Clinical Characteristics of Patients with Staphylococcus aureus Bile Infection.

BACKGROUND: The hepatobiliary system is a sterile micro-environment. Bacterial infection in this system is most commonly associated with anaerobes as well as gram-positive and gram-negative bacteria. Biliary infections with Staphylococcus aureus are poorly characterized. OBJECTIVES: To depict the clinical characteristics and outcome of patients with S. aureus infection of the hepatobiliary system. METHODS: Medical records of patients with bile cultures positive for S. aureus from January 2006 to November 2020 were extracted from the computerized database of a hospital in Israel. RESULTS: We analyzed the results of 28 cases that were found in the database. The mean age of study patients was 62.2 ± 19 years. Hypertension, dyslipidemia, chronic kidney disease, diabetes, and benign prostatic hypertrophy were the most common co-morbidities (57.1%, 32.1%, 25%, 25%, and 25%, respectively). Fourteen of the methicillin-resistant S. aureus (MRSA) bile cultures (82.3%) were a result of primary S. aureus biliary infections (no other source for S. aureus infection) and the remainder were of a secondary infection. Eight of the MRSA cultures (47.1%) were from hospital acquired infections. Increased hospital mortality in patients with S. aureus hepatobiliary infection was associated with hypertension (P = 0.04), bedridden status (P = 0.01), and nursing home residence (P = 0.003). CONCLUSIONS: Hepatobiliary infection with S. aureus can manifest in a variety of ways. S. aureus should be especially considered in patients who are bedridden, present with hypertension, or live in nursing homes because of their association with in-hospital mortality resulting from this entity.

Fetal Urinoma Due to Circulatory Disorders in an Umbilical Artery: Case Report.

Fetal urinoma is defined as an encapsulated accumulation of extravasated urine within the perirenal space or retroperitoneum. It is an uncommon finding in prenatal practice, and the vast majority of known cases are strongly associated with the existence of a urinary obstruction, such as posterior urethral valves, ureteropelvic junction obstruction, or ureterocele. We report a unique case of prenatally detected fetal bladder urinoma that occurred in the absence of an apparent obstructive uropathy, but was associated with extensive ischemic necrosis and calcifications of adjacent bladder wall, coexistent with signs of vascular supply decompensation.

Sleep Disturbances Can Be Prospectively Observed in Patients with an Inactive Inflammatory Bowel Disease.

BACKGROUND: Poor sleep quality is associated with adverse health consequences. Sleep disturbances can impact the immune function and inflammatory processes. Little is known about sleep disturbances in patients with inflammatory bowel disease (IBD), while not in flare, i.e., inactive. AIMS: To prospectively explore the sleep quality of patients with an inactive IBD. METHODS: This pilot study included 36 consecutive patients with IBD and 27 healthy volunteers. All IBD patients had an inactive disease. Participants underwent an overnight ambulatory polysomnography. Data on disease duration, medications, complications, and treatment were collected from the medical records. RESULTS: The mean age of the IBD and the control groups was 39 ± 15 and 34.6 ± 9.6 years. A significantly less rapid eye movement (REM) sleep was noted in the IBD group vs. control (23.7 vs. 27.8%, p = 0.047); light sleep percentage and REM latency were also longer in the IBD group. Moreover, oxygen desaturation below 90% was more common in the IBD group. All other sleep parameters including respiratory disturbance index, apnea-hypopnea index, number of wakes, sleep latency, and snoring strength were similar in both groups. CONCLUSIONS: Inactive IBD is associated with sleep disturbances. A larger prospective study should be conducted to confirm these findings.

Ameliorating Active Ulcerative Colitis via an Orally Available Toll-Like Receptor-9 Modifier: A Prospective Open-Label, Multicenter Phase II Trial.

BACKGROUND: Treatment of active ulcerative colitis is associated with incomplete efficacy, adverse events, and loss of response. Toll-like receptor-9 mediates innate and adaptive immune response toward intestinal microorganisms. The oral synthetic oligonucleotide toll-like receptor-9 modulator has demonstrated anti-inflammatory properties in colitis murine models and a satisfactory safety profile in humans. AIM: To evaluate the efficacy and safety of BL-7040 (a Toll-like receptor-9 modulator) in patients with moderately active ulcerative colitis. METHODS: Moderately active ulcerative colitis patients were included in this multicenter, open-label phase IIa trial. Concomitant mesalamine and steroids at a stable dose were allowed. Clinical outcome was evaluated using the Mayo score, histology, and mucosal cytokine levels. Side effects were registered. RESULTS: Sixteen out of 22 patients completed a 5-week treatment course and 2-week follow-up. Six patients discontinued the study, three of them due to adverse events. Clinical remission was observed in two patients (12.5 %), and clinical response as well as mucosal healing were achieved in half (50 %) of the patients, while all others remained stable. Furthermore, mucosal neutrophil (p = 0.002) and mucosal interleukin-6 levels (p = 0.046) were significantly reduced in responders compared to non-responders. Toll-like receptor-9 was well tolerated with only one unrelated to study drug serious adverse event (hemoglobin decrease) and 29 mild-to-moderate adverse events. CONCLUSIONS: Oral administration of the Toll-like receptor-9 agonist BL-7040 appeared efficacious, safe and well tolerated in patients with moderately active ulcerative colitis.

Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report.

The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment with PODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R.

The Importance of Intestinal Eotaxin-1 in Inflammatory Bowel Disease: New Insights and Possible Therapeutic Implications.

BACKGROUND: Involvement of eotaxin-1 in inflammatory bowel disease has been previously suggested and increased levels of eotaxin-1 have been described in both ulcerative colitis and in Crohn's disease. The association between serum levels of eotaxin-1 and that within the colonic mucosa has not been well defined, as is the potential therapeutic value of targeting eotaxin-1. AIMS: To characterize serum and intestinal wall eotaxin-1 levels in various inflammatory bowel disease patients and to explore the effect of targeting eotaxin-1 by specific antibodies in dextran sodium sulfate-induced colitis model. METHODS: Eotaxin-1 levels were measured in colonic biopsies and in the sera of 60 ulcerative colitis patients, Crohn's disease patients and healthy controls. We also followed in experimental colitis the effect of targeting eotaxin-1 by a monoclonal antibody. RESULTS: Colon eotaxin-1 levels were significantly increased in active but not in quiescent ulcerative colitis and Crohn's disease patients compared to healthy controls. Levels of eotaxin-1 in the colon were correlated with eosinophilia only in tissues from active Crohn's disease patients. Our results did not show any statistically significant change in serum eotaxin-1 levels among ulcerative colitis, Crohn's disease and healthy controls. Moreover, we demonstrate that in dextran sodium sulfate-induced colitis, targeting of eotaxin-1 with 2 injections of anti eotaxin-1 monoclonal antibody ameliorates disease activity along with decreasing colon weight and improving histologic inflammation. CONCLUSION: Eotaxin-1 is increasingly recognized as a major mediator of intestinal inflammation. Our preliminary human and animal results further emphasize the value of targeting eotaxin-1 in inflammatory bowel disease.

Enzyme pattern of biliary colic: A counterintuitive picture.

AIM: To evaluate the diagnostic value of serial biochemical blood tests in the diagnosis of biliary colic. METHODS: Files were reviewed of 1039 patients who were admitted to the Share'e Zedek Medical Center emergency department between the years 2012-2013, and received the coding of acute biliary disease. Of these, the first 100 cases were selected that met the following criteria: (1) a diagnosis of biliary colic or symptomatic cholelithiasis; (2) at least two biochemical blood tests performed; and (3) 18 years of age or older. Patients with other acute biliary diseases were excluded. The biochemical profile of the patients was analyzed as were their clinical and radiological findings. RESULTS: Three-quarters of the patients were women, whose average age of 37 years was younger than the average of the men, at 50 years. According to their histories, 47% of the patients had previously known cholelithiasis. Pain in either the right upper quadrant or the epigastrium was the presenting symptom in 93% cases. The greatest change in serum biochemical results was seen during the first day of the patients' admissions. Alanine aminotransferase (ALT) showed the highest initial rise above the reference range, followed by aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin and alkaline phosphatase (ALKP) - all these increases were statistically significant (P < 0.05). AST showed the sharpest decline followed by bilirubin and ALT. GGT and ALKP did not fall. A sharp rise and fall in liver enzymes, especially during the first day, most prominently in AST and ALT, was seen in 70% percent of cases. In 65% of cases trans-abdominal sonography did not give diagnostic findings. CONCLUSION: Serial serum liver enzyme measurements are helpful in the initial diagnosis of acute biliary colic.

Non-invasive diagnosis of liver fibrosis and cirrhosis.

