Karanjin.

Karanjin [IUPAC: 3-methoxy-2-phenylfuro-(2,3-h-chrome-4-ol)], a bioactive furanoflavonoid and a potent biomolecule, was first isolated from Pongamia pinnata (L.). The crude extracts from root, leaf and seed having active constituent karanjin is highly valued in both traditional and modern knowledge systems. This review highlights, critically assesses, and presents the probable biosynthetic pathways of karanjin and its isolation methodologies with a view to actualizing its full potential. Karanjin exhibits multiple health benefits and applications, with evident anti-diabetic, anti-cancer, anti-inflammatory, anti-hyperglycemic, antioxidant, anti-colitis, anti-ulcer, and anti-Alzheimer properties. Consequently, the physiochemical properties and biological effects of karanjin have been detailed and analyzed. The efficacy of karanjin has been attenuated by toxicological studies that have proven karanjin to be non-toxic at physiological conditions as substantiated by in vitro and in vivo studies. In addition, the multiple insect repellent/insecticidal properties of karanjin and its availability as an acaricide/bio-insecticide have been reviewed. This review article underscores and endorses the immense potential for novel drug leads in various medicinal and industrial applications, suggesting a deeper insight into its metabolic fate, bioavailability, and cellular effects that await further investigations.

Targeted TNF-α Overexpression Drives Salivary Gland Inflammation.

Chronic inflammation of the salivary glands from pathologic conditions such as Sjögren's syndrome can result in glandular destruction and hyposalivation. To understand which molecular factors may play a role in clinical cases of salivary gland hypofunction, we developed an aquaporin 5 (AQP5) Cre mouse line to produce genetic recombination predominantly within the acinar cells of the glands. We then bred these mice with the TNF-αglo transgenic line to develop a mouse model with salivary gland-specific overexpression of TNF-α; which replicates conditions seen in sialadenitis, an inflammation of the salivary glands resulting from infection or autoimmune disorders such as Sjögren's syndrome. The resulting AQP5-Cre/TNF-αglo mice display severe inflammation in the salivary glands with acinar cell atrophy, fibrosis, and dilation of the ducts. AQP5 expression was reduced in the salivary glands, while tight junction integrity appeared to be disrupted. The immune dysregulation in the salivary gland of these mice led to hyposalivation and masticatory dysfunction.

Utilization of Organs From Donors According to Hepatitis C Antibody and Nucleic Acid Testing Status: Time for Change.

Previous studies have grouped all donors positive for hepatitis C virus (HCV) antibody (Ab). Only recently has donor HCV nucleic acid testing (NAT) become routine, and the impact of Ab and NAT status on organ utilization is unknown. Using the United Network for Organ Sharing database, we identified 9290 donors from 2015 to 2016 for whom both HCV Ab and NAT data were available and compared organ utilization by HCV status. Overall, 93.8% of donors were Ab negative and NAT negative (Ab-NAT-), 0.15% were Ab negative and NAT positive, 1.8% were Ab positive and NAT negative (Ab+NAT-), and 4.2% were both Ab and NAT positive (Ab+NAT+). Ab-NAT- donors donated at the highest rate for all organs except livers, of which Ab+NAT- donors donated at a higher rate (81.2% vs 73.2%, p = 0.03). Livers were discarded for reasons related to abnormal biopsies in Ab+NAT+ donors, whereas kidneys from Ab- or NAT-positive donors were discarded for reasons related to HCV status. Using a propensity score-matched model, we estimated that using Ab+NAT- donors at the same rate as Ab-NAT- donors could result in 48 more kidney donors, 37 more heart donors, and 15 more lung donors annually. We urge the use of HCV Ab+NAT- donors for appropriately selected and consenting recipients.

Sensitivity of blood and tissue diagnostics for gastrointestinal cytomegalovirus disease in solid organ transplant recipients.

