Developing Public Health Regulations for Marijuana: Lessons From Alcohol and Tobacco

Until November 2012, no modern jurisdiction had removed the prohibition on the commercial production, distribution, and sale of marijuana for nonmedical purposes—not even the Netherlands. Government agencies in Colorado and Washington are now charged with granting production and processing licenses and developing regulations for legal marijuana, and other states and countries may follow. Our goal is not to address whether marijuana legalization is a good or bad idea but, rather, to help policymakers understand the decisions they face and some lessons learned from research on public health approaches to regulating alcohol and tobacco over the past century.Marijuana legalization is no longer an abstract notion. In November 2012, voters in Colorado and Washington passed initiatives that not only made it legal to possess up to an ounce of marijuana for nonmedical purposes but also allow for-profit firms to supply the market. Colorado’s initiative additionally allows home production. Although marijuana remains illegal under federal law, policymakers in these states are now developing regulatory regimes that will allow licensees to produce and sell marijuana and other cannabis products, including infused candies and other edibles, to anyone who is aged 21 years or older. (“Marijuana” is an American term, customarily applied to the dried leaves and flowers of the cannabis plant. There are other cannabis plant products, including resin, which is referred to in the United States as “hashish.” The majority of cannabis consumed in the United States is in the form of marijuana, which is probably why initial state legalization statutes that have passed are specifically about “marijuana” although even these laws do not mean to be restrictive in their terms. For example, Washington speaks of “marijuana-infused” drinks and edibles, and Colorado’s Amendment 64 defines “marijuana” to be all possible products of the plant except industrial hemp.) Bills to legalize marijuana are being introduced in other states, and we will likely see more ballot initiatives in future elections.Although many jurisdictions have experimented with alternatives to strict marijuana prohibition, including decriminalization, medical marijuana, and the Dutch “coffee shops,” no industrialized nation has legalized the cultivation, processing, distribution, and supply of marijuana for recreational purposes in the modern era—not even the Netherlands. In the Netherlands, de facto legalization extends only to retail sales of up to 5 grams; wholesale distribution of marijuana to coffee shops remains illegal and is actively enforced. That is not to say that it has never been legal; in fact, marijuana was a legal commodity in the United States until the early 1900s. But regulatory policy on the cultivation, processing, distribution, and sale of marijuana and its derivative products is unprecedented in the modern era.Because there are no modern examples of marijuana regulation, policymakers are confronting many new questions about how to manage a marijuana market. Should the number of licensees be restricted, and, if so, how should those scarce licenses be allocated? Should vertical integration be allowed, or should there be separate licenses for growing, processing, and selling marijuana? What product safety requirements should be considered (in terms of specific ingredients allowed or disallowed), and who will be responsible for testing the product? How restrictive should licenses be in terms of permitted quantity and potency? Should taxes be assessed per unit weight, as a percentage of value (ad valorem), or on some other basis, such as Δ-9-tetrahydrocannabinol (THC) content? Should marijuana be sold in conventional stores alongside other products or only in specialized venues? What about within-state Internet sales? Although the questions are new for marijuana, policymakers have grappled with similar questions pertaining to alcohol and tobacco, raising the question of what lessons can be learned from these 2 substances and applied to marijuana policy.We have summarized insights and ideas that grew out of a meeting of alcohol, tobacco, and illicit drug policy experts hosted by the RAND Drug Policy Research Center on February 11, 2013, to foster discussions about how one might regulate marijuana to promote public health objectives assuming a decision to legalize has already been made. The arguments here do not necessarily reflect the opinions of every coauthor but, instead, reflect a general consensus of ideas that grew out of those discussions. The conference was filmed by C-SPAN.1     

Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk

Cancer driver mutations (CDMs) are necessary and causal for carcinogenesis and have advantages as reporters of carcinogenic risk. However, little progress has been made toward developing measurements of CDMs as biomarkers for use in cancer risk assessment. Impediments for using a CDM-based metric to inform cancer risk include the complexity and stochastic nature of carcinogenesis, technical difficulty in quantifying low-frequency CDMs, and lack of established relationships between cancer driver mutant fractions and tumor incidence. Through literature review and database analyses, this review identifies the most promising targets to investigate as biomarkers of cancer risk. Mutational hotspots were discerned within the 20 most mutated genes across the 10 deadliest cancers. Forty genes were identified that encompass 108 mutational hotspot codons overrepresented in the COSMIC database; 424 different mutations within these hotspot codons account for approximately 63,000 tumors and their prevalence across tumor types is described. The review summarizes literature on the prevalence of CDMs in normal tissues and suggests such mutations are direct and indirect substrates for chemical carcinogenesis, which occurs in a spatially stochastic manner. Evidence that hotspot CDMs (hCDMs) frequently occur as tumor subpopulations is presented, indicating COSMIC data may underestimate mutation prevalence. Analyses of online databases show that genes containing hCDMs are enriched in functions related to intercellular communication. In its totality, the review provides a roadmap for the development of tissue-specific, CDM-based biomarkers of carcinogenic potential, comprised of batteries of hCDMs and can be measured by error-correct next-generation sequencing. Environ. Mol. Mutagen. 61:152–175, 2020. Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.     

Development of a realistic in vivo bone metastasis model of human renal cell carcinoma

About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastases. The incidence of RCC is increasing and bone metastatic RCC merits greater focus. Realistic preclinical bone metastasis models of RCC are lacking, hampering the development of effective therapies. We developed a realistic in vivo bone metastasis model of human RCC by implanting precision-cut tissue slices under the renal capsule of immunodeficient mice. The presence of disseminated cells in bone marrow of tissue slice graft (TSG)-bearing mice was screened by human-specific polymerase chain reaction and confirmed by immunohistology using human-specific antibody. Disseminated tumor cells in bone marrow of TSG-bearing mice derived from three of seven RCC patients were detected as early as 1 month after tissue implantation at a high frequency with close resemblance to parent tumors (e.g., CAIX expression and high vascularity). The metastatic patterns of TSGs correlated with disease progression in patients. In addition, TSGs retained capacity to metastasize to bone at high frequency after serial passaging and cryopreservation. Moreover, bone metastases in mice responded to Temsirolimus treatment. Intratibial injections of single cells generated from TSGs showed 100 % engraftment and produced X-ray-visible tumors as early as 3 weeks after cancer cell inoculation. Micro-computed tomography (μCT) and histological analysis revealed osteolytic characteristics of these lesions. Our results demonstrated that orthotopic RCC TSGs have potential to develop bone metastases that respond to standard therapy. This first reported primary RCC bone metastasis model provides a realistic setting to test therapeutics to prevent or treat bone metastases in RCC.     

The Role of Glutathione in Intestinal Dysfunction

Glutathione plays an important cytoprotective role in the gut. Animal studies have demonstrated that the provision of glutathione precursors are protective for different types of free-radical-mediated cellular injury. There is a need to clarify the potential role of glutathione supplementation in ischemia–reperfusion injury and inflammatory bowel disease. More speculative is whether dietary treatment with glutathione precursors can modify the progress of colorectal cancer.     

Transient neutropenia increases macrophage accumulation and cell proliferation but does not improve repair following intratendinous rupture of Achilles tendon

Neutrophils are the first leukocytes to invade tendons after an acute injury. They could modulate both the inflammatory response and early repair processes through the release of reactive species, cytokines, growth factors, and proteinases. However, the exact role of these cells in damaged tendons remains unclear. We investigated their role by inducing a transient neutropenia in C57BL/6 male mice using an anti‐Ly6C/Ly6G antibody. Placebo mice received only serum. The right Achilles tendon was sectioned and sutured using the 8‐strand technique, which allowed immediate weight bearing. A significant increase in macrophage accumulation and cell proliferation was observed in tendons from neutropenic animals compared to the placebo group at days 3 and/or 7 postinjury. However, there was a reduction in cell proliferation in a group of mice depleted in macrophages, indicating that macrophages play a role in cell replication in injured tendons. Lastly, the tendons of neutropenic and placebo mice had similar collagen content and mechanical properties at days 7, 14, and/or 28 postinjury. Our findings demonstrate that neutropenia modulates macrophage accumulation and cell proliferation, but overall, a reduction in neutrophil number has no significant effect on tendon repair. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1084–1091, 2010     

