Characterization and Identification of Colorectal Cancer in Persons Younger Than 50 Years.

The proportion of colorectal cancer (CRC) cases in persons younger than age 50, referred to as early onset CRC (EOCRC), has increased from 6% to 11% over the past 25 years, whereas the incidence of CRC has decreased in persons age 50 and older, referred to as late-onset CRC (LOCRC) in the United States.1 It is not known if EOCRC is caused by the same factors that cause LOCRC, or whether there are unique causes that alter the clinical features.2 This study was designed to analyze the clinical and genetic characteristics of EOCRC as presented at a community hospital.

Clinical and Genetic Characteristics of Colorectal Cancer in Persons under 50 Years of Age: A Review.

BACKGROUND: The incidence of colorectal cancer (CRC) in persons under the age of 50 years (EOCRC) is increasing even as the incidence of CRC in persons over age 50 is decreasing. This has led to recommendations to lower the age of CRC screening to age 45. It is not clear whether EOCRC is identical to CRCs in older patients or whether there are distinctive features between the two groups. AIMS AND METHODS: We reviewed the literature on the clinical and genetic aspects of EOCRC. RESULTS: We found that there is an increased likelihood of a strong genetic basis for EOCRC, but that at least 80% of cases do not come from the known high-penetrance cancer syndromes. Early-onset CRCs tend to occur in the distal colon or rectum, are more likely to be detected due to cancer-related symptoms, appear to be increasing in whites more than non-whites on a population-wide analysis, and are more likely to present in an advanced stage of disease. There are some unique genetic features of EOCRC, including an increased proportion of tumors with LINE-1 hypomethylation, and combined chromosomal and microsatellite stability. CONCLUSIONS: EOCRC deserves additional attention because of the high number of life years at risk with EOCRC, and the implications for earlier CRC screening. Additional focus is needed on determining whether some cases of EOCRC have a unique mechanistic basis.

Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression.

CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.

Pharmacokinetics and dynamics of mycophenolate mofetil after single-dose oral administration in juvenile dachshunds.

Mycophenolate mofetil (MMF) is recommended as an alternative/complementary immunosuppressant. Pharmacokinetic and dynamic effects of MMF are unknown in young-aged dogs. We investigated the pharmacokinetics and pharmacodynamics of single oral dose MMF metabolite, mycophenolic acid (MPA), in healthy juvenile dogs purpose-bred for the tripeptidyl peptidase 1 gene (TPP1) mutation. The dogs were heterozygous for the mutation (nonaffected carriers). Six dogs received 13 mg/kg oral MMF and two placebo. Pharmacokinetic parameters derived from plasma MPA were evaluated. Whole-blood mitogen-stimulated T-cell proliferation was determined using a flow cytometric assay. Plasma MPA Cmax (mean ± SD, 9.33 ± 7.04 µg/ml) occurred at <1 hr. The AUC0-∞ (mean ± SD, 12.84±6.62 hr*µg/ml), MRTinf (mean ± SD, 11.09 ± 9.63 min), T1/2 (harmonic mean ± PseudoSD 5.50 ± 3.80 min), and k/d (mean ± SD, 0.002 ± 0.001 1/min). Significant differences could not be detected between % inhibition of proliferating CD5+ T lymphocytes at any time point (p = .380). No relationship was observed between MPA concentration and % inhibition of proliferating CD5+ T lymphocytes (R = .148, p = .324). Pharmacodynamics do not support the use of MMF in juvenile dogs at the administered dose based on existing therapeutic targets.

Sudden cardiac arrest due to a single sodium channel mutation producing a mixed phenotype of Brugada and Long QT3 syndromes.

Inherited arrhythmia syndromes are a known, albeit rare, cause of sudden cardiac arrest which may present with characteristic electrocardiogram changes in patients with structurally normal heart. There are a variety of distinct arrhythmogenic syndromes that arise from mutations in voltage gated sodium channels, resulting in either gain or loss of function. We describe a patient with a primary inherited arrhythmia syndrome which presented as sudden cardiac arrest. Further workup revealed that her arrest was due to a combination of Brugada syndrome and Long QT3 syndrome secondary to a deleterious mutation of voltage-gated, sodium channel, type V alpha subunit (SCN5A Thr1709Met).

Shin-splints: common exercise-related syndromes affecting the lower leg.

