Altered brain activation during visuomotor integration in chronic active cannabis users: relationship to cortisol levels.

Cannabis is the most abused illegal substance in the United States. Alterations in brain function and motor behavior have been reported in chronic cannabis users, but the results have been variable. The current study aimed to determine whether chronic active cannabis use in humans may alter psychomotor function, brain activation, and hypothalamic-pituitary-axis (HPA) function in men and women. Thirty cannabis users (16 men, 14 women, 18-45 years old) and 30 nondrug user controls (16 men, 14 women, 19-44 years old) were evaluated with neuropsychological tests designed to assess motor behavior and with fMRI using a 3 Tesla scanner during a visually paced finger-sequencing task, cued by a flashing checkerboard (at 2 or 4 Hz). Salivary cortisol was measured to assess HPA function. Male, but not female, cannabis users had significantly slower performance on psychomotor speed tests. As a group, cannabis users had greater activation in BA 6 than controls, while controls had greater activation in the visual area BA 17 than cannabis users. Cannabis users also had higher salivary cortisol levels than controls (p = 0.002). Chronic active cannabis use is associated with slower and less efficient psychomotor function, especially in male users, as indicated by a shift from regions involved with automated visually guided responses to more executive or attentional control areas. The greater but altered brain activities may be mediated by the higher cortisol levels in the cannabis users, which in turn may lead to less efficient visual-motor function.

Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN α-2a/RBV in hepatitis C patients.

BACKGROUND & AIMS: Danoprevir (RG7227; ITMN-191) is a potent inhibitor of the HCV NS3/4A serine protease. The aims of this double-blind, placebo-controlled, multiple-ascending dose phase Ib study were to evaluate safety, tolerability, antiviral activity, resistance, and pharmacokinetics of once- and twice-daily danoprevir in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD)/ribavirin in treatment-naive HCV genotype 1 patients. METHODS: Thirty eligible patients were enrolled into three cohorts and treated with danoprevir/r or placebo/r all in combination with peginterferon alfa-2a (40KD)/ribavirin for 15 days. Cohort 1 received danoprevir/r at 100/100mg twice daily; Cohort 2 200/100mg once daily; and Cohort 3 200/100mg twice daily. RESULTS: The median reductions in HCV RNA from baseline after 14 days of treatment (day 15) were -5.1, -4.8, and -4.6 log(10)IU/ml in Cohorts 1, 2, and 3, respectively, and -2.7 log(10) in placebo/r and peginterferon alfa-2a (40KD)/ribavirin recipients. Viral breakthrough was not observed in any patient. On day 15, HCV RNA was undetectable (<15IU/ml) in 6/9 (67%), 4/8 (50%), and 8/8 (100%) patients in Cohorts 1, 2, and 3, respectively. When co-administered with low dose ritonavir, danoprevir concentrations reached a steady state between 6 to 10 days of dosing. Danoprevir exposures increased more than dose proportionally between 100/100mg and 200/100mg. Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin was well-tolerated with no safety-related discontinuations. CONCLUSIONS: Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin provides profound and robust reductions in serum HCV RNA, at substantially lower systemic exposures compared to those observed with higher doses of danoprevir in the absence of ritonavir. These results support further studies of danoprevir/r.

Bisphosphonate-related osteonecrosis of the jaw presenting as a cutaneous dental sinus tract: a case report and review of the literature.

Bisphosphonates are endogenous pyrophosphate analogs that work to inhibit osteoclast activity. They are commonly used in the treatment of patients with bone related diseases, such as solid tumor metastasis and osteoporosis. One of the infrequent but not rare side effects, especially with high doses of bisphosphonates, is osteonecrosis of the jaw. Although predominantly recognized by dentists because of the bony and intraoral manifestations of the disease, it may also present on the skin. We present a case of osteonecrosis of the jaw resembling two flesh-colored papules associated with dental sinus tracts to highlight the clinical manifestations that dermatologists may encounter, and review the literature on this rare but morbid condition.

The Natural History, Pathobiology, and Clinical Manifestations of SARS-CoV-2 Infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2, is a positive-sense single-stranded RNA virus with epithelial cell and respiratory system proclivity. Like its predecessor, SARS-CoV, COVID-19 can lead to life-threatening disease. Due to wide geographic impact affecting an extremely high proportion of the world population it was defined by the World Health Organization as a global public health pandemic. The infection is known to readily spread from person-to-person. This occurs through liquid droplets by cough, sneeze, hand-to-mouth-to-eye contact and through contaminated hard surfaces. Close human proximity accelerates SARS-CoV-2 spread. COVID-19 is a systemic disease that can move beyond the lungs by blood-based dissemination to affect multiple organs. These organs include the kidney, liver, muscles, nervous system, and spleen. The primary cause of SARS-CoV-2 mortality is acute respiratory distress syndrome initiated by epithelial infection and alveolar macrophage activation in the lungs. The early cell-based portal for viral entry is through the angiotensin-converting enzyme 2 receptor. Viral origins are zoonotic with genomic linkages to the bat coronaviruses but without an identifiable intermediate animal reservoir. There are currently few therapeutic options, and while many are being tested, although none are effective in curtailing the death rates. There is no available vaccine yet. Intense global efforts have targeted research into a better understanding of the epidemiology, molecular biology, pharmacology, and pathobiology of SARS-CoV-2. These fields of study will provide the insights directed to curtailing this disease outbreak with intense international impact. Graphical Abstract.

Psychiatric Symptoms, Salivary Cortisol and Cytokine Levels in Young Marijuana Users.

Psychological maturation continues into young adulthood when substance abuse and several psychiatric disorders often emerge. Marijuana is the most common illicit drug abused by youths, typically preceding other illicit substances. We aimed to evaluate the complex and poorly studied relationships between marijuana use, psychiatric symptoms, and cortisol levels in young marijuana users. Psychiatric symptoms and salivary cortisol were measured in 122 youths (13-23 years old) with and without marijuana use. Psychiatric symptoms were evaluated using the Symptom-Checklist-90-R and Brief Psychiatric Rating Scale. Mid-day salivary cortisol levels were measured. Additionally, salivary cytokine levels were measured in a subset of participants. Although the cortisol levels and salivary cytokine levels were similar, the young marijuana users had more self-reported and clinician rated psychiatric symptoms than controls, especially anxiety-associated symptoms. Moreover, marijuana users with earlier age of first use had more symptoms, while those with longer abstinence had fewer symptoms. Greater cumulative lifetime marijuana use was also associated with greater psychiatric symptoms. The discordant anxiety (feeling stressed or anxious despite normal cortisol) in the marijuana users, as well as symptom exacerbations with early and continued marijuana use in young marijuana users suggest that marijuana use may contribute to an aberrant relationship between stress response and psychiatric symptoms. The greater symptomatology, especially in those with earlier initiation and greater marijuana usage, emphasize the need to intervene for substance use and perceived anxiety in this population.