The evaluation and follow up of liver fibrosis and cirrhosis have been traditionally performed by liver biopsy. However, during the last 20 years, it has become evident that this "gold-standard" is imperfect; even according to its proponents, it is only "the best" among available methods. Attempts at uncovering non-invasive diagnostic tools have yielded multiple scores, formulae, and imaging modalities. All are better tolerated, safer, more acceptable to the patient, and can be repeated essentially as often as required. Most are much less expensive than liver biopsy. Consequently, their use is growing, and in some countries the number of biopsies performed, at least for routine evaluation of hepatitis B and C, has declined sharply. However, the accuracy and diagnostic value of most, if not all, of these methods remains controversial. In this review for the practicing physician, we analyze established and novel biomarkers and physical techniques. We may be witnessing in recent years the beginning of the end of the first phase for the development of non-invasive markers. Early evidence suggests that they might be at least as good as liver biopsy. Novel experimental markers and imaging techniques could produce a dramatic change in diagnosis in the near future.

Sustained virological response with intravenous silibinin: individualized IFN-free therapy via real-time modelling of HCV kinetics.

BACKGROUND & AIMS: Intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR. METHODS: A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR. RESULTS: Based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV was feasible, safe and achieved SVR (week-33). CONCLUSIONS: We report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.

From airway inflammation to inflammatory bowel disease: eotaxin-1, a key regulator of intestinal inflammation.

Eotaxin-1 (CCL-11) is a potent eosinophil chemoattractant that is considered a major contributor to tissue eosinophilia. Elevated eotaxin-1 levels have been described in various pathologic conditions, ranging from airway inflammation, to Hodgkin lymphoma, obesity and coronary artery disease. The main receptor for eotaxin-1 is CCR3; however, recent evidence indicates that eotaxin-1 may also bind to other receptors expressed by various cell types, suggesting a more widespread regulatory role for eotaxin-1 beyond the recruitment of eosinophils. Eotaxin-1 is also strongly associated with various gastrointestinal (GI) disorders. Although the etiology of inflammatory bowel disease (IBD) is still unknown, eotaxin-1 may play a key role in the development of mucosal inflammation. In this review, we summarize the biological context and effects of eotaxin-1, as well as its potential role as a therapeutic target, with a special focus on gastrointestinal inflammation.

Unexpected FDG-PET uptake in the gastrointestinal tract: endoscopic and histopathological correlations.

AIM: To investigate the nature and significance of unexpected positron emission tomography with fluorodeoxyglucose (FDG-PET) uptake within the gastrointestinal tract (GIT). METHODS: Patients with unexpected FDG-PET findings in the GIT were evaluated. All patients had a previous confirmed malignancy, either solid or lymphoproliferative. The radiologic reports were performed by experienced radiologists with an exclusive PET expertise. Endoscopy, i.e., esophagogastroduodenoscopy (EGD) and colonoscopy, and histopathological evaluation of all findings was performed in all patients in accordance to the FDG-PET results. The findings from each of these modalities were compared to each other. Both clinically significant and insignificant findings were assessed. RESULTS: Seventy-two patients were endoscopically evaluated. Twenty-seven patients (37.5%) had primarily a lymphoproliferative tumor and 45 (62.5%) had solid tumors. In 50 patients (69.4%) the endoscopic examination revealed lesions in the same anatomical areas as the FDG-PET findings. Among these 50 patients, malignant and premalignant lesions i.e., adenomatous polyps were found in 16 (32%) and 9 (18%) patients, respectively. Inflammation was noted in an additional 20 patients (40%). Compared to primary solid tumors, a background of primary lymphoproliferative malignancy was more likely to reveal an additional primary malignancy (15.6% vs 33.3%, respectively, P < 0.01). EGD compared to colonoscopy, revealed altogether 11 (25.6%) new malignancies compared to 5 (17.2%), respectively, P = 0.12. No GIT clinically significant findings were overseen by the FDG-PET. CONCLUSION: Unexpected FDG uptake in the GIT is commonly encountered and may contain significant findings. Endoscopy evaluation is justified in order to detect these additional findings.

Normal vitamin D levels are associated with spontaneous hepatitis B surface antigen seroclearance.

AIM: To investigate a possible association between serum vitamin D levels and spontaneous hepatitis B surface antigen (HBsAg) seroclearance. METHODS: Fifty-three patients diagnosed with chronic inactive hepatitis B and spontaneous HBsAg seroclearance were followed up in two Israeli liver units between 2007 and 2012. This retrospective study reviewed medical charts of all the patients, extracting demographic, serological and vitamin D rates in the serum, as well as medical conditions and current medical therapy. Spontaneous HBsAg seroclearance was defined as the loss of serum HBsAg indefinitely. Vitamin D levels were compared to all patients who underwent spontaneous HBsAg seroclearance. RESULTS: Out of the 53 patients who underwent hepatitis B antigen seroclearance, 44 patients (83%) had normal levels of 25-hydroxyvitamin vitamin D compared to 9 patients (17%) who had below normal levels. Multivariate analysis showed that age (> 35 years) OR = 1.7 (95%CI: 1.25-2.8, P = 0.05), serum vitamin D levels (> 20 ng/mL) OR = 2.6 (95%CI: 2.4-3.2, P = 0.02), hepatitis B e antigen negativity OR = 2.1 (95%CI: 2.2-3.1, P = 0.02), low viral load (hepatitis B virus DNA < 100 IU/mL) OR = 3 (95%CI: 2.6-4.2, P = 0.01) and duration of HBsAg seropositivity (> 8 years) OR = 1.6 (95%CI: 1.15-2.6, P = 0.04) were also associated with spontaneous HBsAg seroclearance. CONCLUSION: We found a strong correlation between normal vitamin D levels and spontaneous HBsAg seroclearance.