Lower leg pain is a common complaint of athletically active individuals, often limiting physical activities. As such, the group of lower leg conditions related to athletic pursuits and physical exercise confer considerable operational implications for the military. Whilst acute injuries to the lower limb are commonly encountered and are clearly of significance, this article focuses instead on chronic conditions related to physical activity. These include insults to bone such as stress fractures and medial tibial stress syndrome, and those related to the soft tissues such as chronic exertional compartment syndrome. In this article we will examine the presentation and management of these conditions.

Dissecting the relative contribution of OATP1B1-mediated uptake of xenobiotics into human hepatocytes using siRNA.

1. Organic anion transporting polypeptide 1B1 plays a pivotal role in the disposition of many anionic drugs. Significant overlap in substrate specificity between individual OATP isoforms has hampered the identification of the relative importance of individual isoforms for hepatic uptake of xenobiotics. 2. The present study focused on the use of siRNA technology to decrease OATP1B1 selectively in human hepatocytes. Following delivery of siRNA by the novel lipid, AtuFECT01, mRNA expression of OATP1B1 was reduced by 94%-98% with no significant toxicity. Off-target effects were also shown to be minimal as evidenced by the expression of common drug metabolizing enzymes, transporters, nuclear receptors and associated co-regulators. Uptake of estrone-3-sulfate (5 nM) by OATP1B1 was reduced by 82%-95%. This methodology was subsequently used to assess the relative contribution of OATP1B1 uptake in human hepatocytes for olmesartan (42%-62%), valsartan (28%-81%), rosuvastatin (64%-72%), pitavastatin (84%-98%) and lopinavir (64%-89%). These data are consistent with previous values obtained using a relative activity factor approach. 3. The siRNA approach provides a robust and reproducible method for assessing the relative contribution of OATP1B1 to hepatic uptake of new chemical entities. The technique also has potential utility in facilitating detailed characterization of drug-drug interactions involving hepatic drug transporters.

Advances in acute and chronic pancreatitis.

Acute pancreatitis (AP) and chronic pancreatitis are the third leading gastrointestinal causes for admissions and readmissions to hospitals in the United States. This review of articles published between 2019-2022 (December) from international sources identified four categories of crucial new findings: The report includes (1) New genetic pathogenic mutations (TRPV6); expected genetic outcomes in a Northern European population; (2) a new serum diagnostic marker for AP-fatty acid ethyl esters-distinguishing acute pancreatitis associated with alcohol; explanations of the impact of monocytes/macrophages on the inflammatory process that defines their future in diagnosis, staging, and treatment; (3) innovations in timing of per os low-fat, solid food intake immediately on admission; resolution of concepts of aggressive parenteral fluid intake; dramatic shifts to non-operative from operative treatment of infected pancreatic necrosis. Each modification reduced interventions, complications, and lengths-of-stay; and (4) authoritarian recommendations for medical treatment of chronic pain. These advances offer opportunities to initiate newly proven treatments to enhance outcomes, alter the natural history, and envision the future of two diseases that have no known cure.

Impact of a family history of colorectal cancer on the prevalence of advanced neoplasia at colonoscopy in 4,967 asymptomatic patients.

BACKGROUND AND AIMS: A family history of colorectal cancer is considered an independent risk factor for advanced neoplasia at colonoscopy. The expected outcome for screening colonoscopy in patients with a family history is not well established in all populations. METHODS: We designed a large, prospective study of an unselected population in San Diego, California to assess the impact of a family history of colorectal cancer on the prevalence of advanced neoplasia on screening colonoscopy. RESULTS: We evaluated 6,905 consecutive patients referred for colonoscopy between January 2005 and December 2006. Of the 4,967 who met the inclusion criteria, the mean age was 58.8 and consisted of 58.6% women. Overall 930 (18.7%) had neoplasia and 249 (5%) had advanced neoplasia, eight (0.16%) of which were cancer. The 4,967 patients were divided into 643 with and 4,324 without a family history of colorectal cancer. Of the 643 patients with a family history, 38 (5.9%) had advanced neoplasia, one of which was cancer. Of the 4,324 patients without a family history, 211 (4.9%) had advanced neoplasia including seven cancers. The relative risk for finding advanced neoplasia in patients with a single affected first degree relative was 1.21 (95% CI, 0.87-1.69; P = 0.31). CONCLUSIONS: A family history of one first-degree relative with colorectal cancer did not predict a significantly higher prevalence of advanced neoplasia at screening colonoscopy in this Southwestern cohort.

