Low risk of complications in patients with first-time acute uncomplicated diverticulitis.

PURPOSE: First-time acute uncomplicated diverticulitis (AUD) has been considered to have an increased risk of complication, but the level of evidence is low. The aim of the present study was to evaluate the risk of complications in patients with first-time AUD and in patients with a history of diverticulitis. METHODS: This paper is a population-based retrospective study at Västmanland's Hospital, Västerås, Sweden, where all patients were identified with a diagnosis of colonic diverticular disease ICD-10 K57.0-9 from January 2010 to December 2014. The records of all patients were surveyed and patients with a computed tomography (CT)-verified AUD were included. Complications defined as CT-verified abscess, perforation, colonic obstruction, fistula, or sepsis within 1 month from the diagnosis of AUD were registered. RESULTS: Of 809 patients with AUD, 642 (79%) had first-time AUD and 167 (21%) had a previous history of AUD with no differences in demographic or clinical characteristics. In total, 16 (2%) patients developed a complication within 1 month irrespective of whether they had a previous history of diverticulitis (P = 0.345). In the binary logistic regression analysis, first-time diverticulitis was not associated with increased risk of complications (OR 1.58; CI 0.52-4.81). The rate of antibiotic therapy was about 7-10% during the time period and outpatient management increased from 7% in 2010 to 61% in 2014. CONCLUSIONS: The risk for development of complications is low in AUD with no difference between patients with first-time or recurrent diverticulitis. This result strengthens existing evidence on the benign disease course of AUD.

No antibiotics in acute uncomplicated diverticulitis: does it work?

BACKGROUND: The first randomized multicenter study evaluating the need for antibiotic treatment in patients with acute uncomplicated diverticulitis (AUD) could not demonstrate any benefit gained from antibiotic use. The aim of this study was to review the application of the no antibiotic policy and its consequences in regard to complications and recurrence. METHODS: This retrospective population-based cohort study included all patients diagnosed with all types of colonic diverticulitis during the year 2011 at Västmanland Hospital Västerås, Sweden. All medical records were carefully reviewed. Primary outcomes were the types of treatment adopted for diverticulitis, complications and recurrence. RESULTS: In total, 246 patients with computer tomography-verified diverticulitis were identified, 195 with primary AUD and 51 with acute complicated diverticulitis. Age, sex, and temperature at admission were similar between the groups but there was a significant difference in white blood cell count, C-reactive protein, and length of hospital stay. In the AUD group, 178 (91.3%) patients were not treated with antibiotics. In this group, there were six (3.4%) readmissions but only two developed an abscess. Of the remaining 17 patients (8.7%) who were treated with antibiotics in the AUD group, one developed an abscess. Twenty-five (12.8%) patients in the AUD group presented with a recurrence within 1 year. CONCLUSION: The no-antibiotic policy for AUD is safe and applicable in clinical practice. The previous results of a low complication and recurrence rate in AUD are confirmed. There is no need for antibiotic treatment for AUD. What does this paper add to the literature? Despite published papers with excellent results, there are still doubts about patient safety against the policy to not use antibiotics in acute uncomplicated diverticulitis. This is the first paper, in actual clinical practice, to confirm that the no antibiotic policy for acute uncomplicated diverticulitis is applicable and safe.

KI, WU and Merkel cell polyomaviruses: a new era for human polyomavirus research.

The recent discoveries of KI, WU, and Merkel cell polyomaviruses (PyVs) have rekindled interest in the Polyomaviridae and their relation to human disease. Although it may be too early to draw firm conclusions, it seems apparent that these new viruses follow precedents established by other Py viruses: a benign initial infection at an early age, widespread prevalence in the population, and pathologic consequences only in the elderly and/or immunosuppressed. The discovery of Merkel cell PyV (MCPyV) integration into the malignant cell genome immediately implicates this agent in an oncogenic process predicted by previous research with SV40 and murine PyV (MPyV). Their discovery is another reminder that we certainly have not seen the end of novel human polyomavirus identification, but rather the beginning of a new era.