Endoplasmic reticulum stress induces a caspase-dependent N-terminal cleavage of RBX1 protein in B cells.

Endoplasmic reticulum (ER) stress develops when the ER is overloaded with too many proteins to fold. This elicits a signaling pathway called the unfolded protein response. The unfolded protein response is physiologically required for the terminal development of B cells into antibody-secreting plasma cells. Ring Box Protein 1 (RBX1) is a 14-kDa protein necessary for ubiquitin ligation activity of the multimeric cullin ring ubiquitin ligases (CRLs). As RBX1 is shared by a large number of CRLs, alterations in its activity may lead to global changes in protein stability. We discovered that RBX1 is cleaved in the course of LPS-induced plasma cell differentiation and in multiple myeloma cell lines upon induction of pharmacological ER stress. The cleavage is executed by several caspase proteases that cleave RBX1 eight amino acids from the N terminus. To address the possible implication of RBX1 cleavage for CRL activity, we replaced the endogenous RBX1 homolog of the yeast Saccharomyces cerevisiae, Roc1, with the wild type or the N-terminal Δ8 mutant human RBX1. We show that yeast expressing the cleaved RBX1 are hypersensitive to ER stress and are impaired in CRL-mediated ubiquitination and degradation. We propose a model by which N-terminal cleavage of RBX1 impairs its activity and promotes susceptibility to ER stress induction.

Direct proteasome binding and subsequent degradation of unspliced XBP-1 prevent its intracellular aggregation.

The non-canonical splicing of XBP-1 mRNA is a hallmark of the mammalian unfolded protein response (UPR). The proteasomal degradation of unspliced XBP-1 (XBP-1u) facilitates the termination of the UPR. Thus, understanding the mechanism of XBP-1u degradation may allow control over UPR duration and intensity. We show that XBP-1u interacts with purified 20S proteasomes through its unstructured C-terminus, which leads to its degradation in a manner that autonomously opens the proteasome gate. In living cells, the C-terminus of XBP-1u accumulates in aggresome structures in the presence of proteasome inhibitors. We propose that direct proteasomal degradation of XBP-1u prevents its intracellular aggregation.

Immunostimulatory oligonucleotides inhibit colonic proinflammatory cytokine production in ulcerative colitis.

BACKGROUND: We previously showed that Toll-like receptor-9 (TLR-9) ligands ameliorate experimental colitis. In this study, we evaluated the effect of TLR-9 ligands on the generation of proinflammatory cytokines by human colonic mucosa. MATERIALS AND METHODS: Colonoscopic biopsies were obtained from patients with active ulcerative colitis (UC) and from normal subjects. The tissue was organ cultured for 24 hours in the presence or absence of different types of immunostimulatory (ISS) (CpG)-oligonucleotides (ODNs). Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the medium were determined by enzyme-linked immunosorbent assay. RESULTS: In active UC, hTNF-alpha and hIL-lbeta generation by inflamed colonic mucosa is 7- and 3-fold higher, respectively, than their generation by normal mucosa. Class B CpG ODNs inhibited colonic TNF-alpha and IL-1beta generation by 50%, whereas class A or C ODNs had a partial or no effect, respectively. A novel class of ODNs that is based on multiple TCG repeats was as effective as class B ODNs. This inhibition resulted from the transcriptional suppression of IL-1beta that occurred within the first 2 hours after ISS-ODN incubation. The addition of chloroquine abolished the inhibitory effects of ISS-ODNs on colonic TNF-alpha and IL-1beta generation. CONCLUSIONS: Only certain classes of ISS-ODNs inhibit the enhanced TNF-alpha and IL-1beta generated ex vivo by inflamed colonic mucosa of patients with UC. The effect of ISS-ODNs is mediated by triggering of TLR-9. These results suggest a potential therapeutic value for ISS-ODNs in UC.