Update on prevention and screening of cervical cancer

Cervical cancer is the third most common cause of cancer in women in the world. During the past few decades tremendous strides have been made toward decreasing the incidence and mortality of cervical cancer with the implementation of various prevention and screening strategies. The causative agent linked to cervical development and its precursors is the human papillomavirus(HPV). Prevention and screening measures for cervical cancer are paramount because the ability to identify and treat the illness at its premature stage often disrupts the process of neoplasia. Cervical carcinogenesis can be the result of infections from multiple high-risk HPV types that act synergistically. This imposes a level of complexity to identifying and vaccinating against the actual causative agent. Additionally, most HPV infections spontaneously clear. Therefore, screening strategies should optimally weigh the benefits and risks of screening to avoid the discovery and needless treatment of transient HPV infections. This article provides an update of the preventative and screening methodsfor cervical cancer, mainly HPV vaccination, screening with Pap smear cytology, and HPV testing. It also provides a discussion of the newest United States 2012 guidelines for cervical cancer screening, which changed the age to begin and end screening and lengthened the screening intervals.

Pathogenesis and clinical spectrum of primary sclerosing cholangitis

Primary sclerosing cholangitis(PSC) is a disease of the biliary tract, which has been documented in the literature since 1867. This disease has a strong predilection for affecting men and can be seen in individuals as young as 2 years of age. PSC has a strong associated with inflammatory bowel disease, more commonly with ulcerative colitis, and is also part of the clinical spectrum of Ig G4-related diseases. Smallduct PSC, a variant of PSC, also has an association with inflammatory bowel disease. The exact pathogenesis of PSC is not well understood at present, however, is likely a combination of a genetic predisposition with alteration of the molecular structure of the gut. Abnormal serum liver chemistry and presence of certain autoimmune markers are usually the first indicators leading to a diagnosis of PCS, however, these may often be normal in early stages of this disease. The diagnosis is made by cholangiography, which is now considered the gold standard. PSC is a known pre-malignant condition. Such patients have an increased risk of developing cholangiocarcinoma, gallbladder neoplasia, and colon cancer. Many new treatment modalities have emerged in the recent past, including anti-tumor necrosis factor-α and anti-integrins; however, liver transplantation is the only known cure for PSC. Despite past and present research, PSC remains an enigmatic biliary disease with few viable treatment options.

Suicide transport blockade of motor neuron survival generates a focal graded injury and functional deficit

We describe a pre-clinical spinal cord motor neuron injury model that is minimal invasive, reproducible, focal and easily applied to small rodents.Retrograde axonal transport of a pro-apoptotic phosphatidylinosotol 3'-kinase inhibitor, wortmannin, via the sciatic nerve results in loss of ipsilateral lumbar motor neurons proportional to the level of drug administered.Motor neuron loss was detected by choline acetyltransferase(ChAT) immunostaining and with a transgenic thy1-eGFP marker.The short half-life of wortmannin generates minimal wound spread, and wortmannin does not affect axon transport, as determined by co-injection of a pseudorabies virus tracer.Using quantitative transcript analysis, we found that ChAT transcripts significantly decreased at 14 days post-delivery of 1 μg wortmannin, relative to sham controls, and remained low after 90 days.Smaller effects were observed with 200 ng and 100 ng wortmannin.Wortmannin also generated a transient and significant increase in astrocyte Gfap transcripts after 14 days with a return to control levels at 90 days.Treated mice had hind limb spasticity and a forced motor function defect that was quantified using a water exit test.Controls rapidly exit a shallow water tray, and wortmannin treated animals were up to 12-fold slower, a phenotype that persisted for at least 3 months.Thus the focal delivery of wortmannin to motor neurons generates a reproducible and scalable injury that can facilitate quantitative studies on neural regeneration and repair.The efficacy of sciatic nerve suicide transport can also explain neurotoxin-mediated selective loss of motor neurons in diseases such as amyotrophic lateral sclerosis.All procedures were performed at Rutgers under established Institutional Animal Care and Use protocols(eIACUC_TR201800022, approved on March 20, 2018).