Small Vessel Disease, a Marker of Brain Health: What the Radiologist Needs to Know.

Small vessel disease, a disorder of cerebral microvessels, is an expanding epidemic and a common cause of stroke and dementia. Despite being almost ubiquitous in brain imaging, the clinicoradiologic association of small vessel disease is weak, and the underlying pathogenesis is poorly understood. The STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria have standardized the nomenclature. These include white matter hyperintensities of presumed vascular origin, recent small subcortical infarcts, lacunes of presumed vascular origin, prominent perivascular spaces, cerebral microbleeds, superficial siderosis, cortical microinfarcts, and brain atrophy. Recently, the rigid categories among cognitive impairment, vascular dementia, stroke, and small vessel disease have become outdated, with a greater emphasis on brain health. Conventional and advanced small vessel disease imaging markers allow a comprehensive assessment of global brain heath. In this review, we discuss the pathophysiology of small vessel disease neuroimaging nomenclature by means of the STRIVE criteria, clinical implications, the role of advanced imaging, and future directions.

Prevalence of advanced adenomas in small and diminutive colon polyps using direct measurement of size.

BACKGROUND AND AIMS: Most studies reporting polyp size use visual estimates. Determining the prevalence of advanced histology based on direct measurement of polyp size may help guide the management of polyps found at optical colonoscopy (OC) and CT colonography (CTC). METHODS: We designed a large, prospective study to assess the prevalence of advanced adenomas based on direct measurement of polyp size by a certified pathologists' assistant as reported in the pathology report. Patients between 40 and 89 years of age who presented for screening colonoscopy were included in our study. Advanced adenomas were defined as ≥10 mm or ≥25% villous features, high grade dysplasia or cancer. Polyps were divided by size into three groups: diminutive (≤5 mm), small (6-9 mm) and large (≥10 mm). If more than one adenoma was present, the most advanced was used for analysis. RESULTS: We evaluated 6,905 consecutive patients referred for colonoscopy between January 2005 and December 2006. Of the 4,967 who met the inclusion criteria, the mean age was 58.8 and consisted of 59% women. Overall, 930 (18.7%) had an adenoma; 248 (5%) were advanced adenomas including 8 (0.16%) cancers. Of 89 polyps≥10 mm, 76 (85%) had advanced histology; of 247 polyps 6-9 mm, 67 (27%) were advanced; of 1,025 polyps ≤5 mm, 105 (10%) were advanced. Thus, 172 of 248 (69%) patients with advanced adenomas had small or diminutive adenomas. CONCLUSIONS: Our data indicate the majority (69%) of advanced adenomas are <10 mm. Even among polyps≤5 mm, there was an appreciable prevalence of advanced adenomas (10%). These findings may help guide the management of sub-centimeter colon polyps found by OC or CTC.

Experimental and Theoretical Study of the Electronic Structures of Lanthanide Indium Perovskites LnInO3.

Ternary lanthanide indium oxides LnInO3 (Ln = La, Pr, Nd, Sm) were synthesized by high-temperature solid-state reaction and characterized by X-ray powder diffraction. Rietveld refinement of the powder patterns showed the LnInO3 materials to be orthorhombic perovskites belonging to the space group Pnma, based on almost-regular InO6 octahedra and highly distorted LnO12 polyhedra. Experimental structural data were compared with results from density functional theory (DFT) calculations employing a hybrid Hamiltonian. Valence region X-ray photoelectron and K-shell X-ray emission and absorption spectra of the LnInO3 compounds were simulated with the aid of the DFT calculations. Photoionization of lanthanide 4f orbitals gives rise to a complex final-state multiplet structure in the valence region for the 4f n compounds PrInO3, NdInO3, and SmInO3, and the overall photoemission spectral profiles were shown to be a superposition of final-state 4f n-1 terms onto the cross-section weighted partial densities of states from the other orbitals. The occupied 4f states are stabilized in moving across the series Pr-Nd-Sm. Band gaps were measured using diffuse reflectance spectroscopy. These results demonstrated that the band gap of LaInO3 is 4.32 eV, in agreement with DFT calculations. This is significantly larger than a band gap of 2.2 eV first proposed in 1967 and based on the idea that In 4d states lie above the top of the O 2p valence band. However, both DFT and X-ray spectroscopy show that In 4d is a shallow core level located well below the bottom of the valence band. Band gaps greater than 4 eV were observed for NdInO3 and SmInO3, but a lower gap of 3.6 eV for PrInO3 was shown to arise from the occupied Pr 4f states lying above the main O 2p valence band.

