Mucosal CCL28 Chemokine Improves Protection against Genital Herpes through Mobilization of Antiviral Effector Memory CCR10+CD44+ CD62L-CD8+ T Cells and Memory CCR10+B220+CD27+ B Cells into the Infected Vaginal Mucosa.

Four major mucosal-associated chemokines, CCL25, CCL28, CXCL14, and CXCL17, play an important role in protecting mucosal surfaces from infectious pathogens. However, their role in protection against genital herpes remains to be fully explored. The CCL28 is a chemoattractant for the CCR10 receptor-expressing immune cells and is produced homeostatically in the human vaginal mucosa (VM). In this study, we investigated the role of the CCL28/CCR10 chemokine axis in mobilizing protective antiviral B and T cell subsets into the VM site of herpes infection. We report a significant increase in the frequencies of HSV-specific memory CCR10+CD44+CD8+ T cells, expressing high levels of CCR10, in herpes-infected asymptomatic (ASYMP) women compared with symptomatic women. Similarly, a significant increase in the CCL28 chemokine (a ligand of CCR10), was detected in the VM of herpes-infected ASYMP C57BL/6 mice, associated with the mobilization of high frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and memory CCR10+B220+CD27+ B cells in the VM of HSV-infected ASYMP mice. Inversely, compared with wild-type C57BL/6 mice, the CCL28 knockout (CCL28-/-) mice (1) appeared to be more susceptible to intravaginal infection and reinfection with HSV type 2, and (2) exhibited a significant decrease in the frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and of memory CD27+B220+ B cells in the infected VM. These findings suggest a critical role of the CCL28/CCR10 chemokine axis in the mobilization of antiviral memory B and T cells within the VM to protect against genital herpes infection and disease.

A multi-epitope/CXCL11 prime/pull coronavirus mucosal vaccine boosts the frequency and the function of lung-resident memory CD4+ and CD8+ T cells and enhanced protection against COVID-19-like symptoms and death caused by SARS-CoV-2 infection.

IMPORTANCE: Although the current rate of SARS-CoV-2 infections has decreased significantly, COVID-19 still ranks very high as a cause of death worldwide. As of October 2023, the weekly mortality rate is still at 600 deaths in the United States alone, which surpasses even the worst mortality rates recorded for influenza. Thus, the long-term outlook of COVID-19 is still a serious concern outlining the need for the next-generation vaccine. This study found that a prime/pull coronavirus vaccine strategy increased the frequency of functional SARS-CoV-2-specific CD4+ and CD8+ memory T cells in the lungs of SARS-CoV-2-infected triple transgenic HLA-DR*0101/HLA-A*0201/hACE2 mouse model, thereby resulting in low viral titer and reduced COVID-19-like symptoms.

Clinical Features Associated with Survival Outcome in African-American Patients with Hepatocellular Carcinoma.

BACKGROUND: African-Americans (AA) have a higher incidence of hepatocellular carcinoma (HCC) and lower survival. We characterized survival rates and clinical features associated with survival in AA vs. Caucasians with HCC over the past two decades. METHODS: HCC patients from three US medical centers were matched by year of diagnosis (1991-2016): AA (n = 578)/Caucasian (n = 578) and placed in one of two groups-HCC diagnosed prior to 2010 or 2010 and after. Data were obtained from chart review and the National Death Index. Multivariate and survival analysis controlling for key predictors were conducted. RESULTS: Prior to 2010, there was no difference in survival between Caucasians and AA (p = 0.61). After 2010, AA patients had poorer survival compared to Caucasians (35% vs. 44%, respectively, p = 0.044). Over time, survival improved for Caucasians (32% before 2010 vs. 44% after 2010, p = 0.003), but not AA (36% vs. 35%, p = 0.50). AA on presentation (in the after 2010 cohort) were more likely to have BCLC (Barcelona Clinic Liver Cancer) stage C (24% vs. 15%, p = 0.010) and less likely to receive treatment (85% vs. 93%, p = 0.002) compared to matched Caucasians. BCLC beyond stage A (aHR: 1.75, 95% CI: 1.26-2.43, p = 0.001) and child's class C (aHR 2.05, 95% CI: 1.23-3.41, p = 0.006) were the strongest predictors of mortality, while race was not. CONCLUSIONS: African-Americans presented with more advanced HCC and had poorer survival compared to Caucasians after 2010. Tumor stage was an independent predictor of mortality, but ethnicity was not. Further efforts are needed to improve early HCC diagnosis for AA.