Cell replacement therapy for central nervous system diseases

The brain and spinal cord can not replace neurons or supporting glia that are lost through trau- matic injury or disease. In pre-clinical studies, however, neural stem and progenitor cell transplants can promote functional recovery. Thus the central nervous system is repair competent but lacks endogenous stem cell resources. To make transplants clinically feasible, this field needs a source of histocompatible, ethically acceptable and non-tumorgenic cells. One strategy to generate pa- tient-specific replacement cells is to reprogram autologous cells such as fibroblasts into pluripotent stem cells which can then be differentiated into the required cell grafts. However, the utility of pluripotent cell derived grafts is limited since they can retain founder cells with intrinsic neoplastic potential. A recent extension of this technology directly reprograms fibroblasts into the final graft- able cells without an induced pluripotent stem cell intermediate, avoiding the pluripotent caveat. For both types of reprogramming the conversion efficiency is very low resulting in the need to amplify the cells in culture which can lead to chromosomal instability and neoplasia. Thus to make reprogramming biology clinically feasible, we must improve the efficiency. The ultimate source of replacement cells may reside in directly reprogramming accessible cells within the brain.

A novel fibroblast growth factor 15-dependent and bile acid-independent promotion of liver regeneration in mice

Objective:The role of intestine-derived factors in promoting liver regeneration after partial hepatectomy(PHx)are not entirely known,but bile acids(BAs)and fibroblast growth factor 15(Fgf15)that are highly expressed in the mouse ileum could promote hepatocyte proliferation.Fgf15 strongly suppresses the synthesis of BAs,and emerging evidence indicates that Fgf15 is important for liver regeneration.

Backdoor intrusion: retrotoxicity can explain targeted motor neuron death in amyotrophic lateral sclerosis

To the editor: Amyotrophic lateral sclerosis(ALS) is a fatal disease of unknown cause that selectively targets brain and spinal cord motor neurons(MNs).The lifetime risk is 1 in 2000, and most cases are sporadic although up to 10% of patients are predisposed by familial mutations in MN protection or repair genes(Bruijn et al., 2004).Risk factors include agrochemical exposure and trauma(Walters et al., 2019), although why they target MN is perplexing.Farmers are at a greater risk than non-farming rural residents(Kang et al, 2014), and ALS clusters occur in abrasion prone activities conducted on agrochemical treated fields such as baseball and soccer(Chio et al., 2005).

Inflammatory pseudotumors in the liver associated with influenza:A case report

BACKGROUND Inflammatory pseudotumor(IPT)is a rare and benign lesion that mimics malignancy and can develop in any part of the body.The pathophysiology and etiology of these quasineoplastic lesions remain unclear.CASE SUMMARY We report a case of a 65-year-old male who presented with fevers,night sweats,and unintentional weight loss following an influenza infection and was found to have multiple hepatic IPT’s following an extensive work up.CONCLUSION Our case highlights the importance of considering hepatic IPT’s in the differential in a patient who presents with symptoms and imaging findings mimicking malignancy shortly following a viral infection.

Prevalence of Non-<i>Albicans Candida</i>Infections in Women with Recurrent Vulvovaginal Symptomatology

Background: Candida vulvovaginitis is one of the most frequently diagnosed conditions in women’s care practices. Historically, 90% of cultured yeast species were C. albicans. However, due to a variety of interventions, the proportion of non-albicans Candida (NAC) infections appears to be increasing. We sought to estimate the current prevalence of Candida vulvovaginitis and the species-specific distribution of such infections in recurrent cases. Methods: Women with recurrent vulvovaginal symptomatology referred to an Obstetrics and Gynecology practice were tested by genital fungus culture, Candida-specific polymerase chain reaction (PCR), or both between July 2010 and February 2013. Results: A total of 103 women were tested. Mean age was 45.6 years. Including only their most recent positive test result, 29.1% (30/103) of women tested positive for Candida by any of the above testing measures. Of those, 50% (15/30) tested positive for C. albicans and 50% (15/30) tested positive for a NAC species. Across all visits, 60% (18/30) tested positive for C. albicans, 56.7% (17/30) tested positive for NAC, and 16.7% (5/30) tested positive for both a C. albicans and a NAC species. Among all isolated NAC species, 28.6% (6/21) were determined to be C. glabrata, 23.8% (5/21) C. krusei, 23.8% (5/21) C. parapsilosis, and 23.8% (5/21) other Candida species. Conclusion: Approximately 30% of women with recurrent vulvovaginal symptomatology have detectable Candida strains and it appears that NAC species may cause half of all these infections. This is imperative because NAC infections are usually more difficult to diagnose and are resistant to most treatments.

