Colorectal Serrated Neoplasia: An Institutional 12-Year Review Highlights the Impact of a Screening Programme.

BACKGROUND: As the malignant potential of sessile serrated lesions/polyps (SSL/Ps) and traditional serrated adenomas (TSAs) has been clearly demonstrated, it is important that serrated polyps are identified and correctly classified histologically. AIM: Our aim was to characterize the clinicopathological features of a series of SSL/Ps & TSAs, to assess the accuracy of the pathological diagnosis, the incidence, and the rate of dysplasia in SSL/Ps & TSAs. METHODS: We identified all colorectal serrated polyps between 01/01/2004 and 31/05/2016, by searching the laboratory information system for all cases assigned a "serrated adenoma" SNOMED code. All available and suitable slides were reviewed by one pathologist, who was blinded to the original diagnosis and the site of the polyp. Subsequently discordant cases, SSL/Ps with dysplasia, and all TSAs were reviewed by a second pathologist. RESULTS: Over a 149-month period, 759 "serrated adenoma" polyps were identified, with 664 (from 523 patients) available for review. 41.1% were reviewed by both pathologists; 15.1% (100/664) were reclassified, with the majority being changed from SSL/P to hyperplastic polyp (HYP) (66/664; 9.9%). 80.3% of these HYPs were located in the left colon, and the majority exhibited prolapse effect. There were 520 SSL/Ps (92.2%) & 40 TSAs (7.1%). The majority of SSL/Ps were in the right colon (86.7%) and were small (64.5% <1 cm), while most TSAs were in the left colon (85.7%) and were large (73.1%≥1 cm). 6.7% of SSL/Ps exhibited dysplasia, the majority of which were large (66.7%≥1 cm). Following consensus review, 13/520 (2.5%) SSL/Ps were downgraded from SSL/P with dysplasia to SSL/P without dysplasia. Detection of SSL/Ps peaked in the most recent years reviewed (87.5% reported between 2013 and 2016, inclusive), coinciding with the introduction of "BowelScreen" (the Irish FIT-based colorectal cancer screening programme). CONCLUSIONS: Awareness of, and adherence to, diagnostic criteria is essential for accurate classification of colorectal polyps.

Water and solute mass balance of five small, relatively undisturbed watersheds in the U.S.

Geochemical mass balances were computed for water years 1992-1997 (October 1991 through September 1997) for the five watersheds of the U.S. Geological Survey Water, Energy, and Biogeochemical Budgets (WEBB) Program to determine the primary regional controls on yields of the major dissolved inorganic solutes. The sites, which vary markedly with respect to climate, geology, physiography, and ecology, are: Allequash Creek, Wisconsin (low-relief, humid continental forest); Andrews Creek, Colorado (cold alpine, taiga/tundra, and subalpine boreal forest); Río Icacos, Puerto Rico (lower montane, wet tropical forest); Panola Mountain, Georgia (humid subtropical piedmont forest); and Sleepers River, Vermont (humid northern hardwood forest). Streamwater output fluxes were determined by constructing empirical multivariate concentration models including discharge and seasonal components. Input fluxes were computed from weekly wet-only or bulk precipitation sampling. Despite uncertainties in input fluxes arising from poorly defined elevation gradients, lack of dry-deposition and occult-deposition measurements, and uncertain sea-salt contributions, the following was concluded: (1) for solutes derived primarily from rock weathering (Ca, Mg, Na, K, and H(4)SiO(4)), net fluxes (outputs in streamflow minus inputs in deposition) varied by two orders of magnitude, which is attributed to a large gradient in rock weathering rates controlled by climate and geologic parent material; (2) the net flux of atmospherically derived solutes (NH(4), NO(3), SO(4), and Cl) was similar among sites, with SO(4) being the most variable and NH(4) and NO(3) generally retained (except for NO(3) at Andrews); and (3) relations among monthly solute fluxes and differences among solute concentration model parameters yielded additional insights into comparative biogeochemical processes at the sites.

Murine cytomegalovirus-induced macrophage dysfunction.

