Visual Stimulus Speed Does Not Influence the Rapid Emergence of Direction Selectivity in Ferret Visual Cortex.

Sensory experience is necessary for the development of some receptive field properties of neurons in primary sensory cortical areas. However, it remains unclear whether the parameters of an individual animal's experience play an instructive role and influence the tuning parameters of cortical sensory neurons as selectivity emerges, or rather whether experience merely permits the completion of processes that are fully seeded at the onset of experience. Here we have examined whether the speed of visual stimuli that are presented to visually naive ferrets can influence the parameters of speed tuning and direction selectivity in cortical neurons. Visual experience is necessary for the development of direction selectivity in carnivores. If, during development, cortical neurons had the flexibility to choose from among different inputs with a range of spatial positions and temporal delays, then correlation-based plasticity mechanisms could instruct the precise spatiotemporal selectivity that underlies speed tuning and direction selectivity, and the parameters of an individual animal's experience would influence the tuning that emerges. Alternatively, the tuning parameters of these neurons may already be established at the onset of visual experience, and experience may merely permit the expression of this tuning. We found that providing different groups of animals with either slow (12.5 deg/s) or fast (50 deg/s) visual stimuli resulted in emergence of direction selectivity, but that speed tuning and direction selectivity were similar in the two groups. These results are more consistent with a permissive role for experience in the development of direction selectivity.SIGNIFICANCE STATEMENT The proper development of brain circuits and neural response properties depends on both nature (factors independent of experience) and nurture (factors dependent on experience). In this study, we examined whether the quality of visual experience of an individual animal influences the development of basic sensory detectors in primary visual cortex. We found that, although visual experience is required for the development of direction selectivity, tuning for stimulus speed could not be altered by specific experience with slow or fast stimuli. These results suggest that the tuning parameters for direction selectivity are specified independently of an animal's sensory experience, and that a range of experiences can promote the proper mature expression of direction selectivity in primary visual cortex.

Using Geocoding to Identify COVID-19 Outbreaks in Congregate Residential Settings: San Francisco's Outbreak Response in Single-Room Occupancy Hotels.

More than 500 single-room occupancy hotels (SROs), a type of low-cost congregate housing with shared bathrooms and kitchens, are available in San Francisco. SRO residents include essential workers, people with disabilities, and multigenerational immigrant families. In March 2020, with increasing concerns about the potential for rapid transmission of COVID-19 among a population with disproportionate rates of comorbidity, poor access to care, and inability to self-isolate, the San Francisco Department of Public Health formed an SRO outbreak response team to identify and contain COVID-19 clusters in this congregate residential setting. Using address-matching geocoding, the team conducted active surveillance to identify new cases and outbreaks of COVID-19 at SROs. An outbreak was defined as 3 separate households in the SRO with a positive test result for COVID-19. From March 2020 through February 2021, the SRO outbreak response team conducted on-site mass testing of all residents at 52 SROs with outbreaks identified through geocoding. The rate of positive COVID-19 tests was significantly higher at SROs with outbreaks than at SROs without outbreaks (12.7% vs 6.4%; P < .001). From March through May 2020, the rate of COVID-19 cases among SRO residents was higher than among residents of other settings (ie, non-SRO residents), before decreasing and remaining at an equal level to non-SRO residents during later periods of 2020. The annual case fatality rate for SRO residents and non-SRO residents was similar (1.8% vs 1.5%). This approach identified outbreaks in a setting at high risk of COVID-19 and facilitated rapid deployment of resources. The geocoding surveillance approach could be used for other diseases and in any setting for which a list of addresses is available.

Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis.