Security breach:peripheral nerves provide unrestricted access for toxin delivery into the central nervous system

We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.

Role of telomere shortening in anticipation of inflammatory bowel disease

BACKGROUND The existence of genetic anticipation has been long disputed in inflammatory bowel disease(IBD)in the absence of the explanatory mechanism.AIM To determine whether it was predictive of genetic anticipation,we evaluated telomere length in IBD.We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms.METHODS We studied three IBD families with multiple affected members in three successive generations.We determined telomere length(TL)in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization(flow FISH).We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance.RESULTS Out of twenty-four patients of European descent selected to participate in the study,eleven patients,eight parent-child pairs affected by IBD,were included in the genetic anticipation analysis.Median difference in age at diagnosis between two successive generations was 16.5 years,with earlier age at onset in the younger generations.In most of the affected members,the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations.TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD.NOD2 gene mutations were present in the Crohn’s disease patients of one family.However,no gene variants were identified as potential candidates for inheritance.CONCLUSION Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD.Further studies using a larger sample size are required to confirm or refute our findings.

Determining Environmental Impacts for Sensitive Species: Using Iconic Species as Bioindicators for Management and Policy

Environmental assessment of impacts, management, and policy are important aspects of protection of human health and the environment. Assessing the impacts of human activities requires selection of bioindicator species that can be used to assess, manage, and develop public policies that ensure ecosystem integrity, and therefore sustainability of social, cultural, and economic systems. With the use of Chinook Salmon (Oncorhynchus tshawytscha), Pacific Cod (Gadusmacrocephalus), Mallard (Anas platyrhynchos), and Red Knot (Calidris canutus rufa), we explore assessment and measurement endpoints, and their relationship to management and development of public policy. This combination of fish and birds provides a diversity of life histories, ecosystem roles, human values, and resource use to explore their use as bioindicators and endpoints. It also allows examination of 1) conservation and protection of species and biodiversity, 2) protection of ecosystems, 3) provision of goods and services, and 4) societal well-being.

Prenatal Diagnosis of Abnormal Sternum Development and Dilated Aortic Root in a Fetus with a Novel 204 kb Microdeletion of the TGFRB2 Gene

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is associated with vascular abnormalities, including aggressive aortic aneurysms, as well as skeletal and craniofacial malformations. The molecular mechanism of this syndrome remains to be fully elucidated. In this case, we describe a 29-year-old woman, gravida 2 para 1, who was referred for consultation after urinary tract malformations were observed during her mid-gestation anatomic survey. Following referral to our unit, ultrasound examination of the 21-week fetus was repeated. The fetus was observed to have a dilated aortic root and a poorly ossified sternum with mild pectus deformity. After elective termination, single nucleotide polymorphism microarray testing identified a novel 204 kb microdeletion involving the short arm of chromosome 3. The deleted genetic material included 4 exons of the TGFBR2 gene. Although the phenotype of LDS may be caused by haploinsufficiency of the TGFBR1 or TGFBR2 gene, our experience suggests a more complex picture of LDS. The study of such cases might further elucidate its pathogenesis.

Cardiac arrhythmia with premature ventricular contractures induced by interferon beta in a patient with multiple sclerosis

Multiple sclerosis(MS)is an immune‑mediated inflammatory and neurodegenerative disease of the central nervous system.Interferon(IFN)beta is an active ingredient of five out of twelve disease modifying treatments approved for MS.We report a case of IFN‑beta‑induced cardiac arrhythmia with premature ventricular contractures in a patient recently diagnosed with MS.