Macrophages infected in vitro with murine cytomegalovirus (MCMV) manifest depressed phagocytic uptake of a variety of particles within hours after the initiation of infection. Analysis of kinetics of uptake of radiolabeled Staphylococcus aureus by MCMV-infected macrophages indicates that the diminished uptake results from a depression in the calculated maximum velocity of uptake (Vmax) with the apparent Michaelis constant (KM) remaining unaltered. This pattern of altered uptake is typical of that seen after manipulations that affect the surface interactions of macrophages with ingestible particles. Coincubation of macrophages and radiolabeled Staphylococcus with opsonizing antibody resulted in normalization of the phagocytic rates. The surface localization of the defective phagocytosis was further confirmed by light and scanning electron microscopy of the macrophages incubated with Staphylococcus or latex spherules. These data indicate that defective macrophage surface that interferes with the initial macrophage-particle interactions that initiate nonimmune phagocytosis.

Clinical aspects of CNS cysticercosis.

Central nervous system cysticercosis, caused by infection with the larva of the pork tapeworm, is common throughout the world. Infection occurs after ingestion of fecal contaminants containing the ova of Taenia solium. The clinical manifestations depend on the number, age, and location of the larval cysts disrupting neural tissues. Several disease patterns are apparent: (1) basilar cysticercosis resulting in chronic meningitis or progressive hydrocephalus, (2) parenchymal cysts with focal symptoms, (3) diffuse parenchymal cysts with intracranial hypertension, (4) ventricular localization with episodic acute hydrocephalus, and (5) spinal cord cysticercosis mimicking mass lesions. Mixtures of these basic patterns may occur, and asymptomatic infections are common. In the United States, meningeal cysticercosis is often mistaken for tuberculous or fungal meningitis. A diagnosis of CNS cysticercosis should be considered in any patient with these syndromes who has resided in an area of high prevalence of T solium.

Altered production of GM-CSF and IL-8 in cytomegalovirus-infected, IL-1-primed umbilical cord endothelial cells.

The human cytomegaloviruses (HCMVs) appear to have the potential to disrupt production of hematopoietic cytokines. We examined the production of granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-8 by cultured and CMV-infected human umbilical vein endothelial cells (HUVECs) and compared this production with that of uninfected cells. Endothelial cells are, among other things, an integral component of human bone marrow stroma, and are responsible for production of factors that modulate the proliferation and differentiation of human hematopoietic progenitors. HCMV infection increased the production of GM-CSF in IL-1-primed HUVECs without altering GM-CSF levels in infected but unprimed HUVECs. However, this same virus was capable of causing increased production of the inhibitory cytokine IL-8. Both the viral pellet and the cleared viral supernatant appeared to contribute equally to the increased IL-8 and GM-CSF production, because each of these preparations alone was capable of exerting only half the effect seen with whole virus preparations. That both live virus and soluble protein factors within the viral stock contributed to the enhancement in GM-CSF and IL-8 production was further confirmed by inactivation with either ultraviolet or heat treatment of the viral stocks. Although the identity of the factor within the HCMV stock that contributes to this effect remains unknown, studies conducted in the presence of neutralizing antibodies or polymyxin B ruled out a role for tumor necrosis factor-alpha, IL-6, or endotoxin, all known inducers of GM-CSF. These studies indicate that HCMVs can exert both direct and indirect effects on the production of the hematopoietic factor GM-CSF and the inflammatory/inhibitory cytokine IL-8.

Augmentation of graft-versus-host reaction by cytomegalovirus infection resulting in interstitial pneumonitis.

The severity of the graft-versus-host (GVH) reaction, judged by splenomegaly and immunosuppression, was augmented by murine cytomegalovirus (MCMV) infection. Profound GVH-induced immunosuppression was seen in adult unirradiated MCMV-infected F1, mice even after challenge with extremely low doses of parental spleen cells. Mice receiving MCMV+GVH challenge died from days 16-21, with interstitial pneumonia being the most prominent pathological lesion. Pulmonary disease was unrelated to levels of viral replication in the lung. These results suggest that in human marrow recipients, cytomegalovirus infection may play a primary role both in provoking or accentuating GVH disease, as well as in the development of interstitial pneumonia.

Altered threshold for the induction of graft-versus-host immunodeficiency following murine cytomegalovirus infection. Host and donor contributions.

