct Assessment of Functional Abilities (DAFA): a comparison to an indirect measure of instrumental activities of daily living.
The Direct Assessment of Functional Abilities (DAFA) was designed as a direct measure of instrumental activities of daily living (IADLs) that could be compared with an indirect assessment of IADLs by the Pfeffer Functional Activities Questionnaire (PFAQ). The DAFA (28 demented and 15 control subjects) and PFAQ (subjects and informants) were administered twice, together with a brief cognitive battery. Demented subjects performed significantly worse on direct assessment (DAFA) than predicted by self-report (PFAQ), and overestimation of abilities increased with severity of dementia. In contrast, informants tended to underestimate abilities of demented subjects, but not to a significant degree. Control (nondemented) subjects had comparable results with the two methods. The DAFA may provide a more objective measure of functional status in demented subjects than do indirect methods of assessment.
Activities of Daily Living↗
Infection of a chimpanzee with hepatitis C virus grown in cell culture.
Culture supernatant harvested from Daudi cells, a lymphoplastoid cell line, after 58 days of infection with the H77 strain of hepatitis C virus (HCV), was inoculated into a chimpanzee. HCV RNA, as detected by RT-PCR, first appeared in the serum and liver 5 and 6 weeks, respectively, after inoculation. Peripheral blood mononuclear cells (PBMC) collected on week 7 were also positive for HCV RNA. The major sequences of hypervariable region 1 (HVR1) of the viral genome recovered from the inoculated chimpanzee were the ones which were the majority in the original H77 inoculum and not those which were in the majority in the culture supernatant. Only the sequence recovered from PBMC was the same as the major one found in the cell culture.
Animals↗
Utilization of chimeras between human (HM-175) and simian (AGM-27) strains of hepatitis A virus to study the molecular basis of virulence.
Chimeras between human (HM-175) and simian (AGM-27) strains of hepatitis A virus (HAV) were constructed to evaluate the effect of the 2C gene of AGM-27 on HAV replication in cell culture and virulence in tamarins (Saguinus mystax) and chimpanzees (Pan troglodytes). Kinetic studies and radioimmunofocus assays demonstrated that replacement of the 2C gene of HAV/7, a cell culture-adapted strain of HM-175, with that of AGM-27 drastically reduced the ability of the virus to replicate in cultured cells. Intragenic chimeras containing AGM-27 sequences in either the 5' or 3' half of the 2C gene replicated in cell culture at an intermediate level. Whereas HAV/7 is attenuated for tamarins, a chimera containing the simian virus 2C gene in the HAV/7 background was virulent in tamarins, demonstrating that the simian virus 2C gene alone can confer the phenotype of virulence to an otherwise attenuated virus. Clusters of AGM-27-specific residues near both ends of the 2C protein were required for virulence since a chimera containing AGM-27 sequences in the carboxy-terminal half of 2C was partially attenuated for tamarins while one containing AGM-27 sequences only in the amino-terminal half of 2C was even more attenuated. Chimeras containing either the entire or only the 3' half of the simian virus 2C gene in the HAV/7 background were attenuated for chimpanzees.
Animals↗
Transscleral diode laser retinopexy in retinal detachment surgery: results of a multicenter trial.
PURPOSE: To evaluate the safety and efficacy of transscleral diode laser for retinopexy in rhegmatogenous retinal detachment surgery in a multicenter trial. METHODS: Seventy-two patients with primary rhegmatogenous retinal detachments were enrolled. No patient with chronic detachment, a retinal break greater than 90 degrees, history of uveitis or infectious retinopathy, or proliferative vitreoretinopathy was enrolled. RESULTS: Information from follow-up of 6 months or longer was available on 65 eyes. Retinas were attached at 6 months with a single operation in 58 (89%) of these eyes. Complications included apparent pinpoint breaks in Bruch's membrane in 15 eyes, scleral-thermal effect in 14 eyes, and limited hemorrhage, which was intraretinal in 10 eyes and extended into the vitreous in 3 eyes. In one case, hemorrhage was judged perhaps to have contributed to initial surgical failure. The other complications had no known adverse effects. Complications were significantly associated with the physician's experience in using transscleral laser retinopexy. CONCLUSIONS: In this multicenter study, transscleral diode laser retinopexy served as a safe and effective means of creating chorioretinal adhesion during retinal reattachment surgery. Minor complications were minimized by increasing experience with the technique.
Adolescent↗
Brain aging: changes in the nature of information coding by the hippocampus.