Brain and Lung Imaging Correlation in Patients with COVID-19: Could the Severity of Lung Disease Reflect the Prevalence of Acute Abnormalities on Neuroimaging? A Global Multicenter Observational Study.

PURPOSE: Our aim was to study the association between abnormal findings on chest and brain imaging in patients with coronavirus disease 2019 (COVID-19) and neurologic symptoms. MATERIALS AND METHODS: In this retrospective, international multicenter study, we reviewed the electronic medical records and imaging of hospitalized patients with COVID-19 from March 3, 2020, to June 25, 2020. Our inclusion criteria were patients diagnosed with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection with acute neurologic manifestations and available chest CT and brain imaging. The 5 lobes of the lungs were individually scored on a scale of 0-5 (0 corresponded to no involvement and 5 corresponded to >75% involvement). A CT lung severity score was determined as the sum of lung involvement, ranging from 0 (no involvement) to 25 (maximum involvement). RESULTS: A total of 135 patients met the inclusion criteria with 132 brain CT, 36 brain MR imaging, 7 MRA of the head and neck, and 135 chest CT studies. Compared with 86 (64%) patients without acute abnormal findings on neuroimaging, 49 (36%) patients with these findings had a significantly higher mean CT lung severity score (9.9 versus 5.8, P < .001). These patients were more likely to present with ischemic stroke (40 [82%] versus 11 [13%], P < .0001) and were more likely to have either ground-glass opacities or consolidation (46 [94%] versus 73 [84%], P = .01) in the lungs. A threshold of the CT lung severity score of >8 was found to be 74% sensitive and 65% specific for acute abnormal findings on neuroimaging. The neuroimaging hallmarks of these patients were acute ischemic infarct (28%), intracranial hemorrhage (10%) including microhemorrhages (19%), and leukoencephalopathy with and/or without restricted diffusion (11%). The predominant CT chest findings were peripheral ground-glass opacities with or without consolidation. CONCLUSIONS: The CT lung disease severity score may be predictive of acute abnormalities on neuroimaging in patients with COVID-19 with neurologic manifestations. This can be used as a predictive tool in patient management to improve clinical outcome.

Nonhematopoietic cells selected for resistance to tumor necrosis factor produce tumor necrosis factor.

TNF-resistant lines of L cells can be derived from TNF-sensitive populations by repeated exposure to TNF, and these resistant L cells, in contrast to sensitive L cells and other types of cells, lack demonstrable cell surface receptors for TNF. We have now found that TNF-resistant L cells produce a factor that is cytotoxic for L cells and has the following distinguishing characteristics of mouse TNF: it is a protein of 43 kD, composed of 16 kD subunits, that competes with TNF for receptor binding, induces hemorrhagic necrosis of the TNF-sensitive mouse sarcoma Meth A, has synergistic cytotoxic action with interferon, and its activity is neutralized by antibody to TNF. The two conclusions of this study are that cells selected for TNF resistance spontaneously produce a molecule resembling macrophage TNF, and that cells of nonhematopoietic origin are capable of producing TNF.

High affinity binding of 125I-labeled human tumor necrosis factor (LuKII) to specific cell surface receptors.

125I-labeled TNF(LuKII) (tumor necrosis factor) binds specifically to human and mouse cell lines sensitive to the cytotoxic effect of TNF, but not to cells made resistant to TNF. TNF-sensitive cells have cell surface receptors with a high affinity for TNF(LuKII). Mouse TNF competes with TNF(LuKII) for receptor binding. Scatchard analysis of the binding data yielded linear plots and suggests that TNF(LuKII) binds to homogeneous receptor sites. The number of TNF(LuKII) receptors on two TNF-sensitive cell lines is 200-300 per cell and the affinity constant of the receptor for TNF(LuKII) is approximately 1 X 10(-10) M.

