Randomized, placebo-controlled, double-blinded study of prophylactic cranberries use in women with recurrent uncomplicated cystitis.

BACKGROUND: Τhe adherence of p-fimbriated Escherichia coli (E. coli) to urothelial cells leading to recurrent urinary tract infections (rUTIs) may be prevented by proanthocyanidins (PACs) contained in American cranberries. PURPOSE: The purpose of this clinical trial was to assess the clinical utility of prophylactic use of high-dose PACs daily in women with a history of rUTIs. MATERIALS AND METHODS: 172 adult women with a history of rUTIs, defined as ≥ 2 within a 6-month period or ≥ 3 within a 12-month period were enrolled and randomized in two groups to receive either Cysticlean™ 240 mg or placebo for a 12-month period. Urine samples, vaginal and rectal swabs were collected at initial and quarterly study visits. The primary study endpoints were the number of urinary tract infections (UTIs) and changes in Quality of Life (QoL), assessed by the 36-Item Short Form Survey (SF-36) questionnaire. RESULTS: 160 adult women of median age 40 years old (range 19-82) were finally analyzed in this randomized, placebo-controlled, double-blinded clinical trial. In response to intervention, the number of UTIs was significantly lower (Incidence rate ratio IRR 0.49, p < 0.001) and QoL was slightly improved. The numbers of E. coli isolates detected in vaginal (IRR 0.71, p value < 0.001) and in rectal swabs (IRR 0.87, p value < 0.001) were also significantly decreased. No adverse events were reported. CONCLUSION: The daily use of Cysticlean™ 240 mg was associated with a reduction of UTIs and a prolongation of UTI-free survival compared to placebo treatment, supporting its use as prophylaxis in this patient population. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT03032003.

Extracorporeal organ support for critically ill patients: Overcoming the past, achieving the maximum at present, and redefining the future.

Extracorporeal organ support (ECOS) has made remarkable progress over the last few years. Renal replacement therapy, introduced a few decades ago, was the first available application of ECOS. The subsequent evolution of ECOS enabled the enhanced support to many other organs, including the heart [veno-arterial extracorporeal membrane oxygenation (ECMO), slow continuous ultrafiltration], the lungs (veno-venous ECMO, extracorporeal carbon dioxide removal), and the liver (blood purification techniques for the detoxification of liver toxins). Moreover, additional indications of these methods, including the suppression of excessive inflammatory response occurring in severe disorders such as sepsis, coronavirus disease 2019, pancreatitis, and trauma (blood purification techniques for the removal of exotoxins, endotoxins, or cytokines), have arisen. Multiple organ support therapy is crucial since a vast majority of critically ill patients present not with a single but with multiple organ failure (MOF), whereas, traditional therapeutic approaches (mechanical ventilation for acute respiratory failure, antibiotics for sepsis, and inotropes for cardiac dysfunction) have reached the maximum efficacy and cannot be improved further. However, several issues remain to be clarified, such as the complexity and cost of ECOS systems, standardization of indications, therapeutic protocols and initiation time, choice of the patients who will benefit most from these interventions, while evidence from randomized controlled trials supporting their use is still limited. Nevertheless, these methods are currently a part of routine clinical practice in intensive care units. This editorial presents the past, present, and future considerations, as well as perspectives regarding these therapies. Our better understanding of these methods, the pathophysiology of MOF, the crosstalk between native organs resulting in MOF, and the crosstalk between native organs and artificial organ support systems when applied sequentially or simultaneously, will lead to the multiplication of their effects and the minimization of complications arising from their use.

Prevention, diagnostic evaluation, management and prognostic implications of liver disease in critically ill patients with COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, broke out in December 2019 in Wuhan city of China and spread rapidly worldwide. Therefore, by March 2020, the World Health Organization declared the disease a global pandemic. Apart from the respiratory system, various other organs of the human body are also seriously affected by the virus. Liver injury in patients with a severe form of COVID-19 is estimated to be 14.8%-53.0%. Elevated levels of total bilirubin, aspartate aminotransferase and alanine aminotransferase and low levels of serum albumin and prealbumin are the main laboratory findings. Patients with pre-existing chronic liver disease and cirrhosis are much more prone to develop severe liver injury. This literature review presented the recent scientific findings regarding the pathophysiological mechanisms responsible for liver injury in critically ill patients with COVID-19, the various interactions between drugs used to treat the disease and the function of the liver and the specific tests providing the possibility of early diagnosis of severe liver injury in these patients. Moreover, it highlighted the burden that COVID-19 put on health systems worldwide and its effect on transplant programs and the care provided to critically ill patients in general and particularly to those with chronic liver disease.

