Influence of ceiling fan's speed and direction on efficacy of upperroom, ultraviolet germicidal irradiation: Experimental.

Increasing a ceiling fan's speed from its lowest setting of 61 rpm, which resulted in 0.77 m3/s of airflow, to its highest setting of 176 rpm, which resulted in 2.5 m3/s of airflow, or having the fan blow either upward or downward had no statistically significant effect on the efficacy of upper-room ultraviolet germicidal irradiation (UVGI). This outcome suggests that air circulation due to the ceiling fan was sufficient and that any additional increase would not improve efficacy. Numerous experimental studies on upper-room UVGI in which fans were used to provide air mixing have been published. However, none have quantified the air movement produced by these fans or described their tests in sufficient detail to allow results to be compared to predictions using computational fluid dynamics (CFD). The present work provides the required information. In addition to the usual boundary conditions needed for CFD, we made experimental measurements of UV susceptibility of the microorganisms used in the upper-room UVGI tests. We measured UV susceptibilities for Mycobacterium parafortuitum and Bacillus atrophaeus spores to be 0.074 and 0.018 m2/J, respectively. In a previous publication, we reported the spatial distribution of fluence rate, which is also needed for predicting efficacy from CFD. In a companion paper referred to as Part II, upper-room UVGI efficacy was predicted by both Eulerian and Lagrangian CFD and compared to the experimental results from the present study.

Eggcrate UV: a whole ceiling upper-room ultraviolet germicidal irradiation system for air disinfection in occupied rooms.

A novel whole ceiling upper-room ultraviolet germicidal irradiation (UVGI) system [eggcrate ultraviolet (UV)] has been developed that incorporates open-cell 'eggcrate'-suspended ceiling panels and bare UV lamps with a ceiling fan. Upper-room UVGI is more effective for air disinfection than mechanical ventilation at much lower installation and operating costs. Conventional upper-room UVGI fixtures employ multiple tightly spaced horizontal louvers to confine UV to the upper-room. These louvered fixtures protect occupants in the lower-room from UV-induced eye and skin irritation, but at a major cost to fixture efficiency. Using a lamp and ballast from a conventional upper-room UVGI fixture in the eggcrate UV system, the germicidal efficacy was markedly improved even though the UV radiation emitted by the lamp was unchanged. This fundamental change in the application of upper-room UVGI air disinfection should permit wider, more effective application of UVGI globally to reduce the spread of airborne infection.

Givosiran to treat acute porphyria.

Porphyrias are a family of rare diseases chiefly due to inborn errors of heme biosynthesis. The porphyrias are generally characterized either by the main site of overproduction of heme precursors (hepatic or erythropoietic) or the main clinical manifestations (acute or cutaneous). The regulation of 5- (or δ)-aminolevulinic acid synthase 1 (ALAS1) plays a key role in the pathway of normal hepatic heme synthesis, providing insight into the pathophysiologic mechanisms and potential therapeutic targets for the treatment of the porphyrias. Givosiran (Givlaari; Alnylam Pharmaceuticals) is an ALAS1-directed small interfering RNA (siRNA) which has been developed for the treatment of acute hepatic porphyria (AHP). It was first approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with AHP, and it received also approval in the E.U. in 2020 for the treatment of AHP in adults and adolescents aged 12 years and older.

Regulation of vertebrate striated muscle contraction.

Most current textbooks of cell biology and histology use the steric blocking model to describe the protein mechanism by which vertebrate striated muscle contraction is regulated. Evidence accumulated in the past decade, however, reveals the regulation of muscle contraction to be far more complex than this model predicts.

Methotrexate cytotoxicity for L5178Y/Asn- lymphoblasts: relationship of dose and duration of exposure to tumor cell viability.

