Unusual dynamics of killing of cultured lewis lung cells by the DNA-intercalating antitumour agentN-[2-(dimethylamino)ethyl]acridine-4-carboxamide

Summary The cytotoxicity ofN-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601 316), a new experimental DNA-intercalating antitumour drug, against a cultured Lewis lung adenocarcinoma cell line was compared with that of the DNA-intercalating antitumour drug amsacrine. In contrast to amsacrine, AC demonstrated self-inhibition of cytotoxicity following short (3–9 h) incubation periods and exponential killing (with a shoulder) after long (24–72 h) periods of incubation. The difference between these drugs was best demonstrated using a constant concentration x time (CxT) exposure (AC, 12 mol h l^–1; amsacrine, 3 mol h l^–1). In contrast to amsacrine, AC was minimally effective over exposure periods of 1 h and maximally effective over intermediate periods (4–6 h). The results suggest the possibility of designing AC administration protocols that maximise the drug's cytotoxicity towards solid tumours, which, because of diffusion barriers, are subjected to longer drug exposures than are well-vascularised tumours.Supported by the Auckland Division of the Cancer Society of New Zealand and by the Health Research Council of New Zealand     

A phase I study of SR-4554 via intravenous administration for noninvasive investigation of tumor hypoxia by magnetic resonance spectroscopy in patients with malignancy.

PURPOSE: To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by (19)F magnetic resonance spectroscopy (MRS). EXPERIMENTAL DESIGN: SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant 1H/19F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m(2). Peak plasma concentrations increased linearly with the SR-4554 dose (r(2) = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean +/- SD, 3.28 +/- 0.59 h), and plasma clearance was quite rapid (mean +/- SD, 12.8 +/- 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m(2). The maximum tolerated dose was 1400 mg/m(2). SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m(2). At the highest dose (1600 mg/m(2)), SR-4554 was detectable in tumor at 8 h, but not at 27 h. CONCLUSIONS: SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.     

Dietary fibre and the occurrence of gut symptoms in cystic fibrosis

Accepted 26 October 1996
OBJECTIVE—To evaluate the effect of currently recommended energy rich cystic fibrosis diets on fibre intake and to investigate the relationship between fibre intake and the occurrence of gut symptoms.
METHOD—Prospective completion of non-weighed five day food diaries by 28 children with cystic fibrosis and comparison of mean daily fibre intake with age matched controls who did not have cystic fibrosis. Prospective completion of similar diaries to a total of 68 children with cystic fibrosis and comparison of fibre and lipase intake with the occurrence of gut symptoms.
RESULTS—Mean daily fibre intake in children with cystic fibrosis was 7.00 g compared with 14.65 g in controls (p<0.001). Mean daily fibre intake in eight patients troubled with moderate or severe abdominal pain was 0.144 g/kg. This was significantly lower (p<0.01) than mean values for 22 patients with occasional but mild symptoms (0.249 g/kg) and 38 with no gut symptoms (0.312 g/kg). There was a trend towards higher pancreatic enzyme doses (lipase/kg/day) in children with abdominal pain.
CONCLUSIONS—Currently recommended cystic fibrosis diets have a low fibre content. A low residue diet might be an important factor in the pathogenesis of gastrointestinal symptoms.

     

Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies

Hedonistic homeostatic dysregulation is a neuropsychological behavioural disorder associated with substance misuse and addiction. The disorder has been recognised as a consequence of dopamine replacement therapy (DRT) in 15 patients with Parkinson's disease. The syndrome typically develops in male patients with early onset Parkinson's disease, and can occur with orally and subcutaneously administered DRT. These patients take increasing quantities of their DRT, despite increasingly severe drug induced dyskinesias, and may develop a cyclical mood disorder with hypomania or manic psychosis. There is impairment of social and occupational functioning. Tolerance develops to mood elevating effects of DRT and a negative affective withdrawal state occurs if the drugs are withdrawn or doses decreased. The clinical features and guidelines for managing this syndrome are discussed. A set of diagnostic criteria for further investigating this condition is proposed.     