Steatosis of the liver may arise from a variety of conditions, but the molecular basis for lipid droplet formation is poorly understood. Although a certain amount of lipid storage may even be hepatoprotective, prolonged lipid storage can result in an activation of inflammatory reactions and loss of metabolic competency. Apart from drug-induced steatosis, certain metabolic disorders associated with obesity, insulin resistance, and hyperlipidemia give also rise to nonalcoholic fatty liver diseases (NAFLD). It is noteworthy that advanced stages of nonalcoholic hepatic steatosis and steatohepatitis (NASH) result ultimately in fibrosis and cirrhosis. In this regard, the lipid droplets (LDs) have been discovered to be metabolically highly active structures that play major roles in lipid transport, sorting, and signaling cascades. In particular, LDs maintain a dynamic communication with the endoplasmic reticulum (ER) and the plasma membrane via sphingolipid-enriched domains of the plasma membrane-the lipid rafts. These microdomains frequently harbor receptor tyrosine kinases and other signaling molecules and connect extracellular events with intracellular signaling cascades. Here, we review recent knowledge on the molecular mechanisms of drug and metabolically induced hepatic steatosis and its progression to steatohepatitis (NASH). The contribution of cytokines and other signaling molecules, as well as activity of nuclear receptors, lipids, transcription factors, and endocrine mediators toward cellular dysfunction and progression of steatotic liver disease to NASH is specifically addressed, as is the cross-talk of different cell types in the pathogenesis of NAFLD. Furthermore, we provide an overview of recent therapeutic approaches in NASH therapy and discuss new as well as putative targets for pharmacological interventions.

Development and validation of a sensitive assay for the quantification of imatinib using LC/LC-MS/MS in human whole blood and cell culture.

We developed and validated a semi-automated LC/LC-MS/MS assay for the quantification of imatinib in human whole blood and leukemia cells. After protein precipitation, samples were injected into the HPLC system and trapped onto the enrichment column (flow 5 mL/min); extracts were back-flushed onto the analytical column. Ion transitions [M + H](+) of imatinib (m/z = 494.3 --> 394.3) and its internal standard trazodone (372.5 --> 176.3) were monitored. The range of reliable response was 0.03-75 ng/mL. The inter-day precisions were: 8.4% (0.03 ng/mL), 7.2% (0.1 ng/mL), 6.5% (1 ng/mL), 8.2% (10 ng/mL) and 4.3% (75 ng/mL) with no interference from ion suppression. Autosampler stability was 24 hs and samples were stable over three freeze-thaw cycles. This semi-automated method is simple with only one manual step, uses a commercially available internal standard, and has proven to be robust in larger studies.

Hepatobiliary Events in Migraine Therapy with Herbs-The Case of Petadolex, A Petasites Hybridus Extract.

Petadolex®, a defined butterbur extract has clinically proven efficacy against migraine attacks. However, spontaneous reports indicate cases of herbal induced liver injury (HILI). While most HILI patients presented mild serum biochemistry changes (<3 ULN, dose range 50 to 225 mg/day; treatment duration 4-730 days) nine developed severe HILI (average time-to-onset 103 days, ALT-range 3-153; AST 2-104-fold ULN). HILI cases resolved after medication withdrawal though two patients required liver transplantation. Liver biopsies revealed an inconsistent injury pattern, i.e. necrosis, macrovesicular steatosis, inflammation, cholestasis, and bile duct proliferation. Causality assessment rated 3 cases likely, 13 possible, 8 unlikely and 24 as unclassifiable/unclassified. Note, 22 patients reported hepatotoxic co-medications especially during periods of pain. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At >45 and 90-fold MCD bile duct hyperplasia was observed but could not be confirmed in an explorative minipig study at 218-fold MCD. Human hepatocyte studies at 49-fold Cmax serum petasins (=active ingredient) and therapeutic Ibuprofen, Paracetamol and Naratriptan concentrations evidenced liver transaminase and CYP-monooxygenase changes. Collectively, Petadolex® HILI cases are rare, idiosyncratic and frequently confounded by co-medications. A physician-supervised self-medication plan with herbs and pain relief medication is needed to minimize risk for HILI.