Liver replacement therapy with extracorporeal blood purification techniques current knowledge and future directions.

Clinically, it is highly challenging to promote recovery in patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Despite recent advances in understanding the underlying mechanisms of ALF and ACLF, standard medical therapy remains the primary therapeutic approach. Liver transplantation (LT) is considered the last option, and in several cases, it is the only intervention that can be lifesaving. Unfortunately, this intervention is limited by organ donation shortage or exclusion criteria such that not all patients in need can receive a transplant. Another option is to restore impaired liver function with artificial extracorporeal blood purification systems. The first such systems were developed at the end of the 20th century, providing solutions as bridging therapy, either for liver recovery or LT. They enhance the elimination of metabolites and substances that accumulate due to compromised liver function. In addition, they aid in clearance of molecules released during acute liver decompensation, which can initiate an excessive inflammatory response in these patients causing hepatic encephalopathy, multiple-organ failure, and other complications of liver failure. As compared to renal replacement therapies, we have been unsuccessful in using artificial extracorporeal blood purification systems to completely replace liver function despite the outstanding technological evolution of these systems. Extracting middle to high-molecular-weight and hydrophobic/protein-bound molecules remains extremely challenging. The majority of the currently available systems include a combination of methods that cleanse different ranges and types of molecules and toxins. Furthermore, conventional methods such as plasma exchange are being re-evaluated, and novel adsorption filters are increasingly being used for liver indications. These strategies are very promising for the treatment of liver failure. Nevertheless, the best method, system, or device has not been developed yet, and its probability of getting developed in the near future is also low. Furthermore, little is known about the effects of liver support systems on the overall and transplant-free survival of these patients, and further investigation using randomized controlled trials and meta-analyses is needed. This review presents the most popular extracorporeal blood purification techniques for liver replacement therapy. It focuses on general principles of their function, and on evidence regarding their effectiveness in detoxification and in supporting patients with ALF and ACLF. In addition, we have outlined the basic advantages and disadvantages of each system.

Gastroenterology and liver disease during COVID-19 and in anticipation of post-COVID-19 era: Current practice and future directions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major threat to global public health. The virus causes the clinical syndrome known as coronavirus disease 2019 (COVID-19), in which multiple organs can get affected. Apart from manifestations of the respiratory system, which predominate, its clinical presentation is frequently accompanied by symptoms of the gastro-intestinal (GI) tract and liver abnormalities. The correlation of symptoms and abnormalities with disease severity is discussed, leading to ambiguous results from international literature. Moreover, the disease infects patients with co-existing liver and GI disorders affecting both their health status and the availability of healthcare services provided to them. The risk of transmission of the disease during aerosol-generating procedures has changed the diagnostic approach and follow-up algorithms for liver and GI diseases. For the safety of both doctors and patients, telemedicine and distant evaluation have become everyday practice, whereas several routines and emergency visits at outpatient and emergency departments have been postponed or delayed. Vaccination against SARS-CoV-2 is underway, providing hope to humanity and the expectation that the post-COVID-19 era is near. This review aims to update knowledge about the manifestations of COVID-19 related to liver and GI diseases and the effect of the pandemic on the diagnostic and therapeutic procedures for these diseases with a special focus on how current practices have changed and what changes will possibly remain in the future.

Liver Disease in Human Immunodeficiency Virus Infection.

Liver disease in human immunodeficiency virus (HIV) remains a main cause of morbidity and mortality. Liver-related morbidity and mortality can be caused by multiple etiologic factors, including opportunistic infections, direct and indirect effects of antiretrovirals, direct and indirect effects of HIV, and viral hepatitides. These factors present with varied liver pathophysiologic mechanisms that lead to abnormalities in liver enzymes and synthetic function test, followed by distinct clinical presentations. This article elucidates the direct effects on HIV in the liver and explores the diagnostic and management challenges in patients with HIV in the era of highly active antiretroviral treatment.

