Maternal screening and active and passive immunoprophylaxis have reduced the perinatal, or vertical, transmission of hepatitis
B virus (HBV) dramatically. Without immunoprophylaxis, chronic HBV ...infection occurs in up to 90% of children by age 6 months
if the mother is positive for both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Even with immunoprophylaxis,
perinatal transmission is possible when the mother is highly viremic and HBeAg positive. Antiviral therapy during the third
trimester of pregnancy in high-risk women with chronic HBV infection reduces viral load in the mother and may decrease the
risk of perinatal transmission, although data are lacking. Safety data in pregnancy are most robust with lamivudine and tenofovir
compared with other therapies. Careful discussion with the patient regarding the risks and benefits of therapy is warranted.
Prophylaxis remains the best method of prevention of perinatal transmission.
Key points Hepatitis B immune globulin at the time of birth plus three doses of the recombinant hepatitis B vaccine over the first 6
months of life is up to 95% effective in preventing perinatal transmission.
Key points Despite successful screening and vaccination, perinatal transmission of HBV is still possible if maternal viral load is high.
Key points Antiviral treatment during the third trimester of pregnancy may reduce perinatal transmission of HBV; the benefit appears
most pronounced with high maternal viremia.
Abstract
Prion diseases are progressive and fatal, neurodegenerative disorders described in humans and animals. According to the “protein-only” hypothesis, the normal host-encoded prion protein (PrP
...C
) is converted into a pathological and infectious form (PrP
Sc
) in these diseases. Transgenic knockout models have shown that PrP
C
is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (
PRNP
) effectively blocks PrP
C
synthesis. We inoculated 12 goats (4
PRNP
+/+
, 4
PRNP
+/Ter
, and 4
PRNP
Ter/Ter
) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in
PRNP
+/+
goats and 773 dpi in
PRNP
+/Ter
goats. PrP
Sc
and vacuolation were similarly distributed in the central nervous system (CNS) of both groups and observed in all brain regions and segments of the spinal cord. Generally, accumulation of PrP
Sc
was limited in peripheral organs, but all
PRNP
+/+
goats and 1 of 4
PRNP
+/Ter
goats were positive in head lymph nodes. The four
PRNP
Ter/Ter
goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrP
Sc
was observed in the CNS or peripheral tissues of this group, as assessed by immunohistochemistry, enzyme immunoassay, and real-time quaking-induced conversion. Our study shows for the first time that animals devoid of PrP
C
due to a natural mutation do not propagate prions and are resistant to scrapie. Clinical onset of disease is delayed in heterozygous goats expressing about 50% of PrP
C
levels.
Macro‐encapsulation systems for delivery of cellular therapeutics in diabetes treatment offer major advantages such as device retrievability and high cell packing density. However, microtissue ...aggregation and absence of vasculature have been implicated in the inadequate transfer of nutrients and oxygen to the transplanted cellular grafts. Herein, we develop a hydrogel‐based macrodevice to encapsulate therapeutic microtissues positioned in homogeneous spatial distribution to mitigate their aggregation while concurrently supporting an organized intra‐device network of vascular‐inductive cells. Termed Waffle‐inspired Interlocking Macro‐encapsulation (WIM) device, this platform comprises two modules with complementary topography features that fit together in a lock‐and‐key configuration. The waffle‐inspired grid‐like micropattern of the “lock” component effectively entraps insulin‐secreting microtissues in controlled locations while the interlocking design places them in a co‐planar spatial arrangement with close proximity to vascular‐inductive cells. The WIM device co‐laden with INS‐1E microtissues and human umbilical vascular endothelial cells (HUVECs) maintains desirable cellular viability in vitro with the encapsulated microtissues retaining their glucose‐responsive insulin secretion while embedded HUVECs express pro‐angiogenic markers. Furthermore, a subcutaneously implanted alginate‐coated WIM device encapsulating primary rat islets achieves blood glucose control for 2 weeks in chemically induced diabetic mice. Overall, this macrodevice design lays foundation for a cell delivery platform, which has the potential to facilitate nutrients and oxygen transport to therapeutic grafts and thereby might lead to improved disease management outcome.