Quality and Content of Patient-Provider Communication About Contraception: Differences by Race/Ethnicity and Socioeconomic Status.

INTRODUCTION: Research in family planning has shown that contraceptive counseling has an influence on women's family planning outcomes, but also that women are often dissatisfied with the counseling they receive. Little is known about how contraceptive counseling is conducted in the United States. We describe both the content and interpersonal quality of provider communication during family planning visits, as well as assess whether disparities in counseling exist by patient race/ethnicity and socioeconomic status. METHODS: We obtained audio recordings of contraceptive counseling clinic visits for 339 women ages 15-45, which were coded for content and quality of communication, and collected surveys regarding demographics, contraceptive preferences, and experience with care. We performed descriptive analyses of the content and quality of provider-patient communication, and conducted multivariate logistic regression to assess for racial/ethnic and socioeconomic differences in care. RESULTS: Providers frequently did not communicate with patients about issues relevant to their family planning needs, including their pregnancy intention (assessed in 51% of visits) and their preferences for birth control (64% of visits). Providers also inconsistently offered patients a chance to ask questions (53% of visits). For most measures, there were no differences by patient race/ethnicity and highest level of parental education achieved. Patients whose parents had a high school education or less were significantly less likely to have long-acting reversible contraceptive methods mentioned during the visit (adjusted odds ratio, 0.42; p = .03). CONCLUSIONS: Several deficiencies in contraceptive counseling were found, suggesting areas for further emphasis in training. Differences by race/ethnicity and socioeconomic states were not marked.

Drug-induced phospholipidosis.

Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies, most likely from an impaired phospholipid metabolism of the lysosome. Organs affected by phospholipidosis exhibit inflammatory reactions and histopathological changes. Despite significant advances in the understanding of drug-altered lipid metabolism, the relationship between impaired phospholipid metabolism and drug-induced toxicity remains enigmatic. Here we review molecular features of inheritable lysosomal storage disorders as a molecular mimicry of drug-induced phospholipidosis for an improved understanding of adverse drug reaction.

Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells.

The therapeutic efficacy of imatinib mesylate (Gleevec) is based on its specific inhibition of the BCR-ABL oncogene protein, a widely expressed tyrosine kinase in chronic myelogenous leukemia (CML) cells. The goal of this study was to evaluate glucose metabolism in BCR-ABL-positive cells that are sensitive to imatinib exposure. Two human BCR-ABL-positive cell lines (CML-T1 and K562) and one BCR-ABL-negative cell line (HC-1) were incubated with different imatinib concentrations for 96 hours. Magnetic resonance spectroscopy on cell acid extracts was performed to evaluate [1-13C]glucose metabolism, energy state, and changes in endogenous metabolites after incubation with imatinib. Imatinib induced a concentration-dependent inhibition of cell proliferation in CML-T1 (IC50, 0.69 +/- 0.06 micromol/L) and K562 cells (IC50, 0.47 +/- 0.04 micromol/L), but not in HC-1 cells. There were no metabolic changes in imatinib-treated HC-1 cells. In BCR-ABL-positive cells, the relevant therapeutic concentrations of imatinib (0.1-1.0 micromol/L) decreased glucose uptake from the media by suppressing glycolytic cell activity (C3-lactate at 0.25 mmol/L, 65% for K562 and 77% for CML-T1 versus control). Additionally, the activity of the mitochondrial Krebs cycle was increased (C4-glutamate at 0.25 micromol/L, 147% for K562 and 170% for CML-T1). The improvement in mitochondrial glucose metabolism resulted in an increased energy state (nucleoside triphosphate/nucleoside diphosphate at 0.25 micromol/L, 130% for K562 and 125% for CML-T1). Apoptosis was observed at higher concentrations. Unlike standard chemotherapeutics, imatinib, without cytocidal activity, reverses the Warburg effect in BCR-ABL-positive cells by switching from glycolysis to mitochondrial glucose metabolism, resulting in decreased glucose uptake and higher energy state.