Antiviral therapy and the development of osteopenia/osteoporosis among Asians with chronic hepatitis B.

BACKGROUND: Recent studies have suggested a potential increase in the incidence of osteoporosis for patients receiving tenofovir disoproxil fumarate (TDF), but this issue remains controversial. METHODS: The retrospective cohort study of 1224 Asian chronic hepatitis B (CHB) patients greater than 18 years without baseline osteopenia/osteoporosis seen at four US centers from 2008 to 2016. Patients were categorized into three groups-treatment-naive patients who initiated therapy with TDF (1) or entecavir (ETV) (2), or untreated patients (3). Patients were followed until the development of osteopenia/osteoporosis or end of the study. RESULTS: Of the 1224 study patients, 276 were treated with TDF, 335 with ETV, and 613 were untreated. The prevalence of cirrhosis was lower for untreated patients (2.6% vs 16.3% for TDF and 17.6% for ETV; P < 0.001). The 8-year cumulative incidence rate of osteopenia/osteoporosis was 13.17% for TDF, 15.09% for ETV, and 10.17% for untreated patients, with no statistically significant difference among the three groups ( P = 0.218). On multivariate Cox regression controlling for demographics, osteoporosis risk factors, albumin, and hepatitis B virus (HBV) DNA levels, neither TDF (adjusted hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.34 and 1.59) nor ETV (adjusted HR = 0.98; 95% CI: 0.51 and 1.90) were associated with increased osteopenia/osteoporosis risk compared with untreated patients. CONCLUSIONS: Our retrospective study suggests that there is no significant increase in the incidence of osteopenia/osteoporosis for patients with CHB treated with TDF or ETV during a median follow-up of about 4 to 5 years. However, further study with longer follow-up is needed as an anti-HBV therapy, which is often lifelong or long-term and the development of osteopenia/osteoporosis can be a slow process.

Rising Inpatient Encounters and Economic Burden for Patients with Nonalcoholic Fatty Liver Disease in the USA.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the fastest-growing chronic liver disease. However, little is known about NAFLD inpatient resource utilization and clinical outcomes. AIMS: The aim of this study was to quantify inpatient NAFLD encounters using patient-level data over time. METHODS: This was a retrospective analysis of de-identified data for NAFLD patients from the California Patient Discharge Database from 2006 to 2013. NAFLD patients were identified by ICD9 codes 571.40, 571.41, 571.49, 571.8, and 571.9. RESULTS: NAFLD patients (n = 91,558) were predominantly female (60%), 45-65 years old (44%), and white (53%). Inpatient encounters increased from 8153 in 2006 to 16,457 in 2013 and were associated with a 207% increase in charges ($686 million in 2006 to $1.42 billion in 2013) and average increase in charges of 9.8% per year adjusting for inflation. Comorbidities (obesity, diabetes, hyperlipidemia, cardiovascular disease, other cancer, and renal disease) increased significantly over time (all P < 0.05). From 2006 to 2011, there were 11,463 deaths (1849 for liver-related hospitalizations) (mean follow-up 4.00 ± 2.13 years). The most significant predictors of death were age > 75 (aHR 3.9, P < 0.0001), male gender (aHR 1.10, P < 0.0001), white race (aHR 1.2, P < 0.0001), decompensated cirrhosis (aHR 2.1, P < 0.0001), and cancer other than HCC (aHR 3.2, P < 0.0001). Within the liver-related hospitalization cohort, mortality predictors were similar, except for Hispanic race (aHR 0.92, P < 0.0096) and renal disease (aHR 1.50, P < 0.0001). CONCLUSIONS: The number of NAFLD inpatient encounters increased significantly from 2006 to 2013, as did the inflation-adjusted inpatient charges. The most significant predictors of death were non-liver cancers (HR 3.11, P < 0.0001, CI 3.06-3.16) and age > 75 years (HR 3.94, P < 0.0001, HR 3.86-4.03).