BACKGROUND: Gastrointestinal (GI) cytomegalovirus (CMV) disease is the most common manifestation of tissue-invasive CMV infection in solid organ transplant (SOT) recipients, but the diagnostic yields of blood and tissue testing have not been systematically assessed in a large patient cohort. METHODS: We retrospectively identified consecutive SOT recipients with biopsy-confirmed GI CMV disease who had both tissue and blood (CMV polymerase chain reaction or antigenemia) diagnostic testing performed within 14 days of diagnosis. Descriptive statistics and logistic regression were used to assess the association between patient factors and viremia and the diagnostic yield of tests performed on biopsy specimens. RESULTS: A total of 101 patients (73% donor seropositive/recipient seronegative [D+/R-], 22% recipient seropositive [R+]) had GI CMV disease (58% upper, 22% lower, and 20% both) at a median of 185 days (range, 21-6345 days) post transplant. In multivariate analysis, R+ CMV serostatus (odds ratio [OR] 0.1 [0.0-0.4], P < 0.001) and diagnosis >6 months post transplant (OR 0.3 [0.1-0.9], P = 0.03) were each independently associated with absence of CMV viremia at time of diagnosis. In the subset of patients (n = 29) in whom both histopathology and viral culture were performed on biopsy specimens, 11 (39%) had CMV detected only by culture and had similar clinical characteristics and outcomes to those with positive histopathology (P > 0.05 for all comparisons). CONCLUSIONS: The sensitivity of viremia in SOT recipients with GI CMV disease is significantly lower in CMV-seropositive patients and in those >6 months post transplant. Addition of viral culture to endoscopic biopsy specimens significantly increases the diagnostic yield for GI CMV disease.

The anti-viral effect of sorafenib in hepatitis C-related hepatocellular carcinoma.

BACKGROUND: Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. AIM: To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. METHODS: We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time. RESULTS: Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: -0.1799-0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point. CONCLUSION: Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.

Risk factors for late-onset cytomegalovirus disease in donor seropositive/recipient seronegative kidney transplant recipients who receive antiviral prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) disease occurs frequently after cessation of antiviral prophylaxis in CMV-seronegative kidney transplant recipients from seropositive donors (D+R-), and the risk factors are incompletely defined. METHOD: We retrospectively assessed the incidence, clinical features, and risk factors for CMV disease in a cohort of D+R- kidney transplant recipients who received antiviral prophylaxis at a single US transplant center using descriptive statistics and Cox proportional hazards models. RESULTS: CMV disease developed in 29 of 113 (26%) D+R- patients at a median of 185 days (interquartile range 116-231 days) post transplant, including CMV syndrome (66%) and tissue invasive disease (34%). The incidence of CMV disease was higher in patients who underwent re-transplantation (57% vs. 24%) and this factor was independently associated with a higher risk of CMV disease in multivariable analysis (hazard ratio, 4.02; 95% confidence interval, 1.3-13; P = 0.016). Other demographic and transplant variables were not independently associated with a risk of late-onset CMV disease. CONCLUSIONS: Despite a comprehensive analysis of patient and transplant variables, only re-transplantation was identified as a risk factor for CMV disease in D+R- kidney transplant recipients who received antiviral prophylaxis, but had limited clinical predictive value. The development of novel laboratory markers to identify patients at greatest risk for CMV disease should be a priority for future studies.

The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients.

Late-onset cytomegalovirus (CMV) disease is a significant problem with a standard 3-month prophylaxis regimen. This multicentre, double-blind, randomized controlled trial compared the efficacy and safety of 200 days' versus 100 days' valganciclovir prophylaxis (900 mg once daily) in 326 high-risk (D+/R-) kidney allograft recipients. Significantly fewer patients in the 200-day group versus the 100-day group developed confirmed CMV disease up to month 12 posttransplant (16.1% vs. 36.8%; p < 0.0001). Confirmed CMV viremia was also significantly lower in the 200-day group (37.4% vs. 50.9%; p = 0.015 at month 12). There was no significant difference in the rate of biopsy-proven acute rejection between the groups (11% vs. 17%, respectively, p = 0.114). Adverse events occurred at similar rates between the groups and the majority were rated mild-to-moderate in intensity and not related to study medication. In conclusion, this study demonstrates that extending valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days' prophylaxis, without significant additional safety concerns associated with longer treatment. The number needed to treat to avoid one additional patient with CMV disease up to 12 months posttransplant is approximately 5.

Programmed death-1 receptor and interleukin-10 in liver transplant recipients at high risk for late cytomegalovirus disease.

Despite significant advances in antiviral treatment, solid organ transplant (SOT) recipients remain at heightened risk for developing late cytomegalovirus (CMV) disease. Elevated inhibitory immune signaling suggests a state of immune impairment in SOT recipients, who do not control CMV infection and develop severe clinical symptoms after discontinuation of antiviral prophylaxis. We longitudinally monitored the negative immune modulator programmed death (PD)-1 receptor on both CD4 and CD8 T cells, co-expressing the CD137 surface marker of recent activation, in a liver transplant cohort. Liver recipients who progressed to CMV disease expressed elevated levels of PD-1 on CD137(+) CD4 and CD8 T cells, following stimulation with either full-length peptide libraries or CMV lysate. This novel approach, applicable to a multitude of human leukocyte antigen types, enhances the usefulness of the PD-1 measurements as a clinical strategy to predict late CMV disease. In parallel, we detected an increased level of the immunosuppressive cytokine interleukin (IL)-10, in plasma of liver recipients diagnosed with CMV disease. CMV-specific T cells were still functional when both PD-1 and IL-10 were upregulated; however they showed a marked proliferation deficit, which may limit their ability to contain viremia and lead to CMV disease. Our preliminary observations support further investigation of dual monitoring of PD-1 and IL-10, as potential immune markers of CMV disease.

