Abstract In the dairy industry bacteriophage (phage) contamination significantly impairs the production and quality of products like yogurt and cheese. To combat this issue, the strains of bacteria used as starter cultures possess mechanisms that make them resistant to phage infection, such as envelope resistance, or processes that render them immune to phage infection, such as restriction-modification and CRISPR-Cas. Lactococcus lactis , used to manufacture cheese and other dairy products, can also block the reproduction of infecting phages by abortive infection (Abi), a process in which phage-infected cells die before the phage replicate. We employ mathematical-computer simulation models and experiments with two Lactococcus lactis strains and two lytic phages to investigate the conditions under which Abi can limit the proliferation of phages in L. lactis populations and prevent the extinction of their populations by these viruses. According to our model, if Abi is almost perfect and there are no other populations of bacteria capable of supporting the replication of the L. lactis phages, Abi can protect bacterial populations from succumbing to infections with these viruses. This prediction is supported by the results of our experiment, which indicate that Abi can help protect L. lactis populations from extinction by lytic phage infections. However, our results also predict abortive infection is only one element of L. lactis defenses against phage infection. Mutant phages that can circumvent the Abi systems of these bacteria emerge. The survival of L. lactis populations then depends on the evolution of envelope mutants that are resistant to the evolved host-range phage.
One hundred patients were entered on a randomized prospective protocol to evaluate the effectiveness of hepatic resection of single as well as multiple hepatic metastases from colorectal primaries in combination with continuous hepatic artery infusion (CHAI) of fluorodeoxyuridine (FUDR) via the implantable pump (Infusaid, Intermedics Infusaid Inc., Norwood, MA). The eight patients with single metastases were randomized to hepatic resection alone (three patients) or hepatic resection plus CHAI (five patients). The 22 patients with resectable multiple metastases were randomized between receiving CHAI only (12) or CHAI after resection of all metastases (10). Patients who had positive portal lymph nodes (14) were all treated with CHAI. Patients with unresectable metastases (31) were randomized between intravenous 5-fluorouracil or CHAI of FUDR. FUDR was alternately infused every 2 weeks at a dose of 0.1 mg/kg/24 hour escalated to .3 mg/kg/24 hour with heparinized saline as the alternative infusate. The median follow-up of all patients was 20 months. All patients with multiple resectable metastases had at least a partial response (PR) to the CHAI (PR defined as ≤50% decrease of the sum of the products of the diameters of the lesions measured on computerized axial tomography scans), and four patients given CHAI only had no metastases in the liver on relaparotomy. Patients with resection and CHAI had a better survival than patients with CHAI only; however, the difference was not significant. Patients with positive portal nodes and CHAI had a lower PR (36%) than patients with unresectable disease treated with CHAI (52%). Patients with positive portal nodes or metastatic disease outside of the liver did significantly worse than patients with unresectable disease treated with CHAI.
Alprazolam is a widely used antianxiety agent, yet relatively little is known about the relationship between chronic oral doses and steady-state plasma levels. This study examines the relationship over a wide range of therapeutic doses. We conducted a parallel, double-blind, placebo-controlled study in 36 patients with agoraphobia with panic attacks, or panic disorder with limited phobic avoidance based on DSM- III criteria. Patients received alprazolam (N = 25) or placebo (N = 11) beginning at 1 mg/day and increased weekly until either a maximum tolerated dose or 10 mg/day was achieved. Dosages were then gradually tapered according to a predetermined schedule. The entire study period lasted 14 weeks. Laboratory and clinical assessments were conducted weekly. Doses up to 6 mg/day were tolerated by 80% of patients on alprazolam and doses of 10 mg/day were tolerated by 40% of patients. Twenty-seven percent of the placebo patients reached 10 tablets/day. In the alprazolam group, the principal cause of intolerance was sedation. Throughout the study no significant changes in vital signs or laboratory parameters were observed. Steady state alprazolam, 4-hydroxy alprazolam, and α-hydroxy alprazolam plasma levels were linearly related to dose. A 1 mg dosage increment produced, on the average, a corresponding 10 ng/ml increase in steady state level of the parent drug. Significant response was observed in subjects who achieved concentrations greater than 20 ng/ml, with a maximum of 81% of the samples classified as re- sponders within the 60 ng/ml and above group. During taper, no severe withdrawal symptoms were noted; 12 of 25 alprazolam patients, however, reported rebound anxiety (anxiety rating scale scores higher than baseline), which occurred most commonly at the reduction from 1 mg to 0 mg.
The purpose of this study was to determine if alcohol worsens arrhythmias produced by nonpenetrating cardiac impact. Twenty-three dogs were studied. Twelve underwent nonpenetrating cardiac impact alone at 12 m/sec with a contact compression of 2 cm. Eleven underwent cardiac impact after having received intravenous alcohol (blood level of 197 ± 37 mg/100 ml) (mean ± SD). Three dogs experienced ventricular fibrillation immediately after impact and died: of these, two underwent impact alone and one underwent impact following ethanol. These three dogs were eliminated from the study. All of the dogs had some form of complex arrhythmia during the first 10 minutes of observation, the average cumulative duration of which during the first 10 minutes following trauma was greater among dogs that received ethanol. No complex arrhythmias other than ventricular premature contractions or ventricular tachycardia were observed after the first 10 minutes following impact. During the first 2 hours of observation following cardiac impact, dogs that received alcohol before trauma showed more single premature ventricular contractions (p<0.03), couplets (p<0.01), triplets (p<0.02), runs of 4-20 beats (p<0.05), and total number of premature ventricular contractions (p<0.05) than dogs that underwent trauma alone. Following the first 10 minutes, ventricular irritability increased with time until approximately 1 hour, and then there was a gradual reduction of the frequency of arrhythmias in both dogs that received alcohol and those that did not. In conclusion, nonpenetrating cardiac impact in dogs that previously received ethanol was associated with greater ventricular irritability than in dogs that underwent impact alone.
The coronavirus disease of 2019 (COVID-19) pandemic has necessitated a transition to online courses, prompting widespread consequences for higher education. Ensuring academic integrity poses a serious concern in these circumstances. Drawn from my experiences teaching online programming courses, I discuss the considerable and manifold flaws in our current anti-cheating measures. I propose a series of strategies that instructors can pursue to make assessments more resilient to cheating. Although there is no panacea, we must begin by acknowledging the problem facing us and discussing earnestly how we can refortify academic integrity.