Temporal trends in disease presentation and survival of patients with hepatocellular carcinoma: A real-world experience from 1998 to 2015.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the few cancers whose incidence continues to increase. The goal of the current study was to investigate the presentation and survival trends of patients with HCC presenting to a university hospital between 1998 and 2015. METHODS: Study data were ascertained by individual chart review with survival data also supplemented by National Death Index query up to December 31, 2015. Patients were divided into three 6-year groups by diagnosis date (1998-2003, 2004-2009, and 2010-2015). RESULTS: A total of 2106 consecutive patients with HCC were included. The majority of patients had either hepatitis C (56.7%) or hepatitis B (22.1%), but cases of nonalcoholic steatohepatitis HCC increased by 68% over the most recent time period. Screening/surveillance identified 61% of HCC cases, but only 31% of these patients underwent curative treatment, which did not increase significantly over time. The overall median survival was 29.8 months (2.48 years) and without improvement over time. On multivariable analysis, Asian or Hispanic ethnicity, meeting Milan criteria, and receiving any of the standard HCC treatments were found to be significantly associated with improved survival, but diagnosis time period and liver disease etiology were not. CONCLUSIONS: Over the last 18 years, the percentage of cases of nonalcoholic steatohepatitis HCC has increased but not overall survival. It is interesting to note that only 31% of patients with HCC identified via screening/surveillance received any curative treatment. Further research is needed to better understand the barriers to curative care for patients with HCC and the causes of the lack of improvement in survival in the more recent patient cohort. Cancer 2018;124:2588-98. © 2018 American Cancer Society.

More advanced disease and worse survival in cryptogenic compared to viral hepatocellular carcinoma.

BACKGROUND & AIMS: Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain major risk factors for hepatocellular carcinoma (HCC), non-viral causes of HCC, particularly non-alcoholic fatty liver disease (NAFLD), are becoming increasingly prevalent. The aim of this study was to compare the clinical characteristics and survival of cryptogenic and viral HCC. METHODS: We conducted a retrospective cohort study involving 3878 consecutive HCC patients seen at two tertiary centres in the United States and one in Taiwan from 2004 to 2014. We compared the clinical characteristics, treatment and survival of patients by underlying aetiology: cryptogenic (n = 696), HBV (n = 1304) or HCV (n = 1878). RESULTS: Cirrhosis was present in 66.8% of the cryptogenic HCC patients, compared with 74.7% of HBV-related HCC (HBV-HCC) (P = .001) and 85.9% of HCV-HCC (P < .001). Compared to viral HCC, cryptogenic HCC patients presented with larger tumours and at later stages of disease. Five-year overall survival was 16.3% among cryptogenic HCC patients compared with 31.9% among HBV-HCC patients and 27.7% among HCV-HCC patients (P < .001 for both by the log-rank test). HCC aetiology was not an independent predictor of survival, though ethnicity, cirrhosis status, meeting Milan criteria and treatment allocation were. CONCLUSIONS: Compared with viral HCC patients, those with cryptogenic HCC had lower prevalence of cirrhosis, were diagnosed with larger tumours at more advanced stages of disease, and had poorer overall survival. Additional efforts are needed to identify patients at risk of cryptogenic HCC and to identify cryptogenic HCC at earlier stages of disease.

Ductal carcinoma in situ on core needle biopsy only with no residual disease at surgery.