Medication abortion failure in women with and without previous cesarean delivery.

OBJECTIVE: To investigate the association between previous cesarean delivery and medication abortion failure and the association between parity and failure. METHODS: Data were abstracted from 2035 consecutive charts of women who underwent medication abortion in 2011. All women were at 63 days gestation or less and received mifepristone 200mg orally and misoprostol 800 mcg buccally. We used multivariate logistic regression to assess the relationship between failure, defined as requiring either curettage or additional medication, and prior cesarean delivery. We also examined the relationship between failure and parity. RESULTS: Follow-up was available on 1609 (79%) patients. Overall, 4.5% of patients experienced failure. Neither cesarean delivery nor parity was associated with failure; 6.5% of women with prior cesarean delivery experienced failure, compared to 3.7% of nulliparous women [adjusted odds ratio (aOR), 1.79, 95% confidence interval (CI), 0.83-3.87]. With regard to parity, 4.7% of women with two or more previous births experienced failure, compared to 3.7% of nulliparous women (aOR, 1.07, 95% CI, 0.54-2.14). CONCLUSION: We did not find significant associations between prior cesarean delivery and failure or parity and failure. A previous study of patients who had received a less effective regimen reported significant associations between cesarean delivery and failure and parity and failure. While our results do not rule out the possibility of modest associations due to our limited statistical power, they are reassuring relative to previous findings. IMPLICATIONS: Our results suggest that if there are differences in women's odds of medication abortion failure by obstetric history, such differences are unlikely to be large. Providers and patients may factor this information into decision making about methods of pregnancy termination.

Women's social communication about IUDs: a qualitative analysis.

CONTEXT: Few U.S. women use an IUD, despite the method's efficacy and ease of use. While studies have found that misconceptions about IUDs are prevalent, few have examined the influence of women's social networks on perceptions of the method. METHODS: Twenty-four interviews and three focus groups (comprising 14 participants) were conducted in 2013 with a diverse sample of women aged 15-45 recruited from family planning clinics and the community in San Francisco. Half of participants had used IUDs. Women were asked about their social communication concerning contraceptives, particularly IUDs, and about the content of the information they had received or given. Transcripts were analyzed using a modified grounded theory approach to identify themes of interest. RESULTS: Women reported that communication with female friends and family members was a valued means of obtaining information about contraceptives, and that negative information (which often was incorrect) was more prevalent and memorable than positive information in such communication. Women heard about negative experiences with IUDs from social contacts and television commercials; clinicians were a major source of positive information. Women who had never used IUDs expressed interest in learning about potential side effects and how IUDs feel, while users reported emphasizing to friends and family the method's efficacy and ease of use. CONCLUSIONS: Misinformation and negative information about IUDs are prevalent in social communication, and the information transmitted through social networks differs from the information never-users wish to receive. Findings support the creation of peer-led interventions to encourage IUD users to share positive personal experiences and evidence-based information.

Counseling about IUDs: a mixed-methods analysis.

CONTEXT: IUDs are infrequently used in the United States. Assessing how counseling about this method is delivered can help identify barriers to IUD use that might be overcome by improving services. METHODS: A sample of 342 family planning visits at six clinics in the San Francisco Bay Area in 2009-2012 were audio-recorded, and patients completed surveys both before and after their visits. Descriptive quantitative analyses of counseling were performed, and correlates of IUDs' being mentioned during counseling were investigated using logistic regression. Qualitative analyses investigated the counseling women received about IUDs generally (in a subset of 42 visits), as well as counseling for women who already had an IUD in place (13 visits) or who felt their provider inappropriately expressed a preference for IUDs (five visits). RESULTS: IUDs were mentioned in 75% of visits. Patient-initiated mention of IUDs was more likely in visits by women aged 35 or older than in those by women younger than 20 (odds ratio, 6.4); provider-initiated discussion of this method was less common if the provider was older than 55 than if he or she was younger than 46 (0.3). Providers more often discussed potential adverse effects of IUD use than benefits; counseling often was noninteractive and did not address how patient preferences related to characteristics of IUDs. Counseling was frequently fragmented by the need for return visits or referral elsewhere for insertion. CONCLUSIONS: IUD counseling may be improved by enhancing comprehensiveness and patient-centeredness, and by decreasing fragmentation of care.