Using stated preference discrete choice modelling to evaluate the introduction of varicella vaccination

Applications of stated preference discrete choice modelling (SPDCM) in health economics have been used to estimate consumer willingness to pay and to broaden the range of consequences considered in economic evaluation. This paper demonstrates how SPDCM can be used to predict participation rates, using the case of varicella (chickenpox) vaccination. Varicella vaccination may be cost effective compared to other public health programs, but this conclusion is sensitive to the proportion of the target population immunised. A choice experiment was conducted on a sample of Australian parents to predict uptake across a range of hypothetical programs. Immunisation rates would be increased by providing immunisation at no cost, by requiring it for school entry, by increasing immunisation rates in the community and decreasing the incidence of mild and severe side effects. There were two significant interactions; price modified the effect of both support from authorities and severe side effects. Country of birth was the only significant demographic characteristic. Depending on aspects of the immunisation program, the immunisation rates of children with Australian-born parents varied from 9% to 99% while for the children with parents born outside Australia they varied from 40% to 99%. This demonstrates how SPDCM can be used to understand the levels of attributes that will induce a change in the decision to immunise, the modification of the effect of one attribute by another, and subgroups in the population. Such insights can contribute to the optimal design and targeting of health programs.     

Neurofibroma and schwannoma

PURPOSE OF REVIEW: Neurofibromas and schwannomas are benign peripheral nerve sheath tumours that occur as isolated sporadic lesions, but have their major clinical impact on the neurocutaneous diseases neurofibromatosis 1 and neurofibromatosis 2. The gene products neurofibromin and merlin (schwannomin), respectively, are thought to act as tumour suppressors. The aim of this review is to document recent advances in our understanding of the clinical characteristics and pathogenesis of neurofibromas and schwannomas in the neurofibromatoses. RECENT FINDINGS: Animal models have shed light on the pathogenesis of neurofibromas confirming that the Schwann cell initiates neurofibroma formation. New data suggest that individuals with neurofibromatosis 1 have a 10% lifetime risk of developing malignant peripheral nerve sheath tumours. Positron emission tomography with the glucose analogue 18-fluorodeoxyglucose might be helpful in the diagnosis of malignant peripheral nerve sheath tumours. Such tumours associated with neurofibromatosis 1 show a loss of neurofibromatosis 1 expression and high levels of Ras, but malignant transformation requires additional genetic events that inactivate key cell cycle regulators. Neurofibromatosis 2-associated vestibular schwannomas have variable growth rates that tend to decline with age. Early microsurgery for small tumours results in optimal preservation of hearing and facial nerve function. Currently, radiosurgery for these lesions produces similar results. Systematic follow-up of both groups will determine the best treatment method. Merlin's function as a tumour suppressor has not been elucidated. The control of cell cycle progression and abnormal intracellular and extracellular signalling could all play a part. SUMMARY: Molecular advances will allow a biological approach to targeted therapies for neurofibromas, malignant peripheral nerve sheath tumours and schwannomas. Knowledge of the pathogenesis of these tumours will have implications for our understanding of the neurofibromatoses and of the formation of sporadic tumours.     

Very early-onset familial Alzheimer's disease: a novel presenilin 1 mutation

BACKGROUND: Early-onset familial Alzheimer's disease (EOFAD) is linked to mutations in three autosomal dominant genes: PS1, PS2 and APP. The clinical presentation and age of onset of mutations is variable. OBJECTIVES: The aim of this report is to describe a novel PS1 mutation believed to be causal for a very early onset of AD. METHODS: This is a case history using information from medical records, relative interviews and genetic testing results to describe the pre-clinical prodrome and clinical course of a patient with EOFAD. RESULTS: A previously undescribed G206V mutation in PS1 was found in the proband. CONCLUSION: The G206V mutation in PS1 is probably causal of a case of EOFAD with significant premorbid features.