Acute murine cytomegalovirus (MCMV) infection enhances the ability of parental spleen cells to induce graft-vs.-host immunodeficiency (GVHID) in F1 hybrid mice when the two processes occur simultaneously in the recipient. The present study assessed GVHID as the ability of spleen cells to generate in vitro cytotoxic T lymphocyte responses to trinitrophenyl-modified syngeneic cells. The results indicate that MCMV infection not only reduces the number of parental spleen cells required to induce GVHID, but accelerates the onset of GVHID, which occurs as early as 3 days after cell and virus challenge. To determine whether MCMV infection exerts this synergistic effect primarily through the donor or the host component, we examined the effect of MCMV infection of either donor mice or recipient mice at 3, 10, and 17 days prior to spleen cell transfer. Two weeks after cell transfer, splenocytes were tested for their ability to generate CTL. When donor mice were infected with MCMV three days prior to cell transfer, the ability of donor cells to induce GVHID was reduced. In contrast, MCMV infection of the recipients three days prior to cell transfer increased their susceptibility to GVHID induction. Infection of either donor or host mice 10 days or 17 days prior to parental spleen cell transfer had little effect on the ability to induce or resist GVHID when compared with sham-infected mice. Thus, acute MCMV infection can modulate the severity of GVHID depending on whether it is the donor or the host that is infected. The ability of acute MCMV to alter the course and severity of GVHID may be relevant for human bone marrow transplants in which preceding CMV infection has been associated with chronic GVH. In this setting, CMV may lower the threshold necessary to induce a GVH reaction.

Interstitial pneumonitis during murine cytomegalovirus infection and graft-versus-host reaction. Characterization of bronchoalveolar lavage cells.

Acute murine cytomegalovirus (MCMV) infection alters the course of graft-vs-host (GVH) disease involving major histocompatibility (MHC) antigens and induces interstitial pneumonitis. F1 (B10 x B10.BR) mice given 20 x 10(6) B10.BR spleen cells and MCMV (1 x 10(5) plaque-forming units [PFU]) develop severe, diffuse pneumonitis not seen with either MCMV or GVH alone. As one index of the host immune processes operating in the lungs during MCMV/GVH pneumonitis, we examined the types of cells recovered from the lung by bronchoalveolar lavage (BAL) during pneumonitis. During MCMV/GVH pneumonitis, the total cells recovered significantly increased, due primarily to an influx of Thy 1.2 lymphocytes. Characterization of cells using multiparameter flow cytometric analysis revealed that greater than 80% of all BAL cells were Thy 1.2-positive lymphocytes of donor origin. In addition, donor Thy 1.2-positive cells were of both the L3T4+ (43% of BAL cells) and Lyt 2+ (38% of BAL cells) phenotype. Thus, MCMV infection during GVH to MHC antigens induces interstitial pneumonitis, characterized by an influx of T lymphocytes (both helper and suppressor/cytotoxic) from the donor. The antigenic specificity of these cells is not known.

Review of 59 patients hospitalized with animal bites.

We reviewed the charts of 59 pediatric and adult patients hospitalized because of animal bites (46 dog bites, 10 cat bites, 3 monkey bites). The bites of 40 of the 59 patients were infected at the time of admission. Gram-stained specimens correctly predicted the infecting bacteria in only 5 of 20 cases. Eighty-three percent of the bacterial isolates were penicillin-susceptible. Before admission 14 patients had received outpatient antibiotic prophylaxis and the infections in 11 of these 14 patients were caused by bacteria susceptible to the prophylactic antibiotic. Complications were more common if antimicrobial therapy had not been altered according to susceptibility testing results. Of the 59 patients 19 were admitted immediately after being bitten because of severe uninfected bites. Of these 19 patients 18 received prophylactic antibiotics and none developed a serious complication.

The folate antagonist, methotrexate, is a potent inhibitor of murine and human cytomegalovirus in vitro.

Cytomegalovirus (CMV) is a major source of morbidity for immunocompromised patients, such as AIDS patients. The folic acid antagonists have not been explored as potential antiviral agents against CMV. We examined the effects of methotrexate, compared to acyclovir and ganciclovir, on both murine CMV (MCMV) and human CMV (HCMV) in vitro. Using a plaque assay in mouse embryo cells or human foreskin fibroblasts for MCMV and HCMV respectively, we found that methotrexate, in micromolar concentrations, was a potent inhibitor of both viruses. This effect was due to folic acid antagonism since folinic acid abrogated the antiviral effect of methotrexate, but not ganciclovir. Cellular toxicity due to methotrexate appeared insufficient to account for the antiviral effects. The ability of methotrexate to inhibit CMV in vivo merits exploration.

Chronic pericarditis due to a streptomyces species.

Streptomyces species include a group of aerobic actinomycetes that are generally considered to be saprophytes. Effusoconstrictive pericarditis of mixed etiology developed in a previously healthy patient. The cause of the chronic pericarditis was a Streptomyces species.

A rapid and sensitive radioimmunoassay for the detection of human cytomegalovirus binding and infection of human fibroblasts.