Imaging of hepatocellular carcinoma and early diagnosis.

The incidence of hepatocellular carcinoma (HCC) is steeply rising in industrialized nations, and the vast majority of patients do not qualify for curative treatment at the time of diagnosis. This phenomenon is directly related to the clinician's ability to accurately diagnose HCC at an early stage, which can be quite challenging in the setting of a cirrhotic, nodular liver. A particular difficulty arises in the differentiation of very small neoplastic lesions from hyperplastic nodules. In the past decade, technological advances have made dynamic imaging of the cirrhotic liver more feasible, which in turn improves the sensitivity and specificity of these modalities for the diagnosis of HCC. In this article we describe the typical characteristics of HCCin modalities such as ultrasound, computed tomography, and magnetic resonance imaging, discuss the recent advances in dynamic imaging in each of these modalities, and review the published guidelines for surveillance and diagnosis for HCC.

Invasive Pseudomonas aeruginosa infections: high rate of recurrence and mortality after hematopoietic cell transplantation.

Limited data exist regarding the incidence and factors associated with outcome of invasive Pseudomonal infections in hematopoietic cell transplant (HCT). A retrospective analysis of cases of invasive Pseudomonas aeruginosa infection and factors associated with outcome was performed. P. aeruginosa invasive infection occurred in 95 of 5772 patients (1.65%) a median of 63 days after HCT (range 5-1435). Only 28% of infections occurred during periods of neutropenia (absolute neutrophil count<500 cells/mm(3)). Infection-attributable mortality during the initial episode of infection was 35.8%. Factors associated with initial mortality included the presence of a copathogen and high-dose steroid use. Ten (16.4%) of those who survived the initial infection experienced a recurrence of P. aeruginosa infection at a median of 9 days (range 3-17) after stopping antibiotics and 60% of those died as a result of recurrent infection a median of 1 day (range 1-7) after onset of recurrence. Grade 3-4 graft-versus-host disease was associated with a higher risk of recurrent infection. The risk of recurrence was not influenced by the presence of copathogens. Thus, invasive P. aeruginosa infections are associated with high recurrence rates and mortality in this immunocompromised population. Aggressive attempts to reduce immunosuppression and to treat copathogens may help during the initial infection.

Clinical and radiologic factors associated with pulmonary nodule etiology in organ transplant recipients.

Identifying clinical and radiographic factors that are associated with a specific etiology of pulmonary nodules (PNs) in solid-organ transplant (SOT) recipients might be helpful in guiding empiric therapy. Multivariable logistic regression was used to assess the relationship of clinical and radiographic variables to the etiology of PN in a retrospectively identified cohort of SOT recipients at a single transplant center. PNs in 55 SOT recipients (lung 15%, heart 22%, liver 42%, kidney 18% or kidney/pancreas 5%) were diagnosed at a mean of 1061 days post-transplant and were infectious in 31 of 55 (56%) (bacterial 22%, fungal 33%, viral 2%) and noninfectious in 24 of 55 (44%) [post-transplant lymphoproliferative disorder (PTLD) 25%, carcinoma 18%]. Radiographic 'consolidation' was independently associated with an infectious etiology (OR, 20.2, p < 0.01). Epstein-Barr virus seronegativity and lung transplant were each associated with PTLD (OR, 21.7, p < 0.01) and (OR, 36.6, p < 0.001), respectively. Diagnosis less than 90 days post-transplant was associated with Aspergillus infection (OR, 12.9, p = 0.007). Specific clinical and radiographic features are associated with specific etiologies of PNs in SOT recipients and might be useful for guiding empiric therapy while awaiting results of definitive diagnostic studies.

A prospective cross-sectional study of BK virus infection in non-renal solid organ transplant recipients with chronic renal dysfunction.