BACKGROUND: The treatment of ductal carcinoma in situ (DCIS) remains controversial and may be particularly difficult for patients with minimal disease. There is a dearth of information regarding patients who have been diagnosed with DCIS on core needle biopsy (CNB), who have no residual disease in the lumpectomy specimen. The purpose of this study was to explore the frequency of this presentation and short-term outcomes in these patients. METHODS: Our institutional Breast Cancer Database was queried for all women who were diagnosed with pure DCIS from 2010 to 2016 and treated with lumpectomy. Variables included patient and tumor characteristics, adjuvant treatment, and ipsilateral breast tumor recurrence (IBTR). Statistical analyses included Pearson's chi-square, Fisher's exact tests, and Kaplan-Meier analysis. RESULTS: Of 547 patients with pure DCIS, 50 (14%) had DCIS on CNB only. Of the patients with DCIS on CNB only, 15 were treated with lumpectomy and radiation therapy (RT), while 35 underwent lumpectomy without RT. At a median follow-up of 4 years, there were 3 (6%) IBTR all within the same quadrant as the original lumpectomy site. None of the patients who recurred received adjuvant RT or hormonal therapy. CONCLUSIONS: Despite the minimal extent of disease exhibited in these cases, 6% of patients with DCIS on CNB only had IBTR at a median follow-up of 4 years. These data suggest that even minimal DCIS represents a significant risk of recurrence to the patient. Size and margins are not sufficient criteria to stratify risk and guide decisions for adjuvant therapies.

Open Label Study of 8 vs. 12 Weeks of Ledipasvir/Sofosbuvir in Genotype 6 Treatment Naïve or Experienced Patients.

OBJECTIVES: Hepatitis C genotype 6 (HCV-GT6) is one of the most prevalent genotypes in Southeast Asia. Ledipasvir and sofosbuvir fixed-dose combination (LDV/SOF FDC) for 12 weeks has been shown to be effective for multiple HCV genotypes including treatment-naïve HCV-6. Our goal was to examine treatment outcomes in a diverse HCV-6 population. METHODS: We prospectively enrolled 60 HCV-GT6 patients at four US centers. Treatment -naïve without cirrhosis patients received open-labeled LDV/SOF FDC orally once a day for 8 weeks; All cirrhotic and/or treatment-experienced patients received LDV/SOF FDC for 12 weeks. The primary outcome was sustained virological response 12 weeks after therapy (SVR12). Secondary outcomes were adverse events (AEs) and/or serious adverse events (SAEs). All patients gave written consent. RESULTS: Overall mean age was 58±10 and 58% were male. All patients were Asian and foreign born. The 8-week group included 20 patients (33.3%) and the 12-week included 40 patients (66.7%). There were 2 (5%) patients with decompensation, 3 with liver cancer (7.5%), and 14 with prior treatment (35%) in the 12-week group. SVR12 was 95.0% for the 8-week group (19/20) and 95.0% for the 12-week group (38/40). AEs included fatigue (5%), insomnia (3.3%), headache (1.7%), and nausea (1.7%); however, all patients completed the intended treatment duration. There were two treatment-unrelated SAEs. CONCLUSIONS: LDV/SOF FDC for 8 or 12 weeks was safe and effective for patients without cirrhosis or prior treatment failure as well as for patients with cirrhosis and/or prior treatment failure, respectively.

Increased Prevalence of Metabolic Risk Factors in Asian Americans With Hepatocellular Carcinoma.