Necrolytic acral erythema in a human immunodeficiency virus/hepatitis C virus coinfected patient: A case report.

BACKGROUND: Necrolytic acral erythema (NAE) is a rare dermatological disorder, which is associated with hepatitis C virus (HCV) infection or zinc deficiency. It is characterized by erythematous or violaceous lesions occurring primarily in the lower extremities. The treatment includes systemic steroids and oral zinc supplementation. We report a case of NAE in a 66-year-old human immunodeficiency virus (HIV)/HCV co-infected woman with NAE. NAE is rarely reported in co-infected patients and the exact mechanisms of pathogenesis are still unclear. CASE SUMMARY: A 66-year-old HIV/HCV co-infected female patient presented with painless, non-pruritic rash of extremities for one week and underwent extensive work-up for possible rheumatologic disorders including vasculitis and cryoglobulinemia. Punch skin biopsies of right and left thigh revealed thickened parakeratotic stratum corneum most consistent with NAE. Patient was started on prednisone and zinc supplementation with resolution of the lesions and improvement of rash. CONCLUSION: Clinicians should maintain high clinical suspicion for early recognition of NAE in patients with rash and HCV.

Klebsiella Pneumoniae Liver Abscess: A Case Series of Six Asian Patients.

BACKGROUND Liver abscesses represent a serious infection of hepatic parenchyma and are associated with significant morbidity and mortality. The emergence of a new hypervirulent variant of Klebsiella pneumoniae, which can cause serious infections in the Asian population, is under investigation. We report a case series of six Asian patients hospitalized at our institution from January 2013 to November 2015 for liver abscess due to Klebsiella pneumoniae. CASE REPORT Charts of six Asian patients were retrospectively reviewed. Four patients were male and two were female. The mean age was 53 years (range: 35-64 years). All patients had no known past medical history of immunodeficiency. Three patients had multiple liver abscesses at the time of initial presentation. In five patients, the source of entry of the pathogenic microorganism was unknown and in one patient the suspected source of entry was the gastrointestinal tract. In three patients there was also concomitant Klebsiella pneumoniae bacteremia. The mean duration of antibiotic treatment was seven weeks and the mean duration of hospital stay was 13.5 days. CONCLUSIONS Liver abscess should always be included in the differential diagnosis in cases of sepsis without obvious source and/or in the clinical scenarios of fever, abdominal pain, and liver lesions.

Isolation Rate and Clinical Significance of Uropathogens in Positive Urine Cultures of Hemodialysis Patients.

BACKGROUND: Hemodialysis (HD) patients are known to be vulnerable to infections. However, there are limited data on the urine microbiology spectrum among patients with end-stage renal disease and on the development of antimicrobial resistance of uropathogens in these patients. MATERIALS AND METHODS: A single-center, retrospective study was conducted to assess the spectrum and antimicrobial resistance profile of microorganisms isolated in urine cultures of HD patients who were hospitalized between September 2008 and August 2015 with an admitting diagnosis of fever, sepsis, or urinary tract infection. Characteristics of patients were recorded, and associations between the aforementioned parameters were assessed with Fisher's exact test. RESULTS: We included 75 HD patients (33 males, mean age 73.6 ± 16.6 years) with positive urine cultures. Despite urine culture positivity, the urinary tract was the confirmed source of infection in only 31 (41.3%) patients. Among the different pathogens, Escherichia coli was the predominant microorganism. Identification of E. coli as the involved uropathogen was associated neither with a growth of ≥105 CFU/ml, presence of fever, sepsis, urinary catheter use nor with higher antimicrobial resistance. E. coli growth, however, was significantly associated with polycystic kidney disease (P = 0.027). Extended antimicrobial resistance was noted in 29 (38.7%) patients but was associated neither with higher incidence of fever or sepsis nor with urinary catheter use. CONCLUSIONS: In our series of HD patients with positive urine cultures, the isolation rates of different uropathogens do not seem to differ from the most commonly encountered ones in nondialysis patients although resistance to antimicrobials may be more frequently observed.

Extranodal NK/T-Cell Lymphoma, Nasal Type, Presenting as Refractory Pseudomonas aeruginosa Facial Cellulitis.