BACKGROUND: Polyomavirus (primarily BK virus [BKV]) infection is an important cause of chronic renal dysfunction in renal transplant recipients, but its possible contribution to chronic renal dysfunction in non-renal solid organ transplant (NRSOT) recipients has not been fully explored. METHODS: We performed a prospective, cross-sectional study of consecutive NRSOT recipients with unexplained chronic renal dysfunction of at least a 3 months duration. Medical records were reviewed, and polymerase chain reaction was used to amplify BKV-specific sequences from serum and urine samples. The potential associations between various demographic and transplant variables and BKV infection were assessed. RESULTS: Thirty-four consecutive NRSOT recipients (23 lung, 8 liver, 2 heart, 1 heart-lung) with chronic renal dysfunction were enrolled at a median of 3.5 years (range 0.3-12.5 years) post transplantation. Five of the 34 (15%) patients had BKV viruria (range 1040-1.8 x 10(6) copies/mL), but none had BKV viremia. BK viruria was associated with mycophenolate mofetil use (5 of 19 [26%] vs. 0 of 15, P = 0.03) and a history of cytomegalovirus disease (3 of 4 [75%] vs. 2 of 30 [7%], P < 0.01). However, the mean estimated creatinine clearance was similar in patients with or without BKV viruria (49 vs. 47 mL/min). CONCLUSIONS: BKV viruria was present in a proportion of NRSOT patients with otherwise unexplained chronic renal dysfunction. The possibility that BKV infection might contribute to chronic renal dysfunction in this setting warrants further investigation.

Quantitation of BK virus load in serum for the diagnosis of BK virus-associated nephropathy in renal transplant recipients.

BK virus-associated nephropathy is an increasingly recognized cause of graft dysfunction among kidney transplant recipients, and definitive diagnosis requires renal biopsy. By using a newly developed, quantitative, real-time polymerase chain reaction (PCR) assay for BK virus DNA, a retrospective analysis was done of sequential serum samples (n=28) from 4 transplant recipients with histopathologically documented BK virus nephropathy and from samples (n=76) from 16 transplant recipient control patients. BK virus DNA was detected in serum samples from all 4 case patients versus 0 of 16 control patients (P< .0001, Fisher's exact test) at a median of 32 weeks (range, 17-61 weeks) before the diagnosis of BK virus nephropathy. BK virus load decreased in 3 of 3 patients after the reduction of immunosuppression and/or nephrectomy. It is concluded that quantitative PCR for BK virus DNA in serum is useful both for identifying transplant recipients at risk for BK virus nephropathy and for monitoring the response to therapy.

Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice.

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzyme deficiency leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop painful neuropathy and vascular occlusions that progressively lead to cardiovascular, cerebrovascular, and renal dysfunction and early death. Although enzyme replacement therapy and bone marrow transplantation have shown promise in the murine analog of Fabry disease, gene therapy holds a strong potential for treating this disease in humans. Delivery of the normal alpha-gal A gene (cDNA) into a depot organ such as liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. To investigate this possibility, a recombinant adeno-associated viral vector encoding human alpha-gal A (rAAV-AGA) was constructed and injected into the hepatic portal vein of Fabry mice. Two weeks postinjection, alpha-gal A activity in the livers of rAAV-AGA-injected Fabry mice was 20-35% of that of the normal mice. The transduced animals continued to show higher alpha-gal A levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, we see significant reductions in Gb3 levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart, up to 25 weeks with no significant immune response to the virus or alpha-gal A. Also, no signs of liver toxicity occurred after the rAAV-AGA administration. These findings suggest that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders.

Cytomegalovirus (CMV) DNA load in plasma for the diagnosis of CMV disease before engraftment in hematopoietic stem-cell transplant recipients.

Among hematopoietic stem-cell transplant (HSCT) recipients, cytomegalovirus (CMV) disease before engraftment is rare but often fatal, and cell-based diagnostic tests have low sensitivity in this clinical setting. We used the quantitative real-time polymerase chain reaction (PCR) assay to test for CMV DNA in plasma samples from 15 HSCT recipients who developed CMV disease before engraftment and from 33 matched control patients. CMV DNA was detected in plasma in 14 (93.3%) of the 15 patients who had CMV disease before engraftment, compared with 5 (15.2%) of 33 control patients (P<.001). CMV DNA was detected a median of 13 days before the onset of CMV disease (range, 0-35 days). The maximum CMV virus load in plasma was >1 log(10) higher among case patients than among control patients (median, 1700 [range, 50 to 5.5x107] vs. <50 [range, <50-350] CMV DNA copies/mL plasma, respectively; P<.001). Quantitative PCR for CMV DNA in plasma appears to be useful for the identification of HSCT recipients at risk for CMV disease before engraftment.

Outbreak of Stenotrophomonas maltophilia bacteremia among patients undergoing bone marrow transplantation: association with faulty replacement of handwashing soap.