Correlation versus causation? Pharmacovigilance of the analgesic flupirtine exemplifies the need for refined spontaneous ADR reporting.

Annually, adverse drug reactions result in more than 2,000,000 hospitalizations and rank among the top 10 causes of death in the United States. Consequently, there is a need to continuously monitor and to improve the safety assessment of marketed drugs. Nonetheless, pharmacovigilance practice frequently lacks causality assessment. Here, we report the case of flupirtine, a centrally acting non-opioid analgesic. We re-evaluated the plausibility and causality of 226 unselected, spontaneously reported hepatobiliary adverse drug reactions according to the adapted Bradford-Hill criteria, CIOMS score and WHO-UMC scales. Thorough re-evaluation showed that only about 20% of the reported cases were probable or likely for flupirtine treatment, suggesting an incidence of flupirtine-related liver injury of 1∶100,000 when estimated prescription data are considered, or 0.8 in 10,000 on the basis of all 226 reported adverse drug reactions. Neither daily or cumulative dose nor duration of treatment correlated with markers of liver injury. In the majority of cases (151/226), an average of 3 co-medications with drugs known for their liver liability was observed that may well be causative for adverse drug reactions, but were reported under a suspected flupirtine ADR. Our study highlights the need to improve the quality and standards of ADR reporting. This should be done with utmost care taking into account contributing factors such as concomitant medications including over-the-counter drugs, the medical history and current health conditions, in order to avoid unjustified flagging and drug warnings that may erroneously cause uncertainty among healthcare professionals and patients, and may eventually lead to unjustified safety signals of useful drugs with a reasonable risk to benefit ratio.

Toxicogenomics applied to cultures of human hepatocytes enabled an identification of novel petasites hybridus extracts for the treatment of migraine with improved hepatobiliary safety.

Butterbur extracts (Petasites hybridus) are recommended for the prevention of migraine, but pharmacovigilance reports may be suggestive of rare hepatobiliary toxicity. To evaluate its hepatotoxic potential, a series of in vivo and in vitro studies were carried out. Essentially, there were no signs of hepatocellular toxicity at estimated therapeutic C(max) levels of 60 ng/ml. Nonetheless, in a 28-day toxicity study at approximately 200-fold of therapeutic doses, induced liver transaminases and bilirubin elevations were observed. In a subsequent 6-month chronic toxicity study, the initial hepatobiliary effects were reproduced, but at the end of the study, liver function recovered and returned to normal as evidenced by clinical chemistry measurements. To identify possible mechanisms of hepatotoxicity, we investigated liver function in vitro at > 170-fold of therapeutic C(max) levels, including cytotoxicity (lactate dehydrogenase, MTT, and ATP), transaminase activities (alanine aminotransferase and aspartate aminotransferase), albumin synthesis, urea and testosterone metabolism to assay for cytochrome P450 monooxygenase activity. Only with extracts rich in petasin (37% petasin) and at high and well above therapeutic doses, liver toxicity was observed. A toxicogenomic approach applied to hepatocyte cultures enabled hypothesis generation and was highly suggestive for extracts high in petasin content to impair bile acid transport and lipid and protein metabolism. Importantly, neither chronic rat in vivo nor rat in vitro studies predicted reliably hepatotoxicity, therefore reemphasizing the utility of human-based in vitro investigations for the development of safe medicinal products. Finally, toxicogenomics enabled the characterization of a novel butterbur extract with no signals for hepatotoxicity.