To determine the relative contribution of dose and duration of exposure to methotrexate (MTX) cytotoxicity, suspension cultures of L5178Y/Asn- murine leukemic cells were exposed to 0.1 to 100 microM MTX for 3 to 42 hr. Viability was determined by cloning in soft agar. While there was a linear relationship between dose and MTX cytotoxicity for exposure duration of 3 and 6 hr (r = -0.66), there was a pronounced flattening of this curve at exposure durations of 18 to 42 hr (r = -0.48). Furthermore, there was an excellent correlation (r = -0.85) between MTX cytotoxicity and durations of exposure for 6 to 42 hr (dose range, 1 to 100 microM). Using the linear least-squares method, a best-fit equation for the kinetics of MTX cytotoxicity was determined to be: log viability = 2.25 = 1.76 (log duration) - 0.31 (log dose). In practice, this equation predicts that a 1-log increase in duration of exposure results in almost a 2-log increase in cytotoxicity, whereas a 1-log increase in dose results in only a 0.3-log increase in cytotoxicity. The clinical utility of these data suggest that protracted infusions of lower doses of MTX would be equally as useful as or more useful than short-term high-dose infusions.

Controlled trial of methotrexate and Bacillus Calmette-Guérin therapy for advanced head and neck cancer.

Thirty-eight patients with advanced, inoperable squamous cell carcinoma of the head and neck were randomized to receive methotrexate alone or methotrexate with Bacillus Calmette-Guérin. The response rates with methotrexate (3 of 19) and methotrexate plus B. Calmette-Guérin (4 of 16) were similar, as was the duration of response and survival of the two groups. The results of in vitro immunological studies of lymphocytes were assessed. Marked weight loss, poor performance status, and distant metastases were the most important prognostic factors. The presence of anergy was significantly correlated with weight loss. This study also indicated that a large tumor burden is a frequent occurrence in advanced head and neck cancer and may account for the lack of efficacy of B. Calmette-Guérin.

Effect of DNAase I on muscle tropomyosin polymerization.

DNAase I, an endonuclease which interacts with G-actin, also affects tropomyosin polymerization. With chicken pectoralis or bovine cardiac ventricle tropomyosin, DNAase I both prevents tropomyosin from polymerizing and disrupts already formed tropomysin filaments. DNAase I and filament tropomyosin can also form a precipitable complex. In the electron microscope, the complex is observed as irregularly margined stellate-shaped structures with a maximum size of 9 micron. Isolated DNAase I-tropomyosin stellate complex consists of a 2:1 molar ratio of DNAase I and tropomyosin, suggesting that each tropomyosin subunit can bind DNAase I.

Phase I-II study of recombinant alpha-2 interferon against advanced leukemia and lymphoma in children.

Alpha-2 interferon, produced in Escherichia coli using recombinant DNA techniques, was administered to 17 children with refractory acute lymphoblastic leukemia (ALL) in relapse, two children with TdT-positive, Philadelphia chromosome-positive chronic myelocytic leukemia (CML) in blast crisis, and one child with B cell (SIg+) non-Hodgkin's lymphoma (NHL) in a second extramedullary relapse. An initial 2-week intravenous (IV) phase of interferon was followed by a 3-month subcutaneous (SC) maintenance phase if patients had an objective response or disease stabilization without significant bleeding or infectious complications. When interferon dosages were escalated from 3 to 100 X 10(6) U/m2 in the first phase of therapy, there was rapid progression of disease in the first four patients treated, prompting a modification of the treatment plan. The last 16 patients enrolled received fixed dosages of interferon (ie, 10, 20, 30, and 50 X 10(6) U/m2 administered to four subjects each). One child with T cell ALL had an 11-month complete remission; the patient with lymphoma had a dramatic but brief response; three others (one CML and two ALL) showed disease stabilization for 3 to 6 months with a definite oncolytic effect in two of the three patients. The remaining 15 patients had progressive disease within 2 months and were removed from the study. Acute toxicity included a flu-like syndrome in all patients, increased serum transaminase levels in five, seizures in three (two cases temporally related to fever and one to a thrombocytopenic subarachnoid hemorrhage), and prolonged activated partial thromboplastin times in seven. This phase I-II trial of recombinant alpha-2 interferon demonstrated definite activity without dose-limiting toxicity.

In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma.