Jararhagin and its multiple effects on hemostasis

Jararhagin is a 52 kDa hemorrhagic P-III metalloproteinase isolated from the venom of the medically important Brazilian pit-viper Bothrops jararaca. It is a member of the reprolysin family of zinc metalloproteinases containing a catalytic metalloproteinase domain followed by a disintegrin-like and a cysteine-rich domain. The impact of jararhagin on hemostasis has been extensively studied using in vitro and in vivo model systems as well as in clinical studies. Jararhagin-induced hemorrhage is the result of the degradation of sub-endothelial matrix proteins leading to the disruption of the blood vessel endothelium, with accompanying disturbances in platelet function. The versatility of jararhagin is further demonstrated by its direct action on von Willebrand factor, the degradation of fibrinogen, by its inhibition of platelet adhesion to collagen and by its inability to be affected by the plasma inhibitor ₂-macroglobulin. Collagen-induced platelet aggregation is inhibited by jararhagin though the binding of the molecule to the ₂ subunit I domain of the platelet surface ₂β₁ integrin (collagen receptor). Jararhagin also cleaves the β₁ subunit of the same integrin, inhibiting platelet interaction and ultimately causing impairment of signal transduction. The effect of jararhagin on cell systems other than platelets is evaluated; in fibroblasts, jararhagin functions as a collagen-mimetic substrate and, in endothelial cells, it causes apoptosis and indirectly inhibits cell proliferation by release of angiostatin-like compounds. Jararhagin induces a strong pro-inflammatory response characterized by intense leukocyte accumulation at the site of the injection. Although hemorrhage and edema are a response to the direct effect of jararhagin, jararhagin-induced inflammation and necrosis are dependent on macrophages and key pro-inflammatory cytokines or their receptors. Some data also indicate that the toxin possesses anti-tumorgenic properties. Methods for inhibiting jararhagin are reviewed; this encompasses the use of synthetic peptides to the isolation of naturally occurring mammalian peptides and the development of toxin-specific antibodies through DNA immunisation and monoclonal antibody technologies. The availability of jararhagin makes it an important tool for research into the mechanisms of action of similar toxins, for insights into cellular interactions and for clinical investigations into the treatment of envenomings from B. jararaca.     

Mask wearing in community settings reduces SARS-CoV-2 transmission

The effectiveness of mask wearing at controlling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has been unclear. While masks are known to substantially reduce disease transmission in healthcare settings [D. K. Chu et al., Lancet 395, 1973–1987 (2020); J. Howard et al., Proc. Natl. Acad. Sci. U.S.A. 118, e2014564118 (2021); Y. Cheng et al., Science eabg6296 (2021)], studies in community settings report inconsistent results [H. M. Ollila et al., medRxiv (2020); J. Brainard et al., Eurosurveillance 25, 2000725 (2020); T. Jefferson et al., Cochrane Database Syst. Rev. 11, {"type":"entrez-nucleotide","attrs":{"text":"CD006207","term_id":"30322945","term_text":"CD006207"}}CD006207 (2020)]. Most such studies focus on how masks impact transmission, by analyzing how effective government mask mandates are. However, we find that widespread voluntary mask wearing, and other data limitations, make mandate effectiveness a poor proxy for mask-wearing effectiveness. We directly analyze the effect of mask wearing on SARS-CoV-2 transmission, drawing on several datasets covering 92 regions on six continents, including the largest survey of wearing behavior (n= 20 million) [F. Kreuter et al., https://gisumd.github.io/COVID-19-API-Documentation (2020)]. Using a Bayesian hierarchical model, we estimate the effect of mask wearing on transmission, by linking reported wearing levels to reported cases in each region, while adjusting for mobility and nonpharmaceutical interventions (NPIs), such as bans on large gatherings. Our estimates imply that the mean observed level of mask wearing corresponds to a 19% decrease in the reproduction number R. We also assess the robustness of our results in 60 tests spanning 20 sensitivity analyses. In light of these results, policy makers can effectively reduce transmission by intervening to increase mask wearing.