Extranodal natural killer T-cell lymphoma, nasal type (ENKL), formerly called lethal midline granuloma or angiocentric T-cell lymphoma, is a predominantly extranodal non-Hodgkin lymphoma characterized by vascular damage, necrosis, and an association with Epstein-Barr virus. In the United States, it is more frequently seen in Asian, Asian Pacific Islander, and Hispanic descent populations and is more prevalent in males in their fifth decade. Clinical presentation of NK nasal lymphoma most commonly involves epistaxis; obstruction; discharge; destructive mass in sinuses, palate, and nose; and skin ulceration. These symptoms can mimic invasive fungal infections and other sinonasal disorders. Furthermore, ENKL has a broad cytologic spectrum and induces a mixture of inflammatory cells, causing difficulty in establishing the diagnosis, especially in initial biopsies. We present a case of refractory Pseudomonas aeruginosa facial cellulitis in a young woman whose treatment course was complicated by septic shock and resistance to multiple antibiotics, resulting in a delayed diagnosis of ENKL nasal type.

The Diagnostic Value of Urinalysis in Hemodialysis Patients with Fever, Sepsis or Suspected Urinary Tract Infection.

INTRODUCTION: The diagnostic validity of urinalysis in asymptomatic Hemodialysis (HD) patients is low and there is limited data on the diagnostic value of urinalysis in HD patients with fever, sepsis, or suspected Urinary Tract Infection (UTI). AIM: The aim of this study was to assess the sensitivity, specificity, positive and negative predictive value of pyuria, bacteriuria, Leukocyte Esterase (LE) and nitrite positivity in symptomatic, febrile or/and septic HD patients. MATERIALS AND METHODS: A single-center, retrospective study was performed at New York University Lutheran Medical Center, Brooklyn, New York City, USA, in order to investigate the diagnostic validity of pyuria, bacteriuria, LE and nitrite positivity in HD patients with admitting diagnosis of fever, sepsis or UTI from September 2008 to August 2015. RESULTS: A total of 275 HD patients were included in the study. There was significant association between pyuria of different cut-offs (>5,>10,>50 WBC/HPF) and urine culture positivity (p<0.001) and growth of ≥100,000 CFU/mL (p=0.039), but there was no association with fever or sepsis. The sensitivity and specificity of pyuria >10 WBC/HPF for positive urine culture with >100,000 CFU/mL was 86% and 35% respectively (p=0.025). Pyuria >50 WBC/HPF showed a sensitivity of 66% and a specificity of 58% (p=0.032). There was also association between bacteriuria, LE positivity and positive urine cultures but not with ≥100,000 CFU/mL. CONCLUSION: Our study results suggest that urinalysis is not a reliable diagnostic tool in febrile and/or septic HD patients and a urine culture is needed. In such patients, physicians should also maintain a high level of clinical suspicion for other potential sources of infection, which may not be initially evident.

Elevated lactic acid is a negative prognostic factor in metastatic lung cancer.

BACKGROUND: Hyperlactatemia with or without type B lactic acidosis is a rare complication of cancer, previously observed most often in hematological malignancies. The aim of this study was to assess the prognostic value of lactic acid (LA) in patients with metastatic lung cancer. METHODS: Patients diagnosed with stage IV non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC), were included in this single center retrospective study. Arterial and venous LA level, anion gap (AG), serum LDH and presence of urine ketones were recorded for each patient and their associations with demographic and clinical data and overall survival (OS) were examined. RESULTS: Eighty-five patients (43 males, median age 74, range 45-96 years) were studied. The maximal levels of arterial or venous LA were significantly associated with presence of ≥ 2 metastatic sites (p= 0.001), ICU admission or transfer (p= 0.016), intubation (p= 0.029), elevated serum anion gap (p< 0.001) and LDH levels (p< 0.001). Hyperlactatemia (≥ 1.4 mmol/L) was associated with shorter OS (log-rank p< 0.001). In a multivariate model including LA, ICU, intubation, AG as well as other known prognostic factors of NSCLC and SCLC, including age, sex, smoking status, number and location of metastases, histologic type, performance status (PS), chemotherapy and LDH, LA retained its prognostic value (OR: 1.3; 95%CI: 1.082-1.561; p= 0.005), along with PS (p= 0.039) and chemotherapy (p= 0.039). CONCLUSIONS: The results of the study suggest that a high lactic acid level (≥ 1.4 mmol/L) is associated with significantly shorter overall survival in patients with metastatic non-small cell lung cancer and extensive stage small cell lung cancer. Hyperlactatemia is an independent predictor of poor survival in metastatic lung cancer patients.