BACKGROUND: We used metabolic risk factors to estimate the prevalence and clinical significance of nonalcoholic fatty liver disease in Asian Americans with hepatocellular carcinoma (HCC). METHODS: This is a retrospective cohort study of 824 consecutive Asian HCC patients at Stanford University Medical Center from 1998 to 2015. Patients were subdivided as: Chinese, other East Asian (Japanese and Korean), South East Asian (Vietnamese, Thai, and Laotian), Maritime South East Asian (MSEA: Malaysian, Indonesian, Filipino, and Singaporean), and South West Asian (Indian, Pakistani, and Middle Eastern). Metabolic risk factors studied were body mass index, hypertension, type II diabetes, and hyperlipidemia. RESULTS: Most patients were male (76%) with mean age 63 years. Metabolic risk factors were highly prevalent on presentation and increased over time (P<0.001), as did the prevalence of cryptogenic HCC (P<0.004). Compared with other Asian subgroups, MSEAs had the highest body mass index (26.3) and higher rates of type II diabetes (44% vs. 23% to 35%, P=0.004), hypertension (59% vs. 38% to 55%, P=0.04), and cryptogenic HCC (15% vs. 4% to 10%, P=0.01). They were more likely to be symptomatic on presentation (44% vs. 32% to 58%, P=0.07), less likely to present within Milan criteria (34% vs. 35% to 63%, P<0.0001), and trended toward decreased 10-year survival rates compared with other ethnic subgroups (9% vs. 25% to 32%, P=0.07). CONCLUSIONS: Metabolic risk factors were increasingly prevalent among Asian Americans with HCC. MSEAs, who had the highest incidence of these risk factors, had more advanced tumor stage and trended toward worse survival.

Effects of Cirrhosis on Short-term and Long-term Survival of Patients With Hepatitis B-related Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatitis B virus (HBV) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Unlike other liver diseases, HBV can cause HCC in the absence of cirrhosis. We investigated whether features of HCC in patients with HBV infection without cirrhosis and survival times differ from those of patients who develop HCC after cirrhosis. METHODS: We performed a retrospective cohort study of 487 consecutive cases of HBV-related HCC who were seen from 2000 through 2014 at a tertiary care center. Laboratory values, imaging results, and treatment information were obtained from subjects' medical records. Symptoms of HCC included weight loss, abdominal pain, or new hepatic decompensation. The primary outcome was overall survival, which was categorized as short-term survival (up to 3 years after the diagnosis of HCC) or long-term survival (3-10 years after diagnosis). RESULTS: The mean tumor size at diagnosis was significantly larger in patients without cirrhosis (6.4 ± 4.3 cm) than in patients with cirrhosis (5.0 ± 3.8 cm) (P = .0009). A significantly larger proportion of patients without cirrhosis had symptoms at diagnosis (43.8% vs 35.4% in patients without cirrhosis, P = .09). A significantly higher proportion of patients without cirrhosis survived for the long-term (P = .003), but there was no significant difference between groups in short-term survival (P = .37). Notably, the same proportions of asymptomatic patients with and without cirrhosis survived for the short-term (64.3% vs 64.2%, P = .73), but a lower proportion of asymptomatic patients with cirrhosis survived for the long-term (P = .015). In multivariate Cox regression analysis, cirrhosis was an independent predictor of death in 3-10 years (hazard ratio, 3.76; P = .003) but not in less than 3 years (P = .48). Symptoms at diagnosis predicted death within 3 years (hazard ratio, 1.76; P =.006) but not in 3-10 years (P = .15). CONCLUSIONS: Patients with HBV infection and HCC without cirrhosis present with larger tumors, and a larger percentage have symptoms of cancer than patients with cirrhosis. This may indicate that HCC surveillance is less than optimal for patients with HBV infection without cirrhosis. Despite this suboptimal surveillance, patients without cirrhosis have higher long-term survival than those with cirrhosis, especially when asymptomatic at diagnosis.

Functionalizing the γ-Position of α-Diazo-ß-ketoesters.

Although α-diazo-ß-ketoesters are synthetically versatile intermediates, methodology for introducing this functionality into complex molecules is still limited, most frequently involving a carboxylic acid precursor, which is then activated and transformed into a ß-ketoester, with the diazo group being subsequently added with a diazo transfer reagent. While introducing this highly functional moiety in a convergent one step process would be ideal, such an objective is limited by the relatively few studies which address functionalization of the α-diazo-ß-ketoester at the γ-position. In the present investigation, we evaluate strategies, both new and established, for functionalizing α-diazo-ß-ketoesters, particularly with regard to generating compounds prospectively useful in the synthesis of C1-substituted carbapenems. We report the first δ-aldehydo-α-diazo-ß-ketoester as well as a method for its oxidation to the corresponding methyl ester, and the formation of a new substituted pyrazole under basic conditions.