Molecular characterization of IRF3 and IRF7 in rainbow trout, Oncorhynchus mykiss: functional analysis and transcriptional modulation.

Interferon regulatory factors (IRF) 3 and 7 in mammals are known to be crucial in regulating the type I interferon (IFN) response to viral infection as part of transcriptional complexes binding to IRF-binding elements (IRF-Es) and interferon stimulatory response elements (ISREs) within IFN and interferon-stimulated genes (ISGs). Here we report the sequencing and characterization of full-length cDNA homologues of rainbow trout (rt)IRF7 and, for the first time in fish, IRF3. RtIRF3 consists of 2127 bp with a 159 bp 5'-UTR-containing two upstream AUGs and a 573 bp 3'-UTR. RtIRF7 was found to be 2055 bp, with a 102 bp 5'-UTR and a 705 bp 3'-UTR. The open reading frames (ORFs) translate into 464 amino acid and 415 amino acid proteins, respectively, each possessing a putative DNA-binding domain (DBD) containing a tryptophan cluster, which is characteristic of all IRF family members. The presence of putative IRF association domain (IAD)s, serine-rich C terminal domains (poorly conserved in trout IRF3), and phylogenetic analysis places the two genes in the IRF3 subfamily. Both genes were found to be upregulated by poly I:C, type I recombinant rainbow trout (r) IFN (second isoform, type I rIFN), type II rIFN (rIFNgamma), LPS, and rIL-1beta in the trout macrophage cell line, RTS-11. Poly I:C and type I rIFN also induced IRF3 and IRF7 expression in a trout fibroblast cell line (RTG-2). Transient transfection of RTG-2 cells with each IRF fused to GFP revealed a predominant cytoplasmic distribution found most intensely around the nucleus and, to a lesser extent, within cell nuclei. Transient transfection of rtIRF3 in the Mx-1-luciferase reporter cell line, RTG-P1, revealed a modest increase in luciferase activity relative to the vehicle control, which was lost in cells over-expressing a DBD-truncated form of rtIRF3. Both full-length and DBD-truncated forms of rtIRF7 increased reporter activity relative to the control, although to a non-significant extent. Electromobility shift assays (EMSAs) did not reveal a specific interaction between each IRF and the ISRE element found in the Mx-1 promoter, although the Mx-1 ISRE bound specifically to endogenous transcriptional complexes. These data support the premise that rtIRF3 and rtIRF7 are important molecules in the regulation of antiviral responses in fish, with the impact of rIFNgamma on rtIRF3/7 expression implying a role for these IRFs in immune processes other than type I IFN-driven antiviral responses.

Prospective validation study of an algorithm for triage to MRCP or ERCP for investigation of suspected pancreatico-biliary disease.

BACKGROUND: In patients with suspected pancreatico-biliary disease, endoscopic retrograde cholangiopancreatography (ERCP) should be reserved for those requiring therapeutic intervention. However, difficulty arises in identifying patients likely to require therapy in the early phase of diagnostic work-up. An algorithm has been developed by the authors based upon prospective assessment of ERCP patients for triage of patients to magnetic resonance cholangiopancreatography (MRCP) or ERCP with suspected pancreatico-biliary disease. We aimed to validate this algorithm in an independent group of patients using a different group of endoscopists blinded to the algorithm. METHODS: Patients were stratified into different categories by clinical, ultrasound and liver function test findings. The algorithm stratified patients by the likelihood of therapeutic intervention. The accuracy of the algorithm for a therapeutic outcome was assessed by receiver operator characteristics (ROC) curve analysis. RESULTS: Hundred and twenty-five consecutive patients (Oct 2005 to July 2006) were prospectively assessed by MRCP or ERCP according to the algorithm, and the outcomes recorded. Fifty-seven patients were triaged to MRCP and 63 patients were triaged to ERCP. A category was not assessable in five patients. Three patients from the MRCP group required subsequent therapeutic ERCP. Diagnostic ERCP was performed in three patients in the ERCP group. ERCP-related complications occurred in four patients. The algorithm performed well in predicting the requirement for intervention as determined by the area under the ROC curve [0.84 (95%CI 0.76-0.92)]. CONCLUSIONS: Our study confirms that an algorithm-based approach can reproducibly predict those patients requiring therapeutic biliary intervention.