Fecal DNA testing for colorectal cancer screening: Molecular targets and perspectives.

The early detection of colorectal cancer with effective screening is essential for reduction of cancer-specific mortality. The addition of fecal DNA testing in the armamentarium of screening methods already in clinical use launches a new era in the noninvasive part of colorectal cancer screening and emanates from a large number of previous and ongoing clinical investigations and technological advancements. In this review, we discuss the molecular rational and most important genetic alterations hallmarking the early colorectal carcinogenesis process. Also, representative DNA targets-markers and key aspects of their testing at the clinical level in comparison or/and association with other screening methods are described. Finally, a critical view of the strengths and limitations of fecal DNA tests is provided, along with anticipated barriers and suggestions for further exploitation of their use.

Hashimoto's Thyroiditis and Kikuchi's Disease: Presentation of a Case and Review of the Literature.

We report the case of a 19-year-old woman with a history of Hashimoto's thyroiditis who presented with tender right anterior cervical lymphadenopathy and fever. Workup for infectious, autoimmune, and malignant causes was unremarkable. Surgical removal of cervical lymph nodes after detailed magnetic resonance (MR) imaging disclosed necrotizing lymphadenitis, also known as Kikuchi's disease (KD). The patient was treated with a short-term course of steroids, due to the onset of pancytopenia and borderline antiphospholipid antibodies combined with increased anti-thyroglobulin (anti-TG) titers. Despite being a diagnosis of exclusion, KD should be included in the differential of such patients, particularly in cases of previous or concurrent autoimmune diseases such as Hashimoto's thyroiditis, which necessitate a long-term follow-up.

Alpha-actinin: a multidisciplinary protein with important role in B-cell driven autoimmunity.

Alpha-actinin (α-actinin) is a ubiquitous cytoskeletal protein, which belongs to the superfamily of filamentous actin (F-actin) crosslinking proteins. It is present in multiple subcellular regions of both muscle and non-muscle cells, including cell-cell and cell-matrix contact sites, cellular protrusions and stress fiber dense regions and thus, it seems to bear multiple important roles in the cell by linking the cytoskeleton to many different transmembrane proteins in a variety of junctions. Four isoforms of human α-actinin have already been identified namely, the "muscles" α-actinin-2 and α-actinin-3 and the "non-muscles" α-actinin-1 and α-actinin-4. The precise functions of α-actinin isoforms as well as the precise role and significance of their binding to F-actin particularly in-vivo, have been elusive. They are generally believed to represent key structural components of large-scale F-actin cohesion in cells required for cell shape and motility. α-Actinin-2 has been implicated in myopathies such as nemalin body myopathy, hypertrophic and dilated cardiomyopathy and it may have at least an indirect pathogenetic role in diseases of the central nervous system (CNS) like schizophrenia, epilepsy, ischemic brain damage, CNS lupus and neurodegenerative disorders. The role of "non-muscle" α-actinins in the kidney seems to be crucial as an essential component of the glomerular filtration barrier. Therefore, they have been implicated in the pathogenesis of familial focal segmental glomerulosclerosis, nephrotic syndrome, IgA nephropathy, focal segmental glomerulosclerosis and minimal change disease. α-Actinin is also expressed on the membrane and cytosol of parenchymal and ductal cells of the liver and it seems that it interacts with hepatitis C virus in an essential way for the replication of the virus. Finally α-actinin, especially α-actinin-4, has been implicated in cancer cell progression and metastasis, as well as the migration of several cell types participating in the immune response. Based on these functions, the accumulating reported evidence of the importance of α-actinin as a target autoantigen in the pathogenesis of autoimmune diseases, particularly systemic lupus erythematosus and autoimmune hepatitis, is also discussed along with the possible perspectives that are potentially emerging from the study of this peculiar molecule in health and disease.