Advanced age in rats is associated with a decline in spatial memory capacities dependent on hippocampal processing. As yet, however, little is known about the nature of age-related alterations in the information encoded by the hippocampus. Young rats and aged rats identified as intact or impaired in spatial learning capacity were trained on a radial arm maze task, and then multiple parameters of the environmental cues were manipulated to characterize the changes in firing patterns of hippocampal neurons corresponding to the presence of particular cues or the spatial relationships among them. The scope of information encoded by the hippocampus was reduced in memory-impaired aged subjects, even though the number of neurons responsive to salient environmental cues was not different from that in young rats. Furthermore, after repeated manipulations of the cues, memory-intact aged rats, like young rats, altered their spatial representations, whereas memory-impaired aged rats showed reduced plasticity of their representation throughout testing. Thus changes in hippocampal memory representation associated with aging and memory loss can be characterized as a rigid encoding of only part of the available information.
Aging↗
Brain aging: impaired coding of novel environmental cues.
Studies of the spatial memory capacities of aged animals usually focus on performance during the learning of new environments. By contrast, efforts to characterize age-related alterations in spatial firing information processing by hippocampal neurons typically use an environment that is highly familiar to the animals. In the present study we compared the firing properties of hippocampal neurons in young adult and aged rats as they acquired spatial information about new environmental cues. Hippocampal complex spike cells were recorded while rats performed a radial arm maze task in a familiar environment and then recorded again after many of the spatial cues were changed. After the change in the environment, in aged rats 35-42% of place fields retained their original shape and location with respect to the maze center, although they usually rotated to another arm. By contrast, all place fields in young animals either disappeared or appeared in a new location. Some of the new place fields appeared in the new environment during the first 5 min of exploration, whereas others needed more than 30 min to develop fully. In the familiar environment spatial selectivity of place cells was similar in young and aged rats. By contrast, when rats were placed into a new environment, spatial selectivity decreased considerably in aged memory-impaired rats compared with that of young rats and aged rats with intact memory performance.
Aging↗
Quantitative detection of immune activation transcripts as a diagnostic tool in kidney transplantation.
Procedures to diagnose renal allograft rejection depend upon detection of graft dysfunction and the presence of a mononuclear leukocytic infiltrate; however, the presence of a modest cellular infiltrate is often not conclusive and can be detected in non-rejecting grafts. We have pursued a molecular approach utilizing reverse transcription (RT)-PCR to test the diagnostic accuracy of multiple immune activation gene analysis as means to diagnose renal allograft rejection. The magnitude of intragraft gene expression of 15 immune activation genes was quantified by competitive RT-PCR in 60 renal allograft core biopsies obtained for surveillance or to diagnose the etiology of graft dysfunction. Results were compared with a clinicopathological analysis based upon the histological diagnosis (Banff criteria) and the response to antirejection treatment. During acute renal allograft rejection intragraft expression of the interleukin (IL)-7 (P < 0.001), IL-10 (P < 0.0001), IL-15 (P < 0.0001), Fas ligand (P < 0.0001), perforin (P < 0.0001), and granzyme B (P < 0.0015), but not IL-2, interferon gamma, or IL-4, genes is significantly heightened. Amplified RANTES and IL-8 gene transcripts are sensitive but nonspecific markers of rejection. A simultaneous RT-PCR evaluation of perforin, granzyme B, and Fas ligand identifies acute rejection, including cases with mild infiltration, with extraordinary sensitivity (100%) and specificity (100%). Effective antirejection therapy results in a rapid down-regulation of gene expression. The combined analysis of Fas ligand, perforin, and granzyme B gene expression by quantitative RT-PCR provides a reliable tool for diagnosis and follow-up of acute renal allograft rejection. Its accuracy and a potential rapid application within few hours suggest its use in the clinical management of renal transplant patients.
Adult↗
Evaluation of the concept of "hypoxic fraction" as a descriptor of tumor oxygenation status.