Triethysilyl Enol Ethers in the Synthesis of Carbapenem Precursors.

A diastereoselective process for the formation of intermediates suitable for the preparation of C1 substituted carbapenems was developed. The process is readily scalable and does not involve organometallics or strong bases such as LDA.

Effects of Parental Status on Male Body Mass in the Monogamous, Biparental California Mouse.

Studies of biparental mammals demonstrate that males may undergo systematic changes in body mass as a consequence of changes in reproductive status; however, these studies typically have not teased apart effects of specific social and reproductive factors, such as cohabitation with a female per se, cohabitation with a breeding female specifically, and engagement in paternal care. We aimed to determine whether California mouse (Peromyscus californicus) fathers undergo systematic changes in body mass and if so, which specific social/reproductive factor(s) might contribute to these changes. We compared mean weekly body masses over a 5-week period in 1) males housed with another male vs. males housed with a non-reproductive (tubally ligated) female; 2) males housed with a tubally ligated female vs. males housed with a female that was undergoing her first pregnancy; and 3) experienced fathers housed with vs. without pups during their mate's subsequent pregnancy. Body mass did not differ between males housed with another male and those housed with a non-reproductive female; however, males housed with a non-reproductive female were significantly heavier than those housed with a primiparous female. Among experienced fathers, those housed with pups from their previous litter underwent significant increases in body mass across their mates' pregnancy, whereas fathers housed without pups did not. These results suggest that male body mass is reduced by cohabitation with a breeding (pregnant) female, but not by cohabitation with a non-reproductive female, and that increases in body mass across the mate's pregnancy are associated with concurrent care of offspring rather than cohabitation with a pregnant female. Additional work is needed to determine the mechanisms and functional significance, if any, of these changes in male body mass with reproductive condition.

Graft conditioning with fluticasone propionate reduces graft-versus-host disease upon allogeneic hematopoietic cell transplantation in mice.

Hematopoietic cell transplantation (HCT) treats many blood conditions but remains underused due to complications such as graft-versus-host disease (GvHD). In GvHD, donor immune cells attack the patient, requiring powerful immunosuppressive drugs like glucocorticoids (GCs) to prevent death. In this study, we tested the hypothesis that donor cell conditioning with the glucocorticoid fluticasone propionate (FLU) prior to transplantation could increase hematopoietic stem cell (HSC) engraftment and reduce GvHD. Murine HSCs treated with FLU had increased HSC engraftment and reduced severity and incidence of GvHD after transplantation into allogeneic hosts. While most T cells died upon FLU treatment, donor T cells repopulated in the hosts and appeared less inflammatory and alloreactive. Regulatory T cells (Tregs) are immunomodulatory and survived FLU treatment, resulting in an increased ratio of Tregs to conventional T cells. Our results implicate an important role for Tregs in maintaining allogeneic tolerance in FLU-treated grafts and suggest a therapeutic strategy of pre-treating donor cells (and not the patients directly) with GCs to simultaneously enhance engraftment and reduce GvHD upon allogeneic HCT.

Progression of coronary artery calcification and thoracic aorta calcification in kidney transplant recipients.