Murine pneumotropic virus chimeric Her2/neu virus-like particles as prophylactic and therapeutic vaccines against Her2/neu expressing tumors.

Virus-like particles (VLPs) have increasingly attracted attention as DNA-free and safe antigen carriers in tumor immunotherapy, requiring only minute amounts of antigens. Previously, we have immunized with murine polyomavirus (MPyV) VLPs carrying human Her2/neu and prevented the outgrowth of a human Her2/neu expressing tumor in a transplantable tumor model as well as outgrowth of spontaneous rat Her2/neu carcinomas in BALB-neuT mice. Here, we examine if prophylactic and therapeutic protection could be obtained with murine pneumotropic virus (MPtV) VLPs, and study the cross-reactivity between human and rat Her2/neu. VLPs from MPyV and MPtV carrying human or rat Her2/neu were tested in two transplantable tumor models against a human Her2/neu positive (D2F2/E2) and a rat Her2/neu positive tumor cell line (TUBO). Rat Her2/neu-VLPs were also tested in BALB-neuT mice. Her2/neu-MPtVLPs were as efficient as prophylactic vaccines against D2F2/E2 and TUBO as those from MPyV. Homologous Her2/neu was better than heterologous, i.e. human Her2/neu-VLPs were better than rat Her2/neu-VLPs against D2F2/E2 and vice versa. Moreover, therapeutic immunization with human Her2/neu-VLPs together with CpG given up to 6 days after challenge protected against D2F2/E2. In BALB-neuT mice, rat Her2/neu-VLPs were less efficient than human Her2/neu-VLPs used in our previous study, implying that protection seen in that study was partly due to the use of human rather than rat Her2/neu. In conclusion, Her2/neu-MPtVLPs are effective both as prophylactic and therapeutic tumor vaccines. Homologous Her2/neu-VLPs are superior to heterologous in transplantable tumor models, while the opposite is true in BALB-neuT mice.

A single vaccination with polyomavirus VP1/VP2Her2 virus-like particles prevents outgrowth of HER-2/neu-expressing tumors.

Murine polyomavirus (MPyV) VP1 virus-like particles (VLPs), containing a fusion protein between MPyV VP2 and the extracellular and transmembrane domain of HER-2/neu (Her2), Her2(1-683)PyVLPs, were tested for their ability to vaccinate against Her2-expressing tumors in two different in vivo models. Protection was assessed both against a lethal challenge with a BALB/c mammary carcinoma transfected with human Her2 (D2F2/E2) and against the outgrowth of autochthonous mammary carcinomas in BALB-neuT mice, transgenic for the activated rat Her2 oncogene. A single injection of Her2(1-683)PyVLPs before tumor inoculation induced a complete rejection of D2F2/E2 tumor cells in BALB/c mice. Similarly, a single injection of Her2(1-683)PyVLPs at 6 weeks of age protected BALB-neuT mice with atypical hyperplasia from a later outgrowth of mammary carcinomas, whereas all controls developed palpable tumors in all mammary glands. VLPs containing only VP1 and VP2 did not induce protection. The protection elicited by Her2(1-683)PyVLPs vaccination was most likely due to a cellular immune response because a Her2-specific response was shown in an ELISPOT assay, whereas antibodies against Her2 were not detected in any of the two models. The results show the feasibility of using MPyV-VLPs carrying Her2 fusion proteins as safe and efficient vaccines against Her2-expressing tumors.

[Gastric bypass versus sleeve, pros and cons]. / Gastrisk bypass eller sleeve-gastrektomi ­ vilken är bäst?

Gastric bypass versus sleeve, pros and cons  The most commonly performed bariatric procedure today is gastric bypass, while sleeve gastrectomy has become more common in recent years. Little is known about the long-term effects of sleeve gastrectomy and despite several randomized trials it is still unknown which procedure is the most favourable. Two recently published randomized trials show that the two procedures result in comparable weight loss in the short term while gastric bypass could possibly result in better weight loss in the long term. However, gastric bypass tends to lead to a higher incidence of post-operative complications compared to sleeve gastrectomy.