The presence and significance of tumor hypoxia has been recognized since the 1950's. Hypoxic cells in vitro and in animal tumors in vivo are documented to be three times more resistant to radiation-induced killing compared to aerobic cells. There is now evidence that tumor hypoxia is treatment-limiting in many human cancers. One common way to describe the extent of hypoxia in individual and groups of tumors is the "hypoxic fraction." This measurement infers that cells are present in only two radiobiologically significant states: oxygenated and hypoxic. In this paper, we demonstrate the qualitative and quantitative presence of hypoxic tumor cells using the oxygen dependent metabolism of the 2-nitroimidazole, EF5. Two assumptions concerning the calculation and interpretation of the hypoxic fraction are considered. The first is the use of multiple animals to describe the radiation response at a given radiation dose. We hypothesize that the presence of intertumor variability in radiation response due to hypoxia could negatively influenced the characterization of the change in slope required to calculate the hypoxic fraction. The studies presented herein demonstrate heterogeneity of radioresponse due to hypoxic fraction within and between tumor lines. The 9L subcutaneous tumor studied in air-breathing rats demonstrates a 2 log variation in surviving fraction at 17 Gy. The Morris 7777 hepatoma, in contrast, showed little variability of radiation response. Our second question addresses the limitations of using the "hypoxic fraction" to describe the radiation response of a tumor. This calculated value infers that radiobiological hypoxia is a binary measurement: that a tumor contains two cell populations, aerobic cells with maximal radiosensitivity and hypoxic cells with maximal radioresistance. The classic work of Thomlinson and Gray, however, implies the presence of an oxygen gradient from tumors vessel through the tissues. In both the 9L and Q7 tumors, flow cytometric analysis of EF5 binding demonstrates a continuous range of cellular pO2 levels. These studies suggest that: 1) there is extensive intertumor variability of radiation response in certain tumor lines; 2) the variability in radiation response between individual tumors in a group may affect the ability to describe a particular tumor type's "hypoxic fraction" and 3) The oxygen status of tumor cells is a continuum. This realization affects the ability to apply a binary concept such as the "hypoxic fraction" effectively in radiobiology.
Animals↗
Increasing fungal isolation from clinical specimens: experience in a university hospital over a decade.
The local patterns of fungal isolates were studied by a retrospective analysis of fungal species isolated from clinical specimens in a university hospital in Jerusalem. Between 1984 and 1993, 5630 fungi [4071 patient unique isolates (PUI)] were isolated and identified. During the study decade, the annual incidence of all isolates increased 2.7-fold, and PUI increased 1.6-fold. Candida albicans accounted for 61% of PUI; urine was the source of 53%. The intensive care units (ICUs) and the Bone Marrow Transplantation (BMT) Department had the highest incidence of fungal isolation. The following trends were observed: (1) a decrease in the relative frequency of C. albicans and increase in Candida tropicalis; (2) increased number of isolates from urine, surgical wounds and intra-abdominal sites; (3) increased number of isolates from ICUs and BMT. Fungi are emerging as important hospital-acquired pathogens in tertiary care and teaching hospitals, and are associated with high rates of morbidity and mortality. It is important to be familiar with the local patterns of fungal isolation in order to improve treatment.
Adolescent↗
Use of the ED as a regular source of care: associated factors beyond lack of health insurance.
STUDY OBJECTIVE: To determine the characteristics and health care experiences of patients who identify the ED as their usual source of care. METHODS: We conducted a cross-sectional survey in a Level I trauma center ED at an urban teaching hospital. Our population comprised 892 adults who presented to the ED over the course of 30 days. We asked participants about their regular source of health care, previous health care experiences, and perceptions of the use of the ED. RESULTS: Patients who reported the ED as their regular source of care were three times more likely to have used the ED more than once in the preceding year. Among the regular ED users, 68% desired a physician as their regular source of care, and 46% of these subjects said they had tried unsuccessfully to get one in the preceding year. Five variables were associated with self-report of the ED as the regular source of health care: annual income less than $30,000, having been refused care in an office or clinic in the past, perception that an ED visit costs less than an office visit, absence of chronic illness, and unwillingness to use the ED if a $25 copayment were in effect. CONCLUSION: Low income, perceived mistreatment by health care providers, and misperception about charges contribute to use of the ED as a regular site for health care. These factors suggest the difficulty of altering health care use patterns in this group.
Adolescent↗
Recombinant vaccine against hepatitis E: dose response and protection against heterologous challenge.
Thirty-two rhesus monkeys were used to evaluate the dose response of a recombinant HEV vaccine, and the efficacy of the vaccine based on the ORF2 protein of the Pakistani strain for pre- and post-exposure vaccination against intravenous challenge with homologous or heterologous virus was examined. Post-exposure vaccination did not protect animals against hepatitis. Although primates vaccinated twice with 50-microgram, 10-microgram, 2-microgram, or 0.4-microgram doses of the recombinant 55 kDa ORF-2 protein were infected, they were protected from hepatitis when they were challenged with very high doses of the homologous strain of HEV. Primates vaccinated twice with a 50 micrograms dose of the recombinant protein were protected from hepatitis after heterologous challenge with the Mexican strain, the strain of HEV most genetically distant from the Pakistani strain.