Interferon-gamma (IFN gamma), as produced by recombinant DNA technology, has shown a wide range of immunomodulatory activity in vitro and in vivo. Clinical studies have attempted to establish a dose-response relationship to define optimal dosage ranges for induction of effector cell function and host response in patients with cancer. We conducted a randomized trial to test the in vivo biologic activity of five daily dosages ranging from 3 to 3,000 micrograms/m2, administered by daily 2-hour bolus injection or by continuous infusion for 14 days. We demonstrate comparable immunobiologic effects of recombinant IFN gamma (rIFN gamma; Biogen, Inc, Cambridge, MA) administered by these two schedules at the various dosages tested, and have defined a relationship of dose to biologic response over this 3-log10 dose range. Oligo 2'5' adenylate synthetase (2'5'As) induction, natural-killer (NK) cell activity, and T-cell subset distribution (heightened T helper/suppressor ratio) showed the most consistent treatment-associated changes and the greatest immunobiologic effects at dosages of 300 to 1,000 micrograms/m2. Mononuclear cell DR and DQ antigen expression showed no consistent dose-related treatment effect. The relevance of the phenotypic, functional, and enzymologic effects observed in this trial to any clinical antitumor effects of IFN gamma in cancer therapy must now be established.

A randomized phase I/II study of continuous versus intermittent intravenous interferon gamma in patients with metastatic melanoma.

Thirty patients with documented metastatic melanoma were randomly assigned to receive recombinant DNA-produced gamma-interferon (specific activity approximately, 20 MU/mg) intravenously (IV) over either two or 24 hours at dosages of 3, 30, 300, 1,000, or 3,000 micrograms/m2. Objective toxicity resembled that of alpha-interferon and included fever, chills, myalgias, headache, and fatigue. Neutropenia, elevations in liver enzymes, tachyarrhythmias, and CNS changes also were noted. Dose-limiting toxicity included neutropenia, liver enzyme abnormality, constitutional symptoms, and a change in mental status. The incidence of toxicity was qualitatively similar in both two- and 24-hour treatment arms, but was quantitatively more severe in the 24-hour continuous infusion arm. Maximum tolerated dose was 1,000 micrograms/m2 in both schedules. Pharmacokinetic studies showed a half-life of six to nine hours. One patient had a complete response after two cycles of therapy and an additional patient entered partial remission after three cycles. Recombinant gamma-interferon (rIRN-gamma) is tolerated at dosages of 1,000 micrograms/m2 administered daily either by two or 24 hour infusion for 14 days in patients with metastatic melanoma. The responses documented in this early trial warrant further evaluation for the treatment of metastatic melanoma.

A phase II study of recombinant alpha interferon in patients with recurrent or metastatic breast cancer.

Thirty-three patients with advanced breast cancer were treated with a recombinant alpha interferon (rIFN-alpha 2). All patients were ambulatory (performance status greater than or equal to 50 Karnofsky scale) and almost all had received previous chemotherapy. Large intravenous dosages of 30 to 50 X 10(6) IU/m2 were given for five consecutive days every two to three weeks to 22 patients and smaller subcutaneous dosage of 2 X 10(6) IU/m2 three times a week to 11 patients. No complete or partial responses were seen. Two patients had stable disease and the remainder progressed. Flu-like syndromes were seen in all patients. Nausea, vomiting, and anorexia were frequent. Hypotension and confusion were noted in six and five patients, respectively. Life-threatening leukopenia was noted in two patients receiving intravenous dosage and thrombocytopenia was noted in one; no sepsis or bleeding complications were noted. In this study, a highly purified and biologically active rIFN-alpha 2 was not associated with activity in previously treated women with metastatic breast cancer.

Operational criteria for adverse drug reactions in evaluating suspected toxicity of a popular scabicide.

A recently developed algorithm for the diagnosis of adverse drug reaction (ADR) was used to investigate the quality of evidence in reported cases of ADRs to 1% gamma benzene hexachloride (GBH), a popular scabicide and pediculicide currently under suspicion as a cause of central nervous system (CNS) toxicity, especially in children. Of the 53 reported cases of alleged toxicity, 37 were associated with lindane insecticide (greater than 1% GBH), which is not a pharmaceutical preparation. Of these 37 cases, 34 scored as definite or probable reactions on the algorithm. Of the 26 reports associated with the drug, 1% GBH, none scored as definite and only 6 as probable ADRs. Of these 6 probable cases, 5 represented inappropriate application or unintended ingestion. The use of rigorous operational criteria, such as those developed in this algorithm, permits a scientifically disciplined assessment of whether or not a drug has been fairly indicted, and also provides valuable clinical information about other aspects of suspected drug toxicity.

