Inflammatory bowel disease masquerading as traveller's diarrhoea

Diarrhoea that occurs during or after recent travel is predominantly infectious in nature; however, in atypical or prolonged cases a broader range of aetiologies for diarrhoea must be considered, and a careful history and examination may reveal clues to more sinister causes of diarrhoea. We report two cases in which a recent travel history and a positive stool culture or polymerase chain reaction testing for bacterial pathogens delayed the diagnosis of ulcerative colitis. As a result of severe inflammatory bowel disease, colectomy was the final result in both cases. Early consideration of causes other than infection for traveller's diarrhoea may prevent unnecessary morbidity in young patients.     

The effect of medicare health maintenance organizations on hospitalization rates for ambulatory care-sensitive conditions

OBJECTIVE: The objective of this study was to estimate the effect of Medicare Health Maintenance Organization (HMO) enrollment on hospitalization rates and total inpatient days for ambulatory care-sensitive conditions (ACSCs) after controlling for selection. RESEARCH DESIGN: Simultaneous equations using a discrete factor selection model are used to estimate the probability of HMO enrollment, hospitalization rates, and total inpatient days for ACSCs. SUBJECTS: Enrollment data on Medicare beneficiaries in California were linked to hospital discharge data from the California Office of Statewide Health Planning and Development for January through December 1996. The following beneficiaries were excluded: 1) end-stage renal disease, 2) under 65 years of age, 3) not covered by both Medicare Part A and Part B, 4) switched between HMOs and fee-for-service (FFS), and 5) switched between HMOs. The sample was stratified by age, gender, race, county, disability, Medicaid eligibility, HMO status, and death. A 2% random sample from the 4 California counties with the largest Medicare enrollment yielded 10,448 HMO enrollees and 11,803 FFS beneficiaries. RESULTS: Using a discrete factor selection model, we estimated the rate of ACSC hospitalizations among FFS beneficiaries would decline from 51.2 to 44.2 per 1000 if all FFS beneficiaries joined an HMO. Similarly, the mean total inpatient days for ACSC hospitalizations would be reduced from 7.5 days to 5.1 days if all FFS beneficiaries joined an HMO. CONCLUSIONS: After controlling for selection, Medicare HMO enrollees have lower hospitalization rates and fewer total inpatient days for 15 ACSCs than Medicare FFS beneficiaries. These findings suggest selection of healthier beneficiaries into HMOs does not completely explain their lower rates of ACSC hospitalization.     

Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab')2-ricin toxin A chain immunotoxin

A new pharmacologic agent, anti-CD3F(ab')2-ricin toxin A chain (RTA), was synthesized for the purpose of targeting T cells and as a means of treating established graft-versus-host disease (GVHD). The Fc region of anti-CD3 monoclonal antibody (MoAb) was removed to prevent its ability to activate T cells. The resulting F(ab')2 fragments were conjugated to deglycosylated RTA (dgRTA), a catalytic and potent phytotoxin. The resulting immunotoxin (IT) was potent (greater than 95% inhibition) and selective in inhibiting T-cell mitogenesis in vitro. In vivo, the IT depleted 80% of T cells in mice receiving bone marrow (BM) transplants. Transplantation in an aggressive acute GVHD model using C57BL/6 donor cells and H-2 disparate B10.BR recipients resulted in an infiltration of CD3-expressing cells and a median survival time (MST) of 20 to 30 days. A 5-day course of anti-CD3F(ab')2-RTA (30 micrograms/d intraperitoneally) beginning 7 days after GVHD induction was beneficial in treating established GVHD in these mice, as evidenced by significantly prolonged survival (MST, greater than 80 days), superior mean weight values, and improved clinical appearance. Neither intact anti-CD3, unconjugated anti-CD3 F(ab')2 fragments, nor a mixture of anti-CD4 and anti-CD8 MoAbs (which are highly effective in prophylactic models) were as effective. F(ab')2 fragments made from anti-Lyt-1 (the murine homologue of human anti-CD5) linked to RTA were also not effective, despite the fact that both anti-CD3F(ab')2-RTA and anti-Lyt- 1F(ab')2-RTA had similar half-lives of about 9 hours. The IT also increased MST in two aggressive models of GVHD across non-H-2 minor histocompatibility barriers, indicating that the usefulness of anti- CD3F(ab')2-dgRTA is not limited to a single-strain combination. This agent should be further investigated as an alternative to current strategies for treating steroid refractory GVHD.     

Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.     

Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population‐based cohort study

Aim The aim of this study was to assess the independent role of cerebral lesions on ultrasound scan, and several other neonatal and obstetric factors, as potential predictors of cerebral palsy (CP) in a large population‐based cohort of very preterm infants. Method As part of EPIPAGE, a population‐based prospective cohort study, perinatal data and outcome at 5 years of age were recorded for 1812 infants born before 33 weeks of gestation in nine regions of France in 1997. Results The study group comprised 942 males (52%) and 870 females with a mean gestational age of 30 weeks (SD 2wks; range 24–32wks) and a mean birthweight of 1367g (SD 393g; range 450–2645g). CP was diagnosed at 5 years of age in 159 infants (prevalence 9%; 95% confidence interval [CI] 7–10%), 97 males and 62 females, with a mean gestational age of 29 weeks (SD 2wks; range 24–32wks) and a mean birthweight of 1305g (SD 386g; range 500–2480g). Among this group, 67% walked without aid, 14% walked with aid, and 19% were unable to walk. Spastic, ataxic, and dyskinetic CP accounted for 89%, 7%, and 4% of cases respectively. The prevalence of CP was 61% among infants with cystic periventricular leukomalacia, 50% in infants with intraparenchymal haemorrhage, 8% in infants with grade I intraventricular haemorrhage, and 4% in infants without a detectable cerebral lesion. After controlling for cerebral lesions and obstetric and neonatal factors, only male sex (odds ratio [OR] 1.52; 95% CI 1.03–2.25) and preterm premature rupture of membranes or preterm labour (OR 1.72; 95% CI 0.95–3.14) were predictors of the development of CP in very preterm infants. Interpretation Cerebral lesions were the most important predictor of CP in very preterm infants. In addition, infant sex and preterm premature rupture of membranes or preterm labour were also independent predictors of CP.     

Celiac disease: Prevalence, diagnosis, pathogenesis and treatment

Celiac disease(CD) is one of the most common diseases,resulting from both environmental(gluten) and genetic factors [human leukocyte antigen(HLA) and nonHLA genes].The prevalence of CD has been estimated to approximate 0.5%-1% in different parts of the world.However,the population with diabetes,autoimmune disorder or relatives of CD individuals have even higher risk for the development of CD,at least in part,because of shared HLA typing.Gliadin gains access to the basal surface of the epithelium,and interact directly with the immune system,via both trans-and para-cellular routes.From a diagnostic perspective,symptoms may be viewed as either "typical" or "atypical".In both positive serological screening results suggestive of CD,should lead to small bowel biopsy followed by a favourable clinical and serological response to the gluten-free diet(GFD) to confirm the diagnosis.Positive anti-tissue transglutaminase antibody or antiendomysial antibody during the clinical course helps to confirm the diagnosis of CD because of their over 99% specificities when small bowel villous atrophy is present on biopsy.Currently,the only treatment available for CD individuals is a strict life-long GFD.A greater understanding of the pathogenesis of CD allows alternative future CD treatments to hydrolyse toxic gliadin peptide,prevent toxic gliadin peptide absorption,blockage of selective deamidation of specific glutamine residues by tissue,restore immune tolerance towards gluten,modulation of immune response to dietary gliadin,and restoration of intestinal architecture.     

Novel microsatellite loci for studies of Thamnophis Gartersnake genetic identity and hybridization

Butler??s Gartersnakes (BGS; Thamnophis butleri) are confined to open and semi-open canopy wetlands and adjacent uplands, habitats under threat of development in Wisconsin. To address issues of species identity and putative hybridization with congeneric snakes, a suite of 18 microsatellite loci capable of cross-species amplification of Plains Gartersnakes (T. radix) and Common Gartersnakes (T. sirtalis) was developed. All loci were polymorphic in BGS with mean number of alleles per locus of 16.11 (range?=?3?C41) and mean observed heterozygosity of 0.659 (range?=?0.311?C0.978). Loci amplified efficiently in the congeneric species with high levels of intra- and inter-specific variation. These loci will aid ongoing efforts to effectively identify and manage BGS in Wisconsin.     

High Rate of Mutational Events in SARS-CoV-2 Genomes across Brazilian Geographical Regions,February 2020 to June 2021

Brazil was considered one of the emerging epicenters of the coronavirus pandemic in 2021, experiencing over 3000 daily deaths caused by the virus at the peak of the second wave. In total, the country had more than 20.8 million confirmed cases of COVID-19, including over 582,764 fatalities. A set of emerging variants arose in the country, some of them posing new challenges for COVID-19 control. The goal of this study was to describe mutational events across samples from Brazilian SARS-CoV-2 sequences publicly obtainable on Global Initiative on Sharing Avian Influenza Data-EpiCoV (GISAID-EpiCoV) platform and to generate indexes of new mutations by each genome. A total of 16,953 SARS-CoV-2 genomes were obtained, which were not proportionally representative of the five Brazilian geographical regions. A comparative sequence analysis was conducted to identify common mutations located at 42 positions of the genome (38 were in coding regions, whereas two were in 5′ and two in 3′ UTR). Moreover, 11 were synonymous variants, 27 were missense variants, and more than 44.4% were located in the spike gene. Across the total of single nucleotide variations (SNVs) identified, 32 were found in genomes obtained from all five Brazilian regions. While a high genomic diversity has been reported in Europe given the large number of sequenced genomes, Africa has demonstrated high potential for new variants. In South America, Brazil, and Chile, rates have been similar to those found in South Africa and India, providing enough “space” for new mutations to arise. Genomic surveillance is the central key to identifying the emerging variants of SARS-CoV-2 in Brazil and has shown that the country is one of the “hotspots” in the generation of new variants.