Murine polyomavirus virus-like particles (VLPs) as vectors for gene and immune therapy and vaccines against viral infections and cancer.

This review describes the use of murine polyomavirus "virus-like" particles (MPyV-VLPs), free from viral genes, as vectors for gene and immune therapy and as vaccines. For large-scale MPyV-VLP manufacture, VP1 is produced in a baculovirus insect cell system, E. coli or in yeast. MPyV-VLPs bind eukaryotic DNA and introduce this DNA into various cell types in vitro and in vivo. In normal and T-cell-deficient mice, this results in the production of anti-MPyV-VLP (and MPyV) antibodies. Furthermore, repeated MPyV-VLP vaccination has been shown to prevent primary MPyV infection in normal and T-cell-deficient mice, and the outgrowth of some MPyV-induced tumours in normal mice. Moreover, when inoculated with gene constructs encoding for HIV p24, MPyV-VLPs augment the antibody response to p24. In addition, MPyV-VLPs, containing fusion proteins between the VP2 or VP3 capsid protein and selected antigens, can be used as vaccines. Notably, one vaccination with MPyV-VLPs, containing a fusion protein between VP2 and the extracellular and transmembrane parts of the HER-2/neu oncogene, immunizes against outgrowth of a HER-2/neu-expressing tumour in Balb/c mice and also against the development of mammary carcinomas in BALB-neuT transgenic mice. Finally, a second polyoma VLP-vector based on murine pneumotropic virus (MPtV-VLP), which does not cross-react serologically with MPyV-VLP (and MPyV), has been developed and can be used to conduct prime boost gene and immune therapy and vaccination. In summary, MPyV-VLPs are useful vectors for gene therapy, immune therapy and as vaccines and, in combination with MPyV-VLPs, MPtV-VLPs are potentially useful as prime-boost vectors.

The choice of anaesthetic--sevoflurane or propofol--and outcome from cancer surgery: a retrospective analysis.

BACKGROUND: Commonly used inhalational hypnotics, such as sevoflurane, are pro-inflammatory, whereas the intravenously administered hypnotic agent propofol is anti-inflammatory and anti-oxidative. A few clinical studies have indicated similar effects in patients. We examined the possible association between patient survival after radical cancer surgery and the use of sevoflurane or propofol anaesthesia. PATIENTS AND METHODS: Demographic, anaesthetic, and surgical data from 2,838 patients registered for surgery for breast, colon, or rectal cancers were included in a database. This was record-linked to regional clinical quality registers. Cumulative 1- and 5-year overall survival rates were assessed using the Kaplan-Meier method, and estimates were compared between patients given propofol (n = 903) or sevoflurane (n = 1,935). In a second step, Cox proportional hazard models were calculated to assess the risk of death adjusted for potential effect modifiers and confounders. RESULTS: Differences in overall 1- and 5-year survival rates for all three sites combined were 4.7% (p = 0.004) and 5.6% (p < 0.001), respectively, in favour of propofol. The 1-year survival for patients operated for colon cancer was almost 10% higher after propofol anaesthesia. However, after adjustment for several confounders, the observed differences were not statistically significant. CONCLUSION: Propofol anaesthesia might be better in surgery for some cancer types, but the retrospective design of this study, with uneven distributions of several confounders, distorted the picture. These uncertainties emphasize the need for a randomized controlled trial.

Murine polyomavirus virus-like particles carrying full-length human PSA protect BALB/c mice from outgrowth of a PSA expressing tumor.