OKT3E, an anti-CD3 antibody that does not elicit side effects or antiidiotype responses in chimpanzees.

Chimpanzees were injected with OKT3 and two other anti-CD3 antibodies, OKT3D and OKT3E. Both of the new antibodies were of the mouse IgG2b isotype. Administration of the antibodies was identical to the clinical regimen used for OKT3 in humans: 5 mg i.v., daily for 10 consecutive days. All animals were monitored for fever during administration of the antibodies, and blood samples were taken throughout the treatment period for monitoring the effects of the antibodies on peripheral lymphocyte subsets and the appearance of circulating cytokines. OKT3 produced similar clinical effects to those observed in humans; fever (2/3), as well as elevations in cytokines were observed. As in humans, peripheral T cells were cleared with the first dose and remained absent or modulated of their T cell receptor molecules throughout treatment. OKT3D, IgG2b also produced fevers (2/3) and elevations of cytokines. Although it also cleared circulating T cells with the first dose and T cell counts remained low throughout treatment, remaining circulating T cells were coated with administered antibody and were able to reexpress the CD3 antigen. OKT3E, IgG2b produced no temperature elevations and no elevations in cytokines. Although it cleared the circulation of T cells with the first does, cells reappeared during treatment, modulated of their CD3 antigens or coated with the administered antibody. All three antibodies raised antimouse antibodies, and OKT3 and OKT3D also produced blocking antiidiotype antibodies. OKT3E treatment did not result in anti-OKT3E blocking antibodies.

The radiologic diagnosis of pancreatic cancer. The effect of new imaging techniques.

The objective of this study was to evaluate how the introduction of radiologic studies affected the diagnostic workup for pancreatic cancer, from 1955 through 1979. For 961 patients diagnosed as having pancreatic cancer at three teaching hospitals, we reviewed medical records, autopsy reports, and death certificates for results from all radiologic studies, surgical and pathologic procedures, and for the final diagnosis. The number of radiologic studies per patient increased as new studies were introduced; 1.6 for 1955-1959, 3.5 for 1975-1979 (P less than 0.0001). Depending on the cutoff level chosen, the sensitivity of the overall radiologic diagnosis increased over time, 0.17-0.43 for 1955-1959, to 0.54-0.78 for 1975-1979; CT, US, and ERCP accounted for much of the increase. As newer radiologic studies are introduced, continued use of previously accepted studies should be carefully evaluated.

Reversible arrhythmias observed in patients treated with recombinant alpha 2 interferon.

We have treated 25 patients, 7 with breast cancer and 18 with non-Hodgkin's lymphoma, with recombinant alpha 2 interferon. In 5 patients we observed cardiac arrhythmias that were unexpected and required treatment. No deaths have occurred that we can attribute to interferon, though 1 patient had to be resuscitated. Age, prior cardiac disease, prior treatment with doxorubicin, and interferon dose appear to be predisposing factors for this toxicity.

Comparison of the utility of capillary zone electrophoresis and high-performance liquid chromatography in peptide mapping and separation.

Capillary zone electrophoresis (CZE) and high-performance liquid chromatography (HPLC) have been used in the analysis of the primary structure of recombinant human insulin-like growth factor I (rhIGF-I). CZE both complements and supplements HPLC separations. CZE has been used to resolve peaks which co-elute on HPLC, as well as to help establish the identity of tryptic fragments in peptide mapping experiments.

Crystal structure of calmodulin.