Animals↗
In vitro metabolism of N-(5-chloro-2-methylphenyl)-N'-(2-methylpropyl)thiourea: species comparison and identification of a novel thiocarbamide-glutathione adduct.
The in vitro metabolism of SDZ HDL 376, a thiocarbamide developed for the treatment of atherosclerosis, was investigated in rat, dog, monkey, and human liver microsomes, as well as in rat and human liver slices. [14C]SDZ HDL 376 was extensively metabolized in all the species except human. In rat liver microsomes an S-oxide was the major metabolite. In human and monkey microsomes, carbon hydroxylation was favored. The NADPH-dependent oxidation of SDZ HDL 376 resulted in covalent binding to microsomal protein. Addition of GSH to the incubations decreased protein binding in a concentration-dependent manner and resulted in a novel SDZ HDL 376-GSH adduct. Adduct formation required NADPH and was mediated predominantly by cytochrome P450. Inhibition of cytochrome P450 by 1-aminobenzotriazole resulted in a 95% decrease in adduct formation, while heat inactivation of flavin-containing monooxygenases resulted in a 10% decrease. Unlike other thiocarbamides which form disulfide adducts with GSH, the SDZ HDL 376 adduct contained a thioether linkage as characterized by LC/MS/MS and reference to a synthetic standard. Reactions performed with [35S]GSH resulted in a [35S]SDZ HDL 376-GSH adduct, demonstrating the sulfur was derived from GSH. Adduct formation was faster in rat microsomal reactions compared to human microsomes. Other structurally unrelated thiocarbamides (phenylthiourea, methimazole, 2-mercaptobenzimidazole, 2-mercaptoquinazoline, and 2-propyl-6-thiouracil) did not form similar adducts in rat liver microsomes supplemented with GSH. Therefore, the GSH adduct of SDZ HDL 376 is unique for this type of thiocarbamide. These results suggest that the bioactivation and detoxification of SDZ HDL 376 differ significantly from other thiocarbamides. Furthermore, the in vitro formation of S-oxides and GSH adducts in rat hepatic tissue, and ring hydroxylation and glucuronidation in human hepatic tissue, suggests rats may be more susceptible to the toxicity of SDZ HDL 376 compared to humans.
Animals↗
Diarrheal epidemics among Rwandan refugees in 1994. Management and outcome in a field hospital.
We describe the clinical course and outcome of Rwandan refugees with cholera-like illness (n = 567) and clinical dysentery (n = 1,062) treated at the Israeli Army field hospital in the disaster region of Goma, Zaire, during the summer of 1994. Vigorous fluid administration was the primary therapy, complemented with antibiotics for patients with presumed Shigella infection. Recovery rates were 94% and 96% for patients with cholera and dysentery, respectively. Mortality was substantially affected by comorbid conditions such as pneumonia and meningitis, which occurred in one-quarter of these patients. Infective, metabolic, and surgical complications (including three cases of intussusception) may have contributed to the deaths. The outcome of patients during diarrheal epidemics of cholera or bacillary dysentery may be favorable, even in disaster settings, if patients are evacuated promptly to medical facilities and appropriate therapy is instituted. We close with general observations on procedures to be followed in future epidemics of diarrheal diseases.
Adolescent↗
Invasive pneumococcal infections. A comparison between adults and children.
A similar number of adults and children had invasive pneumococcal infection. There was male predominance, and different ethnic distribution between children and adults. The majority of adults (78%), had underlying diseases, but this was less frequent in children (24%). The presenting illness differed between adults and children. Complications of invasive pneumococcal infection occurred more frequently in adults than in children. The mortality rate in adults was 21.5%; in children, only 3.8%. The rate of penicillin-resistant pneumococci at our hospital was 23%, while cefotaxime resistance was 4.2%. Penicillin-resistant pneumococci were not isolated more frequently from children than from adults. Patients with penicillin-resistant pneumococci had longer duration of hospitalization and more nosocomially acquired infections. No difference in the mortality rate was found between patients with resistant or sensitive pneumococci. Ninety-five percent of strains were included in the current vaccine, but less than 2% of patients had been vaccinated. Isolates prevalent in Europe and the United States (19, 5, 1, 14, 6, 18, 12, 4, 9, 23, 7) were also most prevalent in Jerusalem. The distribution of serotypes differed between children and adults, and between patients from whom resistant organisms were isolated as opposed to sensitive organisms.
Adolescent↗