Virus-like particles (VLPs) consist of capsid proteins from viruses and have been shown to be usable as carriers of protein and peptide antigens for immune therapy. In this study, we have produced and assayed murine polyomavirus (MPyV) VLPs carrying the entire human Prostate Specific Antigen (PSA) (PSA-MPyVLPs) for their potential use for immune therapy in a mouse model system. BALB/c mice immunized with PSA-MPyVLPs were only marginally protected against outgrowth of a PSA-expressing tumor. To improve protection, PSA-MPyVLPs were co-injected with adjuvant CpG, either alone or loaded onto murine dendritic cells (DCs). Immunization with PSA-MPyVLPs loaded onto DCs in the presence of CpG was shown to efficiently protect mice from tumor outgrowth. In addition, cellular and humoral immune responses after immunization were examined. PSA-specific CD4(+) and CD8(+) cells were demonstrated, but no PSA-specific IgG antibodies. Vaccination with DCs loaded with PSA-MPyVLPs induced an eight-fold lower titre of anti-VLP antibodies than vaccination with PSA-MPyVLPs alone. In conclusion, immunization of BALB/c mice with PSA-MPyVLPs, loaded onto DCs and co-injected with CpG, induces an efficient PSA-specific tumor protective immune response, including both CD4(+) and CD8(+) cells with a low induction of anti-VLP antibodies.

CD4+ and CD8+ T cells can act separately in tumour rejection after immunization with murine pneumotropic virus chimeric Her2/neu virus-like particles.

BACKGROUND: Immunization with murine pneumotropic virus virus-like particles carrying Her2/neu (Her2MPtVLPs) prevents tumour outgrowth in mice when given prophylactically, and therapeutically if combined with the adjuvant CpG. We investigated which components of the immune system are involved in tumour rejection, and whether long-term immunological memory can be obtained. METHODOLOGY AND RESULTS: During the effector phase in BALB/c mice, only depletion of CD4+ and CD8+ in combination, with or without NK cells, completely abrogated tumour protection. Depletion of single CD4+, CD8+ or NK cell populations only had minor effects. During the immunization/induction phase, combined depletion of CD4+ and CD8+ cells abolished protection, while depletion of each individual subset had no or negligible effect. When tumour rejection was studied in knock-out mice with a C57Bl/6 background, protection was lost in CD4-/-CD8-/- and CD4-/-, but not in CD8-/- mice. In contrast, when normal C57Bl/6 mice were depleted of different cell types, protection was lost irrespective of whether only CD4+, only CD8+, or CD4+ and CD8+ cells in combination were eradicated. No anti-Her2/neu antibodies were detected but a Her2/neu-specific IFNgamma response was seen. Studies of long-term memory showed that BALB/c mice could be protected against tumour development when immunized together with CpG as long as ten weeks before challenge. CONCLUSION: Her2MPtVLP immunization is efficient in stimulating several compartments of the immune system, and induces an efficient immune response including long-term memory. In addition, when depleting mice of isolated cellular compartments, tumour protection is not as efficiently abolished as when depleting several immune compartments together.

Expression and serological characterization of polyomavirus WUPyV and KIPyV structural proteins.

The polyomaviruses WUPyV and KIPyV were recently discovered. We expressed their structural proteins VP1, VP2, and VP3, and the corresponding proteins of BKV and JCV, for immunoblotting of IgG antibodies from 115 wheezing young children and 25 asymptomatic adults. Furthermore, nasopharyngeal aspirates (NPA) and sera from the children were examined by PCR for viral DNA. The overlapping minor proteins VP2 and VP3 of WUPyV and KIPyV were more reactive in immunoblots than the major protein VP1; of 100 NPA PCR-negative wheezing children aged < or = 4 y, 31 (31%) and 31 (31%) were positive for WUPyV and KIPyV VP2/VP3, compared to only 3 (3%) and 5 (5%) for VP1, respectively. For comparison, the respective WUPyV and KIPyV IgG seroprevalences as determined by immunofluorescence assay (IFA) with nondenatured VP1 were 80% and 54%, respectively, among 50 NPA PCR-negative children aged < or = 2 y. This difference shows the importance of conformational VP1 antigenicity. Of the 25 adults, 52% and 68% were IgG-positive in immunoblots for VP2/VP3 of WUPyV and KIPyV, and 8% and 12% were for VP1, respectively. Of the 192 NPA samples studied by PCR, 7 (3.6%) were positive for WUPyV, and 3 (1.5%) were positive for KIPyV DNA. Unlike the NPA samples, none of the corresponding 443 sera contained WUPyV or KIPyV DNA. Together with the high VP2/VP3 IgG prevalence, this points to a paucity or brevity of KIPyV and WUPyV viremias among immunocompetent children. Our results indicate the significance of protein conformation in immunoreactivity of VP1, and show the antigenic importance of the WUPyV and KIPyV minor proteins VP2 and VP3. The high and rapidly increasing IgG prevalence rates observed in this study for WUPyV and KIPyV support the notion that these novel polyomaviruses are widespread and are acquired early in childhood.