The crystal structure of calmodulin has been determined to 3.6 A resolution. At this resolution the polypeptide chain can be traced. Some of the side chains have tentatively been identified. Refinement of the structure with x-ray diffraction data measured to 1.65 A resolution is continuing. As reported by Babu et al. calmodulin is about 65 A long and 30 A in diameter. Homolog domains 1 and 2 are related by a local twofold axis, as in parvalbumin and in troponin C, and form one end of the molecule. Domains 3 and 4 form the other end. The second alpha-helix of domain 2 and a short interdomain region are continuous with the first helix of domain 3, thereby forming a single helix from residues 67-93. The central region, residues 75-84, of this long helix forms a handle connecting the two pairs of homolog domains. Exclusive of the residues, 75-84, in the handle the closet approach of side chains of pair 1, 2 to pair 3, 4 is 12 A. The spatial relationship of pair 1, 2 to pair 3, 4 is similar in calmodulin to the relationship of the corresponding pairs in troponin C. However, in troponin C there are three additional residues in the handle region of the long alpha-helix and the two pairs are about 5.0 A further apart. On the surface of pair 1, 2 in calmodulin there is one extended region with many hydrophobic side chains from both domain 1 and domain 2. This hydrophobic patch is bounded by two distinct clusters of anionic side chains, one from the beginning of the first helix of domain 1 and on the other side of the hydrophobic surface one from the beginning of the first helix of domain 2. Homologously, the hydrophobic patch on the surface of pair 3, 4 is bounded by two clusters of aspartate and glutamate residues. Either or both of these hydrophobic surfaces may be sites to which calmodulin target proteins bind.

Inhibition of muscle tropomyosin polymerization by DNAse I.

Tropomyosin polymerization is inhibited by DNAse I, an endonuclease which also interacts with G-actin. A 1:4 molar ratio of DNAse I to adult chicken pectoralis muscle tropomyosin almost completely prevents the increased viscosity of tropomyosin under polymerizing ionic conditions. While G-actin binding to DNAse I inhibits the DNAse I hydrolysis of DNA, tropomyosin does not affect this enzymatic activity. G-actin-DNAse I interaction is also not altered by tropomyosin.

A phase I trial of recombinant leukocyte alpha 2 interferon in patients with advanced malignancy.

Seventeen patients with advanced, previously treated malignancies were entered into a phase I trial utilizing recombinant DNA produced alpha 2 leukocyte interferon (rIFN-alpha 2). Sixteen patients were evaluable. Patients were to receive rIFN-alpha 2 by either the I.V. or I.M. route for 35 consecutive days. The dosage was identical by both routes, and patients were escalated from 3 X 10(6) to 10 X 10(6) to 30 X 10(6) to 50 X 10(6) and to 100 X 10(6) I.U. every 7 days. No patient was able to tolerate the consecutive treatment protocol as planned. Dose-limiting toxicity was a flu-like syndrome in 10 patients and was usually associated with a fall in performance status. Confusion resulted in study withdrawal for five patients, four receiving rIFN-alpha 2 by the I.M. route. Hematologic and liver function abnormalities were common, usually transient, and not associated with clinical sequelae. One patient with non-Hodgkin's lymphoma showed substantial improvement; otherwise, all had stable or progressive disease. Pharmacologic studies indicated substantial serum levels at doses greater than or equal to 10 X 10(6) I.U. regardless of route. No consistent changes in NK activity, lymphocyte subpopulations, or immunoglobulin levels were noted, and no patient developed antibodies to rIFN-alpha 2. The dose and schedule used here indicate that high levels of serum rIFN-alpha 2 activity are obtainable by either the I.M. or I.V. route. Intermittent rather than daily dosage is more likely to be better tolerated and should be considered for phase II trials.

Laser-induced fluorescence of pyrene and other polycyclic aromatic hydrocarbons (PAH) in seawater.

Polycyclic aromatic hydrocarbons (PAH) in the marine environment are currently of great concern due to their potential carcinogenicity. The standard methods of detection and quantification of PAH in seawater and sediments are costly, time-consuming and do not account for the heterogeneous nature of their distribution and sources. Laser-induced, time-resolved fluorescence spectroscopy may help to overcome these limitations. Several PAH have relatively long-lived stimulated fluorescence emissions, which allow them to be detected among a background of more intense but shorter-lived chromophores. Using time-delayed techniques we have shown an ability to detect PAH, principally pyrene, at environmental levels (ng l(-1)) both in the laboratory and in situ in Boston Harbor and other study areas. Further development may lead to the rapid determination of several PAH in typical near-shore marine environments.