Using molecular typing methods, we confirmed an outbreak of Stenotrophomonas maltophilia among bone marrow transplant patients. The likely source was a healthcare worker who may have washed with moisturizer instead of soap between patients. Hospital epidemiologists need to go beyond antibiograms when evaluating outbreaks and be vigilant about all aspects of hand washing.

Detection of Epstein-Barr virus DNA in sera from transplant recipients with lymphoproliferative disorders.

Early diagnosis of Epstein-Barr Virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is important because many patients respond to reduction in immunosuppression, especially if PTLD is detected at an early stage. Previous studies have found elevated EBV DNA levels in blood from patients with PTLD, but these assays required isolation of cellular blood fractions and quantitation. We evaluated the presence of cell-free EBV DNA in serum from solid-organ transplant recipients as a marker for PTLD. Five of 6 transplant recipients with histopathologically documented PTLD had EBV DNA detected in serum at the time of diagnosis (sensitivity = 83%), compared with 0 of 16 matched transplant recipients without PTLD (specificity = 100%) (P < 0.001 [Fisher's exact test]). Furthermore, EBV DNA was detected in serum 8 and 52 months prior to the diagnosis of PTLD in two of three patients for whom stored sera were analyzed. Detection of EBV DNA in serum appears to be a useful marker for the early detection of PTLD in solid-organ transplant recipients. Further studies to define the role of such assays in evaluating solid-organ transplant patients at risk for PTLD are warranted.

Successful treatment of severe hepatitis C-associated pulmonary vasculitis in a liver transplant recipient.

BACKGROUND: We report the clinical course of a patient who developed fever, hypoxia, and bilateral pulmonary infiltrates two and a half years after orthotopic liver transplantation (OLT) for cirrhosis due to hepatitis C. The patient had a history of hepatitis C-associated vasculitis manifested by purpuric skin rashes, renal abnormalities, and elevated cryoglobulins, and was receiving interferon-alpha at the time of presentation. RESULTS: The results of bronchoscopy with bronchoalveolar lavage were unrevealing, and open lung biopsy revealed active small vessel vasculitis. The patient responded dramatically to plasmapheresis and the addition of high-dose corticosteroids with resolution of hypoxia, pulmonary infiltrates, and glomerulonephritis. This is, to our knowledge, the first report of the successful treatment of hepatitis C-associated pulmonary vasculitis after OLT. CONCLUSIONS: We conclude that hepatitis C-associated pulmonary vasculitis should be included in the differential diagnosis of a patient presenting with fever, hypoxia, and pulmonary infiltrates after OLT for hepatitis C. Treatment with plasmapheresis and high-dose corticosteroids may be effective in patients with this disorder.

Cytomegalovirus disease occurring before engraftment in marrow transplant recipients.

Little information is available regarding the incidence, clinical course, and response to treatment of cytomegalovirus (CMV) disease that occurs before engraftment in marrow transplant recipients. We identified 25 patients over a 12.5 year period who developed CMV disease before achieving engraftment. Twelve cases were diagnosed during life, and 13 cases were diagnosed at autopsy. The lung was the site most commonly involved (92% of patients), and most of the patients (92%) were CMV seropositive. Significant copathogens were identified in 45% of the patients. All nine patients with CMV pneumonia died within 6 weeks after the diagnosis was made, and one of two patients with gastrointestinal disease also died 6 weeks after the diagnosis was made despite the administration of antiviral therapy. Surveillance cultures were not helpful in identifying patients at risk for disease. Histopathological examination of the lungs of patients with early CMV pneumonia only infrequently showed typical CMV lesions. In conclusion, CMV disease occurring before engraftment in CMV-seropositive recipients was uncommon, was frequently associated with the presence of other opportunistic pathogens, and was associated with a high fatality rate. Better diagnostic methods to identify patients at risk are required in the preengraftment period.

Sarcoidosis associated with recurrent pancreatitis.

A 56-year-old previously healthy man had two episodes of unexplained pancreatitis in the setting of constitutional symptoms, recurrent palsy of the right seventh cranial nerve, and bilateral parotitis. Chest radiography revealed marked bilateral hilar lymphadenopathy, and sarcoidosis was diagnosed by bronchoscopy with transbronchial biopsy showing noncaseating granulomas. The pancreatitis and sarcoidosis responded to corticosteroid therapy but recurred after corticosteroid dosage was reduced. Retreatment with a higher dosage of corticosteroids led to resolution of pancreatitis; 3 months later, the patient remained well and without further recurrence of pancreatitis while taking the higher dose of corticosteroids. Clinically significant pancreatitis should be included as an unusual manifestation of sarcoidosis, and corticosteroid therapy should be considered in the management of pancreatitis associated with sarcoidosis.