Vaccination, immune and gene therapy based on virus-like particles against viral infections and cancer.

Virus-like particles (VLPs) are self-assembling, non-replicating particles lacking the viral genome that are formed by one or several viral structural proteins. VLPs can be purified after expression in yeast cells, insect cells using baculoviruses, Escherichia coli or mammalian cells. Recently, vaccines based on VLPs have come into focus with the FDA approval of a VLP-based vaccine against human papilloma viruses. However, this application of VLPs is just one of many developments within the VLP field. Other potential applications under development besides vaccines against viruses or cancers also include gene delivery and treatment of different disorders.

Identification of a third human polyomavirus.

We have previously reported on a system for large-scale molecular virus screening of clinical samples. As part of an effort to systematically search for unrecognized human pathogens, the technology was applied for virus screening of human respiratory tract samples. This resulted in the identification of a previously unknown polyomavirus provisionally named KI polyomavirus. The virus is phylogenetically related to other primate polyomaviruses in the early region of the genome but has very little homology (<30% amino acid identity) to known polyomaviruses in the late region. The virus was found by PCR in 6 (1%) of 637 nasopharyngeal aspirates and in 1 (0.5%) of 192 fecal samples but was not detected in sets of urine and blood samples. Since polyomaviruses have oncogenic potential and may produce severe disease in immunosuppressed individuals, continued searching for the virus in different medical contexts is important. This finding further illustrates how unbiased screening of respiratory tract samples can be used for the discovery of diverse virus types.

VP1 pseudocapsids, but not a glutathione-S-transferase VP1 fusion protein, prevent polyomavirus infection in a T-cell immune deficient experimental mouse model.

The ability to vaccinate against polyomavirus infection in a T-cell deficient as well as a normal immune context was studied using polyomavirus major capsid protein (VP1) pseudocapsids (VP1-ps) or a glutathione-S-transferase-VP1 (GST-VP1) fusion protein. VP1-ps (1 or 10 microg) were administered subcutaneously, alone or together with Freund's complete and incomplete adjuvant, to CD4(-/-)8(-/-) T-cell deficient or normal C57Bl/6 mice on four occasions. Alternatively, CD4(-/-)8(-/-) and normal mice were inoculated with either GST-VP1 or Py-VP1-ps (5 microg). Following immunisation, antibody titres were tested by ELISA to VP1-ps or GST-VP1 or by haemagglutination inhibition (HAI). Mice were then infected with polyomavirus. Three weeks post-infection, the mice were killed and examined for the presence of polyomavirus DNA by PCR. Viral DNA was not detected in CD4(-/-)8(-/-) mice immunised with either VP1-ps alone or in combination with Freund's complete and incomplete adjuvant, or in any of the normal mice immunised with VP1-ps or GST-VP1. However, viral DNA was detected in 2/5 of the CD4(-/-)8(-/-) mice immunised with GST-VP1 and in non-immunised controls. Greater antibody titres were observed to VP1-ps than to GST-VP1 in CD4(-/-)8(-/-) mice after VP1-ps compared to GST-VP1 immunisation and antibody responses were better in normal than in immune-deficient mice. Only immunisation with VP1-ps resulted in haemagglutination inhibition. Complete protection against polyomavirus infection in the T-cell deficient context was obtained with VP1-ps, but not with GST-VP1, immunisation using the present vaccination protocol.