BACKGROUND: Vascular calcification independently predicts cardiovascular disease, the major cause of death in kidney transplant recipients (KTRs). Longitudinal studies of vascular calcification in KTRs are few and small and have short follow-up. We assessed the evolution of coronary artery (CAC) and thoracic aorta calcification and their determinants in a cohort of prevalent KTRs. STUDY DESIGN: Longitudinal. SETTING & PARTICIPANTS: The Agatston score of coronary arteries and thoracic aorta was measured by 16-slice spiral computed tomography in 281 KTRs. PREDICTORS: Demographic, clinical, and biochemical parameters were recorded simultaneously. OUTCOMES & MEASUREMENTS: The Agatston score was measured again 3.5 or more years later. RESULTS: Repeated analyzable computed tomographic scans were available for 197 (70%) KTRs after 4.40 ± 0.28 years; they were not available for the rest of patients because of death (n = 40), atrial fibrillation (n = 1), other arrhythmias (n = 4), refusal (n = 35), or technical problems precluding confident calcium scoring (n = 4). CAC and aorta calcification scores increased significantly (by a median of 11% and 4% per year, respectively) during follow-up. By multivariable linear regression, higher baseline CAC score, history of cardiovascular event, use of a statin, and lower 25-hydroxyvitamin D(3) level were independent determinants of CAC progression. Independent determinants of aorta calcification progression were higher baseline aorta calcification score, higher pulse pressure, use of a statin, older age, higher serum phosphate level, use of aspirin, and male sex. Significant regression of CAC or aorta calcification was not observed in this cohort. LIMITATIONS: Cohort of prevalent KTRs with potential survival bias; few patients with diabetes and nonwhites, limiting the generalizability of results. CONCLUSION: In contrast to previous small short-term studies, we show that vascular calcification progression is substantial within 4 years in prevalent KTRs and is associated with several traditional and nontraditional cardiovascular risk factors, some of which are modifiable.

Frequent Low-Dose Δ9-Tetrahydrocannabinol in Adolescence Disrupts Microglia Homeostasis and Disables Responses to Microbial Infection and Social Stress in Young Adulthood.

BACKGROUND: During adolescence, microglia are actively involved in neocortical maturation while concomitantly undergoing profound phenotypic changes. Because the teenage years are also a time of experimentation with cannabis, we evaluated whether adolescent exposure to the drug's psychotropic constituent, Δ9-tetrahydrocannabinol (THC), might persistently alter microglia function. METHODS: We administered THC (5 mg/kg, intraperitoneal) once daily to male and female mice from postnatal day (PND) 30 to PND44 and examined the transcriptome of purified microglia in adult animals (PND70 and PND120) under baseline conditions or following either of two interventions known to recruit microglia: lipopolysaccharide injection and repeated social defeat. We used high-dimensional mass cytometry by time-of-flight to map brain immune cell populations after lipopolysaccharide challenge. RESULTS: Adolescent THC exposure produced in mice of both sexes a state of microglial dyshomeostasis that persisted until young adulthood (PND70) but receded with further aging (PND120). Key features of this state included broad alterations in genes involved in microglia homeostasis and innate immunity along with marked impairments in the responses to lipopolysaccharide- and repeated social defeat-induced psychosocial stress. The endocannabinoid system was also dysfunctional. The effects of THC were prevented by coadministration of either a global CB1 receptor inverse agonist or a peripheral CB1 neutral antagonist and were not replicated when THC was administered in young adulthood (PND70-84). CONCLUSIONS: Daily low-intensity CB1 receptor activation by THC during adolescence may disable critical functions served by microglia until young adulthood with potentially wide-ranging consequences for brain and mental health.

Absence of CD11a Expression Identifies Embryonic Hematopoietic Stem Cell Precursors via Competitive Neonatal Transplantation Assay.

Hematopoietic stem cells (HSCs) are defined by their self-renewal, multipotency, and bone marrow (BM) engraftment abilities. How HSCs emerge during embryonic development remains unclear, but are thought to arise from hemogenic endothelium through an intermediate precursor called "pre-HSCs." Pre-HSCs have self-renewal and multipotent activity, but lack BM engraftability. They can be identified functionally by transplantation into neonatal recipients, or by in vitro co-culture with cytokines and stroma followed by transplantation into adult recipients. While pre-HSCs express markers such as Kit and CD144, a precise surface marker identity for pre-HSCs has remained elusive due to the fluctuating expression of common HSC markers during embryonic development. We have previously determined that the lack of CD11a expression distinguishes HSCs in adults as well as multipotent progenitors in the embryo. Here, we use a neonatal transplantation assay to identify pre-HSC populations in the mouse embryo. We establish CD11a as a critical marker for the identification and enrichment of pre-HSCs in day 10.5 and 11.5 mouse embryos. Our proposed pre-HSC population, termed "11a- eKLS" (CD11a- Ter119- CD43+ Kit+ Sca1+ CD144+), contains all in vivo long-term engrafting embryonic progenitors. This population also displays a cell-cycle status expected of embryonic HSC precursors. Furthermore, we identify the neonatal liver as the likely source of signals that can mature pre-HSCs into BM-engraftable HSCs.