A rapid and sensitive radioimmunoassay for the quantitation of HCMV binding and infection of human fibroblasts (HFF) was developed. The protocol involves the use of a monoclonal antibody (27-156) reactive with HCMV gB (alpha-gB), followed by an 125I-labeled second antibody to mouse IgG. Antibody to gB bound specifically to HFF inoculated with HCMV when compared to sham inoculated cells or cells inoculated with HSV (strain KOS). Antibody to gB also bound to HFF infected with HCMV 48 h prior to assay. The binding of antibody to HFF inoculated with HCMV was found to be dependent on antibody concentration and to demonstrate saturable kinetics. Moreover, antibody binding was directly dependent on the concentration of the virus inoculum, using either conventional viral preparations or gradient purified HCMV. The binding of antibody to HFF inoculated with HCMV at 4 degrees C was found to be dependent on antibody concentration and to demonstrate saturable kinetics. Displacement of HCMV binding to HFF with the proteoglycan heparin sulfate could be detected, thus allowing for competitive binding studies. This binding assay allows for the relative quantitation of HCMV binding to cells and will be useful for examining the early events of cell-viral interactions.

The effect of short-chain fatty acids on the susceptibility of human umbilical vein endothelial cells to human cytomegalovirus infection.

We have compared the replication of three strains of human cytomegalovirus (HCMV), HCMV AD-169, HCMV Towne, or HCMV RC-256, an insertional mutant of Towne containing the LacZ gene of E. coli, in human umbilical vein endothelial cells (HUVEC) and human forskin fibroblasts (HFF). We also examine the effects of salts of short-chain fatty acids on the susceptibility of HUVEC to infection by HCMV. All three virus strains replicated in both cell types, but 10-to 100-fold less virus was produced in HUVEC cells than HFF. For all virus strains, expression of HCMV IE-1 antigen in HFF was > 70% 24 h after inoculation. In contrast, the number of HUVEC exhibiting IE-1 antigen at 24 h was < 15%. Treatment of HUVEC with sodium butyrate, sodium hexanoate, or sodium propionate prior to virus inoculation increased the IE-1 and late HCMV antigen expression in a dose- and time-dependent manner. Virus yield was also increased. This increased susceptibility was inhibited by cycloheximide and tunicamycin, indicating a requirement for new cellular protein synthesis. Treatment with both sodium hexanoate and propionate after virus inoculation increased HUVEC susceptibility to HCMV infection. Treatment of HUVEC with sodium butyrate after virus inoculation also increased HCMV IE-1 antigen expression, but only after removal of the drug. These studies demonstrate that the susceptibility of HUVEC to HCMV infection can be increased by the treatment of the host cell with salts of short-chain fatty acids, such as sodium butyrate, before or after virus inoculation.

Periodic sharp complexes in herpes simplex virus encephalitis: survival in an elderly man.

For the electroencephalographer, focal temporal periodic complexes have been strongly associated with herpes simplex virus encephalitis (HSVE). The appearance and subsequent disappearance of these complexes has generally been held to herald a poor prognosis. This report involves an elderly man with HSVE who survived with no neurologic deficits despite the presence and later disappearance of periodic sharp complexes. This supports the view that the periodic complexes are more a function of the pathophysiologic changes caused by HSVE as opposed to a marker of tissue injury.

Coronary ostial embolus and mitral vegetation simulating a left atrial myxoma: a case of probable cryptococcal valvulitis.

A 56 year old man died with disseminated cryptococcosis after immunosuppressive therapy for a hematologic disorder of unknown etiology. The immediate cause of death was cardiogenic shock, probably resulting from a large right coronary ostial embolus and subsequent ischemic myocardial injury. The embolus originated from a bulky mitral vegetation (possibly cryptococcal) demonstrated ante mortem by echocardiography and cardiac angiography, and at autopsy. The differential diagnosis of such an echocardiographic pattern is discussed.

Murine models of cytomegalovirus-associated pneumonitis.

Data derived from the murine models described in this report now serve as the cornerstone for our understanding of at least some of the mechanisms by which MCMV in combination with other cofactors can trigger the series of events that result in the development of interstitial pneumonia in the MCMV-infected mouse. What is clear from the studies completed to date is that MCMV by itself is not particularly pathogenic when it replicates in the lung, but in the presence of a perturbation in the immune system of the host, can produce serious pulmonary disease. It is hoped that the knowledge gained from these studies in mice will someday be shown to be relevant to humans.