Face masks are one of the most prominent interventions against COVID-19, with very high uptake in most countries (1). However, global mask wearing fell substantially in 2021, even in countries with low vaccination rates (Fig. 1). Given ongoing epidemics, establishing the effectiveness of mask wearing in community settings is critical. The following sections review past work on the effectiveness of mask wearing in different settings and at different scales.Open in a separate windowFig. 1.Reported mask wearing in countries with <40% of population fully vaccinated, as of 1 October 2021 [wearing from the UMD/Facebook survey (1); vaccinations from ref. 2]. The y axis is the proportion who reported that, over the last week, they wore masks most or all of the time in public spaces.In the context of healthcare, N95 masks (as defined by ref. 3) work well when worn properly by trained users—reducing transmission of coronaviruses including severe acute respiratory coronavirus syndrome 2 (SARS-CoV-2) by at least half (4, 5). Cheng et al. (6) find that ideal surgical masking (7, 8) of a noninfected person corresponds to a 65 to 75% reduction in their risk of COVID-19.However, the effect of mask wearing in small-scale community settings is more difficult to detect.In particular, four meta-analyses have summarized studies on respiratory infections, conducted in community settings (4, 9–11). They estimate mean decreases in infection risk between 4% and 15% for surgical masks, but with large uncertainty: Individual results ranged from a 7% increase in infection risk to a 61% decrease in infection risk. In addition, few of these studies are randomized controlled trials (RCTs), and those that are RCTs have considerable issues: Bungaard et al. (12) found a small, nonsignificant reduction in infection risk. Abaluck et al. (13), found a significant, 8.6% decrease in symptomatic seropositivity linked to mask wearing. However, limitations of the study included a requirement for unblinded participants to self-report symptoms before testing, use of an antibody test with a very low 5 d sensitivity, and unclear generalization from the specific context (rural villages in Bangladesh).We focus on the effects of mask wearing or mandates (i.e., legal requirements to wear a mask) on transmission in large connected populations. To study mask impacts on transmission, many studies use the timing of mask mandates as a proxy for sharp changes in the level of mask wearing. Some such studies have inferred limited or inconclusive effects in cross-country analyses (14) and within-country studies (15), while others find cross-country evidence that mask mandates and recommendations lead to decreased transmission and mortality (16, 17).Other analyses provide evidence for reduced case growth following subnational mandates within countries such as the United States (18–20) and Germany (21). A potential explanation for the inconsistency and uncertainty of these results is that data on national mandate timing may be poorly suited for analyzing the effects of mask wearing on transmission.Epidemiological studies often use government mask mandates as a proxy for mask wearing. However, the existing literature on the relationship between mandates and actual levels of mask wearing has shown surprisingly weak effects. For example, studying US states, ref. 22 failed to find a statistically significant relationship between mandates and subsequent wearing, while other studies found postmandate increases in wearing of just 13% (23) and 23% (24). Betsch et al. (25) find a ∼40% increase in wearing after local mandates in Germany, but no other study finds a comparably large increase. Given that the link between mandates and wearing is surprisingly weak, it is likely that the link between mandates and transmission is difficult to detect. Three additional factors lead us to suspect that a link between mandates and transmission would be difficult to detect. First, introducing a mandate is a coarse, one-off event that necessarily loses signal by not tracking day-to-day changes in mask wearing. We also have fewer data on mandates: Less than half of the regions we study enforced any mandate during the study period. Second, past studies treat mandates as a binary on/off intervention that is fully implemented at a single point in time. However, modeling the effect of mandates as an instantaneous change in the reproduction number or mortality fails to capture changes in wearing behavior following the announcement of a mandate but before its enforcement (21). Nor does it account for gradual change in behavior after the implementation of a mandate. Finally, the circumstances of mandate policies are highly heterogeneous, both in terms of the preexisting level of voluntary wearing at the time of implementation and in terms of how exactly they are defined, enforced, and complied with. Consequently, averaging the international effect of mandates based on coarse data is unlikely to provide a useful summary of heterogeneous mandate effects. Importantly, these arguments point to the link between mandates and transmission being difficult to detect, not that it is absent.Because of these difficulties in studying the effect of mandates, we instead focus on estimating the effect of mask wearing on transmission, using a large (n = 19.97 million) global survey of self-reported mask wearing (1). Two other studies estimate mask effectiveness from self-reports: In their study of 24 countries, Aravindakshan et al. (26) use YouGov wearing data to infer an overall 3.9 to 10% relative decrease in case growth rate from whole population mask wearing. Rader et al. (22) study US states using a novel SurveyMonkey wearing dataset to infer a ∼10% decrease in transmission between the lowest and highest empirical quartiles of wearing (a 50 to 75% increase in wearing). Rader et al. use data limited to 12 US states during June–July 2020. Our data are richer: We study 56 countries on six continents, and our inferential analyses span May–September 2020.Our analysis goes further than past work in the quality of wearing data—100 times the sample size, with random sampling and poststratification—the geographical scope, the use of a semimechanistic infection model, the incorporation of uncertainty into epidemiological parameters, and the robustness of our results (59 sensitivity tests). See

Willingness to Self-Collect a Sample for HPV-Based Cervical Cancer Screening in a Well-Screened Cohort: HPV FOCAL Survey Results

Self-collection may provide an opportunity for innovation within population-based human papillomavirus (HPV) cervical cancer screening programs by providing an alternative form of engagement for all individuals. The primary objective was to determine willingness to self-collect a vaginal sample for primary HPV screening and factors that impact willingness in individuals who participated in the Human Papillomavirus For Cervical Cancer (HPV FOCAL) screening trial, a large randomized controlled cervical screening trial. A cross-sectional online survey was distributed between 2017 and 2018 to 13,176 eligible participants exiting the FOCAL trial. Bivariate and multivariable logistic regression assessed factors that influence willingness to self-collect on 4945 respondents. Overall, 52.1% of respondents indicated willingness to self-collect an HPV sample. In multivariable analysis, the odds of willingness to self-collect were significantly higher in participants who agreed that screening with an HPV test instead of a Pap test was acceptable to them (odds ratio (OR): 1.45 (95% confidence interval (CI): 1.15, 1.82), those who indicated that collecting their own HPV sample was acceptable to them (p < 0.001), and those with higher educational ascertainment (OR: 1.31, 95% CI: 1.12, 1.54). The findings offer insight into the intentions to self-collect in those already engaged in screening, and can inform cervical cancer screening programs interested in offering alternative approaches to HPV-based screening.