Coronary artery calcification: a strong predictor of cardiovascular events in renal transplant recipients.

BACKGROUND: Coronary artery calcification (CAC) independently predicts cardiovascular events (CVE) in the general population. Whether this applies to renal transplant recipients (RTR) is unknown. This prospective study assessed the prognostic impact of CAC on CVE in RTR. METHODS: We followed up a published cohort of 281 prevalent RTR. At baseline, 16-slice chest spiral computerized tomography scan was performed and classical as well as CKD-related risk factors were recorded. Major CVE (MCVE) was defined as cardiovascular death, myocardial infarction, stroke or transient ischaemic attack. All CVE (ACVE) included MCVE and revascularizations. Prognostic factors were assessed by univariate and multivariate Cox regression. RESULTS: During 2.3 ± 0.5 years of follow-up, 16 patients died from CV (n = 8) or non-CV causes (n = 8). Thirty-one RTR developed at least one CVE (first CVE cardiac in 15, peripheral in 12 and cerebrovascular in 4) for a total of 36 CVE. Thirty-month CV survival, MCVE-free survival and ACVE-free survival was 96.4, 93.9 and 87.9%, respectively. By multivariate analysis, the independent predictors of ACVE were CAC score (hazards ratios [HR] = 1.40 [1.12; 1.75] for a 2.72-fold increase in CAC, P < 0.003) and history of CVE (HR = 2.76 [1.21; 6.39], P < 0.02). CONCLUSION: Our study shows for the first time that CAC is a strong independent predictor of CVE in RTR.

Antiviral therapy and hepatocellular carcinoma risk in hepatitis B patients with cirrhosis.

OBJECTIVES: Our goal was to evaluate the effect of antiviral therapy on hepatocellular carcinoma incidence for cirrhotic patients with lower hepatitis B virus DNA levels. METHODS: Consecutive cirrhosis patients from a US cohort (n = 381) and 408 patients from a Taiwan cohort were enrolled. Patients were classified into a low (<20 IU/ml) and high hepatitis B virus DNA group (≥20 IU/ml), and each was further stratified into treated and untreated subgroups. RESULTS: Except for hepatitis B e antigen, baseline characteristics were similar for both hepatitis B virus DNA groups. Antiviral therapy significantly reduced hepatocellular carcinoma incidence in cirrhotic patients with hepatitis B virus DNA ≥20 IU/ml at 5-years (12.2% vs. 22.8%) and 10-years (23.3% vs. 37.2%) (P = 0.0018). For cirrhotic patients with hepatitis B virus DNA <20 IU/ml, there was no statistically significant difference in cumulative hepatocellular carcinoma incidence between the treated and untreated groups. After adjusting for age, sex, and hepatitis B e antigen status, antiviral therapy was an independent predictor (hazard ratio 0.43, P < 0.0001) for reduced hepatocellular carcinoma risk in patients with hepatitis B virus DNA ≥20 IU/ml. CONCLUSION: Antiviral therapy was associated with a 57% reduction in hepatocellular carcinoma incidence in chronic hepatitis B patients with cirrhosis and hepatitis B virus DNA as low as 20 IU/ml (but no lower). However, hepatocellular carcinoma incidence remained substantial, regardless of hepatitis B virus DNA levels and treatment status, highlighting the need for ongoing hepatocellular carcinoma surveillance for all cirrhotic hepatitis B virus patients.