Hepatitis C virus (HCV) infects approximately 3% of the world's population and has a significant impact on morbidity and mortality. Unfortunately, there is currently a lack of knowledge and awareness ...of HCV among healthcare providers and patients. The ratelimiting factor in the achievement of better treatment outcomes is a lack of access to diagnosis and treatment. Clinicians and patients need better education on the risk factors for HCV to obtain the correct diagnosis and treatment. Once the diagnosis is made, there are a number of factors associated with disease progression, which clinicians must understand to guide appropriate treatment.
Despite the introduction of hepatitis B virus (HBV) vaccination programs, chronic hepatitis B (CHB) remains an important disease burden worldwide and in the United States. A number of clinical ...practice guidelines are available to assist in the clinical management of CHB by providing recommendations regarding screening and diagnosis, treatment indications, and the choice, duration, and monitoring of treatment. Adherence to these guidelines has proven beneficial in terms of better treatment compliance, improved clinical outcomes, and lower likelihoods of emergency admission. This review summarizes current recommendations from the major clinical CHB practice guidelines and presents a simple algorithm for the treatment of patients with CHB to help primary care providers make informed choices in clinical practice. In general, antiviral treatment should be initiated in patients with CHB who have a high risk of liver-related morbidity and who are likely to respond to treatment, that is, patients with persistently elevated serum HBV DNA and either increased serum alanine aminotransferase concentrations or advanced liver disease. In patients who are eligible for antiviral therapy, treatment should be initiated with one of the recommended first-line therapies (pegylated interferon-α, entecavir, or tenofovir), and treatment efficacy should be monitored regularly for serum HBV DNA, alanine aminotransferase, and serologic responses. Patients who are not immediately considered for treatment should be monitored and started on antiviral therapy in case of disease progression. A number of issues in CHB management remain controversial or unresolved, such as identifying treatment candidates, managing partial or nonresponders, and predicting treatment response; we discuss some of the latest evidence around these topics.
6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated ...with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 x 10(8) RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients.
Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis.
Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 x 10(8) RBC versus 3,452 pmol/8 x 10(8) RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4%vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 x 10(8) RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff.
6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.
Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a ...large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B.
The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed.
A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p=0.02) or diagnosis of HBV (p=0.02).
While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5–15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission.
Mycobacterial cellular variations in growth and division increase heterogeneity in cell length, possibly contributing to cell-to-cell variation in host and antibiotic stress tolerance. This may be ...one of the factors influencing
persistence to antibiotics. Tuberculosis (TB) is a major public health problem in developing countries, antibiotic persistence, and emergence of antibiotic resistance further complicates this problem. We wanted to investigate the factors influencing cell-length distribution in clinical
strains. In parallel we examined
cell-length distribution in a large set of clinical strains (
= 158) from
sputum samples,
macrophage models, and
cultures. Our aim was to understand the influence of clinically relevant factors such as host stresses,
lineages, antibiotic resistance, antibiotic concentrations, and disease severity on the cell size distribution in clinical
strains. Increased cell size and cell-to-cell variation in cell length were associated with bacteria in sputum and infected macrophages rather than liquid culture. Multidrug-resistant (MDR) strains displayed increased cell length heterogeneity compared to sensitive strains in infected macrophages and also during growth under rifampicin (RIF) treatment. Importantly, increased cell length was also associated with pulmonary TB disease severity. Supporting these findings, individual host stresses, such as oxidative stress and iron deficiency, increased cell-length heterogeneity of
strains. In addition we also observed synergism between host stress and RIF treatment in increasing cell length in MDR-TB strains. This study has identified some clinical factors contributing to cell-length heterogeneity in clinical
strains. The role of these cellular adaptations to host and antibiotic tolerance needs further investigation.
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